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PubMed2004

A test for patterns of modularity in sequences of developmental events.

This study presents a statistical test for modularity in the context of relative timing of developmental events. The test assesses whether sets of developmental events show special phylogenetic conservation of rank order. The test statistic is the correlation coefficient of developmental ranks of the N events of the hypothesized module across taxa. The null distribution is obtained by taking correlation coefficients for randomly sampled sets of N events. This test was applied to two datasets, including one where phylogenetic information was taken into account. The events of limb development in two frog species were found to behave as a module.

Animals↗
PubMed2002

Children's use of landmarks: implications for modularity theory.

Previous studies have shown that disoriented children use the geometric features of the environment to reorient, but the results have not consistently demonstrated whether children can combine such information with landmark information. Results indicating that they cannot suggest the existence of a geometric module for reorientation. However results indicating that children can use geometric information in combination with landmark information challenge the modularity interpretation. An uncontrolled variable in the studies yielding conflicting results has been the size of the experimental space. In the present studies, which tested young children in spaces of two different sizes, the size of the space affected their ability to use available landmark information. In the small space, the children did not use the landmark to reorient, but in the large space they did. The ability of children to use landmarks in combination with geometric information raises important questions about the existence of an encapsulated geometric module.

Child↗
PubMed2004

IS231-MIC231 elements from Bacillus cereus sensu lato are modular.

Summary IS231A was originally discovered in Bacillus thuringiensis as a typical 1.6 kb insertion sequence (IS) displaying 20 bp inverted repeats (IR) flanking a transposase gene. A first major variation of this canonical organization was found in MIC231A1. This mobile insertion cassette (MIC), delineated by IS231A-related extremities, contained an active d-stereospecific endopeptidase (adp) gene instead of a transposase. Interestingly, it was shown that MIC231A1 can be mobilized in trans by the IS231A transposase. In this paper, we show that this family of IS231-MIC231 elements can be extended to a broad range of related entities displaying higher levels of structural complexity. Several IS231A-like elements contained, upstream of their transposase gene, passenger genes coding for putative antibiotic resistances or regulatory factors. Furthermore, the diversity of the MIC231 elements ranged from empty cassettes to structures carrying up to three passenger genes. Among these, MIC231V carried, in addition to an adp gene, an active fosfomycin resistance determinant. In vivo transposition assays showed that MIC231V is also trans-activated by the IS231A transposase. These results lend further support to the potential contribution of these modular mobile elements to the genome plasticity of the Bacillus cereus/B. thuringiensis group.

Bacillus cereus↗
PubMed2007

The modular nature of genetic diseases.

Evidence from many sources suggests that similar phenotypes are begotten by functionally related genes. This is most obvious in the case of genetically heterogeneous diseases such as Fanconi anemia, Bardet-Biedl or Usher syndrome, where the various genes work together in a single biological module. Such modules can be a multiprotein complex, a pathway, or a single cellular or subcellular organelle. This observation suggests a number of hypotheses about the human phenome that are now beginning to be explored. First, there is now good evidence from bioinformatic analyses that human genetic diseases can be clustered on the basis of their phenotypic similarities and that such a clustering represents true biological relationships of the genes involved. Second, one may use such phenotypic similarity to predict and then test for the contribution of apparently unrelated genes to the same functional module. This concept is now being systematically tested for several diseases. Most recently, a systematic yeast two-hybrid screen of all known genes for inherited ataxias indicated that they all form part of a single extended protein-protein interaction network. Third, one can use bioinformatics to make predictions about new genes for diseases that form part of the same phenotype cluster. This is done by starting from the known disease genes and then searching for genes that share one or more functional attributes such as gene expression pattern, coevolution, or gene ontology. Ultimately, one may expect that a modular view of disease genes should help the rapid identification of additional disease genes for multifactorial diseases once the first few contributing genes (or environmental factors) have been reliably identified.

Computational Biology↗
PubMed1995

Engineering of five 88-residue receptor-adhesive modular proteins containing a parallel alpha-helical coiled coil and two RGD ligand sites.

