Pathogenesis of skin ulcers: lessons from the Mycobacterium ulcerans and Leishmania spp. pathogens

Skin ulcers are most commonly due to circulatory or metabolic disorders and are a major public health concern. In developed countries, chronic wounds affect more than 1 % of the population and their incidence is expected to follow those observed for diabetes and obesity. In tropical and subtropical countries, an additional issue is the occurrence of ulcers of infectious origins with diverse etiologies. While the severity of cutaneous Leishmaniasis correlates with protective immune responses, Buruli ulcers caused by Mycobacterium ulcerans develop in the absence of major inflammation. Based on these two examples, this review aims to demonstrate how studies on microorganism-provoked wounds can provide insight into the molecular mechanisms controlling skin integrity. We highlight the potential interest of a mouse model of non-inflammatory skin ulceration caused by intradermal injection of mycolactone, an original lipid toxin with ulcerative and immunosuppressive properties produced by M. ulcerans.     

Kant and the scope of analogy in the life sciences

In the present paper I investigate the role that analogy plays in eighteenth-century biology and in Kant's philosophy of biology. I will argue that according to Kant, biology, as it was practiced in the eighteenth century, is fundamentally based on analogical reflection. However, precisely because biology is based on analogical reflection, biology cannot be a proper science. I provide two arguments for this interpretation. First, I argue that although analogical reflection is, according to Kant, necessary to comprehend the nature of organisms, it is also necessarily insufficient to fully comprehend the nature of organisms. The upshot of this argument is that for Kant our understanding of organisms is necessarily limited. Second, I argue that Kant did not take biology to be a proper science because biology was based on analogical arguments. I show that Kant stemmed from a philosophical tradition that did not assign analogical arguments an important justificatory role in natural science. Analogy, according to this conception, does not provide us with apodictically certain cognition. Hence, sciences based on analogical arguments cannot constitute proper sciences.     

The many faces of unification and pluralism in economics: The case of Paul Samuelson's Foundations of Economic Analysis

The history of modern economics abounds with pleas for more pluralism as well as pleas for more unification. These seem to be contradictory goals, suggesting that pluralism and unification are mutually exclusive, or at least that they involve trade-offs with more of one necessarily being traded off against less of the other. This paper will use the example of Paul Samuelson's Foundations of Economic Analysis (1947) to argue that the relationship between pluralism and unification is often more complex than this simple dichotomy suggests. In particular, Samuelson's Foundations is invariably presented as a key text in the unification of modern economics during the middle of the twentieth century; and in many ways that is entirely correct. But Samuelson's unification was not at the theoretical (causal and explanatory) level, but rather at the purely mathematical derivational level. Although this fact is recognized in the literature on Samuelson, what seems to be less recognized is that for Samuelson, much of the motivation for this unification was pluralist in spirit: not to narrow scientific economics into one single theory, but rather to allow for more than one theory to co-exist under a single unified derivational technique. This hidden pluralism will be discussed in detail. The paper concludes with a discussion of the implications for more recent developments in economics.     

Identifying the conformational state of bi-liganded haemoglobin

While most researchers agree on the global features of cooperative ligand binding to haemoglobin (Hb), the internal mechanisms remain open to debate. This is not due to inaccurate measurements, but is rather a consequence of the cooperative ligand binding that decreases the equilibrium populations of the partially liganded states and makes observation of the transitions between these substates more difficult. For example, the equilibrium population of the doubly liganded tetramers is typically less than 5% of the total Hb. As a result many models with widely varying mechanisms may fit the oxygen equilibrium curve, but may not be consistent with observations of other parameters, such as ligand-binding kinetics or subunit association equilibria. The wide range of methods and models has led to divergent conclusions about the properties of specific substates. One notable debate concerns the properties of the doubly liganded forms. The simple two-state model predicts a shift in the allosteric equilibrium based on the number of ligands bound, but not on their distribution within the tetramer. From studies of dimer-tetramer equilibria of various pure and hybrid forms, it was concluded that a tetramer with two ligands bound on the same α β dimer (species 21, an asymmetric hybrid) shows an enhanced tetramer stability, similar to singly liganded Hb, relative to the other three types of doubly liganded tetramers which resemble the triply liganded forms [Ackers et al. (1992), Science 255: 54–63]. The implications of this model and the relevant experiments will be reviewed here. Received 27 April 1998; received after revision 17 July 1998; accepted 10 August 1998     

Loss of Siglec-14 reduces the risk of chronic obstructive pulmonary disease exacerbation

