A place for pragmatism in the dynamics of reason?

In Dynamics of Reason Michael Friedman proposes a kind of synthesis between the neokantianism of Ernst Cassirer, the logical empiricism of Rudolf Carnap, and the historicism of Thomas Kuhn. Cassirer and Carnap are to take care of the Kantian legacy of modern philosophy of science, encapsulated in the concept of the relativized a priori and the globally rational or continuous evolution of scientific knowledge, while Kuhn’s role is to ensure that the historicist character of scientific knowledge is taken seriously. More precisely, Carnapian linguistic frameworks, guarantee that the evolution of science proceeds in a rational manner locally, while Cassirer’s concept of an internally defined conceptual convergence of empirical theories provides the means to maintain the global continuity of scientific reason. In this paper it is argued that Friedman’s Neokantian account of scientific reason based on the concept of the relativized a priori underestimates the pragmatic aspects of the dynamics of scientific reason. To overcome this shortcoming, I propose to reconsider C.I. Lewis’s account of a pragmatic priori, recently modernized and elaborated by Hasok Chang. This may be considered as a first step to a dynamics of an embodied reason, less theoretical and more concrete than Friedman’s Neokantian proposal.     

Updating the mechanisms of common fragile site instability: how to reconcile the different views?

Common fragile sites (CFSs) are large chromosomal regions long identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs came from their key role in the formation of DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was notably correlated with the appearance of genome instability in precancerous lesions and during tumor progression. Identification of the molecular mechanisms responsible for their instability therefore represents a major challenge. A number of data show that breaks result from mitotic entry before replication completion but the mechanisms responsible for such delayed replication of CFSs and relaxed checkpoint surveillance are still debated. In addition, clues to the molecular events leading to breakage just start to emerge. We present here the results of recent reports addressing these questions.     

The evolution of X chromosome inactivation in mammals: the demise of Ohno’s hypothesis?

Ohno’s hypothesis states that dosage compensation in mammals evolved in two steps: a twofold hyperactivation of the X chromosome in both sexes to compensate for gene losses on the Y chromosome, and silencing of one X (X-chromosome inactivation, XCI) in females to restore optimal dosage. Recent tests of this hypothesis have returned contradictory results. In this review, we explain this ongoing controversy and argue that a novel view on dosage compensation evolution in mammals is starting to emerge. Ohno’s hypothesis may be true for a few, dosage-sensitive genes only. If so few genes are compensated, then why has XCI evolved as a chromosome-wide mechanism? This and several other questions raised by the new data in mammals are discussed, and future research directions are proposed.     

On glioblastoma and the search for a cure: where do we stand?

Although brain tumours have been documented and recorded since the nineteenth century, 2016 marked 90 years since Percival Bailey and Harvey Cushing coined the term “glioblastoma multiforme”. Since that time, although extensive developments in diagnosis and treatment have been made, relatively little improvement on prognosis has been achieved. The resilience of GBM thus makes treating this tumour one of the biggest challenges currently faced by neuro-oncology. Aggressive and robust development, coupled with difficulties of complete resection, drug delivery and therapeutic resistance to treatment are some of the main issues that this nemesis presents today. Current treatments are far from satisfactory with poor prognosis, and focus on palliative management rather than curative intervention. However, therapeutic research leading to developments in novel treatment stratagems show promise in combating this disease. Here we present a review on GBM, looking at the history and advances which have shaped neurosurgery over the last century that cumulate to the present day management of GBM, while also exploring future perspectives in treatment options that could lead to new treatments on the road to a cure.     

May K+ ions stimulate the formation of cyclic AMP in the brain independently on their depolarizing action?

Summary The effect of potassium ions on the formation of adenosine 3,5-monophosphate (cAMP) in the rat cerebral cortex in vivo was studied under conditions where development of spreading depression had been blocked by pretreatment of the cerebral cortex by topically applied magnesium ions. A linear relationship between potassium concentrations applied to the cortical surface and levels of cAMP has been found. Moreover, potentiation of the K⁺-effect by magnesium ions has been observed.     

The role of the thioredoxin/thioredoxin reductase system in the metabolic syndrome: towards a possible prognostic marker?