Several 88-residue proteins were designed, synthesized and examined as receptor-adhesive modular proteins (RAMPs). Three covalent and two noncovalent dimers were made from two 44-residue peptide chains containing three structural modules: RGD-A23a (ligand-spacer-coil) and A9a-RGD (coil-spacer-ligand). The ligand module contained the tripeptide Arg-Gly-Asp (RGD). The coil modules A9a and A23a were five-heptad alpha-helices engineered by Hodges and co-workers [Int. J. Peptide Protein Res. (1992) 40, 171-179]. By circular dichroic spectroscopy, each of these five RAMPs contained an alpha-helical coiled coil. The disulfide-bridged dimer RGD-A23a/RGD-A23a and its reduced form (RGD-A23a)2 had two N-terminal RGD sites. The disulfide-bridged dimer A9a-RGD/A9a-RGD and its reduced form (A9a-RGD)2 had two C-terminal RGD sites. However, the disulfide-bridged heterodimer RGD-A23a/A9a-RGD had one RGD site at each terminus with a 50 Angstrum coiled coil between them. The temperature at the midpoint of unfolding for each of the covalent homodimers RGD-A23a/RGD-A23a (67 degrees C) and A9a-RGD/A9a-RGD (69 degrees C) was slightly higher than that of the corresponding noncovalent homodimer (RGD-A23a)2 (62 degrees C) or (A9a-RGD)2 (68 degrees C) but much lower than that of the covalent heterodimer RGD-A23a/A9a-RGD (79 degrees C). The enthalpy and entropy of thermal unfolding were also significantly greater for the heterodimer than for the four homodimers, consistent with the heterodimer having the most stable coiled coil. Although the distance between its RGD sites was at least 50 Angstrum greater than that for the homodimers, this heterodimeric RAMP was only as active as the homodimers A9a-RGD/A9a-RGD and (A9a-RGD)2 in inhibiting the adhesion of A2058 melanoma cells to extracellular matrix proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2004

Targeting modular polyketide synthases with iteratively acting acyltransferases from metagenomes of uncultured bacterial consortia.

Bacterial type I polyketide synthases (PKSs) produce a wide range of biomedically important secondary metabolites. These enzymes possess a modular structure that can be genetically re-engineered to yield novel drug candidates not found in nature. Recently, we have reported the putative pederin PKS from an uncultured bacterial symbiont of Paederus fuscipes beetles. It belongs to an architecturally unusual PKS group, the members of which contain iteratively acting acyltransferases that are not integrated into the PKS modules but are encoded by isolated genes. As these systems are rare, often contain additional unusual features and are of smaller size than regular PKSs, the development of a method for the targeted isolation of new group members would be of great interest. Here, we present a phylogenetic approach to identify these systems rapidly in highly complex metagenomic DNA samples. To demonstrate its practical value, we located two pederin-type PKS systems putatively involved in the biosynthesis of antitumour polyketides in the metagenomic DNA of beetles, sponges and their uncultivated bacterial symbionts.

Amino Acid Sequence↗
PubMed1992

Debate and argument: on modularity and development in autism: a reply to Burack.

Burack (this issue) reopens questions first raised by my 1989a article in this Journal, on whether children with autism have a specific delay in the development of a theory of mind, or whether the data reflect deviance rather than delay. His paper is of considerable value in highlighting points for debate. In my response, I focus on three issues: First, the logical possibility that delay and deviance can occur together. Second, the evidence that autism may instantiate this possibility. Finally, the important question of the modularity of theory of mind.

Autistic Disorder↗
PubMedDate not supplied

Modularity and sense organs in the blind cavefish, Astyanax mexicanus.

Mexican tetra (Astyanax mexicanus) exist as two morphs: a sighted (surface) form and a blind (cavefish) form. In the cavefish, some modules are lost, such as the eye and pigment modules, whereas others are expanded, such as the taste bud and cranial neuromast modules. We suggest that modularity can be viewed as being nested in a manner similar to Baupläne so that modules express unique sets of genes, cells, and processes. In terms of evolution, we conclude that natural selection can act on any of these hierarchical levels within modules or on all the sensory modules as a whole. We discuss interactions within and between modules with reference to the blind cavefish from both genetic and developmental perspectives. The cavefish represents an illuminating example of module interaction, uncoupling of modules, and module expansion.

