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Metallothionein (MT) is a ubiquitous mammalian protein comprising 61 or 62 nonaromatic amino acids of which 20 are cysteine residues. The high sulfhydryl content imparts to this protein a unique and remarkable ability to bind multiple metal ions in structurally significant metal-thiolate clusters. MT can bind seven divalent metal ions per protein molecule in two domains with exclusive tetrahedral metal coordination. The domain stoichiometries for the M7S20 structure are M4(Scys)11 (alpha domain) and M3(Scys)9 (beta domain). Up to 12 Cu(I) ions can displace the 7 Zn(2+) ions bound per molecule in Zn-MT. The incoming Cu(I) ions adopt a trigonal planar geometry with domain stoichiometries for the Cu12S20 structure of Cu6(Scys)11 and Cu6(Scys)9 for the alpha and beta domains, respectively. The circular dichroism (CD) spectra recorded as Cu+ is added to Zn-MT to form Cu12-MT directly report structural changes that take place in the metal binding region. The spectrum arises under charge transfer transitions between the cysteine S and the Cu(i); because the Cu(I)-thiolate cluster units are located within the chiral binding site, intensities in the CD spectrum are directly related to changes in the binding site. The CD technique clearly indicates stoichiometries of several Cu(I)-MT species. Model Cu(I)-thiolate complexes, using the tripeptide glutathione as the sulfhydryl source, were examined by CD spectroscopy to obtain transition energies and the Cu(I)-thiolate coordination geometries which correspond to these bands. Possible structures for the Cu(I)-thiolate clusters in the alpha and beta domains of Cu12-MT are proposed.
Numerical taxonomy is defined by Sneath and Sokal as the grouping of taxonomic units on the basis of their character states by numerical methods of multivariate data analysis, and syndromology as the study of multiple congenital anomaly (MCA) syndromes and of their nosology. We present here an application of those methods to the analysis of overlapping syndromes. The main advantage of numerical taxonomy is that it allows simultaneous objective and unweighted analysis of multiple traits, giving the possibility to test mathematically the clinical hypotheses about the heterogeneity between closely resembling syndromes and uncovering objective patterns of anomalies, to be compared with the subjective pattern recognition process which characterizes most of the diagnostic approach in syndromology. In this paper, we explored 5 syndromes whose most severe expression belongs to the cerebroacrovisceral early lethality (CAVE) phenotype: hydrolethalus, severe Smith-Lemli-Opitz, orofaciodigital type VI (Varadi-Papp), holoprosencephaly-polydactyly, and Pallister-Hall syndromes. Fifty-five published cases, including many overlapping cases, were submitted to principal factor analysis followed by hierarchical clustering and graphical scaling. Results show that the 5 syndromes clearly constitute independent phenotypic entities, that some of the original diagnoses have to be reconsidered, and that many of the overlapping cases may be unambiguously set in one category. Hypothalamic hamartoblastoma appears to be a nonspecific dysplasia occurring in any of the 5 disorders.
Original algorithms for simultaneous alignment of protein sequences are presented, including sequence clustering and within- or between-groups multiple alignment. The way of matching similar regions is fundamentally new. Complete matches are formed by segments more similar than expected by random, according to a given probability limit. Any classic or user-defined score matrix can be used to express the similarity between the residues. The algorithm seeks for complete matches common to all the sequences without performing pairwise alignment and regardless of gap weighting. An automatic screening delineates all the similar regions (boxes) that may be defined for a given maximal shift between the sequences. The shift can be large enough to allow the matching of any region of a sequence with any region of another one. It can also be short and used to refine the alignment around anchor points. The algorithm provides the most likely optimal alignment and a comprehensive list of the alignment dilemma. Duality between automatism and interactivity is provided. Depending on the problem complexity, a final alignment is obtained fully automatically or requires some interactive handling to discriminate alternative pathways.
A program was recently developed to promote adaptive responses and upright head position in students with multiple disabilities through the use of microswitch clusters (i.e., combinations of two microswitches). The five students exposed to the program showed a significant increase in adaptive responses performed with head upright. The first purpose of this study was to carry out a long-term follow-up assessment of the five students' frequencies of adaptive responses and percentages of those responses combined with head upright. Recordings were also made of the length of time the head position was kept during each stimulation period following a successful response event and through the sessions. The second purpose of this study was to arrange a program revision for the students with less favorable data on head upright. The revision consisted of making the stimulation following successful response events synchronous with head upright with a maximum duration of 9s per event. The results of the follow-up assessment showed that two of the students kept the upright head position for nearly the entire stimulation periods that followed successful response events as well as much of the session time. The other three students kept such position for small or intermediate portions of the stimulation periods and of the session time. For these three students, the revised program was applied with substantial benefits. Implications of the findings were discussed.
