Cell-to-cell coupling studied in isolated ventricular cell pairs

Summary Cell pairs isolated from adult rat and guinea pig ventricles were used to study the electrical properties of the nexal membrane. Each cell of a pair was connected to a voltage-clamp system so as to enable whole-cell, tight-seal recording. The current-voltage relationship of the nexal membrane was found to be linear, revealing a resistance r_n of 2–4 M. r_n was insensitive to the sarcolemmal membrane potential (range:–90 to +30 mV), and exerted no time-dependent gating behavior (range: 0.1 to 10 s). Lowering pH_i yielded a small increase in r_n. Vigorous elevations in [Ca²⁺]_i gave rise to an increase in r_n which was associated with a cell shortening. Uncoupling caused by aliphatic alcohols or halothane did not produce cell shortening. Cell pairs were also used to study action potential transfer.     

Effect of hydrogen peroxide on the binding of Merocyanine 540 to human erythrocytes

The fluorescent dye Merocyanine 540 (MC540) is often used as a probe to monitor the molecular packing of phospholipids in the outer leaflet of biomembranes. In a previous study we showed that the increased staining of erythrocytes with a perturbed membrane structure was mainly due to an increase in the fluorescence yield of cell-bound MC540, rather than to an increase of the number of bound molecules. Erythrocytes and ghosts exposed to continuous fluxes of H₂O₂ exhibited pronounced lipid peroxidation. Further, red blood cells subjected to this form of oxidative stress also showed increased staining with MC540. It appeared that this was caused by a strong increase in binding of MC540, together with a slight red shift of the fluorescence emission maximum and a small increase in the fluorescence yield of bound MC540. The changed MC540 binding characteristics were not observed when lipid peroxidation was suppressed by the presence of the antioxidant BHT in the incubation medium. However, open ghosts exposed to H₂O₂ showed no increase of MC540 binding, excluding a direct involvement of lipid peroxidation. Measurement of fluorescence emission spectra and gel filtration studies showed that MC540 can bind to H₂O₂-exposed hemoglobin. Experiments with erythrocytes lysed in hypotonic medium after exposure to H₂O₂ revealed that peroxidation of lipids with H₂O₂ induced a non-specific permeabilization of the plasma membrane to MC540, thereby allowing MC540 to bind to the oxidatively denatured, more hydrophobic hemoglobin. These results indicate that conclusions about packing of phospholipids in the outer leaflet of the membrane based on increased MC540-staining should be drawn with care. Received 27 September 1996; received after revision 5 November 1996; accepted 27 November 1996     

Atomism, Poincaré and Planck

Planck's change in attitude to the question of whether atomic hypotheses were scientifically accessible, is discussed. It is argued contra Holton, that Planck's change in attitude to this question did not signal a methodological shift towards realism. The point of doing this is not just to investigate a significant episode in the history of quantum theory, but also to use the episode as a case study in support of a broader historical thesis. This thesis is that there was a widespread late-nineteenth century methodological tradition which motivated the change in status of certain ontological claims — e.g., that atoms exist — from ‘inaccessible to science’ to ‘scientifically acceptable’ even though those claims were not strictly ‘observable’. This methodological tradition is a hybrid of positivist and realist views. Thus, contrary to one popular view, the fin de siécle triumph of atomism is not to be seen as a triumph for a realist view of science Poincare's views are also used as an illustration.     

Science, truth and history, part II. Metaphysical bolt-holes for the Sociology of Scientific Knowledge?

Historians of science have frequently sought to exclude modern scientific knowledge from their narratives. Part I of this paper, published in the previous issue, cautioned against seeing more than a literary preference at work here. In particular, it was argued—contra advocates of the Sociology of Scientific Knowledge (SSK)—that a commitment to epistemological relativism should not be seen as having straightforward historiographical consequences. Part II considers further SSK-inspired attempts to entangle the currently fashionable historiography with particular positions in the philosophy of science. None, I argue, is promising. David Bloor’s proposed alliance with scientific realism relies upon a mistaken view of contrastive explanation; Andrew Pickering’s appeal to instrumentalism is persuasive for particle physics but much less so for science as a whole; and Bruno Latour’s home-grown metaphysics is so bizarre that its compatibility with SSK is, if anything, a further blow to the latter’s plausibility.     

