Neither metaphysical dichotomy nor pure identity:: Clarifying the emergentist creed

Emergentism is often misleadingly described as a monolithic “third way” between radical monism and pluralism. In the particular case of biology, for example, emergentism is perceived as a middle course between mechanicism and vitalism. In the present paper I propose to show that the conceptual landscape between monism and pluralism is more complex than this classical picture suggests. On the basis of two successive analyses—distinguishing three forms of tension between monism and pluralism and a distinction between derivational and functional reduction—I define three different versions of emergentism that can be considered as consistent middle courses between monism and pluralism (respectively theoretical, explanatory and causal emergence). I then emphasise the advantage of this taxonomy of the concepts of emergence by applying the results of my analysis to the historical controversy that pertains to the relationship between life and matter.     

The Australian Dominative Medical System: A Reflection of Social Relations in the Larger Society

This paper posits a working or tentative model of medical pluralism, a pattern in which multiple medical sub‐systems co‐exist, or what I term the Australian dominative medical system. I argue that whereas the Australian medical system with its various medical sub‐systems was pluralistic, that is more or less on an equal footing, in the nineteenth century, by the early twentieth century it became a plural or dominative one in the sense that biomedicine came to clearly dominate other medical sub‐systems. This paper also explores the growing interest of biomedicine and the Australian Government in complementary medicine to which Australians have increasingly turned over the course of the past three decades or so.     

DEADLY PLURALISM? WHY DEATH‐CONCEPT,DEATH‐DEFINITION,DEATH‐CRITERION AND DEATH‐TEST PLURALISM SHOULD BE ALLOWED,EVEN THOUGH IT CREATES SOME PROBLEMS

Death concept, death definition, death criterion and death test pluralism has been described by some as a problematic approach. Others have claimed it to be a promising way forward within modern pluralistic societies. This article describes the New Jersey Death Definition Law and the Japanese Transplantation Law. Both of these laws allow for more than one death concept within a single legal system. The article discusses a philosophical basis for these laws starting from John Rawls' understanding of comprehensive doctrines, reasonable pluralism and overlapping consensus. It argues for the view that a certain legal pluralism in areas of disputed metaphysical, philosophical and/or religious questions should be allowed, as long as the disputed questions concern the individual and the resulting policy, law or acts based on the policy/law, do not harm the lives of other individuals to an intolerable extent. However, while this death concept, death definition, death criterion and death test pluralism solves some problems, it creates others.     

Differential lipid specificities of the repeated domains of annexin IV

The roles of the four domains of annexin IV in binding to phospholipids and glycolipids were assessed by analyzing the binding of a group of mutant annexins IV in which one or more of the four domains was inactivated by replacing a critical amino residue(s) (Asp or Glu) with the neutral residue Ala. The data reveal that individual annexin domains may have characteristic affinities for different lipids. In particular, inactivation of the fourth domain inhibits the binding to phosphatidylserine (PS) and phosphatidylinositol (PI) but not to phosphatidylglycerol (PG), suggesting that this domain specifically can accommodate the larger head groups of PS and PI whereas the other three domains may form more restricted binding pockets. In order to block binding to PG, domain 1, or both domains 2 and 3 must be inactivated in addition to domain 4, suggesting that all four domains may be able to accommodate the headgroup of PG to some extent. Binding to acidic glycolipids (sulfatides) was also sensitive to inactivation of domain 4. However, in the case of sulfatides the nature of the binding reaction is fundamentally different compared with the binding to phospholipids since the interaction with sulfatides was highly sensitive to an increase in ionic strength. The binding to sulfatides may depend therefore on charge-charge interactions whereas the binding to phospholipid may involve a more specific interaction between the lipid headgroup and the protein surface, and/or interaction of the protein with the hydrophobic portion of a lipid bilayer.     

Cross-word morphologically conditioned scalar tone shift in Guébie

This paper presents data bearing on two key issues in morphophonological theory: 1) the domain of phonological evaluation, and 2) the item- versus process-morphology debate. I present data from Guébie (Kru) [Côte d’Ivoire] showing that imperfective aspect is exponed by a scalar shift in surface tone, which can affect either the tone of the inflected verb, or the subject noun phrase. There are four tone heights in Guébie, and the first syllable of a verb can underlyingly be associated with any of the four tones. In imperfective contexts only, that initial verb tone lowers one step on the four-tone scale. If the tone of the verb is already low, the final tone of the subject raises one step instead. This paper demonstrates that in order to account for the cross-word tonal effects of the imperfective morpheme, phonological evaluation must scope over more than one word at a time; specifically, it must scope over a syntactic phase. Additionally, I show that with phonological constraint rankings sensitive to morphosyntactic construction, no abstract phonological underlying form of the imperfective morpheme is necessary.     

