The we gene is a modifier of the wal gene in mice

Interaction of gene wellhaarig (we) with genes waved alopecia (wal) and hairless (hr) was studied in mice. The mutant gene we is responsible for the development of a specific waved coat in homozygotes. Homozygous mice carrying mutant gene wal also have a wavy coat, though a partial alopecia develops with time in these animals. In homozygotes for the hr gene, hair loss is observed beginning from the age of ten days. A series of crosses we/we and wal/wal yielded animals with we/+wal/wal and we/we wal/wal genotypes. In mice we/+wal/wal carrying gene we at a single dose, alopecia is accelerated significantly as compared to the single-dose homozygotes +/+wal/wal. In we/we wal/wal mice, alopecia starts earlier than in we/+wal/wal mice; by the age of one month, the double homozygotes are almost hairless except for small body areas covered with a sparse coat. In addition, curliness of the first-generation hair in mice we/we wal/wal is much more expressed than in +/+wal/wal and we/we+/+ mice. The obtained evidence suggests that the we gene is a modifier of the wal gene because the former enhances the effects of the wal gene, which is confirmed by the earlier onset of alopecia and progression of the latter in mice having the we/+wal/wal genotype and especially in we/we wal/wal animals. The we/we hr/+ mice do not differ in coat from we/we+/+ mice; in both cases, the coat is wavy. The coat of double homozygotes we/we hr/hr, is similar to that of we/we+/+ mice until ten days of age, when the signs of alopecia appear. By the age of 21 days, mice we/we hr/hr have lost their coat completely like mice +/+ hr/hr. Hence, the we gene is a modifier of the wal gene though it does not interact with hr gene during the coat formation.     

A global phenomenological model of ischemic stroke with stress on spreading depressions

In this paper, we establish a new global phenomenological model of ischemic stroke. It takes into account local ischemia, energy reduction, propagation of spreading depressions (SD), damages to the cells and cellular death by apoptosis or necrosis. The spatial diffusion of the ions in the extracellular space which triggers the propagation of SD is a central point here. First we expose the various biological hypotheses that we have made in this model, and then we explain how to determine the parameters and solve the system of equations that we obtain. Next we present some results of this model: we simulate a KCl injection and then a local ischemia. Finally we discuss results and propose some improvements for this model.     

Counterfactual thinking and emotions: regret and envy learning

Emotions like regret and envy share a common origin: they are motivated by the counterfactual thinking of what would have happened had we made a different choice. When we contemplate the outcome of a choice we made, we may use the information on the outcome of a choice we did not make. Regret is the purely private comparison between two choices that we could have taken, envy adds to this the information on outcome of choices of others. However, envy has a distinct social component, in that it adds the change in the social ranking that follows a difference in the outcomes. We study the theoretical foundation and the experimental test of this view.     

Reflections on the responsible conduct of cancer research

Most cancer researchers regularly practice the responsible conduct of research (RCR) without consciously considering it. As professional scientists, we simply do what we are trained to do. However, as we train a new generation of cancer researchers in our laboratories, we must be vigilant against undue complacency. In an age when misconduct in research is receiving more media attention than ever before, we should periodically take a moment of pause and reflect upon the meaning and practice of responsibly conducting research. Rather than meeting minimum standards in a compliance-driven manner, we should practice forethought and periodically consider how we can improve. We, as leaders in cancer research, must then push our peers to do the same. By embedding RCR into the culture of cancer research through a multilayer approach, including regular assessment at the levels of individual research groups, departmentally, and institutionally, we will become a model discipline in the responsible conduct of research.     