Recent studies reveal important and distinct roles for cardiac alpha(1a) adrenergic receptors (alpha(1a)ARs). Surprisingly, given their importance in myocardial ischemia/reperfusion, hypoxia, and hypertrophy as well as frequent use of rat cardiomyocyte model systems, the rat alpha(1a)AR gene promoter has never been characterized. Therefore, we isolated 3.9 kb of rat alpha(1a)AR 5'-untranslated region and 5'-regulatory sequences and identified multiple transcription initiation sites. One proximal (P1) and several clustered upstream distal promoters (P2, P3, and P4) were delineated. Sequences surrounding both proximal and distal promoters lack typical TATA or CCAAT boxes but contain cis-elements for multiple myocardium-relevant nuclear regulators including Sp1, GATA, and CREB, findings consistent with enhanced cardiac basal alpha(1a)AR expression seen in Northern blots and reporter constructs. Promoter analysis using deletion reporter constructs reveals, in addition to a powerful upstream enhancer, a key region (-558/-542) important in regulating all alpha(1a)AR promoters with hypoxic stress. Gel shift analysis of this 14-bp region confirms a hypoxia-induced shift independent of direct hypoxia-inducible factor binding. Mutational analysis of this sequence identifies a novel 9-bp hypoxia response element, the loss of which severely attenuates hypoxia-mediated repression of alpha(1a)AR transcription. These findings for the alpha(1a) gene should facilitate elucidation of alpha(1)AR-mediated mechanisms involved in distinct myocardial pathologies.
IgA nephropathy (IgAN) has been assumed to develop sporadically in individuals. We review the recent clinical and laboratory evidence that supports a genetic influence in the immunopathogenesis in some patients. These data include (1) families with multiple members with the disease not sharing a known nephrotoxic factor, (2) clustering of the birthplaces of ancestors of large pedigrees with multiple affected members, suggesting a "founder effect," (3) DNA alleles and protein phenotypes associated with IgAN (or a clinical subset) in some patient populations or that cosegregate with the disease in families with multiple affected members, and (4) immunologic abnormalities of patients shared by relatives with renal disease. However, the lack of understanding the fundamental pathogenetic mechanisms hinders progress in the pursuit of genetically controlled process in this disease. Furthermore, the diagnosis requires a renal biopsy, and no therapy has been proven effective. Therefore, asymptomatic family members with IgAN may forego the invasive diagnostic procedure necessary to establish the diagnosis, and instances of familial disease may not be investigated. Nonetheless, the increasing awareness of families with multiple affected members offers an opportunity to investigate the hypothesized genetic influence in the pathogenesis of IgAN.
A total of 127 biopsy-proven clustered mammographic calcifications were diagnosed and evaluated using multiple parameters. The results were subjected to computer analysis. The number of calcifications/cm2 was the most important parameter. Less than 10 calcifications/cm2 resulted in an 82% chance of being benign while 10 or more calcifications/cm2 had a 44% chance of being malignant. The average distance between the calcifications in the cluster was also significant, with a 92% chance of being benign if greater than 1 mm and a 52% chance of being malignant if less than 1 mm. The remaining parameters did not yield statistically significant results, but there were trends which suggest that less than 10 clustered calcifications that are regular in size and shape and orderly in appearance tend to be benign while disorderly clusters tend to be malignant. In order to decrease the number of false positive biopsies and improve the cost-effectiveness of screening mammography, radiologists should consider 6-month follow-up mammography as a reasonable alternative for clustered calcifications that appear benign.