Chromosomal position effects in chicken lysozyme gene transgenic mice are correlated with suppression of DNase I hypersensitive site formation.

The complete chicken lysozyme gene locus is expressed copy number dependently and at a high level in macrophages of transgenic mice. Gene expression independent of genomic position can only be achieved by the concerted action of all cis regulatory elements located on the lysozyme gene domain. Position independency of expression is lost if one essential cis regulatory region is deleted. Here we compared the DNase I hypersensitive site (DHS) pattern formed on the chromatin of position independently and position dependently expressed transgenes in order to assess the influence of deletions within the gene domain on active chromatin formation. We demonstrate, that in position independently expressed transgene all DHSs are formed with the authentic relative frequency on all genes. This is not the case for position dependently expressed transgenes. Our results show that the formation of a DHS during cellular differentiation does not occur autonomously. In case essential regulatory elements of the chicken lysozyme gene domain are lacking, the efficiency of DHS formation on remaining cis regulatory elements during myeloid differentiation is reduced and influenced by the chromosomal position. Hence, no individual regulatory element on the lysozyme domain is capable of organizing the chromatin structure of the whole locus in a dominant fashion.     

Protein unfolding is not a prerequisite for endoplasmic reticulum-to-cytosol dislocation

We examined the effects of protein folding on endoplasmic reticulum (ER)-to-cytosol transport (dislocation) by exploiting the well-characterized dihydrofolate reductase (DHFR) domain. DHFR retains the capacity to bind folate analogues in the lumen of microsomes and in the ER of intact cells, upon which it acquires a conformation resistant to proteinase K digestion. Here we show that a Class I major histocompatibility complex heavy chain fused to DHFR is still recognized by the human cytomegalovirus-encoded glycoproteins US2 and US11, resulting in dislocation of the fusion protein from the ER in vitro and in vivo. A folded state of the DHFR domain does not impair dislocation of Class I MHC heavy chains in vitro or in living cells. In fact, a slight acceleration of the dislocation of DHFR heavy chain fusion was observed in vitro in the presence of a folate analogue. These results suggest that one or more of the channels used for dislocation can accommodate polypeptides that contain a tightly folded domain of considerable size. Our data raise the possibility that the Sec61 channel can be modified to accommodate a folded DHFR domain for dislocation, but not for translocation into the ER, or that a channel altogether distinct from Sec61 is used for dislocation.     

Cu(I) affinities of the domain 1 and 3 sites in the human metallochaperone for Cu,Zn-superoxide dismutase

The delivery of copper by the human metallochaperone CCS is a key step in the activation of Cu,Zn-superoxide dismutase (SOD1). CCS is a three-domain protein with Cu(I)-binding CXXC and CXC motifs in domains 1 and 3, respectively. A detailed analysis of the binding of copper to CCS, including variants in which the Cys residues from domains 1 and 3 have been mutated to Ser, and also using separate domain 1 and 3 constructs, demonstrates that CCS is able to bind 1 equiv of Cu(I) in both of these domains. The Cu(I) affinity of domain 1 is approximately 5 × 10(17) M(-1) at pH 7.5, while that of domain 3 is at least 1 order of magnitude weaker. The CXXC site will therefore be preferentially loaded with Cu(I), suggesting that domain 1 plays a role in the acquisition of the metal. The delivery of copper to the target occurs via domain 3 whose structural flexibility and ability to be transiently metalated during copper delivery appear to be more important than the Cu(I) affinity of its CXC motif. The Cu(I) affinity of domain 1 of CCS is comparable to that of HAH1, another cytosolic copper metallochaperone. CCS and HAH1 readily exchange Cu(I), providing a mechanism whereby cross-talk can occur between copper trafficking pathways.     

