Examination and measurement of coping among adolescents with spinal cord injury.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: To describe coping strategy use in adolescents with spinal cord injury (SCI), to explore the underlying factor structure of a measure of coping among adolescents with SCI and to assess relationships between coping and psychosocial outcomes. SETTING: Multiple pediatric SCI centers in the United States. METHODS: One hundred and eighty-two participants aged 13-17 years who experienced an SCI completed measures including the Kidcope, Children's Depression Inventory, Revised Children's Manifest Anxiety Scale and the Pediatric Quality of Life Inventory. RESULTS: Participants reported that cognitive restructuring and resignation are the most used coping strategies, whereas social support, emotional regulation (calming) and cognitive restructuring are the most effective coping strategies. An exploratory factor analysis revealed that a three-factor solution provided the most parsimonious model for the relationships between the different coping strategies. However, only one of the three factors had acceptable internal consistency. This factor comprised escape-oriented coping strategies or an avoidant approach to coping with the sequelae of SCI. After controlling for demographic/injury-related factors, higher scores on the escape-oriented factor were associated with the lower quality of life and higher levels of depression and anxiety symptomatology. CONCLUSION: Escape-oriented coping is associated with maladaptive psychosocial outcomes in adolescents with SCI. These adolescents report that active coping strategies are most effective in reducing SCI-related distress. Coping strategy use may mediate psychosocial outcomes in adolescents with SCI and represent an intervention target in adolescents who overly rely on escape-oriented coping.

Superconductivity of alpha-uranium and the role of 5f electrons.

A much sharper and lower superconducting transition has been found for alpha-uranium than any reported previously. A model that explains the unusual volume dependence of alpha-uranium below 43 degrees K and the unusual pressure dependence of its superconducting transition temperature is presented.

The WD repeat: a common architecture for diverse functions.

Our knowledge of the large family of proteins that contain the WD repeat continues to accumulate. The WD-repeat proteins are found in all eukaryotes and are implicated in a wide variety of crucial functions. The solution of the three-dimensional structure of one WD-repeat protein and the assumption that the structure will be common to all members of this family has allowed subfamilies of WD-repeat proteins to be defined on the basis of probable surface similarity. Proteins that have very similar surfaces are likely to have common binding partners and similar functions.

Transcription unit conservation in the three domains of life: a perspective from Escherichia coli.

Here we address the question of the degree to which genes within experimentally characterized operons in one organism (Escherichia coli) are conserved in other genomes. We found that two genes adjacent within an operon are more likely both to have an ortholog in other organisms, regardless of relative position, than genes adjacent on the same strand but in two different transcription units. They are also more likely to occur next to, or fused to, one another in other genomes. Genes frequently conserved adjacent to each other, especially among evolutionarily distant species, must be part of the same transcription unit in most of them.

Global optimum protein threading with gapped alignment and empirical pair score functions.

We describe a branch-and-bound search algorithm for finding the exact global optimum gapped sequence-structure alignment ("threading") between a protein sequence and a protein core or structural model, using an arbitrary amino acid pair score function (e.g. contact potentials, knowledge-based potentials, potentials of mean force, etc.). The search method imposes minimal conditions on how structural environments are defined or the form of the score function, and allows arbitrary sequence-specific functions for scoring loops and active site residues. Consequently the search method can be used with many different score functions and threading methodologies; this paper illustrates five from the literature. On a desktop workstation running LISP, we have found the global optimum protein sequence-structure alignment in NP-hard search spaces as large as 9.6 x 10(31), at rates ranging as high as 6.8 x 10(28) equivalent threadings per second (most of which are pruned before they ever are examined explicitly). Continuing the procedure past the global optimum enumerates successive candidate threadings in monotonically increasing score order. We give efficient algorithms for search space size, uniform random sampling, segment placement probabilities, mean, standard deviation and partition function. The method should prove useful for structure prediction, as well as for critical evaluation of new pair score functions.

Visible volume: a robust measure for protein structure characterization.

