Paul David Pavy II: A Correction

Careful analysis of Nacireman academies does not bear out the conclusion of Walker (1970) that these are dysfunctional. Indeed, they are an integral part of Nacireman age-grade structure and play an important role in initiation into a Nacireman adult age-grade.     

Knowledge-based potential defined for a rotamer library to design protein sequences

A knowledge-based potential for a rotamer library was developed to design protein sequences. Protein side-chain conformations are represented by 56 templates. Each of their fitness to a given structural site-environment is evaluated by a combined function of the three knowledge-based terms, i.e. two-body side-chain packing, one-body hydration and local conformation. The number of matches between the native sequence and the structural site-environment in the database and that of the virtually settled mismatches, counted in advance, were transformed into the energy scores. In the best-14 test (assessment for the reproduction ability of the native rotamer on its structural site within a quarter of 56 fitness rank positions), the structural stability analysis on mutants of human and T4 lysozymes and the inverse-folding search by a structure profile against the sequence database, this function performs better than the function deduced with the conventional normalization and our previously developed function. Targeting various structural motifs, de novo sequence design was conducted with the function. The sequences thus obtained exhibit reasonable molecular masses and hydrophobic/hydrophilic patterns similar to the native sequences of the target and act as if they were the homologs to the target proteins in BLASTP search. This significant improvement is discussed in terms of the reference state for normalization and the crucial role of short-range repulsion to prohibit residue bumps.     

Statistical mechanics analysis of sparse data

Inferential structure determination uses Bayesian theory to combine experimental data with prior structural knowledge into a posterior probability distribution over protein conformational space. The posterior distribution encodes everything one can say objectively about the native structure in the light of the available data and additional prior assumptions and can be searched for structural representatives. Here an analogy is drawn between the posterior distribution and the canonical ensemble of statistical physics. A statistical mechanics analysis assesses the complexity of a structure calculation globally in terms of ensemble properties. Analogs of the free energy and density of states are introduced; partition functions evaluate the consistency of prior assumptions with data. Critical behavior is observed with dwindling restraint density, which impairs structure determination with too sparse data. However, prior distributions with improved realism ameliorate the situation by lowering the critical number of observations. An in-depth analysis of various experimentally accessible structural parameters and force field terms will facilitate a statistical approach to protein structure determination with sparse data that avoids bias as much as possible.     

Structural properties of a collagenous heterotrimer that mimics the collagenase cleavage site of collagen type I

Collagens contain sequence- and conformation-dependent epitopes responsible for their digestion by collagenases at specific loci. A synthetic heterotrimer construct containing the collagenase cleavage site of collagen type I was found to mimic perfectly native collagen in terms of selectivity and mode of enzymatic degradation. The NMR conformational analysis of this molecule clearly revealed the presence of two structural domains, i.e. a triple helix spanning the Gly-Pro-Hyp repeats and a less ordered portion corresponding to the collagenase cleavage site where the three chains are aligned in extended conformation with loose interchain contacts. These structural properties allow for additional insights into the very particular mechanism of collagen digestion by collagenases.     

Correspondences between low-energy modes in enzymes: dynamics-based alignment of enzymatic functional families

Proteins that show similarity in their equilibrium dynamics can be aligned by identifying regions that undergo similar concerted movements. These movements are computed from protein native structures using coarse-grained elastic network models. We show the existence of common large-scale movements in enzymes selected from the main functional and structural classes. Alignment via dynamics does not require prior detection of sequence or structural correspondence. Indeed, a third of the statistically significant dynamics-based alignments involve enzymes that lack substantial global or local structural similarities. The analysis of specific residue-residue correspondences of these structurally dissimilar enzymes in some cases suggests a functional relationship of the detected common dynamic features. Including dynamics-based criteria in protein alignment thus provides a promising avenue for relating and grouping enzymes in terms of dynamic aspects that often, though not always, assist or accompany biological function.     

