On meta-analytic assessment of surrogate outcomes

We discuss the strengths and weaknesses of the meta-analytic approach to estimating the effect of a new treatment on a true clinical outcome measure, T, from the effect of treatment on a surrogate response, S. The meta-analytic approach (see Daniels and Hughes (1997) 16, 1965-1982) uses data from a series of previous studies of interventions similar to the new treatment. The data are used to estimate relationships between summary measures of treatment effects on T and S that can be used to infer the magnitude of the effect of the new treatment on T from its effects on S. We extend the class of models to cover a broad range of applications in which the parameters define features of the marginal distribution of (T, S). We present a new bootstrap procedure to allow for the variability in estimating the distribution that governs the between-study variation. Ignoring this variability can lead to confidence intervals that are much too narrow. The meta-analytic approach relies on quite different data and assumptions than procedures that depend, for example, on the conditional independence, at the individual level, of treatment and T, given S (see Prentice (1989) 8, 431-440). Meta-analytic calculations in this paper can be used to determine whether a new study, based only on S, will yield estimates of the treatment effect on T that are precise enough to be useful. Compared to direct measurement on T, the meta-analytic approach has a number of limitations, including likely serious loss of precision and difficulties in defining the class of previous studies to be used to predict the effects on T for a new intervention.     

Statistical fluctuations in processes of gene expression regulation: consideration of the problem from point of view of statistical mechanics

The regulation of gene expression is a basic problem of biology. In some cases, the gene activity is regulated by specific binding of regulatory proteins to DNA. In terms of statistical mechanics, this binding is described as the process of adsorption of ligands on the one-dimensional lattice and has a probability nature. As a random physical process, the adsorption of regulatory proteins on DNA introduces a noise to the regulation of gene activity. We derived equations, which make it possible to estimate this noise in the case of the binding of the lac repressor to the operator and showed that these estimates correspond to experimental data. Many ligands are able to bind nonspecifically to DNA. Nonspecific binding is characterized by a lesser equilibrium constant but a greater number of binding sites on the DNA, as compared with specific binding. Relations are presented, which enable one to estimate the probability of the binding of a ligand on a specific site and on nonspecific sites on DNA. The competition between specific and nonspecific binding of regulatory proteins plays a great role in the regulation of gene activity. Similar to the one-dimensional "lattice gas" of particles, ligands adsorbed on DNA produce "one-dimensional" pressure on proteins located at the termini of free regions of DNA. This pressure, an analog of osmotic pressure, may be of importance in processes leading to changes in chromatin structure and activation of gene expression.     

Electrophysiological and immunocytochemical characterization of DRG neurons on an organosilane surface in serum-free medium

We are attempting to recreate a stretch reflex circuit on a patterned Bio-MEMS (bio-microelectromechanical systems) chip with deflecting micro-cantilevers. The first steps to recreate this system is to be able to grow individual components of the circuit (sensory neuron, motoneuron, skeletal muscle, and muscle spindle) on a patternable, synthetic substrate coating the MEMS device. Sensory neurons represent the afferent portion of the stretch reflex arc and also play a significant role in transmitting the signal from the muscle spindle to the spinal cord motoneurons. We have utilized a synthetic silane substrate N-1[3-(trimethoxysilyl) propyl) diethylenetriamine (DETA) on which to grow and pattern the cells. DETA forms a self-assembled monolayer on a variety of silicon substrates, including glass, and can be patterned using photolithography. In this paper, we have evaluated the growth of sensory neurons on this synthetic silane substrate. We have investigated the immunocytochemical and electrophysiological properties of the sensory neurons on DETA and compared the resultant properties with a biological control substrate (ornithine/laminin). Immunocytochemical studies revealed the survival and growth of all three subtypes of sensory neurons: trkA, trkB, and trkC on both surfaces. Furthermore, whole-cell patch clamp recordings were used to study the electrophysiological properties of the sensory neurons on the two surfaces. There were no significant differences in the electrical properties of the neurons grown on either surface. This is the first study analyzing the immunocytochemical and electrophysiological properties of sensory neurons grown long-term in a completely defined environment and on a nonbiological substrate.     

