Research that includes non-human animal experimentation is fundamentally a dilemmatic enterprise. Humans use other animals in research to improve life for their own species. Ethical principles are established to deal with this dilemma. But despite this ethical apparatus, people who in one way or another work with animal experimentation have to interpret and understand the principles from their individual points of view. In interviews with members of Swedish animal ethics committees, different views on what the term ethics really means were (...) articulated. For one member, the difficult ethical dilemma of animal experimentation is the lack of enriched cages for mice. For another, the ethical problem lies in regulations restraining research. A third member talks about animals’ right not to be used for human interests. These different views on “ethics” intersect once a month in the animal ethics committee meetings. There is no consensus on what constitutes the ethical problem that the members should be discussing. Therefore, personal views on what ethics means, and hierarchies among committee members, characterise the meetings. But committee traditions and priorities of interpretation as well are important to the decisions. The author discusses how “ethics” becomes situated and what implications this may have for committees’ decisions. (shrink)

Physicists regularly invoke universal laws, such as those of motion and electromagnetism, to explain events. Biological and medical scientists have no such laws. How then do they acquire a reliable body of knowledge about biological organisms and human disease? One way is by repeatedly returning to, manipulating, observing, interpreting, and reinterpreting certain subjects—such as flies, mice, worms, or microbes—or, as they are known in biology, “model systems.” Across the natural and social sciences, other disciplinary fields have developed canonical examples that (...) have played a role comparable to that of biology’s model systems, serving not only as points of reference and illustrations of general principles or values but also as sites of continued investigation and reinterpretation. The essays in this collection assess the scope and function of model objects in domains as diverse as biology, geology, and history, attending to differences between fields as well as to epistemological commonalities. Contributors examine the role of the fruit fly Drosophila and nematode worms in biology, troops of baboons in primatology, box and digital simulations of the movement of the earth’s crust in geology, and meteorological models in climatology. They analyze the intensive study of the prisoner’s dilemma in game theory, ritual in anthropology, the individual case in psychoanalytic research, and Athenian democracy in political theory. The contributors illuminate the processes through which particular organisms, cases, materials, or narratives become foundational to their fields, and they examine how these foundational exemplars—from the fruit fly to Freud’s Dora—shape the knowledge produced within their disciplines. Contributors Rachel A. Ankeny Angela N. H. Creager Amy Dahan Dalmedico John Forrester Clifford Geertz Carlo Ginzburg E. Jane Albert Hubbard Elizabeth Lunbeck Mary S. Morgan Josiah Ober Naomi Oreskes Susan Sperling Marcel Weber M. Norton Wise. (shrink)

AP‐2 is a recent significant addition to the list of transcription factors that have been demonstrated by targeted gene disruption to be essential for normal development. Two recent reports of AP‐2 null mutant mice(1,2) indicate that AP‐2 holds a key position in the network of genes and proteins controlling developmental pattern and morphogenesis, and that it is particularly important for development of the cranial region and for midline fusions.

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)

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)

Sex dimorphism occurs when group means differ by four or more standard deviations. However, the average size of the corpus callosum is greater in males by about one standard deviation in rats, 0.2 standard deviation in humans, and virtually zero in mice. Furthermore, variations in corpus callosum size are related to brain size and are not sex specific.

The zona pellucida is an extracellular coat that surrounds all mammalian eggs. It is a porous matrix of interconnected filaments that are assembled from glycoproteins synthesized and secreted by growing oocytes. The zona pellucida is responsible both for species‐specific binding of sperm to unfertilized eggs and inducing bound sperm to undergo the acrosome reaction. The latter enables sperm to penetrate the extracellular coat and fertilize the egg. The zona pellucida also aids in prevention of polyspermy following fertilization and in protection (...) of preimplantation embryos. In mice, several of these important functions can now be ascribed to specific zona pellucida glycoproteins that have been purified and characterized. Furthermore, the enzyme responsible for hatching of embryos from the zona pellucida, just prior to implantation, has been identified and characterized. (shrink)

The development of the vertebrate skeleton is under complex genetic control, and good progress is being made towards identifying the genes responsible. A recent paper(1) contributes to this progress by describing transgenic mice in which the homeobox‐containing MHox gene has been disrupted. MHox(−/−) mice have a range of skeletal defects, involving loss or shortening of structures in the skull, face and limb. Puzzling features of the MHox(−/−) mutation, which has similar effects on bones with very different embryological origins and yet (...) spares other bones completely, may hold clues to the mechanisms that shape the skeleton. MHox(−/−) mice, used in conjunction with other skeletal mutants, will be important tools for exploring these mechanisms further. (shrink)

