Why Axiomatize?

Axiomatization is uncommon outside mathematics, partly for being often viewed as embalming, partly because the best-known axiomatizations have serious shortcomings, and partly because it has had only one eminent champion, namely David Hilbert (Math Ann 78:405–415, 1918). The aims of this paper are (a) to describe what will be called dual axiomatics, for it concerns not just the formalism, but also the meaning (reference and sense) of the key concepts; and (b) to suggest that every instance of dual axiomatics presupposes some philosophical view or other. To illustrate these points, a theory of solidarity will be crafted and axiomatized, and certain controversies in both classical and quantum physics, as well as in the philosophy of mind, will be briefly discussed. The upshot of this paper is that dual axiomatics, unlike the purely formal axiomatics favored by the structuralists school, is not a luxury but a tool helping resolve some scientific controversies.     

Project regularity: Development and evaluation of a new project characteristic

The ability to accurately characterize projects is essential to good project management. Therefore, a novel project characteristic is developed that reflects the value accrue within a project. This characteristic, called project regularity, is expressed in terms of the newly introduced regular/irregular-indicator RI. The widely accepted management system of earned value management (EVM) forms the basis for evaluation of the new characteristic. More concretely, the influence of project regularity on EVM forecasting accuracy is assessed, and is shown to be significant for both time and cost forecasting. Moreover, this effect appears to be stronger than that of the widely used characteristic of project seriality expressed by the serial/parallel-indicator SP. Therefore, project regularity could also be useful as an input parameter for project network generators. Furthermore, the introduction of project regularity can provide project managers with a more accurate indication of the time and cost forecasting accuracy that is to be expected for a certain project and, correspondingly, of how a project should be built up in order to obtain more reliable forecasts during project control.     

Toward simpler and faster genome-wide mutagenesis in mice

Here we describe a practical Cre-loxP and piggyBac transposon-based mutagenesis strategy to systematically mutate coding sequences and/or the vast noncoding regions of the mouse genome for large-scale functional genomic analysis. To illustrate this approach, we first created loxP-containing loss-of-function alleles in the protocadherin alpha, beta and gamma gene clusters (Pcdha, Pcdhb and Pcdhg). Using these alleles, we show that, under proper guidance, Cre-loxP site-specific recombination can mediate efficient trans-allelic recombination in vivo, facilitating the generation of large germline deletions and duplications including deletions of Pcdha, and Pcdha to Pcdhb, simply by breeding (that is, at frequencies of 5.5%-21.6%). The same breeding method can also generate designed germline translocations between nonhomologous chromosomes at unexpected frequencies of greater than 1%. By incorporating a piggyBac transposon to insert and to distribute loxP sites randomly throughout the mouse genome, we present a simple but comprehensive method for generating genome-wide deletions and duplications, in addition to insertional loss-of-function and conditional rescue alleles, again simply by breeding.     

A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition

Disruption of histone acetylation patterns is a common feature of cancer cells, but very little is known about its genetic basis. We have identified truncating mutations in one of the primary human histone deacetylases, HDAC2, in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome. The presence of the HDAC2 frameshift mutation causes a loss of HDAC2 protein expression and enzymatic activity and renders these cells more resistant to the usual antiproliferative and proapoptotic effects of histone deacetylase inhibitors. As such drugs may serve as therapeutic agents for cancer, our findings support the use of HDAC2 mutational status in future pharmacogenetic treatment of these individuals.     

Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells

Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma.     

Experience, Awareness and Consciousness:Suggestions for Definitions as Offered by an Evolutionary Approach

An evolutionary point of view is proposed to make more appropriate distinctions between experience, awareness and consciousness. Experience can be defined as a characteristic linked closely to specific pattern matching, a characteristic already apparent at the molecular level at least. Awareness can be regarded as the special experience of one or more central, final modules in the animal neuronal brain. Awareness is what experience is to animals.Finally, consciousness could be defined as reflexive awareness. The ability for reflexive awareness is distinctly different from animal and human awareness and depends upon the availability of a separate frame of reference, as provided by symbolic language. As such, words have made reflexive awareness – a specific and infrequent form of awareness – possible. Conciousness might be defined as the experience evoked by considering, i.e. thinking about experiences themselves.If there is a hard problem of explaining consciousness, than this actually must be considered as the hard problem already met when trying to explain basic experience, since its nature remains elusive.     

Glycine receptors and glycine transporters: targets for novel analgesics?

Glycinergic neurotransmission has long been known for its role in spinal motor control. During the last two decades, additional functions have become increasingly recognized—among them is a critical contribution to spinal pain processing. Studies in rodent pain models provide proof-of-concept evidence that enhancing inhibitory glycinergic neurotransmission reduces chronic pain symptoms. Apparent strategies for pharmacological intervention include positive allosteric modulators of glycine receptors and modulators or inhibitors of the glial and neuronal glycine transporters GlyT1 and GlyT2. These prospects have led to drug discovery efforts in academia and in industry aiming at compounds that target glycinergic neurotransmission with high specificity. Available data show promising analgesic efficacy. Less is currently known about potential unwanted effects but the presence of glycinergic innervation in CNS areas outside the nociceptive system prompts for a careful evaluation not only of motor function, but also of potential respiratory impairment and addictive properties.     

Discrimination between alternate membrane protein topologies in living cells using GFP/YFP tagging and pH exchange

Membrane protein function is determined by the relative organization of the protein domains with respect to the membrane. We have experimentally verified the topology of a protein with diverse orientations arising from a single primary sequence (the cellular prion protein, PrP^C), a novel somatostatin truncated receptor, and the Golgi-associated protein GPBP₉₁. Tagging with fluorescent proteins (FP) allows location of their expression at the plasma membrane or at endomembranes, but does not inform about their orientation. Exploiting the pH dependency of some FPs, we developed a pH exchange assay in which extracellularly exposed FPs are quenched by application of low pH buffer. We constructed standards to demonstrate and calibrate the assay, and the method was adapted for acidic organelle membrane proteins. This method can serve as a proof of concept, experimentally confirming and/or discriminating in living cells among theoretical topology predictions, providing the proportion of inside/outside orientation for proteins with multiple forms.