Ten experiments that would make a difference in understanding immune mechanisms

Jacques Monod used to say, “Never trust an experiment that is not supported by a good theory.” Theory or conceptualization permits us to put order or structure into a vast amount of data in a way that increases understanding. Validly competing theories are most useful when they make testably disprovable predictions. Illustrating the theory–experiment interaction is the goal of this exercise. Stated bleakly, the answers derived from the theory-based experiments described here would impact dramatically on how we understand immune behavior.     

Knowing what would happen: The epistemic strategies in Galileo's thought experiments

While philosophers have subjected Galileo's classic thought experiments to critical analysis, they have tended to largely ignored the historical and intellectual context in which they were deployed, and the specific role they played in Galileo's overall vision of science. In this paper I investigate Galileo's use of thought experiments, by focusing on the epistemic and rhetorical strategies that he employed in attempting to answer the question of how one can know what would happen in an imaginary scenario. Here I argue we can find three different answers to this question in Galileo later dialogues, which reflect the changing meanings of ‘experience’ and ‘knowledge’ (scientia) in the early modern period. Once we recognise that Galileo's thought experiments sometimes drew on the power of memory and the explicit appeal to ‘common experience’, while at other times, they took the form of demonstrative arguments intended to have the status of necessary truths; and on still other occasions, they were extrapolations, or probable guesses, drawn from a carefully planned series of controlled experiments, it becomes evident that no single account of the epistemological relationship between thought experiment, experience and experiment can adequately capture the epistemic variety we find Galileo's use of imaginary scenarios. To this extent, we cannot neatly classify Galileo's use of thought experiments as either ‘medieval’ or ‘early modern’, but we should see them as indicative of the complex epistemological transformations of the early seventeenth century.     

Of the morphogenes that make a ring, a rod and a sphere in Escherichia coli

In 1993, William Donachie wrote "The success of molecular genetics in the study of bacterial cell division has been so great that we find ourselves, armed with much greater knowledge of detail, confronted once again with the same naive questions that we set to answer in the first place". Indeed, attempts to answer the apparently simple question of how a bacterial cell divides have led to a wealth of new knowledge, in particular over the past decade and a half. And while some questions have been answered to a great extent since the early reports of isolation of division mutants of Escherichia coli, some key pieces of the puzzle remain elusive. In addition to it being a fundamental process in bacteria that merits investigation in its own right, studying the process of cell division offers an abundance of new targets for the development of new antibacterial compounds that act directly against key division proteins and other components of the cytoskeleton, which are encoded by the morphogenes of E. coli. This review aims to present the reader with a snapshot summary of the key players in E. coli morphogenesis with emphasis on cell division and the rod to sphere transition.     

Language understanding is grounded in experiential simulations: a response to Weiskopf

Several disciplines within the cognitive sciences have advanced the idea that people comprehend the actions of others, including the linguistic meanings they communicate, through embodied simulations where they imaginatively recreate the actions they observe or hear about. This claim has important consequences for theories of mind and meaning, such as that people’s use and interpretation of language emerges as a kind of bodily activity that is an essential part of ordinary cognition. Daniel Weiskopf presents several arguments against the idea that experiential simulations play a major role in immediate language use and meaning. We offer several rebuttals to Weiskopf, in which we critique his interpretation of simulation theory, present additional psycholinguistic evidence supportive of the simulation perspective, and suggest that a more traditional theory of linguistic meaning and processing has little psychological and empirical validity.     

EGFR-dependent mechanisms in glioblastoma: towards a better therapeutic strategy

Glioblastoma is a particularly resilient cancer, and while therapies may be able to reach the brain by crossing the blood–brain barrier, they then have to deal with a highly invasive tumor that is very resistant to DNA damage. It seems clear that in order to kill aggressive glioma cells more efficiently and with fewer side effects on normal tissue, there must be a shift from classical cytotoxic chemotherapy to more targeted therapies. Since the epidermal growth factor receptor (EGFR) is altered in almost 50 % of glioblastomas, it currently represents one of the most promising therapeutic targets. In fact, it has been associated with several distinct steps in tumorigenesis, from tumor initiation to tumor growth and survival, and also with the regulation of cell migration and angiogenesis. However, inhibitors of the EGFR kinase have produced poor results with this type of cancer in clinical trials, with no clear explanation for the tumor resistance observed. Here we will review what we know about the expression and function of EGFR in cancer and in particular in gliomas. We will also evaluate which are the possible molecular and cellular escape mechanisms. As a result, we hope that this review will help improve the design of future EGFR-targeted therapies for glioblastomas.     

Aristotle and Galen on sex difference and reproduction: a new approach to an ancient rivalry

[I]n contrast to Aristotle's male oriented explanation of procreation the Galenic was 'feminist' inasmuch as both sexes were presented as contributing equally in conception and accordingly both had to experience pleasure... Anatomically, the two sexes were presented in Galenic accounts as complementary, the difference being that the man's genitalia were on the outside and the woman's on the inside. The clitoris was likened to the penis and the ovaries considered 'testicles' or 'stones' that produced seed. The male seed was, it is true, depicted by Galenists as superior in having 'spiritual' qualities lacking in the female, but Galen's reproductive schema was far more egalitarian than Aristotle's. (McLaren, 1985, p. 327)     

Cone mosaic in a teleost retina: No difference between light and dark adapted states

Summary The mosaic arrangement of retinal cones in the eye of the African cichlid fish,Haplochromis burtoni, is the same in both light and dark adapted states. This is in contrast to Kunz' claim² that the retinal mosaic pattern changes from a square to a row type during dark adaptation, in the guppy (Poecelia reticulata). Kunz' histological procedure may account for this difference in results.Acknowledgments. This work was supported by grants from the Whitehall Foundation and NIH EY02284. I thank L. Shelton for expert histological assistance.     

