Anomalous stability of insulin at very high pressure

Insulin is unaffected by pressures of 48,000 b in the solid state at room temperature, as elucidated both by spectroscopic measurements and bioassay. Its compression curve is reversible. The presence of water does not alter this property. Of a number of other proteins investigated insulin appears to be unique with regard to its pressure stability. The relative rigidity of the molecule combined with its small size may account for some of these properties.     

The peroxisomal protein import machinery – a case report of transient ubiquitination with a new flavor

The peroxisomal protein import machinery displays remarkable properties. Be it its capacity to accept already folded proteins as substrates, its complex architecture or its energetics, almost every aspect of this machinery seems unique. The list of unusual properties is still growing as shown by the recent finding that one of its central components, Pex5p, is transiently monoubiquitinated at a cysteine residue. However, the data gathered in recent years also suggest that the peroxisomal import machinery is not that exclusive and similarities with p97/Cdc48-mediated processes and with multisubunit RING-E3 ligases are starting to emerge. Here, we discuss these data trying to distill the principles by which this complex machinery operates. Received 16 July 2008; received after revision 25 August 2008; accepted 29 August 2008     

Modeling for fairness: A Rawlsian approach

In this paper we introduce the overlapping design consensus for the construction of models in design and the related value judgments. The overlapping design consensus is inspired by Rawls’ overlapping consensus. The overlapping design consensus is a well-informed, mutual agreement among all stakeholders based on fairness. Fairness is respected if all stakeholders’ interests are given due and equal attention. For reaching such fair agreement, we apply Rawls’ original position and reflective equilibrium to modeling. We argue that by striving for the original position, stakeholders expel invalid arguments, hierarchies, unwarranted beliefs, and bargaining effects from influencing the consensus. The reflective equilibrium requires that stakeholders’ beliefs cohere with the final agreement and its justification. Therefore, the overlapping design consensus is not only an agreement to decisions, as most other stakeholder approaches, it is also an agreement to their justification and that this justification is consistent with each stakeholders’ beliefs. For supporting fairness, we argue that fairness qualifies as a maxim in modeling. We furthermore distinguish values embedded in a model from values that are implied by its context of application. Finally, we conclude that for reaching an overlapping design consensus communication about properties of and values related to a model is required.     

Rationality and irrationality in the history of continental drift: Was the hypothesis of continental drift worthy of pursuit?

The revolution in geology, initiated with Alfred Wegener’s theory of continental drift, has been the subject of many philosophical discussions aiming at resolving the problem of rationality underlying this historical episode. Even though the debate included analyses in terms of scientific methodology, applications of concrete accounts of epistemic justification to this case study have been rare. In particular, the question as to whether Wegener’s theory was epistemically worthy of pursuit in the first half of the twentieth century, that is, in its early development, remained open or inadequately addressed. The aim of this paper is to offer an answer to this question. The evaluation of Drift will be done by means of an account of theory evaluation suitable for the context of pursuit, developed in ?e?elja and Straßer (accepted for publication). We will argue that pursuing the theory of continental drift was rational, i.e., that it was irrational to reject its pursuit as unworthy.     

Forecasting capacity and capacity utilization in the U.S. aerospace industry

The forecasting of capacity and its utilization is particularly relevant in the aerospace industry because of long product delivery lead-times and the forward-pricing system. The objective of this paper is to develop a method for forecasting both the industry's capacity and its capacity utilization so that decision makers who must rely on this information may have policy guidance. The result shows that the aerospace industry's capacity expansion rate is closely tied to its present and recent past state of capacity utilization, and to anticipated changes in output. Output, in turn, can be predicted by using Five Year Defense Plans data and information on the cyclical nature of commercial business. Based on these findings, we were able to build an accurate model for forecasting aerospace industry capacity utilization.     