Improving water stress tolerance of the biocontrol yeast Candida sake grown in molasses-based media by physiological manipulation

The biocontrol agent Candida sake was cultured on either an unmodified molasses-based medium (water activity, a(w) 0.996) or on water stressed media produced by the addition of glycerol, glucose, NaCl, sorbitol, or proline to 0.98, and 0.96 a(w) for 24, 48, and 72 h, to study their impact on subsequent cell viability, and on concentrations of endogenous sugars (trehalose and glucose) and polyols (glycerol, erythritol, arabitol, and mannitol). The viability of cells of different ages cultured on these media was evaluated on NYDA medium with freely available water (a(w) 0.995), and on medium modified with polyethylene glycol to a(w) 0.95. Regardless of solute used, viable counts of cells grown on molasses-based medium (a(w) 0.98) were equal to or higher than those obtained from the medium with water freely available. The amino acid proline stimulated growth at 10% concentration. In contrast, water stress induced by addition of NaCl, glucose, or sorbitol at a(w) 0.96 caused a significant reduction in viable counts. Older cultures were more resistant to water stress. Glycerol and arabitol were the main solutes accumulated by C. sake cells in response to lowered a(w). Intracellular concentration of these polyols depended more on the solute used to adjust the a(w) than on the a(w) itself. Candida sake was more resistant to water stress with higher intracellular concentration of glycerol and erythritol.     

Protein and carbohydrate composition of larval food affects tolerance to thermal stress and desiccation in adult Drosophila melanogaster

Larval nutrition may affect a range of different life history traits as well as responses to environmental stress in adult insects. Here we test whether raising larvae of fruit flies, Drosophila melanogaster, on two different nutritional regimes affects resistance to cold, heat and desiccation as well as egg production and egg-to-adult viability. We raised larvae on a carbohydrate-enriched and a protein-enriched growth medium. We found that flies developed on the high protein medium had increased heat and desiccation tolerance compared to flies developed on the carbohydrate-enriched medium. In contrast, flies developed on the carbohydrate-enriched growth medium recovered faster from chill coma stress compared to flies developed on a protein-enriched medium. We also found gender differences in stress tolerance, with female flies being more tolerant to chill coma, heat knockdown and desiccation stress compared to males. Egg production was highest in females that had developed on the protein-enriched medium. However, there was a sex-specific effect of nutrition on egg-to-adult viability, with higher viability for males developing on the sucrose-enriched medium, while female survival was highest when developing on the protein-enriched medium. Our study indicates that larval nutrition has a strong impact on the ability to cope with stress, and that the optimal nutrient composition varies with the type of stress.     

Cladistic information in phylogenetic definitions and designated phylogenetic contexts for the use of taxon names

A phylogenetic definition of a taxon name associates that name with a clade through its reference to a particular ancestor and all of its descendants. Depending on one's perspective, phylogenetic definitions name either clades on the one true, but unknown, phylogeny, or components on cladograms (clades on hypotheses regarding the true phylogeny). Phylogenetic definitions do not contain enough information to identify components without a reference cladogram. As a result, (1) if clades are equated with components on cladograms, a phylogenetic definition may associate a taxon name with different clades on different cladograms, and (2) the inclusiveness, diagnostic synapomorphies, and distribution in time and space of the clade with a particular name can differ markedly depending on the phylogenetic hypothesis one chooses to adopt. This potentially unacceptable lability in the clade to which a name refers can be avoided by using a taxon name in conjunction with only phylogenetic hypotheses on which specific taxa are related in a particular fashion. This designated phylogenetic context can be described in an n-taxon statement that would be appended to the phylogenetic definition. Use of the taxon name would be considered inappropriate in conjunction with cladograms on which the relationships contradict those in the n-taxon statement. Whereas phylogenetic definitions stabilize the meaning of taxon names, designated phylogenetic contexts would stabilize the usage of those names.     

Plant cues influence searching behaviour and parasitism in the egg parasitoid Trichogramma nr. brassicae

Abstract. 1. The effect of experience of plant cues at emergence on searching behaviour and parasitism was investigated in two strains of Trichogramma nr. brassicae (Hymenoptera: Trichogrammatidae).
2. Wasps reared on Sitotroga cereallela were allowed to emerge on a tomato plant or in a vial, with or without food. For one of the strains, females emerging on tomato searched significantly longer on a tomato seedling than females emerging in a vial.
3. The experience effect lasted between 1 and 2 days. It involves associating plant stimuli with the remains of the host, because females emerging from their host on a tomato plant had an increased searching response to tomato, but females transferred to the plant immediately after emergence did not.
4. The effect of emergence environment on parasitism of the host Helicoverpa punctigera on tomato and lettuce seedlings was tested. Wasps were allowed to emerge on seedlings of tomato or lettuce, or in an empty vial. For one strain, females experienced with tomato at emergence parasitized significantly more hosts on tomato than did females emerging on lettuce or in a vial. Parasitism on lettuce was not influenced by the treatments.     