The buzz on caffeine in invertebrates: effects on behavior and molecular mechanisms

A number of recent studies from as diverse fields as plant–pollinator interactions, analyses of caffeine as an environmental pollutant, and the ability of caffeine to provide protection against neurodegenerative diseases have generated interest in understanding the actions of caffeine in invertebrates. This review summarizes what is currently known about the effects of caffeine on behavior and its molecular mechanisms in invertebrates. Caffeine appears to have similar effects on locomotion and sleep in both invertebrates and mammals. Furthermore, as in mammals, caffeine appears to have complex effects on learning and memory. However, the underlying mechanisms for these effects may differ between invertebrates and vertebrates. While caffeine’s ability to cause release of intracellular calcium stores via ryanodine receptors and its actions as a phosphodiesterase inhibitor have been clearly established in invertebrates, its ability to interact with invertebrate adenosine receptors remains an important open question. Initial studies in insects and mollusks suggest an interaction between caffeine and the dopamine signaling pathway; more work needs to be done to understand the mechanisms by which caffeine influences signaling via biogenic amines. As of yet, little is known about whether other actions of caffeine in vertebrates, such as its effects on GABA_A and glycine receptors, are conserved. Furthermore, the pharmacokinetics of caffeine remains to be elucidated. Overall behavioral responses to caffeine appear to be conserved amongst organisms; however, we are just beginning to understand the mechanisms underlying its effects across animal phyla.     

From immune response to cancer: a spot on the low molecular weight protein tyrosine phosphatase

Reversible tyrosine phosphorylation is a key posttranslational regulatory modification of proteins in all eukaryotic cells in normal and pathological processes. Recently a pivotal janus-faced biological role of the low molecular weight protein tyrosine phosphatase (LMWPTP) has become clear. On the one hand this enzyme is important in facilitating appropriate immune responses towards infectious agents, on the other hand it mediates exaggerated inflammatory responses toward innocuous stimuli. The evidence that LMWPTP plays a role in oncological processes has added a promising novel angle. In this review we shall focus on the regulation of LMWPTP enzymatic activity of signaling pathways of different immunological cells, the relation between genetic polymorphism of LMWPTP and predisposition to some type of inflammatory disorders and the contribution of this enzyme to cancer cell onset, growth and migration. Therefore, the LMWPTP is an interesting target for pharmacological intervention, thus modifying both inappropriate cellular immune responses and cancer cell aggressiveness. Received 15 August 2008; received after revision 06 October 2008; accepted 14 October 2008     

Effect of sodium deoxycholate on net transintestinal movement in the uraemic rat: Acute experiments

Zusammenfassung In vivo gelingt der Nachweis, dass der Transport von Kreatinin, Phosphor, Natrium und Kalium vom Blut in das Lumen des Dünndarms bei urämischen Ratten durch Natriumdesoxycholat gesteigert wird.

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This work has been supported in part by a research grant from the Deutsche Forschungsgemeinschaft Nr. Dr 74/2     

Soluble polysialylated NCAM: a novel player of the innate immune system in the lung

Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing “neutrophil extracellular traps”, which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.     

Moving towards a paradigm: common mechanisms of chemotactic signaling in Dictyostelium and mammalian leukocytes

Chemotaxis, or directed migration of cells along a chemical gradient, is a highly coordinated process that involves gradient sensing, motility, and polarity. Most of our understanding of chemotaxis comes from studies of cells undergoing amoeboid-type migration, in particular the social amoeba Dictyostelium discoideum and leukocytes. In these amoeboid cells the molecular events leading to directed migration can be conceptually divided into four interacting networks: receptor/G protein, signal transduction, cytoskeleton, and polarity. The signal transduction network occupies a central position in this scheme as it receives direct input from the receptor/G protein network, as well as feedback from the cytoskeletal and polarity networks. Multiple overlapping modules within the signal transduction network transmit the signals to the actin cytoskeleton network leading to biased pseudopod protrusion in the direction of the gradient. The overall architecture of the networks, as well as the individual signaling modules, is remarkably conserved between Dictyostelium and mammalian leukocytes, and the similarities and differences between the two systems are the subject of this review.     

Types of experiments and causal process tracing: What happened on the Kaibab Plateau in the 1920s

In a well-cited book chapter, ecologist Jared Diamond characterizes three main types of experiment performed in community ecology: laboratory experiment, field experiment, and natural experiment. Diamond argues that each form of experiment has strengths and weaknesses, with respect to, for example, realism or the ability to follow a causal trajectory. But does Diamond's typology exhaust the available kinds of cause-finding practices? Some social scientists have characterized something they call “causal process tracing.” Is this a fourth type of experiment or something else? I examine Diamond's typology and causal process tracing in the context of a case study concerning the dynamics of wolf and deer populations on the Kaibab Plateau in the 1920s, a case that has been used as a canonical example of a trophic cascade by ecologists but which has also been subject to controversy. I argue that ecologists have profitably deployed causal process tracing together with other types of experiment to help settle questions of causality in this case. It remains to be seen how widespread the use of causal process tracing outside of the social sciences is (or could be), but there are some potentially promising applications, particularly with respect to questions about specific causal sequences.     

Evidence for a selective cytotoxic effect of carrageenan on cells of the immune system in vivo and in vitro

Summary Carrageenan suppressed antibody production to sheep erythrocytes in the mouse only when injected together with or 24 h prior to antigen. Pretreatment of sensitized spleen cell cultures with carrageenan reduced the degree of stimulation obtained using antigen but not PHA.