Mammalian thioredoxin reductase (TrxR) is a selenoprotein with three existing isoenzymes (TrxR1, TrxR2, and TrxR3), which is found primarily intracellularly but also in extracellular fluids. The main substrate thioredoxin (Trx) is similarly found (as Trx1 and Trx2) in various intracellular compartments, in blood plasma, and is the cell’s major disulfide reductase. Thioredoxin reductase is necessary as a NADPH-dependent reducing agent in biochemical reactions involving Trx. Genetic and environmental factors like selenium status influence the activity of TrxR. Research shows that the Trx/TrxR system plays a significant role in the physiology of the adipose tissue, in carbohydrate metabolism, insulin production and sensitivity, blood pressure regulation, inflammation, chemotactic activity of macrophages, and atherogenesis. Based on recent research, it has been reported that the modulation of the Trx/TrxR system may be considered as a new target in the management of the metabolic syndrome, insulin resistance, and type 2 diabetes, as well as in the treatment of hypertension and atherosclerosis. In this review evidence about a possible role of this system as a marker of the metabolic syndrome is reported.     

Narrative and evidence. How can case studies from the history of science support claims in the philosophy of science?

A common method for warranting the historical adequacy of philosophical claims is that of relying on historical case studies. This paper addresses the question as to what evidential support historical case studies can provide to philosophical claims and doctrines. It argues that in order to assess the evidential functions of historical case studies, we first need to understand the methodology involved in producing them. To this end, an account of historical reconstruction that emphasizes the narrative character of historical accounts and the theory-laden character of historical facts is introduced. The main conclusion of this paper is that historical case studies are able to provide philosophical claims with some evidential support, but that, due to theory-ladenness, their evidential import is restricted.     

The politics of environments before the environment: Biopolitics in the longue durée

Our understanding of body–world relations is caught in a curious contradiction. On one side, it is well established that many concepts that describe interaction with the outer world – ‘plasticity’ or ‘metabolism’- or external influences on the body - ‘environment’ or ‘milieu’ – appeared with rise of modern science. On the other side, although premodern science lacked a unifying term for it, an anxious attentiveness to the power of ‘environmental factors’ in shaping physical and moral traits held sway in nearly all medical systems before and alongside modern Europe. In this article, I build on a new historiography on the policing of bodies and environments in medieval times and at the urban scale to problematize Foucault's claim about biopolitics as a modern phenomenon born in the European eighteenth-century. I look in particular at the collective usage of ancient medicine and manipulation of the milieu based on humoralist notions of corporeal permeability (Hippocrates, Galen, Ibn Sīnā) in the Islamicate and Latin Christendom between the 12th and the 15th century. This longer history has implications also for a richer genealogy of contemporary tropes of plasticity, permeability and environmental determinism beyond usual genealogies that take as a starting point the making of the modern body and EuroAmerican biomedicine.     

The quest for the size of the universe in early relativistic cosmology (1917–1930)

Before the discovery of the expanding universe, one of the challenges faced in early relativistic cosmology was the determination of the finite and constant curvature radius of space-time by using astronomical observations. Great interest in this specific question was shown by de Sitter, Silberstein, and Lundmark. Their ideas and methods for measuring the cosmic curvature radius, at that time interpreted as equivalent to the size of the universe, contributed to the development of the empirical approach to relativistic cosmology. Their works are a noteworthy example of the efforts made by modern cosmologists toward the understanding of the universe as a whole, its properties, and its content.     

'Through thousands of errors we reach the truth' - but how? On the epistemic roles of error in scientific practice

This essay is concerned with the epistemic roles of error in scientific practice. Usually, error is regarded as something negative, as an impediment or obstacle for the advancement of science. However, we also frequently say that we are learning from error. This common expression suggests that the role of error is not - at least not always - negative but that errors can make a fruitful contribution to the scientific enterprise. My paper explores the latter possibility. Can errors play an epistemically productive role in scientific research? The paper begins with a review of several twentieth-century approaches to error and the various agendas behind them. It is shown that only very few scholars have considered whether errors can be productive. The main part of the paper examines a concrete debate in early nineteenth-century on this material, the article offers some terminological clarifications of the common notion 'learning from error'. The conclusion argues that error can indeed play epistemically productive roles in scientific practice.     

The eagle and the starlings: Galileo’s argument for the autonomy of science—how pertinent is it today?

After Galileo’s argument for the autonomy of science is analysed and adapted to take into account later developments of scientific practices, we conclude that, in the final analysis, it is not compelling. Nevertheless, Galileo’s argument still provides a useful point of reference, for aspects of it can be interpreted to anticipate central components of the often acclaimed ideal of science as value free, so that appraising it contributes to the larger purpose of exploring how well that ideal stands up today. Finally, we will argue that residue from Galileo’s struggle with the Church remains with us, making it difficult to identify the conditions that would need to be put into place today for any robust sense of the autonomy of science to be defensible.     