The ovarian reserve defines female reproductive lifespan, which in humans spans decades. The ovarian reserve consists of oocytes residing in primordial follicles arrested in meiotic prophase I and is maintained independent of DNA replication and cell proliferation, thereby lacking stem cell‐based maintenance. Largely unknown is how cellular states of the ovarian reserve are established and maintained for decades. Our recent study revealed that a distinct chromatin state is established during ovarian reserve formation in mice, uncovering a novel window of epigenetic (...) programming in female germline development. We showed that an epigenetic regulator, Polycomb Repressive Complex 1 (PRC1), establishes a repressive chromatin state in perinatal mouse oocytes that is essential for prophase I‐arrested oocytes to form the ovarian reserve. Here we discuss the biological roles and mechanisms underlying epigenetic programming in ovarian reserve formation, highlighting current knowledge gaps and emerging research areas in female reproductive biology. (shrink)

Adversities in pregnancy, including poor diet and stress, are associated with increased risk of developing both metabolic and mental health disorders later in life, a phenomenon described as fetal programming or developmental origins of disease. Predominant hypotheses proposed to explain this relationship suggest that the adversity imposes direct changes to the developing fetus which are maintained after birth resulting in an increased susceptibility to ill health. However, during pregnancy the mother, the developing fetus, and the placenta are all exposed to (...) the adversity. The same adversities linked to altered offspring outcome can also result in suboptimal maternal care, which is considered an independent adverse exposure for the offspring. Recent key experiments in mice reveal the potential of prenatal adversity to drive alterations in maternal care through abnormal maternal–pup interactions and via alterations in placental signaling. Together, these data highlight the critical importance of viewing fetal programming holistically paying attention to the intimate, bidirectional, and reiterative relationship between mothers and their offspring. (shrink)

Meiotic recombination occurs preferentially at certain regions called hot spots and is important for generating genetic diversity and proper segregation of chromosomes during meiosis. Hot spots have been characterized most extensively in yeast, mice and humans. The development of methods based on sperm typing and population genetics has facilitated rapid and high‐resolution mapping of hot spots in mice and humans in recent years. With increasing information becoming available on meiotic recombination in different species, it is now possible to compare several (...) molecular features associated with hot‐spot loci. Further, there have been advances in our knowledge of the factors influencing hot‐spot activity and the role that they play in structuring the genome into haplotype blocks. We review the molecular features associated with hot spots in terms of their properties and mechanisms underlying their function and distribution. A large number of these features seem to be shared among hot spots from different species suggesting common mechanisms for their formation and function. BioEssays 28:45–56, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Interferon (IFN) induced during a virus infection mediates antiviral effects both by direct inhibition of virus replication and by influencing the proliferation, differentiation, and chemotaxis of cyto‐toxic lymphocytes which control the infection. Cells from tissue taken from virus‐infected mice are conditioned by IFN to resist lysis by natural killer (NK) cells, while they become increasingly susceptible to lysis by cytotoxic Tlymphocytes (CTL). This is due to marked IFN‐induced biochemical changes, including an up‐regulation of major histocompatibility antigens, which are targets for (...) CTL. Cytopathic viruses, which inhibit cellular RNA and protein synthesis, render target cells refractory to IFN‐mediated protection against NK cells, thereby providing a mechanism for NK cells to mediate antiviral effect by preferentially lysing virus‐infected but not uninfected cells. (shrink)

The Chinese Room Argument purports to show that‘ syntax is not sufficient for semantics’; an argument which led John Searle to conclude that ‘programs are not minds’ and hence that no computational device can ever exhibit true understanding. Yet, although this controversial argument has received a series of criticisms, it has withstood all attempts at decisive rebuttal so far. One of the classical responses to CRA has been based on equipping a purely computational device with a physical robot body. This (...) response, although partially addressed in one of Searle’s original contra arguments - the ‘robot reply’ - more recently gained friction with the development of embodiment and enactivism1, two novel approaches to cognitive science that have been exciting roboticists and philosophers alike. Furthermore, recent technological advances - blending biological beings with computational systems - have started to be developed which superficially suggest that mind may be instantiated in computing devices after all. This paper will argue that (a) embodiment alone does not provide any leverage for cognitive robotics wrt the CRA, when based on a weak form of embodiment and that (b) unless they take the body into account seriously, hybrid bio-computer devices will also share the fate of their disembodied or robotic predecessors in failing to escape from Searle’s Chinese room. (shrink)

Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor (...) cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

Leishmania major infection of inbred mice leads to a major dichotomous response—death or survival—that depends on the strain of mice. This finding has motivated efforts to locate genetic determinants of disease susceptibility. Genotyping studies have confirmed a complex multilocus trait, but studies directed at the biology of the response suggest identifiable components of susceptibility that may direct the genetic investigations. A confluence of parasite variables—residence in macrophages, class II-dependent immunity, and avoidance of early IL-12 induction—with host factors—a prominent helper T-cell (...) precursor frequency to a dominant parasite epitope and a bias in IL-4 gene activation—conspires to drive an aberrant immune response in animals that suffer fatal disease. These insights may lead to an understanding of factors that focus responses on dominant antigens and that mold the naive T-cell repertoire. Collectively, such factors might contribute to the pathogenesis of other infectious and autoimmune diseases. BioEssays 21:510–518, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Multidrug resistance resulting from expression of an energy‐dependent drug efflux pump encoded by the human MDR1 gene is a major impediment to effective cancer therapy. Pharmacologic intervention aimed at inhibiting this multidrug transporter should improve existing chemotherapy of human cancer, but drug development has been delayed by the difficulty and expense of developing valid animal models. Using recombinant DNA technology, a transgenic mouse has been engineered whose bone marrow is protected from the toxic effects of chemotherapy by expression of the (...) MDR1 gene. This animal system allows the rapid screening of drugs which inhibit the multidrug transporter and heralds a new era of using transgenic animals for pharmacologic screening. (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)

In humans over 15% of X‐linked genes have been shown to ‘escape’ from X‐chromosome inactivation (XCI): they continue to be expressed to some extent from the inactive X chromosome. Mono‐allelic expression is anticipated within a cell for genes subject to XCI, but random XCI usually results in expression of both alleles in a cell population. Using a study of allelic expression from cultured lymphoblasts and fibroblasts, many of which showed substantial skewing of XCI, we recently reported that the expression of (...) genes lies on a contiunuum between those that are subject to inactivation, and those that escape. We now review allelic expression studies from mouse, and discuss the variability in escape seen in both humans and mice in genic expression levels, between X chromosomes and between tissues. We also discuss current knowledge of the heterochromatic features, DNA elements and three‐dimensional topology of the inactive X that contribute to the balance of expression from the otherwise inactive X chromosome. (shrink)

Beckwith‐Wiedemann syndrome is a human congenital disorder characterized by a wide variety of growth abnormalities, including developmental defects and predisposition to certain tumors. Genetic evidence has suggested a role for p57KIP2, a member of a family of cell cycle inhibitory genes, in Beckwith‐Wiedemann syndrome. Two independent groups(1,2) have reported the generation and characterization of mice lacking functional p57KIP2, These mice demonstrate a number of abnormal phenotypes which overlap with, although do not completely recapitulate, Beckwith‐Wiedemann syndrome. These findings advance the molecular (...) characterization of a human disorder, and provide insight into the interplay between regulation of cell division and development. (shrink)

Alzheimer's disease is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide . The rate-limiting step in the production of Abeta is the processing of Abeta precursor protein by beta-site APP-cleaving enzyme . Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Abeta within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was (...) suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of beta-galactoside alpha-2,6-sialyltransferase I . In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. (shrink)