A Time‐Simultaneous Prediction Box for a Multivariate Time Series

A sample‐based method in Kolsrud (Journal of Forecasting 2007; 26 (3): 171–188) for the construction of a time‐simultaneous prediction band for a univariate time series is extended to produce a variable‐ and time‐simultaneous prediction box for a multivariate time series. A measure of distance based on the L_∞ ‐norm is applied to a learning sample of multivariate time trajectories, which can be mean‐ and/or variance‐nonstationary. Based on the ranking of distances to the centre of the sample, a subsample of the most central multivariate trajectories is selected. A prediction box is constructed by circumscribing the subsample with a hyperrectangle. The fraction of central trajectories selected into the subsample can be calibrated by bootstrap such that the expected coverage of the box equals a prescribed nominal level. The method is related to the concept of data depth, and thence modified to increase coverage. Applications to simulated and empirical data illustrate the method, which is also compared to several other methods in the literature adapted to the multivariate setting. Copyright © 2015 John Wiley & Sons, Ltd.     

The interaction of superoxide with nitric oxide destabilizes hypoxia-inducible factor-1α

In renal carcinoma cells (RCC4) hypoxia inducible factor-1 (HIF-1) is constitutively expressed due to a von Hippel Lindau protein deficiency, but can be degraded by calpain, independently of the 26S proteasome, when exposed to hypoxia/nitric oxide (NO). In this study we examined molecular mechanisms to explain calpain activation. The inability of hypoxia/NO to degrade HIF-1α in respiratory-deficient RCC4-ρ0 cells pointed to the requirement for mitochondria-derived reactive oxygen species. A prerequisite for O ₂ ⁻ in combination with NO to destabilize HIF-1α was corroborated in RCC4-p0 cells, when the redox cycler 2,3-dimethoxy-1,4-naphthoquinone was used as a source of superoxide. Degradation of HIF-1α required intracellular calcium transients and calpain activation. Using uric acid to interfere with signal transmission elicited by NO/O ₂ ⁻ blocked HIF-1α degradation and attenuated a calcium increase. We conclude that an oxidative signal as a result of NO/O ₂ ⁻ coformation triggers a calcium increase that activates calpain to degrade HIF-1α, independently of the proteasome. Received 14 August 2007; received after revision 4 October 2007; accepted 22 October 2007     

Signs, toy models, and the a priori: from Helmholtz to Wittgenstein

The Marburg neo-Kantians argue that Hermann von Helmholtz’s empiricist account of the a priori does not account for certain knowledge, since it is based on a psychological phenomenon, trust in the regularities of nature. They argue that Helmholtz’s account raises the ‘problem of validity’ (Gültigkeitsproblem): how to establish a warranted claim that observed regularities are based on actual relations. I reconstruct Heinrich Hertz’s and Ludwig Wittgenstein’s Bild theoretic answer to the problem of validity: that scientists and philosophers can depict the necessary a priori constraints on states of affairs in a given system, and can establish whether these relations are actual relations in nature. The analysis of necessity within a system is a lasting contribution of the Bild theory. However, Hertz and Wittgenstein argue that the logical and mathematical sentences of a Bild are rules, tools for constructing relations, and the rules themselves are meaningless outside the theory. Carnap revises the argument for validity by attempting to give semantic rules for translation between frameworks. Russell and Quine object that pragmatics better accounts for the role of a priori reasoning in translating between frameworks. The conclusion of the tale, then, is a partial vindication of Helmholtz’s original account.     

A pyruvate kinase variant in different mouse transplanted tumors

Summary Mouse transplanted tumors, in contrast to normal tissues, contain a pyruvate kinase (PK) variant sensitive to the inhibitory action of L-cysteine and less sensitive to saturated fatty acids than the normal enzyme. In selected normal and tumor materials two fractions of PK were separated. Fraction A (20–30% (NH₄)₂SO₄ saturation) dominated in normal liver, and fraction B (50–60% (NH₄)₂SO₄ saturation) in skeletal muscles and Ehrlich ascites tumor. Only this fraction B from tumor material was sensitive to L-cysteine, and seems to contain a tumor-specific PK variant which might be considered as a marker of neoplastic transformation in a broad spectrum of mouse experimental tumors.     

Vitamin B12 amplifies circadian phase shifts induced by a light pulse in rats

Vitamin B₁₂ (VB₁₂) is a putative modulator of the human circadian clock, improving entrainability to the 24 h light-dark cycle. The present study was intended to elucidate the mechanism of VB₁₂ action in an animal model. In male rats free-running under constant dim illumination, a single light pulse of 50–1000 lux for 20 min given at circadian time (CT) 20 induced a 0.28 to 1.08 h phase advance and at CT 14 induced a 0.54 to 2.10 h phase delay. A 3 h intracerebroventricular (icv) infusion of 30 nmol VB₁₂ starting 2 h prior to a 20 min 200 lux light pulse significantly amplified phase shifts in comparison with saline-treated or untreated controls. The mean phase advance (1.13 h) was 1.8-fold greater than that of saline-infused controls, whereas the mean phase delay (2.28 h) was 2.9-fold greater. These values were comparable to the maximal phase shifts caused by 1000 lux light pulses in untreated rats. Since the same VB₁₂ treatment alone had failed to induce a phase shift in a previous experiment, these results indicate that VB₁₂ strongly enhanced light pulse-induced phase shifts and thus augmented the entrainability of the circadian clock to light.     

