In this review, we discuss the application of mouse models to the identification and pre‐clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large‐scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross‐species comparative ‘omics‐based approaches to this problem. We highlight recent progress in modelling late‐stage disease using (...) mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection. (shrink)

There has always been great interest in animal models of human genetic disease, and mice provide the largest number of examples. A mutation in the homologous gene in mice does not always lead to the same phenotype as is found in man, however. Recent studies made it apparent that one mutation can have markedly different phenotypes when placed on different genetic backgrounds. This variation is due to different alleles at modifying loci in various inbred strains. Thus, if one wishes to (...) obtain the optimal mouse model for a human disease, one needs to choose the correct genetic background as well as the correct mutation. (shrink)

Mouse models of human genetic disorders provide a valuable resource for investigating the pathogenesis of genetic disease and for testing potential therapies. The high degree of resolution of linkage mapping in the mouse allows mutant phenotypes to be mapped precisely which, combined with the accurate definition of areas of homology between the mouse and human genomes, greatly facilitates the identification of mouse models. We describe here mouse models of human single gene disorders dividing them into (...) three categories depending on the information available; phenotypic similarities, comparative mapping and identification of the underlying genetic lesion. (shrink)

Alzheimer's disease, a form of senile dementia, is characterised by two kinds of pathological deposits in the brain, called plaques and tangles. The molecular nature of the deposits has been identified but there is as yet little understanding of the underlying biochemistry and cell biology that lead to their formation. Progress in this area would be greatly aided by a realistic animal model. Two recent papers describe the production of transgenic mice that develop significant aspects of Alzheimer‐like pathology. The (...) mice produced by Games et al.(1) develop plaques while those produced by Götz et al.(2) display the early stages of tangle pathology. (shrink)

Melatonin, the neuro‐hormone synthesized during the night, has recently seen an unexpected extension of its functional implications toward type 2 diabetes development, visual functions, sleep disturbances, and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein‐coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of (...) mouse MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. (shrink)

The primary aim of biomedical research is to discover and develop new knowledge to advance human medicine. Frequently a ‘mouse model’ is taken to be a necessary step towards understanding a disease, biological mechanism or intervention. We argue for caution with respect to the mouse model: theoretical reasons, meta-analyses of empirical data, and viable alternatives all support a more restricted use of animals in laboratories than is current practice. On its own terms, a utilitarian scientific justification (...) for using animals in biomedical research converges more closely with welfarist claims than is usually recognised. (shrink)

Over the past several years, discoveries from mouse genetics have had direct impact on our understanding of vitamin A metabolism. Although the metabolism of vitamin A in the mouse does have some special features (for example very large stores of liver and pulmonary retinyl esters), the ability to construct knockout and transgenic mouse models has yielded an impressive amount of information directly relevant to understanding the general principles of vitamin A transport, storage and degradation. We discuss below (...) the metabolism of vitamin A through a number of genetically engineered mouse strains with alterations in genes that affect this metabolism. The novelty of this experimental approach is evidenced by the fact that the oldest of these strains was first reported only eight years ago.1) BioEssays 23:409–419, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

This paper examines processes of translation through which molecular genetic technologies and practices are incorporated into environmental health research and regulation. Specifically, it considers how scientists, risk assessors, and regulators have used genetically modified mouse models to translate across scientific disciplines, articulate emergent molecular forms, standards, and practices with the extant? gold standard,? and establish roles for molecular knowledge in risk assessment and regulation. Noting variation both within and between regulatory agencies in responses to data from these models, the (...) article describes also the role of public-private networks and their effects on professional and institutional imperatives which shape regulators? responses to the potential applications of these models. The conclusions address the importance of translation for understanding the wider implications of the molecularization of environmental health science. (shrink)