TTDN1 is a Plk1-interacting protein involved in maintenance of cell cycle integrity

Polo-like kinase 1 (Plk1) is a highly conserved serine/threonine kinase that plays critical roles in many cell cycle events, especially in mitosis. In the present study, we identified TTDN1 as a potential interacting partner of Plk1 in yeast two-hybrid screens. Sequence analysis indicates that TTDN1 contains a consensus Plk1-binding motif at its C terminus. TTDN1 colocalizes with Plk1 at the centrosome in mitosis and the midbody during cytokinesis. TTDN1 is phosphorylated by Cdk1 in mitosis, and this is required for its interaction with Plk1. Site-directed mutagenesis indicates that TTDN1 is phosphorylated at multiple residues, including Ser93 and Ser104. Mutation of Thr120 of TTDN1 abolishes its interaction with Plk1, suggesting phosphorylation of Thr120 in the consensus Plk1-binding motif is required for its interaction with Plk1. Overexpression of TTDN1 or its knockdown by siRNA causes multi-polar spindles and multiple nuclei, suggesting that TTDN1 plays a role in regulating mitosis and cytokinesis. Received 27 November 2006; received after revision 4 January 2007; accepted 25 January 2007 Y. Zhang, Y. Tian: These authors contribute equally to this work.     

Über die durch Licht bedingte «Missweisung» bei den Tänzen im Bienenstock

Summary Bees are able to indicate direction to their hive comrades by means of a waggling dance of 2 kinds: in the horizontal plane with regard to the sun they point directly towards the goal by a waggling walk using the same angle to the sun as they took in their flight. Inside the dark hive in the vertical honey-comb, they transpose the angle between goal and sun to the field of gravity, whereby the sun's direction is shown by a waggling walk upwards, and the angle to the right or left of the sun's position is given by a dance-direction in the corresponding angle to the right or left of the zenith.If a piece of blue sky is made visible in an observation hive to the bees which are dancing in orientation by gravity, they recognise the position of the sun by this polarisation sample, and the effort to orientate themselves directly by the sun (as in the horizontal plane) comes into conflict with the orientation by gravity. The result is a dance direction which corresponds remarkably well with the halving of the angle between what the dance direction should have been by gravity and what it should have been by light orientation (Figure 1). This is also true when the bee is orientating itself by polarised sky light over its back, while the sun is at the other side of the honey-comb under its front (Figure 2), a situation which does not occur during flight but which is important for its dance in the swarm. The bees receiving the information compensate the deviation of the angle determined by light, and fly to the right goal.As the sun itself, as well as the piece of blue sky, was made visible to the dancers, its influence dominated and they orientated themselves by its light (Figure 3).     

Structural realism beyond physics

The main purpose of this paper is to test structural realism against (one example from) the historical record. I begin by laying out an existing challenge to structural realism – that of providing an example of a theory exhibiting successful structures that were abandoned – and show that this challenge can be met by the miasma theory of disease. However, rather than concluding that this is an outright counterexample to structural realism, I use this case to show why it is that structural realism, in its current form, has trouble dealing with theories outside physics. I end by making some concrete suggestions for structural realists to pursue if, indeed, they are serious about extending structural realism to other domains.     

Extrapineal melatonin: sources,regulation, and potential functions

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.     

The plasma membrane proton-translocating ATPase

Living cells require membranes and membrane transporters for the maintenance of life. After decades of biochemical scrutiny, the structures and molecular mechanisms by which membrane transporters catalyze transmembrane solute movements are beginning to be understood. The plasma membrane proton-translocating adenosine triphosphatase (ATPase) is an archetype of the P-type ATPase family of membrane transporters, which are important in a wide variety of cellular processes. The H+-ATPase has been crystallized and its structure determined to a resolution of 8 angstrom in the membrane plane. When considered together with the large body of biochemical information that has been accumulated for this transporter, and for enzymes in general, this new structural information is providing tantalizing insights regarding the molecular mechanism of active ion transport catalyzed by this enzyme.     