Effects of the mutant gene wellhaarig in chimeric mice

The mutant gene wellhaaring (we) confers the waved coat in mice, which is most pronounced in homozygotes at 10 to 21 days of postnatal development. Abnormal hair growth and structure in the we/we mutant mice results from defective cell differentiation in the inner root sheath of a hair follicle. To localize the site of the we gene action, we obtained ten chimeric mice by aggregation of the early C57BL/6-2we/we and BALB/c embryos. The chimera coat was waved, shaggy, or almost normal depending on the percentage of the mutant component. In the we/we +/+ chimeric animals of the first generation (G1) aged 21 days, both mutant and normal hair phenotypes were observed, which was especially discernible in zigzag hair. Note that none of the chimeras exhibited the alternating patterns of transversely oriented stripes or patches of either mutant or normal hair; i.e., they had a mixed parental hair phenotype. We also did not observe the animals with an intermediate phenotype, which suggests a discontinuous hair formation in chimeras according to the "all or nothing" principle. The data obtained indicate that the dermal papilla cells of a hair follicle are the sites for the we gene action. During the embryonic development, dermal cells are strongly mixed, which accounts for the lack of the clear-cut transverse stripes of either mutant or normal hair. The mutant gene we is probably responsible for a disrupted induction signal from the dermal papilla towards ectodermal cells of a hair follicle.     

Mixed-mode oscillations in a self-replicating dimerization mechanism

Recently, self-replicating molecules have been synthesized in the laboratory by Rebek. Given the importance of such molecules, we proposed a simple model of a self-replicating dimer, which works as a template for its own formation. Here we consider a three variable model. For the model, we obtain mixed-mode and chaotic oscillations. Also, we find coexistence between two periodic attractors as well as a periodic and a chaotic attractor.     

On the epistemology of mental illness.

The most important epistemological problem in psychiatry is the detection of malingering. This is a consequence of the fact that there is no objective way to confirm any psychiatric diagnosis. Psychiatric diagnosis is based on subjective complaints. The discovery of objective markers for psychiatric diagnosis is problematic because it presupposes we can tell valid from faked subjective symptoms. But this is the difficulty. If we use pervasive irrationality as a sign of mental illness, we encounter the problem of identifying pervasive irrationality. To understand someone's behaviour, we have to assume it is largely rational. This precludes us from using behaviour to separate genuine from faked mental illness. There are a number of strategies used to solve any epistemological problem, and the most successful is the hypothetico-deductive method. If we use this, we can solve our epistemological problem. Genuine mental illness can be identified when it is the best explanation of the person's overall behaviour. Consilience of inductions is critical in supporting the validity of such explanations. This implies that it is merely a hypothesis that mental illness exists, and that we might discover that many mental illnesses, perhaps all, do not exist. We must embrace this possibility--only if we take a risk will we gain any knowledge.     

Accounting for variability in sample size estimation with applications to nonadherence and estimation of variance and effect size

We consider sample size calculations for testing differences in means between two samples and allowing for different variances in the two groups. Typically, the power functions depend on the sample size and a set of parameters assumed known, and the sample size needed to obtain a prespecified power is calculated. Here, we account for two sources of variability: we allow the sample size in the power function to be a stochastic variable, and we consider estimating the parameters from preliminary data. An example of the first source of variability is nonadherence (noncompliance). We assume that the proportion of subjects who will adhere to their treatment regimen is not known before the study, but that the proportion is a stochastic variable with a known distribution. Under this assumption, we develop simple closed form sample size calculations based on asymptotic normality. The second source of variability is in parameter estimates that are estimated from prior data. For example, we account for variability in estimating the variance of the normal response from existing data which are assumed to have the same variance as the study for which we are calculating the sample size. We show that we can account for the variability of the variance estimate by simply using a slightly larger nominal power in the usual sample size calculation, which we call the calibrated power. We show that the calculation of the calibrated power depends only on the sample size of the existing data, and we give a table of calibrated power by sample size. Further, we consider the calculation of the sample size in the rarer situation where we account for the variability in estimating the standardized effect size from some existing data. This latter situation, as well as several of the previous ones, is motivated by sample size calculations for a Phase II trial of a malaria vaccine candidate.     

Evolution: an axiomatic perspective.