Recent studies uncovered critical roles of the adhesion protein E‐cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E‐cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E‐cadherin's functions beyond development, numerous mouse lines with tissue‐specific disruption of Cdh1 have been generated. The consequences of E‐cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete loss of tissue (...) structure and function. This review focuses on these studies and discusses how they provided important insights into E‐cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial‐to‐mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research. (shrink)

Mitochondrial ATP synthesis, calcium buffering, and trafficking affect neuronal function and survival. Several genes implicated in mitochondrial functions map within the genomic region associated with 22q11.2 deletion syndrome (22q11DS), which is a key genetic cause of neuropsychiatric diseases. Although neuropsychiatric diseases impose a serious health and economic burden, their etiology and pathogenesis remain largely unknown because of the dearth of valid animal models and the challenges in investigating the pathophysiology in neuronal circuits. Mouse models of 22q11DS are becoming valid (...) tools for studying human psychiatric diseases, because they have hemizygous deletions of the genes that are deleted in patients and exhibit neuronal and behavioral abnormalities consistent with neuropsychiatric disease. The deletion of some 22q11DS genes implicated in mitochondrial function leads to abnormal neuronal and synaptic function. Herein, we summarize recent findings on mitochondrial dysfunction in 22q11DS and extend those findings to the larger context of schizophrenia and other neuropsychiatric diseases. (shrink)

Current theories of breast cancer progression have been greatly influenced by the development and refinement of mouse transgenic and gene targeting technologies. Early transgenic mouse models confirmed the involvement of oncogenes, previously implicated in human breast cancer, by establishing a causal relationship between overexpression or activation of these genes and mammary tumorigenesis. More recently, the importance of genes located at sites of loss of heterozygosity in human breast cancer have been examined in mice by their targeted disruption via (...) homologous recombination. The union of these two approaches allows the generation of complex animal models that more accurately reflect the multistep nature of human breast cancer. This review will examine how the study of transgenic mice has increased our understanding of the molecular events responsible for oncogenic transformation of the mammary gland. BioEssays 22:554–563, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

The nonobese diabetic (NOD) mouse spontaneously develops an autoimmune diabetes that shares many immunogenetic features with human insulin-dependent diabetes mellitus (IDDM), type 1 diabetes. The mononuclear cell infiltrates in the islet, which results in the development of insulitis (a prerequisite step for the development of diabetes) are primarily composed of T cells. It is now well accepted that these T cells play important roles in initiating and propagating an autoimmune process, which in turn destroys insulin-producing islet β cells in (...) the pancreas. T cells are subdivided into CD4+ helper T cells and CD8+ cytotoxic T cells. CD4+ T cells are further subdivided into Th1 and Th2 cells based on profiles of cytokine production, and these two T-cell populations counterregulate each other. Because many autoimmune diseases are Th1 T-cell mediated, current studies have focused on manipulating the Th1/Th2 imbalance to suppress the autoimmune process in the NOD model. Furthermore, the incidence of disease is much higher in females than that in males, suggesting an involvement of sex-steroid hormones in the development of diabetes. Understanding insights of the mechanism of immune-mediated islet cell destruction and the interaction between the immune and the neuroendocrine system may, therefore, provide new therapeutic means of preventing this chronic debilitating disease. BioEssays 20:750–757, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Ultraviolet (UV) radiation is a very common carcinogen in our environment, but epidemiological data on the relationship between skin cancers and ambient solar UV radiation are very restricted. In hairless mice the process of UV carcinogenesis can be studied in depth. Experiments with this animal model have yielded quantitative data on how tumor development depends on dose, time and wavelength of the UV radiation. In combination with epidemiological data, these experimental results can be transposed to humans. Comparative studies on (...) molecular, cellular and physiological changes in mouse and man can further our fundamental understanding of UV carcinogenesis in man. This is likely to improve risk assessments such as those related to a stratospheric ozone depletion, and to yield well‐targeted intervention schemes, e.g. prescribing a specific drug or diet, for high‐risk individuals. (shrink)