β-Lactam resistance in Staphylococcus aureus: the adaptive resistance of a plastic genome

Staphylococci have two mechanisms for resistance to β-lactam antibiotics. One is the production of β-lactamases, enzymes that hydrolytically destroy β-lactams. The other is the expression of penicillin-binding protein 2a (PBP 2a), which is not susceptible to inhibition by β-lactam antibiotics. Strains of S. aureus exhibiting either β-lactamase or PBP 2a-directed resistance (or both) have established a considerable ecological niche among human pathogens. The emergence and subsequent spread of bacterial strains designated as methicillin-resistant S. aureus (MRSA), from the 1960s to the present, has created clinical difficulties for nosocomial treatment on a global scale. The recent variants of MRSA that are resistant to glycopeptide antibiotics (such as vancomycin) have ushered in a new and disconcerting chapter in the evolution of this organism. Received 2 April 2005; received after revision 15 July 2005; accepted 25 July 2005     

Antibody against purified viper neurotoxin

Résumé L'anticorps contre la neurotoxine du venin deVipera palestinae est obtenu chez des lapins par immunisation de la neurotoxine purifiée liée à la cellulose carbométhylique.

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This work is part of a thesis submitted byN. Shaham to the

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This work is part of a thesis submitted byN. Shaham to the

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This work is part of a thesis submitted byN. Shaham to the

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This work is part of a thesis submitted byN. Shaham to the

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This work is part of a thesis submitted byN. Shaham to the     

Aberrant,canavanyl protein formation and the ability to tolerate or utilize L-canavanine

Summary L-Canavanine, 2-amino-4-(guanidinooxy)butyric acid, and L-arginine incorporation into de novo synthesized proteins was compared in six organisms. Utilizing L-[guanidinooxy¹⁴C]canavanine and L-[guanidino¹⁴C]arginine at substrate saturation, the canavanine to arginine incorporation ratio was determined in de, novo synthesized proteins.Caryedes brasiliensis andSternechus tuberculatus, canavanine utilizing insects;Canavalia ensiformis, a canavanine storing plant; and to a lesser extentHeliothis virescens, a canavanine resistant insect, failed to accumulate significant canavanyl proteins. By contrast,Manduca sexta, a canavanine-sensitive insect, andGlycine max, a canavanine free plant, readily incorporated canavanine into newly synthesized proteins. This study supports the contention that the incorporation of canavanine into proteins in place of arginine contributes significantly to canavanine's antimetabolic properties.     

Integrins and cardiovascular disease

Cardiovascular diseases involve abnormal cell-cell interactions leading to the development of atherosclerotic plaque, which when ruptured causes massive platelet activation and thrombus formation. Parts of a loose thrombus may detach to form an embolus, blocking circulation at a more distant point. The integrins are a family of adhesive cell receptors interacting with adhesive proteins or with counterreceptors on other cells. There is now solid evidence that the major integrin on platelets, the fibrinogen receptor α _IIb  β ₃ , has an important role in several aspects of cardiovascular diseases and that its regulated inhibition leads to a reduction in incidence and mortality due to these disorders. The development of α _IIb  β ₃ inhibitors is an important strategy of many pharmaceutical companies which foresee a large market for the treatment of acute conditions in surgery, the symptoms of chronic conditions and, it is hoped, maybe even the successful prophylaxis of these conditions. Although all the associated problems have not been solved, the undoubted improvements in patient care resulting from the first of these treatments in the clinic have stimulated further research on the role of integrins on other vascular cells in these processes and in the search for new inhibitors. Both the development of specific inhibitors and of mice with specific integrin subunit genes ablated have contributed to a better understanding of the function of integrins in development of the cardiovascular system.     