Folk Zoological Life-Forms: Their Universality and Growth

Folk zoological life-form terms, like folk botanical life-form terms (Brown 1977a), are added to languages in a highly regular manner. Life-forms of the triad FISH, BIRD, and SNAKE are lexically encoded first, although in no particular order, followed by WUG (e.g., American English hug) and then MAMMAL. Four general principles of naming-behavior underlie these regularities: (1) criteria clustering; (2) conjunctivity (including binary opposition); (3) dimension salience; and (4) marking. In addition, size of folk zoological life-form vocabularies is positively correlated with societal complexity. This is caused by the decay of folk biological taxonomies as societies become more complex. [cognitive anthropology, ethnobiology, folk classification, language universals, language change]     

Nested allostery of arthropodan hemocyanin (Eurypelma californicum and Homarus americanus). The role of protons

Continuous oxygen binding curves for two arthropodan hemocyanins were performed at different pH values ranging from 7.0 to 8.7 and in the presence of physiological concentrations of the bivalent ions Ca2+ and Mg2+. The arthropods Eurypelma californicum and Homarus americanus are classified as chelicerata and crustaceans, respectively. Their structurally well-characterized hemocyanins are composed of, in the case of E. californicum 24 subunits, and in the case of H. americanus 12 subunits. The role of protons as allosteric effectors of the oxygen binding was analysed in terms of the nesting model, which assumes hierarchies of allosteric equilibria that are based on obvious structural hierarchies. For each hemocyanin, the smallest structural repeating unit, the 12-mer or the 6-mer, respectively, was regarded as the "allosteric unit". Two allosteric units are allosterically coupled within the native molecules. The analysis revealed that in accordance with the postulations of the classical Monod-Wyman-Changeux model protons as allosteric effectors do not change the oxygen affinities of the four postulated conformations, but influence the allosteric equilibria between them at two different hierarchical levels. Model-independent determination of the affinity constants for the binding of the first and the last oxygen molecule to the native hemocyanins and to the isolated half-molecules confirmed the affinities calculated according to the nesting model. The stepwise establishment of new conformations during the assembly process from monomers to the structurally identical repeating unit and further on to the native molecule is shown. Possible physiological advantages of allosterically coupled allosteric units in contrast to allosterically uncoupled ones are thought to be (1) the option to regulate oxygen binding on different levels of structural hierarchy and (2) the increase of the oxygen-carrying capacity.     

Thermal stability and aggregation of sulfolobus solfataricus beta-glycosidase are dependent upon the N-epsilon-methylation of specific lysyl residues: critical role of in vivo post-translational modifications

Methylation in vivo is a post-translational modification observed in several organisms belonging to eucarya, bacteria, and archaea. Although important implications of this modification have been demonstrated in several eucaryotes, its biological role in hyperthermophilic archaea is far from being understood. The aim of this work is to clarify some effects of methylation on the properties of beta-glycosidase from Sulfolobus solfataricus, by a structural comparison between the native, methylated protein and its unmethylated counterpart, recombinantly expressed in Escherichia coli. Analysis by Fourier transform infrared spectroscopy indicated similar secondary structure contents for the two forms of the protein. However, the study of temperature perturbation by Fourier transform infrared spectroscopy and turbidimetry evidenced denaturation and aggregation events more pronounced in recombinant than in native beta-glycosidase. Red Nile fluorescence analysis revealed significant differences of surface hydrophobicity between the two forms of the protein. Unlike the native enzyme, which dissociated into SDS-resistant dimers upon exposure to the detergent, the recombinant enzyme partially dissociated into monomers. By electrospray mapping, the methylation sites of the native protein were identified. A computational analysis of beta-glycosidase three-dimensional structure and comparisons with other proteins from S. solfataricus revealed analogies in the localization of methylation sites in terms of secondary structural elements and overall topology. These observations suggest a role for the methylation of lysyl residues, located in selected domains, in the thermal stabilization of beta-glycosidase from S. solfataricus.     