In this paper we present an axiomatic theory of evolution which is inspired by the reading of a paper written by G.V. Schiaparelli in 1898. Schiaparelli was a famous astronomer, but he also studied the Darwinian ideas. We propose five axioms which can characterize the theory of evolution. We have also written these axioms using the language of the logic of predicates of first order with some constant monadic and dyadic predicates and appropriate functionals. But we can use other types of logic. So we can examine the concepts of species and of speciation. Then we introduce the interesting notion of generation distance. Moreover we give a theorem which establishes a geometrical model of our theory. If we analyze further the fourth axiom (which concerns the notion of generation distance) we can propose an elementary dynamical model by which we can represent possible evolutionary dynamics. These dynamics partially depend on random quantities.     

Data-Driven Engineering of Social Dynamics: Pattern Matching and Profit Maximization

In this paper, we define a new problem related to social media, namely, the data-driven engineering of social dynamics. More precisely, given a set of observations from the past, we aim at finding the best short-term intervention that can lead to predefined long-term outcomes. Toward this end, we propose a general formulation that covers two useful engineering tasks as special cases, namely, pattern matching and profit maximization. By incorporating a deep learning model, we derive a solution using convex relaxation and quadratic-programming transformation. Moreover, we propose a data-driven evaluation method in place of the expensive field experiments. Using a Twitter dataset, we demonstrate the effectiveness of our dynamics engineering approach for both pattern matching and profit maximization, and study the multifaceted interplay among several important factors of dynamics engineering, such as solution validity, pattern-matching accuracy, and intervention cost. Finally, the method we propose is general enough to work with multi-dimensional time series, so it can potentially be used in many other applications.     

Seeing and acting at the same time: challenges for brain (and) research

Traditionally, studies of the visual system of nonhuman primates have investigated neurons while the animal fixates a target in a static environment. Clearly, this is not what our everyday life is like; neither the environment nor we are stationary while we act in our world. On the contrary, we constantly move our eyes or limbs. Here we review a number of recent studies describing the brain in a more realistic mode of operation.     

Peptide signaling in Hydra

Peptides play a number of crucial roles as signaling molecules in metazoans. In order to elaborate a more complete picture of the roles played by peptides in a single organism, we launched the "Hydra Peptide Project". For this project, we used Hydra magnipapillata, a species belonging to Cnidaria, one of the most basal metazoan phyla, and using a peptidomic approach, we systematically identified a number of peptide signaling molecules, their encoding genes and their functions. In this article, we report the peptides isolated from Hydra and other cnidarians, as well as their synthesis, processing and release from the cells to the target. Possible peptide signaling pathways are overviewed and finally we discuss the evolution of the peptide signaling system.     

Systems biology of lactic acid bacteria: a critical review

Understanding the properties of a system as emerging from the interaction of well described parts is the most important goal of Systems Biology. Although in the practice of Lactic Acid Bacteria (LAB) physiology we most often think of the parts as the proteins and metabolites, a wider interpretation of what a part is can be useful. For example, different strains or species can be the parts of a community, or we could study only the chemical reactions as the parts of metabolism (and forgetting about the enzymes that catalyze them), as is done in flux balance analysis. As long as we have some understanding of the properties of these parts, we can investigate whether their interaction leads to novel or unanticipated behaviour of the system that they constitute. There has been a tendency in the Systems Biology community to think that the collection and integration of data should continue ad infinitum, or that we will otherwise not be able to understand the systems that we study in their details. However, it may sometimes be useful to take a step back and consider whether the knowledge that we already have may not explain the system behaviour that we find so intriguing. Reasoning about systems can be difficult, and may require the application of mathematical techniques. The reward is sometimes the realization of unexpected conclusions, or in the worst case, that we still do not know enough details of the parts, or of the interactions between them. We will discuss a number of cases, with a focus on LAB-related work, where a typical systems approach has brought new knowledge or perspective, often counterintuitive, and clashing with conclusions from simpler approaches. Also novel types of testable hypotheses may be generated by the systems approach, which we will illustrate. Finally we will give an outlook on the fields of research where the systems approach may point the way for the near future.     