Pericytes, like vascular smooth muscle cells, are perivascular cells closely associated with blood vessels throughout the body. Pericytes are necessary for vascular development and homeostasis, with particularly critical roles in the brain, where they are involved in regulating cerebral blood flow and establishing the blood-brain barrier. A role for pericytes during neurovascular disease pathogenesis is less clear—while some studies associate decreased pericyte coverage with select neurovascular diseases, others suggest increased pericyte infiltration in response to hypoxia or traumatic brain injury. Here, (...) we used an endothelial loss-of-function Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)/Notch mediated mouse model of brain arteriovenous malformation (AVM) to investigate effects on pericytes during neurovascular disease pathogenesis. We tested the hypothesis that pericyte expansion, via morphological changes, and Platelet-derived growth factor B/Platelet-derived growth factor receptor β (Pdgf-B/Pdgfrβ)-dependent endothelial cell-pericyte communication are affected, during the pathogenesis of Rbpj mediated brain AVM in mice. Our data show that pericyte coverage of vascular endothelium expanded pathologically, to maintain coverage of vascular abnormalities in brain and retina, following endothelial deletion of Rbpj. In Rbpj-mutant brain, pericyte expansion was likely attributed to cytoplasmic process extension and not to increased pericyte proliferation. Despite expanding overall area of vessel coverage, pericytes from Rbpj-mutant brains showed decreased expression of Pdgfrβ, Neural (N)-cadherin, and cluster of differentiation (CD)146, as compared to controls, which likely affected Pdgf-B/Pdgfrβ-dependent communication and appositional associations between endothelial cells and pericytes in Rbpj-mutant brain microvessels. By contrast, and perhaps by compensatory mechanism, endothelial cells showed increased expression of N-cadherin. Our data identify cellular and molecular effects on brain pericytes, following endothelial deletion of Rbpj, and suggest pericytes as potential therapeutic targets for Rbpj/Notch related brain AVM. (shrink)

Two strains of male mice have bred over fortygenerations, starting with the work of RobertCairns and his colleagues, one strain with ahigh level of intra-species aggression, theother a low level of aggression. Thehigh-aggression mice tend to establishdominance hierarchies and particularly fight inthe presence of female mice. Thelow-aggression mice tend, in groups of theirown, to have a high degree of low-intensity,peaceful social contact, and to be more timidin initiating action than the high-aggressionmice. Biochemical differences have beenobserved between the two strains, and (...) confirmedby the present data: the high-aggression micehave greater dopamine concentrations (in thecaudate nucleus and nucleus accumbens), lowerlevels of the stress hormone corticosterone,and higher levels of testosterone than thelow-aggression mice. The current experimentswere designed to answer questions about theflexibility of adaptive behaviors:specifically, what is the effect of early dailymaternal separation on adult stress response ineach strain? What are the behavioral andhormonal mechanisms by which, as has beenobserved, low-aggression mice achieve adominant status when brought into situationswhere they compete for territory withhigh-aggression mice? Finally, what are thesocial and neurochemical mechanisms by whichhigh-aggression mice can develop low-aggressionbehavior if brought out of isolation and intogroups?Maternal separation was found to lead todecreases in stress levels, as measured bycorticosterone, in the low-aggression but notthe high-aggression, mice – presumably becauseof the surplus of maternal care the pupsreceive on returning to the nest. When alow-aggression mouse became dominant and ahigh-aggression mouse became submissive, theirusual pattern of corticosterone andtestosterone levels was found to be reversed. The change to low-aggression behavior inhigh-aggression mice switching from anisolation condition to a group condition, wasmediated by a decrease in D 1 dopaminereceptor densities.These results, like the ones on which theybuild, argue for substantial developmentalinfluences in expressions of the genesinfluencing aggressive or cooperative behavior. In this approach to evolution, epigenesis istreated not as a set of traits and behaviorspredetermined by the genome, but as a set ofprobabilistic tendencies toward certain traitsand behaviors. (shrink)

Cyclin-dependent kinase 5 has been implicated in Alzheimer's disease pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a (...) targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis. (shrink)

© 2015 Elsevier Inc.Toxoplasma gondii is a protozoan pathogen in the phylum Apicomplexa that resides within an intracellular parasitophorous vacuole that is selectively permeable to small molecules through unidentified mechanisms. We have identified GRA17 as a Toxoplasma-secreted protein that localizes to the parasitophorous vacuole membrane and mediates passive transport of small molecules across the PVM. GRA17 is related to the putative Plasmodium translocon protein EXP2 and conserved across PV-residing Apicomplexa. The PVs of GRA17-deficient parasites have aberrant morphology, reduced permeability to (...) small molecules, and structural instability. GRA17-deficient parasites proliferate slowly and are avirulent in mice. These GRA17-deficient phenotypes are rescued by complementation with Plasmodium EXP2. GRA17 functions synergistically with a related protein, GRA23. Exogenous expression of GRA17 or GRA23 alters the membrane conductance properties of Xenopus oocytes in a manner consistent with a large non-selective pore. Thus, GRA17 and GRA23 provide a molecular basis for PVM permeability and nutrient access. (shrink)