Animals↗
PubMed1996

Modular structure of the Rhizobium meliloti DctB protein.

To investigate the modular structure of the Rhizobium meliloti dicarboxylic acid sensor protein, DctB, three truncated DctB proteins (DctB4, DctB5 and DctB4G) were constructed, overproduced in Escherichia coli and purified. The DctB4G protein was composed of 446 amino acids of the DctB C-terminus and displayed strong autophosphorylation activity in vitro. This activity was sustained when a further 120 amino acids at the N-terminus of the polypeptide were deleted (DctB5). This protein which has an intact transmitter domain exhibits specific but inefficient phospho-transfer capabilities. Removal of 58 amino acids from the DctB4G C-terminus which included blocks F and G2 of the transmitter domain, rendered the resultant protein (DctB4) incompetent in autophosphorylation. Phosphorylation activity was restored to DctB4 through intramolecular complementation with DctB. Therefore, it would appear that the R. meliloti DctB protein is active as a dimer (or higher order oligomer). Furthermore, the intramolecular complementation experiments indicate that the amino acids 171-291, a predicted periplasmic stretch, play an important role in the dimerization process.

Bacterial Proteins↗
PubMed1996

A modular xylanase from mesophilic Cellulomonas fimi contains the same cellulose-binding and thermostabilizing domains as xylanases from thermophilic bacteria.

The xynC gene from mesophilic Cellulomonas fimi encodes a large 125 kDa modular xylanase (XYLC), consisting of six distinct functional domains. In addition to a single Family 10 catalytic domain, XYLC contains a domain homologous with the nodulation protein, NodB, from nitrogen-fixing bacteria and thermostabilizing and cellulose-binding domains found previously only in xylanases from thermophilic bacteria.

Actinomycetales↗
PubMed1998

The modular architecture of leukocyte cell-surface receptors.

Cells of the immune system have a large number of protein receptors on their surfaces, with a wide range of binding functions. They are, however, constructed from a limited set of protein structural units, which are recognisable at the sequence level. The 3D structure of many of these domains, or modules, is now known. These modular units and their structures are reviewed here. The ways in which they are assembled into multidomain receptor chains and oligomeric complexes of receptors are also discussed.

Animals↗
PubMed2005

Chain initiation on type I modular polyketide synthases revealed by limited proteolysis and ion-trap mass spectrometry.

Limited proteolysis in combination with liquid chromatography-ion trap mass spectrometry (LC-MS) was used to analyze engineered or natural proteins derived from a type I modular polyketide synthase (PKS), the 6-deoxyerythronolide B synthase (DEBS), and comprising either the first two extension modules linked to the chain-terminating thioesterase (TE) (DEBS1-TE); or the last two extension modules (DEBS3) or the first extension module linked to TE (diketide synthase, DKS). Functional domains were released by controlled proteolysis, and the exact boundaries of released domains were obtained through mass spectrometry and N-terminal sequencing analysis. The acyltransferase-acyl carrier protein required for chain initiation (AT(L)-ACP(L)), was released as a didomain from both DEBS1-TE and DKS, as well as the off-loading TE as a didomain with the adjacent ACP. Mass spectrometry was used successfully to monitor in detail both the release of individual domains, and the patterns of acylation of both intact and digested DKS when either propionyl-CoA or n-butyryl-CoA were used as initiation substrates. In particular, both loading domains and the ketosynthase domain of the first extension module (KS1) were directly observed to be simultaneously primed. The widely available and simple MS methodology used here offers a convenient approach to the proteolytic mapping of PKS multienzymes and to the direct monitoring of enzyme-bound intermediates.

Acyl Coenzyme A↗
PubMed2006

Domain deletions and substitutions in the modular protein evolution.