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. COPD exacerbation, or episodic worsening of symptoms, often results in hospitalization and increased mortality rates. Airway infections by new bacterial strains, such as nontypeable Haemophilus influenzae (NTHi), are a major cause of COPD exacerbation. NTHi express lipooligosaccharides that contain sialic acids, and may interact with Siglec-14, a sialic acid recognition protein on myeloid cells that serves as an activating signal transduction receptor. A null allele polymorphism in SIGLEC14 may attenuate the inflammatory responses to NTHi by eliminating Siglec-14 expression. We asked if the loss of Siglec-14 attenuates the inflammatory response by myeloid cells against NTHi, and if the SIGLEC14-null polymorphism has any effect on COPD exacerbation. We found that NTHi interacts with Siglec-14 to enhance proinflammatory cytokine production in a tissue culture model. Inhibitors of the Syk tyrosine kinase suppress this response. Loss of Siglec-14, due to SIGLEC14-null allele homozygosity, is associated with a reduced risk of COPD exacerbation in a Japanese patient population. Taken together, Siglec-14 and its downstream signaling pathway facilitate the “infection–inflammation–exacerbation” axis of COPD disease progression, and may represent promising targets for therapeutic intervention.     

Germline-specific dgcr8 knockout in zebrafish using a BACK approach

Zebrafish is an important model to study developmental biology and human diseases. However, an effective approach to achieve spatial and temporal gene knockout in zebrafish has not been well established. In this study, we have developed a new approach, namely bacterial artificial chromosome-rescue-based knockout (BACK), to achieve conditional gene knockout in zebrafish using the Cre/loxP system. We have successfully deleted the DiGeorge syndrome critical region gene 8 (dgcr8) in zebrafish germ line and demonstrated that the maternal-zygotic dgcr8 (MZdgcr8) embryos exhibit MZdicer-like phenotypes with morphological defects which could be rescued by miR-430, indicating that canonical microRNAs play critical role in early development. Our findings establish that Cre/loxP-mediated tissue-specific gene knockout could be achieved using this BACK strategy and that canonical microRNAs play important roles in early embryonic development in zebrafish.     

Project knowledge and its resituation in the design of research projects: Seymour Benzer's behavioral genetics, 1965-1974

The article introduces a framework for analyzing the knowledge that researchers draw upon when designing a research project by distinguishing four types of “project knowledge”: goal knowledge, which concerns possible outcomes, and three forms of implementation knowledge that concern the realization of the project: 1) methodological knowledge that specifies possible experimental and non-experimental strategies to achieve the chosen goal; 2) representational knowledge that suggests ways to represent data, hypotheses, or outcomes; and 3) organizational knowledge that helps to build or navigate the material and social structures that enable a project. In the design of research projects such knowledge will be transferred from other successful projects and these processes will be analyzed in terms of modes of resituating knowledge. The account is developed by analyzing a case from the history of biology. In a reciprocal manner, it enables a better understanding of the historical episode in question: around 1970, several researchers who had made successful careers in the emerging field of molecular biology, working with bacterial model systems, attempted to create a molecular biology of the physiological processes in multicellular organisms. One of them was Seymour Benzer, who designed a research project addressing the physiological processes underlying behavior in Drosophila.     

The opportunistic pathogen Pseudomonas aeruginosa activates the DNA double-strand break signaling and repair pathway in infected cells

Highly hazardous DNA double-strand breaks can be induced in eukaryotic cells by a number of agents including pathogenic bacterial strains. We have investigated the genotoxic potential of Pseudomonas aeruginosa, an opportunistic pathogen causing devastating nosocomial infections in cystic fibrosis or immunocompromised patients. Our data revealed that infection of immune or epithelial cells by P. aeruginosa triggered DNA strand breaks and phosphorylation of histone H2AX (γH2AX), a marker of DNA double-strand breaks. Moreover, it induced formation of discrete nuclear repair foci similar to gamma-irradiation-induced foci, and containing γH2AX and 53BP1, an adaptor protein mediating the DNA-damage response pathway. Gene deletion, mutagenesis, and complementation in P. aeruginosa identified ExoS bacterial toxin as the major factor involved in γH2AX induction. Chemical inhibition of several kinases known to phosphorylate H2AX demonstrated that Ataxia Telangiectasia Mutated (ATM) was the principal kinase in P. aeruginosa-induced H2AX phosphorylation. Finally, infection led to ATM kinase activation by an auto-phosphorylation mechanism. Together, these data show for the first time that infection by P. aeruginosa activates the DNA double-strand break repair machinery of the host cells. This novel information sheds new light on the consequences of P. aeruginosa infection in mammalian cells. As pathogenic Escherichia coli or carcinogenic Helicobacter pylori can alter genome integrity through DNA double-strand breaks, leading to chromosomal instability and eventually cancer, our findings highlight possible new routes for further investigations of P. aeruginosa in cancer biology and they identify ATM as a potential target molecule for drug design.     