Random binding of dimers to chains

We develop a probabilistic model for the binding of a small linear polymer to a larger chain. We assume that we can approximate the energy of interaction of the two chains by summing the pairwise interactions between subunits. Because the energy of interaction between a pair of subunits can depend on neighboring subunits, which we assume vary along the chain, we assign the pairwise energies of interactions according to a specified probability distribution. Thus we develop a statistical model for the binding of two molecules. While such models may not be appropriate for studying the interaction of a particular pair of molecules, they can provide insight into questions that deal with populations of molecules, such as why do MHC molecules bind peptides of a certain size? Here we analyze in detail the special case of a heterodimer binding to a polymer.     

Resolution of Ultramicroscopy and Field of View Analysis

In a recent publication we described a microscopical technique called Ultramicroscopy, combined with a histological procedure that makes biological samples transparent. With this combination we can gather three-dimensional image data of large biological samples. Here we present the theoretical analysis of the z-resolution. By analyzing the cross-section of the illuminating sheet of light we derive resolution values according to the Rayleigh-criterion. Next we investigate the resolution adjacent to the focal point of the illumination beam, analyze throughout what extend the illumination beam is of acceptable sharpness and investigate the resolution improvements caused by the objective lens. Finally we conclude with a useful rule for the sampling rates. These findings are of practical importance for researchers working with Ultramicroscopy to decide on adequate sampling rates. They are also necessary to modify deconvolution techniques to gain further image improvements.     

Haplotype reconstruction from SNP alignment.

In this paper, we describe a method for statistical reconstruction of haplotypes from a set of aligned SNP fragments. We consider the case of a pair of homologous human chromosomes, one from the mother and the other from the father. After fragment assembly, we wish to reconstruct the two haplotypes of the parents. Given a set of potential SNP sites inferred from the assembly alignment, we wish to divide the fragment set into two subsets, each of which represents one chromosome. Our method is based on a statistical model of sequencing errors, compositional information, and haplotype memberships. We calculate probabilities of different haplotypes conditional on the alignment. Due to computational complexity, we first determine phases for neighboring SNPs. Then we connect them and construct haplotype segments. Also, we compute the accuracy or confidence of the reconstructed haplotypes. We discuss other issues, such as alternative methods, parameter estimation, computational efficiency, and relaxation of assumptions.     

The risk of competitive exclusion during evolutionary branching: Effects of resource variability, correlation and autocorrelation

Evolutionary branching has been suggested as a mechanism to explain ecological speciation processes. Recent studies indicate however that demographic stochasticity and environmental fluctuations may prevent branching through stochastic competitive exclusion. Here we extend previous theory in several ways; we use a more mechanistic ecological model, we incorporate environmental fluctuations in a more realistic way and we include environmental autocorrelation in the analysis. We present a single, comprehensible analytical result which summarizes most effects of environmental fluctuations on evolutionary branching driven by resource competition. Corroborating earlier findings, we show that branching may be delayed or impeded if the underlying resources have uncorrelated or negatively correlated responses to environmental fluctuations. There is also a strong impeding effect of positive environmental autocorrelation, which can be related to results from recent experiments on adaptive radiation in bacterial microcosms. In addition, we find that environmental fluctuations can lead to cycles of repeated branching and extinction.     

Multimedia information retrieval and environmental monitoring: Shared perspectives on data fusion

Computer-based remote monitoring of our environment is increasingly based on combining data derived from in-situ-sensors with data derived from remote sources, such as satellite images or CCTV. In such deployments it is necessary to continuously monitor the accuracy of each of the sensor data streams so that we can account for sudden failures of sensors, or errors due to calibration drive or biofouling. In multimedia information retrieval (MMIR), we search through archives of multimedia artefacts like video programs, by implementing several independent retrieval systems or agents, and we combine the outputs of each retrieval agent in order to generate an overall ranking. In this paper we draw parallels between these seemingly very different applications and show how they share several similarities. In the case of environmental monitoring we also need some mechanism by which we can establish the trust and reputation of each contributing sensor, though this is something we do not need in MMIR. In this paper we present an outline of a trust and reputation framework we have developed and deployed for monitoring the performance of sensors in a heterogeneous sensor network.