What's new in translation initiation? The first translation determines the fate of mRNA

The two terms 'translation' and 'protein synthesis' are interchangeable in describing the process whereby the genetic code in the form of messenger RNA (mRNA) is deciphered such that amino acids cognate with the triplet code are joined end to end to form a peptide chain. However, new data suggest that the initial act of translation on newly synthesised mRNA also functions to proofread mRNA for errors. Aberrant mRNAs detected in this way are rapidly degraded before their encoded proteins impede normal cell function. Initiation of surveillance translation appears to differ from that of regular protein synthesis in three ways: (i) composition of the substrate; (ii) temporal and spatial restrictions; (iii) factors used to recruit the ribosome. This review discusses translational aspects of mRNA surveillance, primarily in the context of the mammalian system, although much information has come from studies in yeast and other organisms.     

The professor and the pea: Lives and afterlives of William Bateson’s campaign for the utility of Mendelism

As a defender of the fundamental importance of Mendel’s experiments for understanding heredity, the English biologist William Bateson (1861–1926) did much to publicize the usefulness of Mendelian science for practical breeders. In the course of his campaigning, he not only secured a reputation among breeders as a scientific expert worth listening to but articulated a vision of the ideal relations between pure and applied science in the modern state. Yet historical writing about Bateson has tended to underplay these utilitarian elements of his program, to the extent of portraying him, notably in still-influential work from the 1960s and 1970s, as a type specimen of the scientist who could not care less about application. This paper offers a corrective view of Bateson himself—including the first detailed account of his role as an expert witness in a courtroom dispute over the identity of a commercial pea variety—and an inquiry into the historiographic fate of his efforts in support of Mendelism’s productivity. For all that a Marxian perspective classically brings applied science to the fore, in Bateson’s case, and for a range of reasons, it did the opposite during the Cold War.     

Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention?

Although the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal–maternal interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer.     

The role of mammalian target of rapamycin (mTOR) in the regulation of pancreatic β-cell mass: implications in the development of type-2 diabetes

Type-2 diabetes mellitus (T2DM) is a disorder that is characterized by high blood glucose concentration in the context of insulin resistance and/or relative insulin deficiency. It causes metabolic changes that lead to the damage and functional impairment of organs and tissues resulting in increased morbidity and mortality. It is this form of diabetes whose prevalence is increasing at an alarming rate due to the 'obesity epidemic', as obesity is a key risk factor in the development of insulin resistance. However, the majority of individuals who have insulin resistance do not develop diabetes due to a compensatory increase in insulin secretion in response to an increase in insulin demand. This adaptive response is sustained by an increase in both β-cell function and mass. Importantly, there is increasing evidence that the Serine/Threonine kinase mammalian target of rapamycin (mTOR) plays a key role in the regulation of β-cell mass and therefore likely plays a critical role in β-cell adaptation. Therefore, the primary focus of this review is to summarize our current understanding of the role of mTOR in stimulating pancreatic β-cell mass and thus, in the prevention of type-2 diabetes.     

The chemical versatility of the β–α–β fold: Catalytic promiscuity and divergent evolution in the tautomerase superfamily

Tautomerase superfamily members have an amino-terminal proline and a β–α–β fold, and include 4-oxalocrotonate tautomerase (4-OT), 5-(carboxymethyl)-2-hydroxymuconate isomerase (CHMI), trans- and cis-3-chloroacrylic acid dehalogenase (CaaD and cis-CaaD, respectively), malonate semialdehyde decarboxylase (MSAD), and macrophage migration inhibitory factor (MIF), which exhibits a phenylpyruvate tautomerase (PPT) activity. Pro-1 is a base (4-OT, CHMI, the PPT activity of MIF) or an acid (CaaD, cis-CaaD, MSAD). Components of the catalytic machinery have been identified and mechanistic hypotheses formulated. Characterization of new homologues shows that these mechanisms are incomplete. 4-OT, CaaD, cis-CaaD, and MSAD also have promiscuous activities with a hydratase activity in CaaD, cis-CaaD, and MSAD, PPT activity in CaaD and cis-CaaD, and CaaD and cis-CaaD activities in 4-OT. The shared promiscuous activities provide evidence for divergent evolution from a common ancestor, give hints about mechanistic relationships, and implicate catalytic promiscuity in the emergence of new enzymes. Received 22 May 2008; received after revision 20 June 2008; accepted 02 July 2008