Anti-Candida activity of 1–18 fragment of the frog skin peptide esculentin-1b: in vitro and in vivo studies in a Caenorhabditis elegans infection model

Candida albicans represents one of the most prevalent species causing life-threatening fungal infections. Current treatments to defeat Candida albicans have become quite difficult, due to their toxic side effects and the emergence of resistant strains. Antimicrobial peptides (AMPs) are fascinating molecules with a potential role as novel anti-infective agents. However, only a few studies have been performed on their efficacy towards the most virulent hyphal phenotype of this pathogen. The purpose of this work is to evaluate the anti-Candida activity of the N-terminal 1–18 fragment of the frog skin AMP esculentin-1b, Esc(1–18), under both in vitro and in vivo conditions using Caenorhabditis elegans as a simple host model for microbial infections. Our results demonstrate that Esc(1–18) caused a rapid reduction in the number of viable yeast cells and killing of the hyphal population. Esc(1–18) revealed a membrane perturbing effect which is likely the basis of its mode of action. To the best of our knowledge, this is the first report showing the ability of a frog skin AMP-derived peptide (1) to kill both growing stages of Candida; (2) to promote survival of Candida-infected living organisms and (3) to inhibit transition of these fungal cells from the roundish yeast shape to the more dangerous hyphal form at sub-inhibitory concentrations.     

(Mis)Understanding scientific disagreement: Success versus pursuit-worthiness in theory choice

Scientists often diverge widely when choosing between research programs. This can seem to be rooted in disagreements about which of several theories, competing to address shared questions or phenomena, is currently the most epistemically or explanatorily valuable—i.e. most successful. But many such cases are actually more directly rooted in differing judgments of pursuit-worthiness, concerning which theory will be best down the line, or which addresses the most significant data or questions. Using case studies from 16^th-century astronomy and 20^th-century geology and biology, I argue that divergent theory choice is thus often driven by considerations of scientific process, even where direct epistemic or explanatory evaluation of its final products appears more relevant. Broadly following Kuhn's analysis of theoretical virtues, I suggest that widely shared criteria for pursuit-worthiness function as imprecise, mutually-conflicting values. However, even Kuhn and others sensitive to pragmatic dimensions of theory ‘acceptance’, including the virtue of fruitfulness, still commonly understate the role of pursuit-worthiness—especially by exaggerating the impact of more present-oriented virtues, or failing to stress how ‘competing’ theories excel at addressing different questions or data. This framework clarifies the nature of the choice and competition involved in theory choice, and the role of alternative theoretical virtues.     

Contemporary Darwinism as a worldview

The most public-facing forms of contemporary Darwinism happily promote its worldview ambitions. Popular works, by the likes of Richard Dawkins, deflect associations with eugenics and social Darwinism, but also extend the reach of Darwinism beyond biology into social policy, politics, and ethics. Critics of the enterprise fall into two categories. Advocates of Intelligent Design and secular philosophers (like Mary Midgley and Thomas Nagel) recognise it as a worldview and argue against its implications. Scholars in the rhetoric of science or science communication, however, typically take the view that Darwinism isn't a worldview, but a scientific theory, which has been improperly embellished by some; they uphold the distinction between is and ought and argue that science is restricted to the former. This prompts an is–ought problem on another level. I catalogue the ways in which Darwinism plainly is a worldview and why commentators' beliefs that it ought not to be distorts their analysis. Hence, it is their own worldview that precludes them from accepting Darwinism's worldview implications.     

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC₃, MC₄, and MC₅ receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r?/? mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC₃ PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.     

Defective germinal center B-cell response and reduced arthritic pathology in microRNA-29a-deficient mice

MicroRNA (miR) are short non-coding RNA sequences of 19–24 nucleotides that regulate gene expression by binding to mRNA target sequences. The miR-29 family of miR (miR-29a, b-1, b-2 and c) is a key player in T-cell differentiation and effector function, with deficiency causing thymic involution and a more inflammatory T-cell profile. However, the relative roles of different miR-29 family members in these processes have not been dissected. We studied the immunological role of the individual members of the miR-29 family using mice deficient for miR-29a/b-1 or miR-29b-2/c in homeostasis and during collagen-induced arthritis. We found a definitive hierarchy of immunological function, with the strong phenotype of miR-29a-deficiency in thymic involution and T-cell activation being reduced or absent in miR-29c-deficient mice. Strikingly, despite elevating the Th1 and Th17 responses, loss of miR-29a conferred near-complete protection from collagen-induced arthritis (CIA), with profound defects in B-cell proliferation and antibody production. Our results identify the hierarchical structure of the miR-29 family in T-cell biology, and identify miR-29a in B cells as a potential therapeutic target in arthritis.     