We propose a new characterization of protein structure based on the natural tetrahedral geometry of the beta-carbon and a new geometric measure of structural similarity, called visible volume. In our model, the side-chains are replaced by an ideal tetrahedron, the orientation of which is fixed with respect to the backbone and corresponds to the preferred rotamer directions. Visible volume is a measure of the non-occluded empty space surrounding each residue position after the side-chains have been removed. It is a robust, parameter-free, locally computed quantity that accounts for many of the spatial constraints that are of relevance to the corresponding position in the native structure. When computing visible volume, we ignore the nature of both the residue observed at each side and the ones surrounding it. We focus instead on the space that, together, these residues could occupy. By doing so, we are able to quantify a new kind of invariance beyond the apparent variations within protein families, namely, the conservation of the physical space available at structurally equivalent positions for side-chain packing. Corresponding positions in native structures are likely to be of interest in protein structure prediction, protein design, and homology modeling. Visible volume is related to the degree of exposure of a residue position and to the actual rotamers in native proteins. Here, we discuss the properties of this new measure, namely, its robustness with respect to both crystallographic uncertainties and naturally occurring variations in atomic coordinates, and the remarkable fact that it is essentially independent of the choice of the parameters used in calculating it. We also show how visible volume can be used to align protein structures, to identify structurally equivalent positions that are conserved in a family of proteins, and to single out positions in a protein that are likely to be of biological interest. These properties qualify visible volume as a powerful tool in a variety of applications, from the detailed analysis of protein structure to homology modeling, protein structural alignment, and the definition of better scoring functions for threading purposes.

Open lung biopsy in immunocompromised patients.

From January 1978 through December 1980, ninety-five immunocompromised patients underwent diagnostic open lung biopsy (OLB) at the Mayo Clinic, Rochester, Minn. A specific causative diagnosis was made in 77 patients (81%); 12 patients (13%) had more than one specific causative diagnosis. Of the 77 patients with a specific causative diagnosis, 52 patients (68%) had infections, 19 patients (24%) had malignant pulmonary disease, 12 patients (15%) had cytotoxic lung disease, ten patients (13%) had interstitial fibrosis (not related to cytotoxins), and one patient (1%) had vasculitis. In 36 (47%) of the 77 patients with a specific causative diagnosis, the diagnosis was made, by frozen sections or stains, within three hours of OLB. In 35 additional patients (45%), the diagnosis was established within 24 hours. Twelve patients (13%) had minor complications of OLB; no deaths were attributed to the OLB procedure.

Multiple domain protein diagnostic patterns.

We have implemented an iterative algorithm for the identification of diagnostic patterns from sets of multiple-domain proteins, where domains need not be common to all the proteins in the defining set. Our algorithm was applied to sequences gathered using a variety of methods, including BLAST, common keywords, and common E.C. numbers. In all cases, useful diagnostic patterns were obtained, possessing both high sensitivity and specificity. The patterns were found to correlate in several cases with both functional and structural domains. Patterns generated from a large number of sequence families were analyzed for probable multiple-domain structure.

A homology identification method that combines protein sequence and structure information.

A new method is presented for identifying distantly related homologous proteins that are unrecognizable by conventional sequence comparison methods. The method combines information about functionally conserved sequence patterns with information about structure context. This information is encoded in stochastic discrete state-space models (DSMs) that comprise a new family of hidden Markov models. The new models are called sequence-pattern-embedded DSMs (pDSMs). This method can identify distantly related protein family members with a high sensitivity and specificity. The method is illustrated with trypsin-like serine proteases and globins. The strategy for building pDSMs is presented. The method has been validated using carefully constructed positive and negative control sets. In addition to the ability to recognize remote homologs, pDSM sequence analysis predicts secondary structures with higher sensitivity, specificity, and Q3 accuracy than DSM analysis, which omits information about conserved sequence patterns. The identification of trypsin-like serine proteases in new genomes is discussed.

Thirty-plus functional families from a single motif.

It is now possible to identify over 30 functional subfamilies among the WD-repeat-containing proteins found in the completed genomes. The majority of these subfamilies have at least one member for which experimental data allow assignment to a cellular pathway or process. Half of the 63 WD-repeat-containing proteins in Saccharomyces cerevisiae, half of the 70 in Caenorhabditis elegans, and a third of the 100 plus predicted in Drosophila can be assigned to 23 of these functional subfamilies. Perhaps indicative of the future, 33 WD-repeat-containing proteins from the partial genome of Arabidopsis thaliana can now be assigned to 18 of these subfamilies. These assignments have been made possible by combining traditional sequence similarity with an implied common beta propeller structural context to obtain measures of protein-protein surface similarity. The beta propeller structural context is represented in the form of a Hidden Markov Model. The procedure is completely automated.

Structural analysis based on state-space modeling.