From personality to party: the creation and transmission of Hutchinsonianism, c. 1725-1750

This paper represents a provisional attempt to chart the intellectual construction of Hutchinsonianism over approximately a quarter of a century from the mid-1720s through to the early 1750s. It looks at how Hutchinson’s works were received and fashioned by his first followers, the means they used to communicate their conviction to others, and the extent to which their outlook can be characterised as anti-Newtonian. The paper argues for a slow take up of ‘Hutchinsonian’ views before Spearman and Bate published a collected edition of the master’s works in 1748. This single edition gave Hutchinson’s writings a coherence and a unity they were ill-designed to carry, but it created Hutchinsonianism as an appreciable force in Oxford and elsewhere. The paper concludes that the anti-Newtonian rhetoric of the movement’s founder was increasingly muted in the hands of his followers (with the exception of Bate), and by the 1750s the main bone of contention was less attitudes to Newton than approaches to Hebrew scholarship.     

Why the Afshar experiment does not refute complementarity

A modified version of Young's experiment by Shahriar Afshar demonstrates that, prior to what appears to be a “which-way” measurement, an interference pattern exists. Afshar has claimed that this result constitutes a violation of the Principle of Complementarity. This paper discusses the implications of this experiment and considers how Cramer's Transactional Interpretation easily accommodates the result. It is also shown that the Afshar experiment is analogous in key respects to a spin one-half particle prepared as “spin up along x”, subjected to a nondestructive confirmation of that preparation, and post-selected in a specific state of spin along z. The terminology “which-way” or “which-slit” is critiqued; it is argued that this usage by both Afshar and his critics is misleading and has contributed to confusion surrounding the interpretation of the experiment. Nevertheless, it is concluded that Bohr would have had no more problem accounting for the Afshar result than he would in accounting for the aforementioned pre- and post-selection spin experiment, in which the particle's preparation state is confirmed by a nondestructive measurement prior to post-selection. In addition, some new inferences about the interpretation of delayed choice experiments are drawn from the analysis.     

Publishing and the classics: Paley’s Natural theology and the nineteenth-century scientific canon

This article seeks a new way to conceptualise the ‘classic’ work in the history of science, and suggests that the use of publishing history might help avoid the antagonism which surrounded the literary canon wars. It concentrates on the widely acknowledged concept that the key to the classic work is the fact of its being read over a prolonged period of time. Continued reading implies that a work is able to remain relevant to later generations of readers, and, although some of this depends upon the openness of the original text, much more depends on the actions of subsequent publishers and editors in repackaging the work for later audiences.This is illustrated through an examination of the long publishing history of William Paley’s Natural theology (1802). Over the course of the century, Natural theology was read as a work of gentlemanly natural theology, as a work which could be used in a formal or informal education in science, and as a work of Christian apologetic. These transformations occurred because of the actions of the later publishers and editors who had to make the work suit the current interests of the literary marketplace. Comparisons are made to Constitution of man, Vestiges of the natural history of creation and Origin of species.     

Microbial legradation of bitumen

Summary Bitumen is commonly employed as a matrix for the long-term storage of low and intermediate level radioactive waste. As bitumen can be degraded by microbial activity, it is of great significance to determine the rates at which it may occur in nuclear waste repositories.Experiments have been carried out under optimal culture conditions using bitumen with a highly increased surface area. The potential of different microbial consortia to degrade bitumen has been examined. The investigations showed clearly that bitumen-degrading organisms are ubiquitous. In general the organisms formed biofilms on the accessible substrate surface area. Under oxic culture conditions a bitumen degradation rate of 20–50 g bitumen · m^–2· y^–1 leading to a CO₂ liberation of 15–40 l was observed. Anoxic conditions yielded a 100 times smaller degradation rate of 0.2–0.6 g bitumen · m^–2 · y^–1 and a CO₂ production of 0.15–0.45 l.Based on linear extrapolation the experimentally determined degradation rates would lead to a 25–70% deterioration of the bitumen matrix under oxic and 0.3–0.8% under anoxic conditions within 1000 years.     

The functional bias of the dual nature of technical artefacts program

In 2006, in a special issue of this journal, several authors explored what they called the dual nature of artefacts. The core idea is simple, but attractive: to make sense of an artefact, one needs to consider both its physical nature—its being a material object—and its intentional nature—its being an entity designed to further human ends and needs. The authors construe the intentional component quite narrowly, though: it just refers to the artefact’s function, its being a means to realize a certain practical end. Although such strong focus on functions is quite natural (and quite common in the analytic literature on artefacts), I argue in this paper that an artefact’s intentional nature is not exhausted by functional considerations. Many non-functional properties of artefacts—such as their marketability and ease of manufacture—testify to the intentions of their users/designers; and I show that if these sorts of considerations are included, one gets much more satisfactory explanations of artefacts, their design, and normativity.