The admiR-able advances in cardiovascular biology through the zebrafish model system

MicroRNAs are small non-coding RNAs endogenously expressed by all tissues during development and adulthood. They regulate gene expression by controlling the stability of targeted messenger RNA. In cardiovascular tissues microRNAs play a role by modulating essential genes involved in heart and blood vessel development and homeostasis. The zebrafish (Danio rerio) system is a recognized vertebrate model system useful to study cardiovascular biology; recently, it has been used to investigate microRNA functions during natural and pathological states. In this review, we will illustrate the advantages of the zebrafish model in the study of microRNAs in heart and vascular cells, providing an update on recent discoveries using the zebrafish to identify new microRNAs and their targeted genes in cardiovascular tissues. Lastly, we will provide evidence that the zebrafish is an optimal model system to undercover new microRNA functions in vertebrates and to improve microRNA-based therapeutic approaches.     

Epigenetic regulation of mmp-9 gene expression

Matrix metalloproteinase 9 (MMP-9) is one of the most studied enzymes in cancer. MMP-9 can cleave proteins of the extracellular matrix and a large number of receptors and growth factors. Accordingly, its expression must be tightly regulated to avoid excessive enzymatic activity, which is associated with disease progression. Although we know that epigenetic mechanisms play a central role in controlling mmp-9 gene expression, predicting how epigenetic drugs could be used to suppress mmp-9 gene expression is not trivial because epigenetic drugs also regulate the expression of key proteins that can tip the balance towards activation or suppression of MMP-9. Here, we review how our understanding of the biology and expression of MMP-9 could be exploited to augment clinical benefits, most notably in terms of the prevention and management of degenerative diseases and cancer.     

Public scientific testimony in the scientific image

In this paper, I draw on philosophy of science to address a challenge for science communication. Empirical research indicates that some people who trust a meteorologist's report that they are in the path of a storm do not trust a climate scientist's report that we are on a path to global warming. Such selective skepticism about climate science exemplifies a more general challenge:

The Challenge of Selective UptakeLaypersons who generally accept public scientific testimony nevertheless fail to accept public scientific testimony concerning select, equally well warranted, scientific hypotheses.

A prominent response arising from the novel interdisciplinary science of science communication is a principle called Consensus Reporting. According to this principle, science reporters should, whenever feasible, report the scientific consensus or lack thereof for a reported scientific view.However, philosophy of science may offer a different perspective on the issue. This perspective is critical insofar as it indicates some inadequacies of Consensus Reporting. But it is also constructive insofar as it guides the development of an alternative principle, Justification Reporting, according to which science reporters should, whenever feasible, report aspects of the nature and strength of scientific justification or lack thereof for a reported scientific view. A central difference between these proposals is that Consensus Reporting appeals to the authority of the scientists whereas Justification Reporting appeals to the authority of scientific justification. As such, Justification Reporting reflects the image of science.The paper considers the philosophical and empirical motivation for Justification Reporting and its limitations. This includes prospects and problems for implementing it in a way that addresses The Challenge of Selective Uptake. From a methodological point of view, the paper illustrates how empirically informed philosophy of science may help address challenges for science communication.     

Understanding as explanatory knowledge: The case of Bjorken scaling

In this paper, we develop and refine the idea that understanding is a species of explanatory knowledge. Specifically, we defend the idea that S understands why p if and only if S knows that p, and, for some q, S’s true belief that q correctly explains p is produced/maintained by reliable explanatory evaluation. We then show how this model explains the reception of James Bjorken’s explanation of scaling by the broader physics community in the late 1960s and early 1970s. The historical episode is interesting because Bjorken’s explanation initially did not provide understanding to other physicists, but was subsequently deemed intelligible when Feynman provided a physical interpretation that led to experimental tests that vindicated Bjorken’s model. Finally, we argue that other philosophical models of scientific understanding are best construed as limiting cases of our more general model.     

Biological teleology: Questions and explanations

This paper gives an account of evolutionary explanations in biology. Briefly, the explanations I am primarily concerned with are explanations of adaptations. (‘Adaptation’ is a technical term and defining it requires a fairly lengthy digression.) These explanations are contrasted with other nonteleological evolutionary explanations. The distinction is made by distinguishing the different kinds of questions these different explanations serve to answer. The sense in which explanations of adaptations are teleological is spelled out.