Interrelationship Between Fractal Ornament and Multilevel Selection Theory

Interdisciplinarity is one of the features of modern science, defined as blurring the boundaries of disciplines and overcoming their limitations or excessive specialization by borrowing methods from one discipline into another, integrating different theoretical assumptions, and using the same concepts and terms. Often, theoretical knowledge of one discipline and technological advances of another are combined within an interdisciplinary science, and new branches or disciplines may also emerge. Biosemiotics, a field that arose at the crossroads of biology, semiotics, linguistics, and philosophy, enables scientists to borrow theoretical assumptions from semiotics and extend them to different biological theories. The latter applies especially to extended synthesis, wherein culture is viewed as one of the factors influencing evolution. In the present research, the semiotic system of Ukrainian folk ornament is analyzed through the theory of fractals, key features of which are recursion and self-similarity. As a result, an assumption is made about the fractal structure of culture and social life on a conceptual level. What follows is a discussion of how this assumption can contribute to the multilevel selection theory, one of the foundations of extended synthesis, which employs the concept of self-similarity at all levels of the biological hierarchy.     

Analysis of the plasma elimination kinetics and conformational stabilities of native, proteinase-complexed, and reactive site cleaved serpins: comparison of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, antithrombin III, alpha 2-antiplasmin, angiotensinogen, and ovalbumin.

Proteinase inhibitors of the serpin superfamily may exist in one of three distinct conformations: the native form, a fully active protein with the reactive site loop intact; the proteolytically modified form in which inhibitory capacity is abolished; and the proteinase-complexed form, a stable equimolar complex between the inhibitor and a target proteinase. Here, the specificity and kinetics of the plasma elimination of different serpin conformations are compared. Proteinase-complexed serpins were rapidly cleared from the circulation. However, the native and modified forms were not cleared rapidly, indicating that the receptor-mediated pathways which recognize the complexes fail to recognize the native and modified forms. This result suggests that significant structural differences exist between modified and proteinase-complexed serpins. The structural differences were probed by using transverse urea gradient gel electrophoresis, a technique that allows comparisons of the conformational stabilities of proteins. With the exception of the noninhibitory serpins ovalbumin and angiotensinogen, the modified and proteinase-complexed serpins were both stabilized thermodynamically compared to the native forms. In addition, the proteinase component of the serpin-proteinase complex was usually thermodynamically stabilized. These data are used to compare the conformations of serpin-proteinase complexes with those of native and modified serpins; they are discussed in terms of a model whereby serpins inhibit proteinases in a manner similar to that described for other types of protein inhibitors of serine proteinases.     

Parallel structures in professional and folk health care: A model applied to rural Hati

The paper argues that professional and folk sectors of pluralistic health care systems share certain structural features that in some respects have equal or greater importance than obvious differences. A model based on the concepts of primary, secondary and tertiary care is adapted to an analysis of both folk and professional domains of the rural Haitian health care system. Ethnographic and survey data are presented to support the position that underlying similarities are evident in patterns of cost, accessibility, specialization, recruitment and training of practitioners in both health sectors. The level of care model provides an analytic framework which gives proper attention to diversity in traditional healing, which is applicable to other health care systems, and which has relevance for the development of primary care resources in developing areas.     

Which groups are mostly responsible for problems in your neighbourhood?

Abstract

Why and under which conditions do people employ ethnic categories rather than others (such as age, class, gender, and so on) to conceptually organize their social environment? This article analyses an open-ended question on who is seen as responsible for neighbourhood problems taken from a recently conducted large-scale survey in Germany. By doing so, this study tries to give novel insight on native Germans' use of ethnic folk classifications and aims to identify contextual factors that might explain why people characterize problem-groups in ethnic terms. This article shows that drunkards, the elderly and especially teenagers are seen as problem-groups more frequently than any ethnic minority. Conditions of economic decline and out-group size are analysed as to whether they are associated with a higher likelihood of using ethnic categories. The findings suggest that the effects of out-group size are diminishing in their impact, whereas the effects of economic decline are accumulating in strength.     