During development of the anterior eye segment, cells that originate from the surface epithelium or the neuroepithelium need to interact with mesenchymal cells, which predominantly originate from the neural crest. Failures of proper interaction result in a complex of developmental disorders such Peters' anomaly, Axenfeld–Rieger's syndrome or aniridia. Here we review the role of transcription factors that have been identified to be involved in the coordination of anterior eye development. Among these factors is PAX6, which is active in both epithelial (...) and mesenchymal cells during ocular development, albeit at different doses and times. We propose that PAX6 is a key element that synchronizes the complex interaction of cell types of different origin, which are all needed for proper morphogenesis of the anterior eye. We discuss several molecular mechanisms that might explain the effects of haploinsufficiency of PAX6 and other transcription factors, and the broad variation of the resulting phenotypes. BioEssays 26:374–386, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

We desperately need to know more of the biological details of the onset and progression of breast cancer. The disease is of startlingly high incidence (approaching 1 in 9 women), our current therapies for the disease are inadequate once it has metastasized, and the disease is characterized by excessive morbidity and mortality.Most of the growth and differentiation of the mammary gland occurs relatively late in life: during sexual maturation, and then cyclically during pregnancy and lactation. Normal as well as malignant (...) growth is regulated by endocrine hormones as well as by local tissue factors, such as polypeptide growth factors, Cancer seems to progress as hyperplastic ductal or lobular epithelial growth, acquiring progressive genetic changes (including those of oncogenes and tumor suppressor genes) leading to clonal outgrowths of progressively more malignant cells. The nature of proliferative controls and the relevant genetic changes are the subjects of the current review. (shrink)

Mouse tracking, a new action‐based measure of behavior, has advanced theories of decision making with the notion that cognitive and social decision making is fundamentally dynamic. Implicit in this theory is that people's decision strategies, such as discounting delayed rewards, are stable over task design and that mouse trajectory features correspond to specific segments of decision making. By applying the hierarchical drift diffusion model and the Bayesian delay discounting model, we tested these assumptions. Specifically, we investigated (...) the extent to which the “mouse‐tracking” design of decision‐making tasks (delay discounting task, DDT and stop‐signal task, SST) deviate from the standard “keypress” design of decision making tasks. We found remarkable agreement in delay discounting rates (intertemporal impatience) obtained in the keypress and mouse‐tracking versions of DDT (ρ = 0.90) even though these tasks were given about 1 week apart. Rates of evidence accumulation converged well in the two versions (DDT, ρ =.86; SST, ρ =.55). Omission/commission error in SST showed high agreement (ρ =.42, ρ =.53). Mouse‐motion features such as maximum velocity and AUC (area under the curve) correlated well with nondecision time (ρ = −.42) and boundary separation (ρ =.44)—the amount of information needed to accumulate prior to making a response. These results indicate that the response time (RT) and motion‐based decision tasks converge well at a fundamental level, and that mouse‐tracking features such as AUC and maximum velocity do indicate the degree of decision conflict and impulsivity. (shrink)

Neural tube defects are one of the commonest human birth defects, with more than 0.5% of some populations affected. Mouse models are being used in an attempt to identify genes that could be involved in these malformations. Only two mouse mutations are known to lead to craniorachischisis, failure of closure of almost the entire neural tube. Two recent papers report that the gene for one of these, Loop‐tail, has now been identified and sequenced.1, 2 It has been given (...) the designation Ltap/Lpp1 and appears to function in floor plate formation. It will be of great interest to investigate the role of this gene in human neural tube defects. BioEssays 24:580–583, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Patient-derived xenografts are currently promoted as new translational models in precision oncology. PDXs are immunodeficient mice with human tumors that are used as surrogate models to represent specific types of cancer. By accounting for the genetic heterogeneity of cancer tumors, PDXs are hoped to provide more clinically relevant results in preclinical research. Further, in the function of so-called “mouse avatars”, PDXs are hoped to allow for patient-specific drug testing in real-time. This paper examines the circulation of knowledge and bodily (...) material across the species boundary of human and personalized mouse model, historically as well as in contemporary practices. PDXs raise interesting questions about the relation between animal model and human patient, and about the capacity of hybrid or interspecies models to close existing translational gaps. We highlight that the translational potential of PDXs not only depends on representational matching of model and target, but also on temporal alignment between model development and practical uses. Aside from the importance of ensuring temporal stability of human tumors in a murine body, the mouse avatar concept rests on the possibility of aligning the temporal horizons of the clinic and the lab. We examine strategies to address temporal challenges, including cryopreservation and biobanking, as well as attempts to speed up translation through modification and use of faster developing organisms. We discuss how featured model virtues change with precision oncology, and contend that temporality is a model feature that deserves more philosophical attention. (shrink)