A peripheral membrane protein of approximately 43 kDa (rapsyn) clusters muscle nicotinic acetylcholine receptors (AChRs), but molecules relevant to clustering neuronal AChRs have not been identified. Here, we have detected rapsyn transcripts in the chick nervous system, localized rapsyn mRNA in ciliary ganglion (CG) neurons, which are known to cluster AChRs, and identified three rapsyn cDNAs derived from the ganglion. Our initial Northern blots, performed using a mouse probe, revealed rapsyn-like transcripts in chick muscle and brain. To develop species-specific probes, we prepared a chick rapsyn cDNA construct, Ch43K.1, that encodes a protein having extensive homology to mouse rapsyn. Using primers designed to anneal near the 5' and 3' boundaries of Ch43K.1, three prominent cDNAs were amplified from chick muscle templates by reverse transcriptase based-PCR. Products of similar size were also amplified using cDNA prepared from neuronal tissues expected to contain clustered AChRs (CG and brain), whereas none were detected using templates from tissues not displaying clustered AChRs (sensory ganglia and liver). In situ hybridization confirmed that rapsyn mRNA is expressed both in chick muscle fibers and in CG neurons. Sequencing the three cDNAs amplified from CG templates revealed the largest to be Ch43K.1, whereas the smaller two may represent splice variants. These findings suggest that multiple rapsyn-like molecules are involved in clustering the distinct AChRs expressed by muscle fibers and neurons.
In 1918 the Norwegian neurologist Raeder was the first to describe a syndrome consisting of unilateral headache, facial pain and a Horner's syndrome which is incomplete; this syndrome is accompanied by multiple parasellar cranial nerve involvement. This syndrome was named "Raeder's syndrome" or paratrigeminal syndrome. A survey of the literature concerning "Raeder's syndrome" is given; there a two varieties of Raeder's syndrome, the migrainous or reflex type and the symptomatic type with multiple parasellar cranial nerve involvement. The first variety has a close relationship to cluster headache and to the so-called pericarotid syndrome. A case of an own patient suffering from multiple sclerosis and a migrainous type of Raeder's syndrome is described, assuming that his basic disease MS is independent of his Raeder's syndrome.
Molecular cloning has revealed a multiplicity of neurotransmitter receptor isoforms with different subunit compositions. Additionally, there is growing evidence that such receptors are clustered at postsynaptic sites of neurons. Thus, the questions arise whether individual neurons express different receptor isoforms and, if so, whether different isoforms are present within the same cluster or are aggregated at distinct postsynaptic sites. We have studied with immunofluorescence methods and antibodies that recognize specific subunits the distribution of glycine and GABA(A) receptors in mammalian retinae. Alpha ganglion cells were injected in rat or rabbit retinae with a fluorescent marker and then immunostained for receptor localization. Clusters of glycine receptors and clusters of the alpha1, and alpha2, alpha3, and gamma2 subunits of the GABA(A) receptor were found on the somatodendritic membranes of Alpha ganglion cells. Double-immunofluorescence experiments with different combinations of the subunit-specific antibodies showed that the alpha1, alpha2, and alpha3 subunits of the GABA(A) receptor are not colocalized within the same clusters. These results indicate that an individual neuron can express several isoforms of the GABA(A) receptor and that these different isoforms are aggregated at distinct postsynaptic sites. This suggests individual sorting mechanisms of GABAa receptors at GABAergic synapses.
The plasma phospholipid transfer protein (PLTP) belongs to the lipid transfer/lipopolysaccharide binding protein (LT/LBP) family, together with the cholesteryl ester transfer protein, the lipopolysaccharide binding protein (LBP) and the bactericidal permeability increasing protein (BPI). In the present study, we used the crystallographic data available for BPI to build a three-dimensional model for PLTP. Multiple sequence alignment suggested that, in PLTP, a cluster of hydrophobic residues substitutes for a cluster of positively charged residues found on the surface of LBP and BPI, which is critical for interaction with lipopolysaccharides. According to the PLTP model, these hydrophobic residues are situated on an exposed hydrophobic patch at the N-terminal tip of the molecule. To assess the role of this hydrophobic cluster for the functional activity of PLTP, single point alanine mutants were engineered. Phospholipid transfer from liposomes to high density lipoprotein (HDL) by the W91A, F92A, and F93A PLTP mutants was drastically reduced, whereas their transfer activity toward very low density lipoprotein and low density lipoprotein did not change. The HDL size conversion activity of the mutants was reduced to the same extent as the PLTP transfer activity toward HDL. Based on these results, we propose that a functional solvent-exposed hydrophobic cluster in the PLTP molecule specifically contributes to the PLTP transfer activity on HDL substrates.