Integrative Pluralism

The `fact' of pluralism in science is nosurprise. Yet, if science is representing andexplaining the structure of the oneworld, why is there such a diversity ofrepresentations and explanations in somedomains? In this paper I consider severalphilosophical accounts of scientific pluralismthat explain the persistence of bothcompetitive and compatible alternatives. PaulSherman's `Levels of Analysis' account suggeststhat in biology competition betweenexplanations can be partitioned by the type ofquestion being investigated. I argue that thisaccount does not locate competition andcompatibility correctly. I then defend anintegrative model for understanding pluralism. This view is based on taking seriously both thecomplexity and contingency of biologicalorganization and the idealized character ofbiological models. On this view, explanationbecomes, among other things, the location forthe integration of diverse models. I explicatemy argument by an analysis of explanations ofdivision of labor in social insects.     

Frequency characteristics of signals and instrumentation: implication for EMG biofeedback studies

Signals can be analyzed in either the time or frequency domain. In the time domain, the analysis consists of manipulating and measuring one or more characteristics of the signal that may vary with time. One can, for instance, rectify a signal, filter it, calculate its mean value, display the histogram of its amplitude, and so forth. Frequency analysis is less well understood because it requires a lengthy mathematical treatment most easily done by computer. However, it gives exclusive information on a signal. For instance, when the frequency content of a signal is known, it is easy to specify which characteristics an amplifier must have in order to amplify the signal without distortion, or to set the cutoff frequencies of filters to eliminate noise. Also, in many circumstances, frequency spectra are more easily interpreted than the original raw data. Such is the case with the EMG where the random aspect of the signal makes some form of processing (i.e., rectification, filtering, etc.) necessary, but not always as meaningful as we would like. Thus we present here the principal characteristics of frequency analysis, and discuss its usefulness in analyzing EMG signals and its application to biofeedback, clinical practice, and research.     

Bacillus thuringiensis delta-endotoxin Cry1C domain III can function as a specificity determinant for Spodoptera exigua in different, but not all, Cry1-Cry1C hybrids

In order to test our hypothesis that Bacillus thuringiensis delta-endotoxin Cry1Ca domain III functions as a determinant of specificity for Spodoptera exigua, regardless of the origins of domains I and II, we have constructed by cloning and in vivo recombination a collection of hybrid proteins containing domains I and II of various Cry1 toxins combined with domain III of Cry1Ca. Cry1Ab, Cry1Ac, Cry1Ba, Cry1Ea, and Cry1Fa all become more active against S. exigua when their domain III is replaced by (part of) that of Cry1Ca. This result shows that domain III of Cry1Ca is an important and versatile determinant of S. exigua specificity. The toxicity of the hybrids varied by a factor of 40, indicating that domain I and/or II modulate the activity as well. Cry1Da-Cry1Ca hybrids were an exception in that they were not significantly active against S. exigua or Manduca sexta, whereas both parental proteins were highly toxic. Incidentally, in a Cry1Ba-Cry1Ca hybrid, Cry1Ca domain III can also strongly increase toxicity for M. sexta.     

Can a reductionist be a pluralist?

Pluralism is often put forth as a counter-position to reductionism. In this essay, I argue that reductionism and pluralism are in fact consistent. I propose that there are several potential goals for reductions and that the proper form of a reduction should be considered in tandem with the goal that it aims to achieve. This insight provides a basis for clarifying what version(s) of reductionism are currently defended, for explicating the notion of a fundamental level of explanation, and for showing how one can be both a reductionist and a pluralist.     

Direct association of ligand-binding and pore domains in homo- and heterotetrameric inositol 1,4,5-trisphosphate receptors

Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are a family of intracellular Ca(2+) channels that exist as homo- or heterotetramers. In order to determine whether the N-terminal ligand-binding domain is in close physical proximity to the C-terminal pore domain, we prepared microsomal membranes from COS-7 cells expressing recombinant type I and type III IP(3)R isoforms. Trypsin digestion followed by cross-linking and co-immunoprecipitation of peptide fragments suggested an inter-subunit N- and C-terminal interaction in both homo- and heterotetramers. This observation was further supported by the ability of in vitro translated C-terminal peptides to interact specifically with an N-terminal fusion protein. Using a (45)Ca(2+) flux assay, we provide functional evidence that the ligand-binding domain of one subunit can gate the pore domain of an adjacent subunit. We conclude that common structural motifs are shared between the type I and type III IP(3)Rs and propose that the gating mechanism of IP(3)R Ca(2+) channels involves the association of the N-terminus of one subunit with the C-terminus of an adjacent subunit in both homo- and heterotetrameric complexes.     