Building on the work of Schimmerling [Coherent sequences and threads, Adv. Math.216 89–117] and Steel [PFA implies AD L, J. Symbolic Logic70 1255–1296], we show that the failure of square principle at a singular strong limit cardinal implies that there is a nontame mouse. The proof presented is the first inductive step beyond L of the core model induction that is aimed at getting a model of ADℝ + "Θ is regular" from the failure of square at (...) a singular strong limit cardinal or PFA. (shrink)

We identify a particular mouse, [Formula: see text], the minimal ladder mouse, that sits in the mouse order just past [Formula: see text] for all [Formula: see text], and we show that [Formula: see text], the set of reals that are [Formula: see text] in a countable ordinal. Thus [Formula: see text] is a mouse set. This is analogous to the fact that [Formula: see text] where [Formula: see text] is the sharp for the minimal inner (...) model with a Woodin cardinal, and [Formula: see text] is the set of reals that are [Formula: see text] in a countable ordinal. More generally [Formula: see text]. The mouse [Formula: see text] and the set [Formula: see text] compose the next natural pair to consider in this series of results. Thus we are proving the mouse set theorem just past projective. Some of this is not new. [Formula: see text] was known in the 1990s. But [Formula: see text] was open until Woodin found a proof in 2018. The main goal of this paper is to give Woodin’s proof. (shrink)

Mechanisms involved in the regulation of development and its genetic control are receiving ever‐increasing attention in studies of mammalian developmental genetics. The potential success of such studies is strongly enhanced by the availability of suitable systems of analysis. Such a system was identified in a series of radiation‐induced chromosomal deletions at and around the albino (c) locus of the mouse associated with cell type‐specific effects on liver differentiation. Their detailed study has aided the analysis of possible machanisms of cell (...) type‐specific gene expression. As summarized in this review, the experimental results strongly suggest that specific trans‐acting developmental regulatory genes are concerned with the differentiation of hormone‐inducible expression of a cluster of hepatocyte specific structural genes mapping in different parts of the genome. (shrink)

In this paper we explore a connection between descriptive set theory and inner model theory. From descriptive set theory, we will take a countable, definable set of reals, A. We will then show that , where is a canonical model from inner model theory. In technical terms, is a “mouse”. Consequently, we say that A is a mouse set. For a concrete example of the type of set A we are working with, let ODnω1 be (...) the set of reals which are ∑n definable over the model Lω1 , from an ordinal parameter. In this paper we will show that for all n 1, ODnω1 is a mouse set. Our work extends some similar results due to D.A. Martin, J.R. Steel, and H. Woodin. Several interesting questions in this area remain open. (shrink)

Affective computing research has advanced emotion recognition systems using facial expressions, voices, gaits, and physiological signals, yet these methods are often impractical. This study integrates mouse cursor motion analysis into affective computing and investigates the idea that movements of the computer cursor can provide information about emotion of the computer user. We extracted 16–26 trajectory features during a choice-reaching task and examined the link between emotion and cursor motions. Participants were induced for positive or negative emotions by music, film (...) clips, or emotional pictures, and they indicated their emotions with questionnaires. Our 10-fold cross-validation analysis shows that statistical models formed from “known” participants could predict nearly 10%–20% of the variance of positive affect and attentiveness ratings of “unknown” participants, suggesting that cursor movement patterns such as the area under curve and direction change help infer emotions of computer users. (shrink)