Inter-joint coordination of posture on a seesaw device

Even though specific adjustments of the multi-joint control of posture have been observed when posture is challenged, multi-joint coordination on a seesaw device has never been accurately assessed. The current study was conducted in order to investigate the multi-joint coordination when subjects were standing on either a seesaw device or on a stable surface, with the eyes open or closed. Eighteen healthy active subjects were recruited. A principal component analysis and a Self-Organizing Maps analysis were performed on the joint angles in order to detect and characterize dominant coordination patterns. Intermuscular EMG coherence was analysed in order to assess the neurophysiological mechanisms associated with these coordination patterns. The results illustrated a multi-joint organization of posture on both stable ground and on the seesaw, with a higher variability among the individual postural responses observed when standing on the seesaw. These findings challenge the classical assumption of ankle mechanisms as dominating control on seesaw devices and confirm that inter-joint coordination in postural control is strongly modulated by stance conditions. When standing on the seesaw without vision, a decrease in intermuscular coherence was observed without any impact on the joint coordination patterns, likely due to an increase dependence on proprioceptive information.     

Growing old in a transnational social field: belonging,mobility and identity among Italian migrants

This article focuses on ageing in transnationalism. Drawing on the experiences of Italians in the UK as a paradigmatic example of settled European migrants, it explores the lived experiences of this group of older migrants. Using Levitt and Glick Schiller's framework, it concentrates first on migrants' ways of being and then on their ways of belonging. The article argues that a transnational lens is necessary to understand the experiences of older migrants and that a focus on older people needs to be incorporated into studies of transnationalism. Through a discussion of their narratives and experiences, the article offers a long view on the migration process and brings attention to the significance of gender, time and the life course to understand both migrants' transnationalism and their integration.     

A fluorescent antibody assay for hyphae and glomalin from arbuscular mycorrhizal fungi

Studies on the role of arbuscular mycorrhizal (AM) fungi in soil have been aided by the use of a monoclonal antibody that detects a molecule common to all isolates of these fungi studied to date. The molecule, glomalin, is a glycoprotein that forms on hyphae, but apparently sloughs off and adheres to soil particles or imbedded plastic mesh. An indirect immunofluorescence (IF) assay is described for detection of glomalin on hyphae attached to roots, in roots, on hyphae traps and on the surface of soil aggregates. Small sieves are used to process hyphae attached to roots and soil aggregates. Glomalin on hyphae and glomalin attached to plastic or nylon are assayed on a 1 cm² section of meshes. Examples of IF assay results are shown and discussed. This revised version was published online in June 2006 with corrections to the Cover Date.     

A Note on Probabilistic Models over Strings: The Linear Algebra Approach

Probabilistic models over strings have played a key role in developing methods that take into consideration indels as phylogenetically informative events. There is an extensive literature on using automata and transducers on phylogenies to do inference on these probabilistic models, in which an important theoretical question is the complexity of computing the normalization of a class of string-valued graphical models. This question has been investigated using tools from combinatorics, dynamic programming, and graph theory, and has practical applications in Bayesian phylogenetics. In this work, we revisit this theoretical question from a different point of view, based on linear algebra. The main contribution is a set of results based on this linear algebra view that facilitate the analysis and design of inference algorithms on string-valued graphical models. As an illustration, we use this method to give a new elementary proof of a known result on the complexity of inference on the “TKF91” model, a well-known probabilistic model over strings. Compared to previous work, our proving method is easier to extend to other models, since it relies on a novel weak condition, triangular transducers, which is easy to establish in practice. The linear algebra view provides a concise way of describing transducer algorithms and their compositions, opens the possibility of transferring fast linear algebra libraries (for example, based on GPUs), as well as low rank matrix approximation methods, to string-valued inference problems.     

Judgement post-stratification with imprecise rankings

Judgement post-stratification, which is based on ideas similar to those in ranked set sampling, relies on the ability of a ranker to forecast the ranks of potential observations on a set of units. In practice, the authors sometimes find it difficult to assign these ranks. This note shows how one can borrow techniques from the literature on finite population sampling to allow a probabilistic ranking of the units in a set, thus facilitating use of these sampling plans and improving estimation. The same techniques provide one approach to estimation using a judgement post-stratified sample with multiple rankers. The technique is illustrated on allometric data relating brain weight to body weight in different species of mammals, and on a study of student performance in graduate school.     