The dual role model for p53 in maintaining genomic integrity

The tumour suppressor p53 is a potent mediator of cellular responses against genotoxic insults. In this review we describe the multiple functions of p53 in response to DNA damage, with an emphasis on p53's role in DNA repair. We summarize data demonstrating that p53 actively participates in various processes of DNA repair and DNA recombination via its ability to interact with components of the repair and recombination machinery, and by its various biochemical activities. An important aspect in evaluating p53 functions is provided by the finding that the core domain of p53 harbours two mutually exclusive biochemical activities, sequence-specific DNA binding required for its transactivation function, and 3'-5' exonuclease activity, possibly involved in aspects of DNA repair. Based on the finding that modifications of p53 which lead to activation of its sequence-specific DNA-binding activity result in inactivation of its 3'-5' exonuclease activity, we propose that p53 exerts its functions as a 'guardian of the genome' at various levels: in its noninduced state, p53 should not be regarded as a 'dead' protein but, for example, via its exonuclease activity might be actively involved in prevention and repair of endogenous DNA damage. Upon induction through exogenous DNA damage, p53 will exert its well-documented functions as a superior response element in various types of cellular stress. This dual role model for p53 in maintaining genomic integrity significantly enhances p53's possibilities as a guardian of the genome.     

Characterization of Plasmodium falciparum co-chaperone p23: its intrinsic chaperone activity and interaction with Hsp90

It is well known that the co-chaperone p23 regulates Hsp90 chaperone activity in protein folding. In Plasmodium falciparum, a putative p23 (Pfp23) has been identified through genome analysis, but its authenticity has remained unconfirmed since co-immunoprecipitation experiments failed to show its interaction with P. falciparum Hsp90 (PfHsp90). Thus, recombinant Pfp23 and PfHsp90 proteins purified from expressed clones were used in this study. It was clear that Pfp23 exhibited chaperone activity by virtue of its ability to suppress citrate synthase aggregation at 45°C. Pfp23 was also shown to interact with PfHsp90 and to suppress its ATPase activity. Analyses of modeled Pfp23-PfHsp90 protein complex and site-directed mutagenesis further revealed strategically placed amino acid residues, K91, H93, W94 and K96, in Pfp23 to be crucial for binding PfHsp90. Collectively, this study has provided experimental evidence for the inherent chaperone function of Pfp23 and its interaction with PfHsp90, a sequel widely required for client protein activation.     

L'absorption du facteur «L.E.» par des noyaux cellulaires isolés

Summary The serum containing the L.E. factor loses its activity after having been put in contact with isolated cell nuclei. The electrophoretic examination shows a clear diminution of the gamma globulin and a slight diminution of the globulin alpha 2. That the factor responsible for the L.E. phenomenon can be absorbed by isolated cell nuclei is an argument in favor of the hypothesis that this factor is a substance having the character of an antinuclear anti-body, without one being able to exclude with certitude the possibility that this factor is an enzyme.     

Genetic studies of diseases

Since the identification of RNA-mediated interference (RNAi) in 1998, RNAi has become an effective tool to inhibit gene expression. The inhibition mechanism is triggered by introducing a short interference double-stranded RNA (siRNA,19 approximately 27 bp) into the cytoplasm, where the guide strand of siRNA (usually antisense strand) binds to its target messenger RNA and the expression of the target gene is blocked. RNAi has been widely applied in gene functional analysis, and as a potential therapeutic strategy in viral diseases, drug target discovery, and cancer therapy. Among the factors which may compromise inhibition efficiency, how to design siRNAs with high efficiency and high specificity to its target gene is critical. Although many algorithms have been developed for this purpose, it is still difficult to design such siRNAs. In this review, we will briefly discuss prediction methods for siRNA efficiency and the problems of present approaches.     

Collaborative explanation,explanatory roles,and scientific explaining in practice

Scientific explanation is a perennial topic in philosophy of science, but the literature has fragmented into specialized discussions in different scientific disciplines. An increasing attention to scientific practice by philosophers is (in part) responsible for this fragmentation and has put pressure on criteria of adequacy for philosophical accounts of explanation, usually demanding some form of pluralism. This commentary examines the arguments offered by Fagan and Woody with respect to explanation and understanding in scientific practice. I begin by scrutinizing Fagan's concept of collaborative explanation, highlighting its distinctive advantages and expressing concern about several of its assumptions. Then I analyze Woody's attempt to reorient discussions of scientific explanation around functional considerations, elaborating on the wider implications of this methodological recommendation. I conclude with reflections on synergies and tensions that emerge when the two papers are juxtaposed and how these draw attention to critical issues that confront ongoing philosophical analyses of scientific explanation.