Mice with alterations to specific endogenous genes can be produced by gene targeting in embryonic stem cells. The field has developed rapidly over the past decade, so that large numbers of mice with different gene deficiencies have been generated. Knockout mice provide an ideal opportunity to analyse the function of individual mammalian genes and to model a range of human inherited disorders. This powerful approach has also identified numerous examples of gene redundancy and has highlighted the need to consider (...) metabolic differences between man and mouse in disease modelling. More sophisticated gene‐targeting methods are now being used to introduce subtle gene alterations. In the future, more refined genetic analysis and genome, rather than individual gene, alterations will be achieved by incorporating site‐specific recombination into targeting strategies. Gene targeting could also make a contribution to improved protocols for gene therapy. (shrink)

Although mouse‐tracking has been taken as a real‐time window on different aspects of human decision‐making processes, whether purely semantic information affects response conflict at the level of motor output as measured through mouse movements is still unknown. Here, across two experiments, we investigated the effects of semantic knowledge by predicting participants’ performance in a standard keyboard task and in a mouse‐tracking task through distributional semantics, a usage‐based modeling approach to meaning. In Experiment 1, participants were shown word (...) pairs and were required to perform a two‐alternative forced choice task selecting either the more abstract or the more concrete word, using standard keyboard presses. In Experiment 2, participants performed the same task, yet this time response selection was achieved by moving the computer mouse. Results showed that the involvement of semantic components in the task at hand is observable using both standard reaction times (Experiment 1) as well as using indexes extracted from mouse trajectories (Experiment 2). In particular, mouse trajectories reflected the response conflict and its temporal evolution, with a larger deviation for increasing word semantic relatedness. These findings support the validity of mouse‐tracking as a method to detect deep and implicit decision‐making features. Additionally, by demonstrating that a usage‐based model of meaning can account for the different degrees of cognitive conflict associated with task achievement, these findings testify the impact of the human semantic memory on decision‐making processes. (shrink)

Early morphogenesis of mouse submandibular gland provides an excellent model for the formation of epithelial lobules as a consequence of epithelial‐mesenchymal interactions. Both proteoglycans and a glycosaminoglycan, high molecular weight components which contain amino‐sugars and hexuronic acids, seem to be important in maintaining the lobular structure through the formation of epithelial basal lamina. Collagen also appears to play a crucial role in this morphogenesis. By visualizing the distribution of collagen fibrils and by changing the concentration of collagen in (...) the gland, we have developed a new hypothesis which emphasizes the mechanical role of mesenchyme in epithelial cleft formation. Precise mechanisms for the involvement of these molecules have not been elucidated, yet it is now clear that knowledge of the function of the extracellular matrix components is a prerequisite for understanding the epithelial‐mesenchymal interactions. (shrink)

Early morphogenesis of mouse submandibular gland provides an excellent model for the formation of epithelial lobules as a consequence of epithelial‐mesenchymal interactions. Both proteoglycans and a glycosaminoglycan, high molecular weight components which contain amino‐sugars and hexuronic acids, seem to be important in maintaining the lobular structure through the formation of epithelial basal lamina. Collagen also appears to play a crucial role in this morphogenesis. By visualizing the distribution of collagen fibrils and by changing the concentration of collagen in (...) the gland, we have developed a new hypothesis which emphasizes the mechanical role of mesenchyme in epithelial cleft formation. Precise mechanisms for the involvement of these molecules have not been elucidated, yet it is now clear that knowledge of the function of the extracellular matrix components is a prerequisite for understanding the epithelial‐mesenchymal interactions. (shrink)