Extracellular myocilin affects activity of human trabecular meshwork cells

The trabecular meshwork (TM), a specialized eye tissue, is a major site for regulation of the aqueous humor outflow. Malfunctioning of this tissue is believed to be responsible for development of glaucoma, a blinding disease. Myocilin is a gene linked to the most common form of glaucoma. The protein product has been localized to both intra and extracellular sites, but its function still remains unclear. This study was to determine whether extracellular myocilin presented in the matrix affects adhesion, morphology, and migratory and phagocytic activities of human TM cells in culture. Cell adhesion assays indicated that TM cells, while adhering readily on fibronectin, failed to attach on recombinant myocilin purified from bacterial cultures. Adhesion on fibronectin was also compromised by myocilin in a dose dependent manner. Myocilin in addition triggered TM cells to assume a stellate appearance with broad cell bodies and microspikes. Loss of actin stress fibers and focal adhesions was observed. TM cell migration on fibronectin/myocilin to scratched wounds was reduced compared to fibronectin controls. Myocilin, however, had little impact on phagocytic activities of TM cells. Cell attachment on fibronectin and migration of corneal fibroblasts, a control cell type, were not altered by myocilin. These results demonstrate that extracellular myocilin elicits anti-adhesive and counter-migratory effects on TM cells. Myocilin in the matrix of tissues could be exerting a similar influence on TM cells in vivo, impacting the flexibility and resilience required for maintenance of the normal aqueous outflow.     

Decision between small and large prey: reduced energy acquisition by pre-migratory purple sandpipers,Calidris maritima,on Svalbard

On Svalbard, purple sandpipers forage on the shores when preparing for autumn migration to the European continent after a period of food shortage on the tundra in summer. Their food choice was studied on a beach when they were faced with the choice between two abundant prey species: a small collembolan (springtail) and a much larger amphipod. In spite of several times higher gain of energy when foraging on amphipops, the birds did not show a distinct preference for either of the two prey species in this situation. Alternative explanations for this behaviour are discussed. We suggest that this could be a consequence of adaptations to their summer diet on Svalbard, when they rely on Collembola as food to a considerable extent. Higher variance in energy gain rate when foraging on amphipods might also be important. Collembolan densities high enough to trigger predation from birds occurred only on some days, with cloudy calm weather. This, together with the possible existence of a dietary bottleneck, may reduce the cost associated with the switch to Collembola. Accepted: 25 April 1999     

The fluid shear stress distribution on the membrane of leukocytes in the microcirculation

Recent in-vivo and in-vitro evidence indicates that fluid shear stress on the membrane of leukocytes has a powerful control over several aspects of their cell function. This evidence raises a question about the magnitude of the fluid shear stress on leukocytes in the circulation. The flow of plasma on the surface of a leukocyte at a very low Reynolds number is governed by the Stokes equation for the motion of a Newtonian fluid. We numerically estimated the distribution of fluid shear stress on a leukocyte membrane in a microvessel for the cases when the leukocyte is freely suspended, as well as rolling along or attached to a microvessel wall. The results indicate that the fluid shear stress distribution on the leukocyte membrane is nonuniform with a sharp increase when the leukocyte makes membrane attachment to the microvessel wall. In a microvessel (10 microns diameter), the fluid shear stress on the membrane of a freely suspended leukocyte (8 microns diameter) is estimated to be several times larger than the wall shear stress exerted by the undisturbed Poiseuille flow, and increases on an adherent leukocyte up to ten times. High temporal stress gradients are present in freely suspended leukocytes in shear flow due to cell rotation, which are proportional to the local shear rate. In comparison, the temporal stress gradients are reduced on the membrane of leukocytes that are rolling or firmly adhered to the endothelium. High temporal gradients of shear stress are also present on the endothelial wall. At a plasma viscosity of 1 cPoise, the peak shear stresses for suspended and adherent leukocytes are of the order of 10 dyn/cm2 and 100 dyn/cm2, respectively.     

Isolation and Characterization of Neutral Peptides in Soy Sauce

A soy sauce sample was fractionated by gel filtration on a Sephadex G–15 column, then the fractions were subfractionated on the basis of acidity by ion exchange chromatography on a QAE-Sephadex A–25 column. After preliminary fractionation, the components in the neutral subfractions were transformed to copper salts, and the salts were chromatographed on a DEAE-Sephadex A–25 column with a borate buffer and aqueous acetic acid to separate neutral peptide substances from a large amount of free amino acids. The peptide fractions were further fractionated on a preparative amino acid analyzer and by paper chromatography to separate the peptide substances.