Cancer patients may experience multiple concurrent symptoms caused by the cancer, cancer treatment, or their combination. The complex relationships between and among symptoms, as well as the clinical antecedents and consequences, have not been well described. This paper examines the literature on cancer symptom clusters focusing on the conceptualization, design, measurement, and analytic issues. The investigation of symptom clustering is in an early stage of testing empirically whether the characteristics defined in the conceptual definition can be observed in cancer patients. Decisions related to study design include sample selection, the timing of symptom measures, and the characteristics of symptom interventions. For self-report symptom measures, decisions include symptom dimensions to evaluate, methods of scaling symptoms, and the time frame of responses. Analytic decisions may focus on the application of factor analysis, cluster analysis, and path models. Studying the complex symptoms of oncology patients will yield increased understanding of the patterns of association, interaction, and synergy of symptoms that produce specific clinical outcomes. It will also provide a scientific basis and new directions for clinical assessment and intervention.
Research over the past 20 years has shown, with the help of molecular markers, that the population genetics and distribution patterns of freshwater invertebrates in North America are often more complex than was previously believed. Here we extend this research to an, as yet, unstudied but widespread and common group, the freshwater bryozoans. Colonies of the bryozoan Cristatella mucedo were collected from a number of lakes across central North America, and were characterized genetically by analysis of microsatellite loci and mitochondrial DNA (mtDNA) cytochrome b sequences. The microsatellites illustrate a pattern of generally diverse and highly differentiated populations that contain little evidence of recent gene flow. The mtDNA sequences yielded highly variable levels of divergence, ranging from 0.0 to 8.8% within populations, and 0.0 to 9.8% among populations. The multiple divergent mtDNA lineages within populations provide evidence for repeated colonization events. The lack of clustering of haplotypes by site suggests that there has been widespread dispersal of multiple genetic lineages since the last ice age. While some of the haplotype lineages may have evolved in disjunct glacial refugia, the maximum levels of divergence predate the time since the last glacial-interglacial cycles. It is likely that multiple factors including vicariance events, patterns of dispersal, localized extinction, and an unusual life history, explain the unique phylogeographic patterns evident today in populations of C. mucedo.
Biological membranes contain a high density of protein molecules, many of which associate into two-dimensional microdomains with important physiological functions. We have used Monte Carlo simulations to examine the self-association of idealized protein species in two dimensions. The proteins have defined bond strengths and bond angles, allowing us to estimate the size and composition of the aggregates they produce at equilibrium. With a single species of protein, the extent of cluster formation and the sizes of individual clusters both increase in non-linear fashion, showing a "phase change" with protein concentration and bond strength. With multiple co-aggregating proteins, we find that the extent of cluster formation also depends on the relative proportions of participating species. For some lattice geometries, a stoichiometric excess of particular species depresses cluster formation and moreover distorts the composition of clusters that do form. Our results suggest that the self-assembly of microdomains might require a critical level of subunits and that for optimal co-aggregation, proteins should be present in the membrane in the correct stoichiometric ratios.
This study extends the application of the Sonority Sequencing Principle, as reported in J. A. Gierut (1999), to acquisition of word-initial 3-element clusters by children with functional phonological delays (ages in years;months: 3;4 to 6;3). The representational structure of 3-element clusters is complex and unusual because it consists of an s-adjunct plus a branching onset, which respectively violate and conform to the Sonority Sequencing Principle. Given the representational asymmetry, it is unclear how children might learn these clusters in treatment or whether such treatment may even be effective. Results of a single-subject staggered multiple-baseline experiment demonstrated that children learned the treated 3-element cluster in treatment but showed no further generalization to similar types of (asymmetric) onsets. Treatment of 3-element clusters did, however, result in widespread generalization to untreated singletons, including affricates. Moreover, there was differential generalization to untreated 2-element clusters, with individual differences being traced to the composition of children's singleton inventories. Theoretically, the results suggest a segmental-syllabic interface that holds predictive potential for determining the effectiveness and effects of clinical treatment as based on the notion of linguistic complexity.
In this article a procedure is derived to obtain a performance gain for molecular dynamics (MD) simulations on existing parallel clusters. Parallel clusters use a wide array of interconnection technologies to connect multiple processors together, often at different speeds, such as multiple processor computers and networking. It is demonstrated how to configure existing programs for MD simulations to efficiently handle collective communication on parallel clusters with processor interconnections of different speeds.
Results from a study on health-related lifestyles of Munich citizens aged between 55 and 65 were compared with an independent data set from Bern. Cluster analysis identified eight health-related behavior patterns in the Munich sample which were also found in the Bern sample. Predictors of health-relevant behavior patterns were analysed via multiple logistic regressions. Most results showed different effects on cluster membership between the two samples. Gender, professional status, social support from friends, and paying attention to regular meals were identified as predictor variables in both samples. Other variables identified as predictors occurred either in only one of the two samples or differed in the direction of their effect.