The Higgs particle has been detected a few years ago, that is what newspapers tell us. For many physicists, the Standard Model of particle physics has accomplished all the jobs. Or to put it simply: The game is over. Is it true? Then some physicists began to ask: can go beyond the Standard Model? Because the supersymmetric extension of the Standard Model has failed. If you feel that theoretical physics is becoming boring, you are not alone. Fortunately, (...) there is good news: a new generation of physicists are doing table-top experiments in their basements. Can we expect new results later? If so, what will the future of physics look like? This article discusses this question, starting with a blunt look at the relationship between mathematics and physical reality, written from the perspectives of a mathematician and a cosmologist. (shrink)

The purpose of this paper is to outline some recent progress in descriptive inner model theory, a branch of set theory which studies descriptive set theoretic and inner model theoretic objects using tools from both areas. There are several interlaced problems that lie on the border of these two areas of set theory, but one that has been rather central for almost two decades is the conjecture known as the Mouse Set Conjecture. One particular motivation for resolving (...) MSC is that it provides grounds for solving the inner model problem which dates back to 1960s. There have been some new partial results on MSC and the methods used to prove the new instances suggest a general program for solving the full conjecture. It is then our goal to communicate the ideas of this program to the community at large. (shrink)

How cell commitment and differentiation are controlled in the early stages of embryogenesis is a problem that has long fascinated developmental biologists. Retinoic acidinduced differentiation of embryonal carcinoma cells in culture provides a model in which these questions can be explored. Recent work has yielded exciting insights into the central series of molecular changes which drives the commitment of these cells to formation of a new phenotype. Interacting with the key molecules in this central pathway is a variety of (...) transcription factors, many of which show changes in availability and/or activity during differentiation. In various combinations, these modulate the activities of genes involved in both cell proliferation and in the production of extracellular matrix and other proteins characteristic of differentiated cells. (shrink)

Let κ R be the least ordinal κ such that L κ (R) is admissible. Let $A = \{x \in \mathbb{R} \mid (\exists\alpha such that x is ordinal definable in L α (R)}. It is well known that (assuming determinacy) A is the largest countable inductive set of reals. Let T be the theory: ZFC - Replacement + "There exists ω Woodin cardinals which are cofinal in the ordinals." T has consistency strength weaker than that of the theory ZFC + (...) "There exists ω Woodin cardinals", but stronger than that of the theory ZFC + "There exists n Woodin Cardinals", for each n ∈ ω. Let M be the canonical, minimal inner model for the theory T. In this paper we show that A = R ∩ M. Since M is a mouse, we say that A is a mouse set. As an application, we use our characterization of A to give an inner-model-theoretic proof of a theorem of Martin which states that for all n, every Σ * n real is in A. (shrink)

Many neurodegenerative and neuropsychiatric diseases and other brain disorders are accompanied by impairments in high-level cognitive functions including memory, attention, motivation, and decision-making. Despite several decades of extensive research, neuroscience is little closer to discovering new treatments. Key impediments include the absence of validated and robust cognitive assessment tools for facilitating translation from animal models to humans. In this review, we describe a state-of-the-art platform poised to overcome these impediments and improve the success of translational research, the Mouse Translational (...) Research Accelerator Platform (MouseTRAP), which is centered on the touchscreen cognitive testing system for rodents. It integrates touchscreen-based tests of high-level cognitive assessment with state-of-the art neurotechnology to record and manipulate molecular and circuit level activity in vivo in animal models during human-relevant cognitive performance. The platform also is integrated with two Open Science platforms designed to facilitate knowledge and data-sharing practices within the rodent touchscreen community, touchscreencognition and mousebytes. Touchscreencognition includes the Wall, showcasing touchscreen news and publications, the Forum, for community discussion, and Training, which includes courses, videos, SOPs, and symposia. To get started, interested researchers simply create user accounts. We describe the origins of the touchscreen testing system, the novel lines of research it has facilitated, and its increasingly widespread use in translational research, which is attributable in part to knowledge-sharing efforts over the past decade. We then identify the unique features of MouseTRAP that stand to potentially revolutionize translational research, and describe new initiatives to partner with similar platforms such as McGill’s M3 platform. (shrink)