Three glycodipeptides and eight dipeptides were isolated and characterized as the major neutral peptide components in soy sauce. However, it was difficult to anticipate any direct contribution of these peptides to the flavor construction in soy sauce on the basis of their taste intensities and contents.     

Effect of intrauterine iodine infusion on luteal function and blood PGF2a concentration in cycling goats

Studies were conducted to determine the effect of iodine infusion on the luteal function of goats, as evident by blood progesterone concentration, and on plasma PGF2a levels. Ten cycling mixed breed goats were synchronized for estrus by PGF2a (5 mg) and given a single intrauterine iodine infusion on day 5 and on day 15 of the estrous cycle. Iodine infusion on day 5 (group II) resulted in shorter estrous length (8.2 days) and a 7-fold increase in plasma PGF2a concentration as compared to control animals (group I) given distilled water infusion. Similar infusion on day 15 (group III), on the other hand, failed to alter the estrous cycle length but induced a moderate increase in PGF2a concentration which lasted only for a brief period. The progesterone levels declined concomitantly as PGF2a levels rose after iodine infusion in group II animals but failed to decline until after 24 hours in group III animals. The studies indicate that the endometrium reacts to the chemical stimuli and releases PGF2a which, in turn, alters the luteal function.     

To Be Or Not to Be? Variable selection can change the projected fate of a threatened species under future climate

Species distribution models (SDMs) are commonly used to project future changes in the geographic ranges of species, to estimate extinction rates and to plan biodiversity conservation. However, these models can produce a range of results depending on how they are parameterized, and over‐reliance on a single model may lead to overconfidence in maps of future distributions. The choice of predictor variable can have a greater influence on projected future habitat than the range of climate models used. We demonstrate this in the case of the Ptunarra Brown Butterfly, a species listed as vulnerable in Tasmania, Australia. We use the Maxent model to develop future projections for this species based on three variable sets; all 35 commonly used so‐called ‘bioclimatic’ variables, a subset of these based on expert knowledge, and a set of monthly climate variables relevant to the species’ primary activity period. We used a dynamically downscaled regional climate model based on three global climate models. Depending on the choice of variable set, the species is projected either to experience very little contraction of habitat or to come close to extinction by the end of the century due to lack of suitable climate. The different conclusions could have important consequences for conservation planning and management, including the perceived viability of habitat restoration. The output of SDMs should therefore be used to define the range of possible trajectories a species may be on, and ongoing monitoring used to inform management as changes occur.     

Host bromeliads and their associated frog species: Further considerations on the importance of species interactions for conservation

Bromeliads constitute a good example of symbiosis with organisms that spend their entire life cycle inside the plants, and often depend on them to breed. The bromeliads benefit from this interaction by increasing their nutrients intake. Conservation efforts tend to focus on a single endangered species, but in symbiotic associations, the viability of one species depends on that of the other. Based on IUCN criteria, any species that depends on another to complete its life cycle should be assigned a conservation status equivalent to that of the host taxon, where appropriate. We gathered published plus fieldwork data on the frog-bromeliad mutualism and compiled a checklist of 99 bromeligenous frogs species associated to 69 bromeliad hosts, and found threatened bromeliads hosting non-threatened frogs. We found that 62% bromeligenous frogs inhabit unspecified bromeliads. Finally, we propose strategies for improving understanding and conservation of the frog-bromeliad mutualism.     

Ticks associated with wild mammals in Ghana

The host ranges of a collection of 21 tick species found on wild mammals in the savanna, forests and coastal zone of Ghana suggested that most species were adapted to feeding mainly on host species within a single mammalian order, i.e. on artiodactyls (bovids/suids), carnivores, rodents or pholidotes (pangolins). Only a few species were dispersed evenly across a range of orders. Seven out of ten of the most common ticks on forest mammals were significantly associated with a particular host species or a group of closely related host species, which could be viewed as their major host or hosts, but they were also recorded much less frequently on a wide range of host species. Two other species were confined to their major hosts. Only one species appeared to be widely dispersed on forest mammals and to lack a particular major host. The majority of tick species therefore occurred on hosts with very distinctive biological, behavioural and ecological characteristics. The study provided no evidence to support the view that host specificity is an artefact of sampling. Finding that the tick species on Ghanaian wild mammals occurred on particular hosts, as well as in distinct habitats, indicated that tick-host associations are important for tick survival and confirmed the importance of climate and vegetation in tick distribution.