Urban Folk Medicine: A Functional Overview

Social and economic functions of folk illness and folk medicine are fairly well known for rural contexts but still lack codification for urban milieus. In this exploratory paper, folk health practices are examined in terms of their response to urban socioeconomic characteristics. Such practices appear to serve functions of acculturation, guilt displacement resulting from failure to achieve, and subgroup identity maintenance, among others. Folk practices are resilient, readily shifting to adjunct functions of healing under pressure from effective modern medical and welfare systems . [medical anthropology, urban anthropology, curanderismo, ethnology, health]     

The conformational properties of methyl alpha-(2,8)-di/trisialosides and their N-acyl analogues: implications for anti-Neisseria meningitidis B vaccine design

The conformational properties of di- and trisaccharide fragments of the polysialic acid O-antigen capsular polysaccharide (CPS) of Neisseria meningitidis B (NmB) have been investigated by a combination of solution phase NMR spectroscopy and explicit-solvent molecular dynamics (MD) simulations. Simulations employing 100 ns of conventional MD, as well as 160 ns of replica exchange MD (REMD), with the GLYCAM06 force field were shown to be in agreement with experimental NMR scalar J-coupling and NOE values. The presence of conformational families has been determined by monitoring interglycosidic torsion angles, by comparing structural superimpositions, as well as via a Bayesian statistical analysis of the torsional data. Attempts to augment the immunogenicity of NmB CPS often involve chemical modifications of the N-acetyl moiety. Here the effects of these chemical group modifications on the conformational properties of the trisialoside have been probed via REMD simulations of the N-glycolyl, N-propionyl, N-propyl and N-butanoyl analogues. Although there were conformational families unique to each non-native analogue, the chemical modifications resulted in largely equivalent overall conformational phase-spaces compared to the native trisialoside. On the basis of the conformational distributions, these shared conformational properties suggest that a recurrent global conformational epitope may be present in both the native and chemically modified CPS fragments. Explanations are therefore provided for monoclonal antibody cross-reactivity, in terms of recognition of a shared global CPS conformation, as well as for lack of cross-reactivity, in terms of fine structural differences associated with the N-acyl groups, which may be dominant in highly matured antibody responses.     

The NMR structures of the major intermediates of the two-domain tick carboxypeptidase inhibitor reveal symmetry in its folding and unfolding pathways

There is a lack of experimental structural information about folding intermediates of multidomain proteins. Tick carboxypeptidase inhibitor (TCI) is a small, disulfide-rich protein consisting of two domains that fold and unfold autonomously through the formation of two major intermediates, IIIa and IIIb. Each intermediate contains three native disulfide bonds in one domain and six free cysteines in the other domain. Here we have determined the NMR structures of these two intermediates trapped and isolated at acidic pH in which they are stable and compared their structures with that of the native protein analyzed under the same conditions. Both IIIa and IIIb were found to contain a folded region that corresponds to the N- and C-terminal domains of TCI, respectively, with structures very similar to the corresponding regions of the native protein. The remainder of the polypeptide chains of the intermediates was shown to be unfolded in a random coil conformation. Solvent exchange measurements further indicated that the two protein domains are not completely independent, but affect each other in terms of dynamics and stability, in agreement with reported inhibitory activity data. The derived results provide structural evidence for symmetric TCI folding and unfolding mechanisms that converge in IIIa and IIIb and reveal the structural basis that accounts for the strong and simultaneous accumulation of both intermediates. Altogether, this work has important implications for a better understanding of the folding mechanisms of multidomain, disulfide-rich proteins.     

Reactivity-based analysis of domain structures in native replication protein A

Replication protein A (RPA) is an essential heterotrimeric ssDNA binding protein that participates in DNA repair, replication, and recombination. Though X-ray and NMR experiments have been used to determine three-dimensional structure models of the protein's domain fragments, a complete RPA structural model has not been reported. To test whether the fragment structures faithfully represent the same portions in the native solution-state protein, we have examined the structure of RPA under biologically relevant conditions. We have probed the location of multiple amino acids within the native RPA three-dimensional structure using reactivity of these amino acids toward proteolytic and chemical modification reagents. In turn, we evaluated different structural models by comparing the observed native RPA reactivities with anticipated reactivities based on candidate structural models. Our results show that our reactivity analysis approach is capable of critically assessing structure models and can be a basis for selecting the most relevant from among alternate models of a protein structure. Using this analytical approach, we verified the relevance of RPA fragment models to the native protein structure. Our results further indicate several important features of native RPA's structure in solution, such as flexibility at specific locations in RPA, particularly in the C-terminal region of RPA70. Our findings are consistent with reported DNA-free structural models and support the role of conformational change in the ssDNA binding mechanism of RPA.