The mode and timing of germ-cell specification has been studied in diverse organisms, however, the molecular mechanism regulating germ-cell-fate determination remains to be elucidated. In some model organisms, maternal germ-cell determinants play a key role. In mouse embryos, some germ-line-specific gene products exist as maternal molecules and play critical roles in a pluripotential cell population at preimplantation stages. From those cells, primordial germ cells (PGCs) are specified by extracellular signaling mediated by tissue, as well as cell–cell interaction during (...) gastrulation. Thus, establishment of germ-cell lineage in mammalian embryos appears to be regulated by a multistep process, including formation and maintenance of a pluripotential cell population, as well as specification of PGCs. PGCs can be generated from pluripotential embryonic stem (ES) cells in a simple monolayer culture in which tissue interaction does not occur. This raises the possibility that ES cells, as well as, possibly, pluripotential cells in preimplantation embryos, are more closely related to the PGC precursors than pluripotential cells after implantation. BioEssays 27:136–143, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Shortly after implantation the embryonic lineage transforms from a coherent ball of cells into polarized cup shaped epithelium. Recently we elucidated a previously unknown apoptosis‐independent morphogenic event that reorganizes the pluripotent lineage. Polarization cues from the surrounding basement membrane rearrange the epiblast into a polarized rosette‐like structure, where subsequently a central lumen is established. Thus, we provided a new model revising the current concept of apoptosis‐dependent epiblast morphogenesis. Cell death however has to be tightly regulated during embryogenesis to ensure (...) developmental success. Here, we follow the stages of early mouse development and take a glimpse at the critical signaling and morphogenic events that determine cells destiny and reshape the embryonic lineage. (shrink)

Researchers have recently begun to question the specificity and reliability of conflict adaptation effects, also known as sequential congruency effects, a highly cited effect in cognitive psychology. Some have even used the lack of reliability across tasks to argue against models of cognitive control that have dominated the field for decades. The present study tested the possibility that domain-general processes across tasks might appear on more sensitive mouse-tracking metrics rather than overall reaction times. The relationship between SCE effects on (...) the Stroop and Flanker tasks were examined for the first time using a mouse-tracking paradigm. Three main findings emerged: Robust SCEs were observed for both the Stroop and Flanker tasks at the group level, Within-task split-half reliabilities for the SCE across dependent variables were weak at best and non-existent in many cases, and SCEs for the Flanker and Stroop tasks did not correlate with each other for overall reaction times, but did show significant correlations between tasks on more dynamic measures that captured processes before response execution. These findings contribute to the literature by highlighting how mouse-tracking may be a fruitful avenue by which future studies can examine the specificity and reliability of conflict adaptation and tease apart different theoretical models producing the effects. (shrink)

This article examines what was, for many decades, to a large audience the paradigmatic example of the short film, i.e. the animated short. Focussing on the first two Mickey Mouse shorts (i.e. Plane Crazy and Steamboat Willie (both 1928)), which I understand as highly self-conscious reflections on animation, I explore how animation relies on a set of pleasures, sensations and fascinations that differ profoundly from what mainstream (‘photographic’) feature-length cinema has on offer, and thereby opens to a series of (...) insights into ‘cinematic experiences’ that cannot be grasped within the logic of the voyeuristic model of the cinematic apparatus that has until recently dominated classical film theory. (shrink)

Classical ethology encourages a causal approach to animal behaviour, using Tinbergen's four questions concerning evolution, function, mechanism and development of behaviour. It sets aside the study of mental processes, which could otherwise help to unify our picture of the relationships between animal and environment. Here the steps in research focused on the psychological meaning of a peculiar behaviour in the mouse — carrying its tail — and what this implies regarding the mouse's cognitive world are given. Initial empirical (...) observations suggested epistemic choices concerning space and object notions in the mouse; this led us to go beyond the first stage in exploring the significance of this behaviour. Later experiments showed the limitations of an explanation based on a cause-effect relationship. An interpretative model integrating a phenomenological conceptual framework is proposed. (shrink)