Explanatory pluralism in evolutionary biology

The ontological dependence of one domain on another is compatible with the explanatory autonomy of the less basic domain. That autonomy results from the fact that the relationship between two domains can be very complex. In this paper I distinguish two different types of complexity, two ways the relationship between domains can fail to be transparent, both of which are relevant to evolutionary biology. Sometimes high level explanations preserve a certain type of causal or counterfactual information which would be lost at the lower level; I argue that this is central to the proper understanding of the adaptationist program. Sometimes high level kinds are multiply realised by lower level kinds: I argue that this is central to the understanding of macroevolution.     

Potential contact sites between the protein and RNA subunit in the Bacillus subtilis RNase P holoenzyme.

We have detected by nucleotide analog interference mapping (NAIM) AMPalphaS and IMPalphaS modifications in Bacillus subtilis RNase P RNA that interfere with binding of the homologous protein subunit. Interference as well as some enhancement effects were clustered in two main areas, in P10.1a/L10.1 and P12 of the specificity domain (cluster 1, domain I) and in P2, P3, P15.1, J18/2 and J19/4 of the catalytic domain (cluster 2a, domain II). Minor interferences in P1 and P19 and a strong and weak enhancement effect in P19 represent a third area located in domain II (cluster 2b). Our results suggest that P3, P2-J18/2 and J19/4 are key elements for anchoring of the protein to the catalytic domain close to the scissile phosphodiester in enzyme-substrate complexes. Sites of interference or enhancement in clusters 1 and 2a are located at distances between 65 and 130 A from each other in the current 3D model of a full-length RNase P RNA-substrate complex. Taking into account that the RNase P protein monomer can bridge a maximum distance of about 40 A, simultaneous direct contacts to the two aforementioned potential RNA-binding areas would be incompatible with our current understanding of bacterial RNase P RNA architecture. Our findings suggest that the current 3D model has to be rearranged in order to reduce the distance between clusters 1 and 2a. Alternatively, based on the recent finding that B. subtilis RNase P forms a tetramer consisting of two protein and two RNA subunits, cluster 1 may reflect one protein contact site in domain I, and cluster 2a a separate one in domain II.     

Determination of lysine residues affinity labeled in the active site of yeast RNA polymerase II(B) by mutagenesis.

In a previous study, yeast RNA polymerase II(B) was affinity labeled with two nucleotide derivatives (III and VIII) (1). In both cases, the labeled site was localized to the C-terminal part of the B150 subunit. The potential target lysyl residues of derivative III were mapped to the conserved domain H, between Asn946 and Met999. In the present work, we have mutagenized to arginine the five lysines present in domain H. Three lysines can be replaced, individually or simultaneously, without affecting cell growth, and each mutated enzyme can still be affinity labeled. Hence one or both of the other two lysyl residues, Lys979 and Lys987, is the target of the affinity reagent. These two lysines were each found to be essential for cell viability. Derivative VIII labeled another domain in addition to domain H. Supported by analogous results obtained for E. coli RNA polymerase using derivative VIII (2), we hypothesized that the second domain labeled by this derivative in the B150 subunit was domain I. Mutagenesis of the unique lysine present in domain I demonstrated that Lys 1102 was the target of derivative VIII. These results indicate that in both prokaryotic and eukaryotic RNA polymerases, domains H and I are in close proximity and participate to the active site.     

Computational design of an integrin I domain stabilized in the open high affinity conformation

We have taken a computational approach to design mutations that stabilize a large protein domain of approximately 200 residues in two alternative conformations. Mutations in the hydrophobic core of the alphaMbeta2 integrin I domain were designed to stabilize the crystallographically defined open or closed conformers. When expressed on the cell surface as part of the intact heterodimeric receptor, binding of the designed open and closed I domains to the ligand iC3b, a form of the complement component C3, was either increased or decreased, respectively, compared to wild type. Moreover, when expressed in isolation from other integrin domains using an artificial transmembrane domain, designed open I domains were active in ligand binding, whereas designed closed and wild type I domains were inactive. Comparison to a human expert designed open mutant showed that the computationally designed mutants are far more active. Thus, computational design can be used to stabilize a molecule in a desired conformation, and conformational change in the I domain is physiologically relevant to regulation of ligand binding.