The main mechanisms shaping the modular evolution of proteins are gene duplication, fusion and fission, recombination and loss of fragments. While a large body of research has focused on duplications and fusions, we concentrated, in this study, on how domains are lost. We investigated motif databases and introduced a measure of protein similarity that is based on domain arrangements. Proteins are represented as strings of domains and comparison was based on the classic dynamic alignment scheme. We found that domain losses and duplications were more frequent at the ends of proteins. We showed that losses can be explained by the introduction of start and stop codons which render the terminal domains nonfunctional, such that further shortening, until the whole domain is lost, is not evolutionarily selected against. We demonstrated that domains which also occur as single-domain proteins are less likely to be lost at the N terminus and in the middle, than at the C terminus. We conclude that fission/fusion events with single-domain proteins occur mostly at the C terminus. We found that domain substitutions are rare, in particular in the middle of proteins. We also showed that many cases of substitutions or losses result from erroneous annotations, but we were also able to find courses of evolutionary events where domains vanish over time. This is explained by a case study on the bacterial formate dehydrogenases.

Amino Acid Motifs↗
PubMed2007

Modular metabolic control analysis of large responses.

Deciphering the laws that govern metabolic responses of complex systems is essential to understand physiological functioning, pathological conditions and the outcome of experimental manipulations of intact cells. To this aim, a theoretical and experimental sensitivity analysis, called modular metabolic control analysis (MMCA), was proposed. This field was previously developed under the assumptions of infinitesimal changes and/or proportionality between parameters and rates, which are usually not fulfilled in vivo. Here we develop a general MMCA for two modules, not relying on those assumptions. Control coefficients and elasticity coefficients for large changes are defined. These are subject to constraints: summation and response theorems, and relationships that allow calculating control from elasticity coefficients. We show how to determine the coefficients from top-down experiments, measuring the rates of the isolated modules as a function of the linking intermediate (there is no need to change parameters inside the modules). The novel formalism is applied to data of two experimental studies from the literature. In one of these, 40% increase in the activity of the supply module results in less than 4% increase in flux, while infinitesimal MMCA predicts more than 30% increase in flux. In addition, it is not possible to increase the flux by manipulating the activity of demand. The impossibility of increasing the flux by changing the activity of a single module is due to an abrupt decrease of the control of the modules when their corresponding activities are increased. In these cases, the infinitesimal approach can give highly erroneous predictions.

Algorithms↗
PubMed1978

A modular approach to dental studies.

At the commencement of the 1979 Academic Year a "modular approach" to degree studies in Dentistry will be instituted at the University of Papua New Guinea. This course of studies will be comprised of four progression modules and includes a one-year programme of community service and clinical experience in a dental clinic of the Department of Health.

Curriculum↗
PubMedDate not supplied

A practical, modular hyperthermia phantom.

A catheterized, three-component slab phantom has been fabricated for use in mapping specific absorption rate (SAR) distributions from hyperthermia applicators. A planar array of 21 closely spaced catheters, located at one surface of the 1-cm-thick slab, can be positioned at depths of 0-7 cm below the phantom surface, in 1-cm steps, through appropriate placement and orientation of this slab within the three-slab set. Owing to its modular design, the phantom can be prepared, and also purged of degraded material rapidly and without damage to the catheter tracks.

Humans↗
PubMed1995

Time-domain modeling of peripheral auditory processing: a modular architecture and a software platform.

A software package with a modular architecture has been developed to support perceptual modeling of the fine-grain spectro-temporal information observed in the auditory nerve. The package contains both functional and physiological modules to simulate auditory spectral analysis, neural encoding, and temporal integration, including new forms of periodicity-sensitive temporal integration that generate stabilized auditory images. Combinations of the modules enable the user to approximate a wide variety of existing, time-domain, auditory models. Sequences of auditory images can be replayed to produce cartoons of auditory perceptions that illustrate the dynamic response of the auditory system to everyday sounds.

Auditory Perception↗
PubMed2002

Proterozoic modular biomineralized metazoan from the Nama Group, Namibia.

We describe a Proterozoic, fully biomineralized metazoan from the Omkyk Member (approximately 549 million years before the present) of the northern Nama Group, Namibia. Namapoikia rietoogensis gen. et sp. nov. is up to 1 meter in diameter and bears a complex and robust biomineralized skeleton; it probably represents a cnidarian or poriferan. Namapoikia encrusts perpendicular to the walls of vertical synsedimentary fissures in microbial reefs. This finding implies that large, modular metazoans with biologically controlled mineralization appeared some 15 million years earlier than previously documented.

Animals↗