The existence of a genetic program of development was proposed by molecular biologists in the nineteen-sixties. Historians and philosophers of science have since thoroughly criticized this notion. To fully appreciate its significance, it is interesting to consider the research which was pursued during this period by molecular biologists who proposed this notion. This study focuses on François Jacob's work and on the model of development supported by his lab in the early seventies, the T-complex model. This episode of (...) Jacob's scientific activity has since been forgotten. Characterization of this model shows that the notion of program was used in a metaphoric way and that it did not put any constraint on the work pursued in the lab at that time. Some attention is devoted to the origin of this metaphor in the context of the nineteen-seventies. (shrink)

The vertebrate Cdx genes (Cdx1 Cdx2 and Cdx4 in the mouse) encode homeodomain transcription factors related to the Drosophila caudal gene. The vertebrate Cdx gene products have been implicated in the development of the posterior embryo. In particular, loss‐ and gain‐of‐function experiments suggest that Cdx members are direct regulators of Hox genes and likely impart posterior information, in part, through this mechanism. Several signaling molecules, notably retinoic acid (RA*) and members of the Wnt (wingless) and fibroblast growth factor (FGF) (...) families, are also implicated in patterning of the posterior vertebrate embryo. Interestingly, recent work indicates that members of the Cdx family are targets of Wnt, RA and FGF signaling, suggesting that Cdx factors act to convey the activity of these signaling molecules to Hox genes. This article will briefly review Cdx expression and function, with particular emphasis on vertebrate model systems. BioEssays 25:971–980, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Assuming $V=L+AD$, using methods from inner model theory, we give a new proof of the strong partition property for ${\sim}{ \delta }^{2}_{1}$. The result was originally proved by Kechris et al.

In 2013, Gail Davies and Helen Scalway launched Micespace.org, an interactive web-based art and research project that uses the platform of a mock mouse model repository to visualize the complex spa...

The zona pellucida is an extracellular coat that surrounds mammalian eggs and early embryos. This insoluble matrix separates germ from somatic cells during folliculogenesis and plays critical roles during fertilization and early development. The mouse and human zona pellucida contain three glycoproteins (ZP1 or ZPB, ZP2, ZP3), the primary structures of which have been deduced by molecular cloning. Targeted mutagenesis of endogenous mouse genes and transgenesis with human homologues provide models to investigate the roles of individual zona components. (...) Collectively, the genetic data indicate that no single mouse zona pellucida protein is obligatory for taxon‐specific sperm binding and that two human proteins are not sufficient to support human sperm binding. An observed post‐fertilization persistence of mouse sperm binding to “humanized” zona pellucida correlates with uncleaved ZP2. These observations are consistent with a model for sperm binding in which the supramolecular structure of the zona pellucida necessary for sperm binding is modulated by the cleavage status of ZP2. BioEssays 26:29–38, 2004. Published 2003 Wiley Periodicals, Inc. (shrink)

Physiologically accurate mouse models of cancer are critical in the pre‐clinical development of novel cancer therapies. However, current standardized animal‐housing temperatures elicit chronic cold‐associated stress in mice, which is further increased in the presence of tumor. This cold‐stress significantly impacts experimental outcomes. Data from our lab and others suggest standard housing fundamentally alters murine physiology, and this can produce altered immune baselines in tumor and other disease models. Researchers may thus underestimate the efficacy of therapies that are benefitted by (...) immune responses. A potential mediator, norepinephrine, also underlies stress pathways common in mice and humans. Therefore, research into mechanisms connecting cold‐stress and norepinephrine signaling with immune depression in mice could highlight new combination therapies for humans to simultaneously target stress while stimulating anti‐tumor immunity. (shrink)