A new method has been developed to compute the probability that each amino acid in a protein sequence is in a particular secondary structural element. Each of these probabilities is computed using the entire sequence and a set of predefined structural class models. This set of structural classes is patterned after Jane Richardson's taxonomy for the domains of globular proteins. For each structural class considered, a mathematical model is constructed to represent constraints on the pattern of secondary structural elements characteristic of that class. These are stochastic models having discrete state spaces (referred to as hidden Markov models by researchers in signal processing and automatic speech recognition). Each model is a mathematical generator of amino acid sequences; the sequence under consideration is modeled as having been generated by one model in the set of candidates. The probability that each model generated the given sequence is computed using a filtering algorithm. The protein is then classified as belonging to the structural class having the most probable model. The secondary structure of the sequence is then analyzed using a "smoothing" algorithm that is optimal for that structural class model. For each residue position in the sequence, the smoother computes the probability that the residue is contained within each of the defined secondary structural elements of the model. This method has two important advantages: (1) the probability of each residue being in each of the modeled secondary structural elements is computed using the totality of the amino acid sequence, and (2) these probabilities are consistent with prior knowledge of realizable domain folds as encoded in each model. As an example of the method's utility, we present its application to flavodoxin, a prototypical alpha/beta protein having a central beta-sheet, and to thioredoxin, which belongs to a similar structural class but shares no significant sequence similarity.

A noncanonical WD-repeat protein from the cyanobacterium Synechocystis PCC6803: structural and functional study.

SYNECHOCYSTIS: PCC6803 possesses several open reading frames encoding putative WD-repeat proteins. One, the Hat protein, is involved in the control of a high-affinity transport system for inorganic carbon that is active when the cells are grown under a limiting concentration of this carbon substrate. The protein is composed of two major domains separated by a hydrophobic linker region of 20 amino acid residues. The N-terminal domain of Hat has no homolog in standard databases and does not display any particular structural features. Eleven WD repeats have been identified in the C-terminal moiety. The region encompassing the four terminal WD repeats is essential for growth under a limiting inorganic carbon regime. The region encompassing the two most terminal WD repeats is required for the activity of the high-affinity transport system. However, because the Hat protein is located in the thylakoids, it should not be itself an element of the transport system. The structural organization of the WD-containing domain of Hat was modeled from the crystal structure of the G protein beta subunit (with seven WD repeats) and of hemopexin (a structural analog with four blades). Functional and structural data argue in favor of an organization of the Hat WD moiety in two subdomains of seven and four WD repeats. The C-terminal 4-mer subdomain might interact with another, yet unknown, protein/peptide. This interaction could be essential in modulating the stability of the 4-mer structure and, thus, the accessibility of this subdomain, or at least of the region encompassing the last two WD repeats.

The binding domain structure of retinoblastoma-binding proteins.

The retinoblastoma gene product (Rb), a cellular growth suppressor, complexes with viral and cellular proteins that contain a specific binding domain incorporating three invariant residues: Leu-X-Cys-X-Glu, where X denotes a nonconserved residue. Hydrophobic and electrostatic properties are strongly conserved in this segment even though the nonconserved amino acids vary considerably from one Rb-binding protein to another. In this report, we present a diagnostic computer pattern for a high-affinity Rb-binding domain featuring the three conserved residues as well as the conserved physico-chemical properties. Although the pattern encompasses only 10 residues (with only 4 of these explicitly defined), it exhibits 100% sensitivity and 99.95% specificity in database searches. This implies that a certain pattern of structural and physico-chemical properties encoded by this short sequence is sufficient to govern specific Rb binding. We also present evidence that the secondary structural conformation through this region is important for effective Rb binding.

Mapping the order of DNA restriction fragments.

A straightforward method was designed for mapping the order of DNA restriction fragments obtained by a double and two single digestions, without the necessity of using a computer or a radioactive label. All possible solutions compatible with a pre-set level of error in the determination of sequence lengths are obtained. The primary assumptions are given, and the appropriate modifications of the algorithm are presented as a function of any assumptions one is unable (or unwilling) to make. Use of the method in connection with end-labeled fragments is also described.

Antibodies to varicella zoster in cerebrospinal fluid.

The neurologic complications of varicella-zoster (VZ) virus infections are manifested as zoster with or without CNS involvement, encephalomyelitis, or ocular involvement. Usually the association of VZ virus in these conditions has been determined by finding VZ antibodies in the serum. In a few instances, VZ antibodies have been detected in the CSF. We report two cases of VZ virus infection followed by neurologic complications involving the CNS in which VZ antibodies were present in the CSF. These two cases underscore the need and value of determining the presence of VZ antibodies in the CSF in certain instances.

Aneurysmal subarachnoid hemorrhage and viral infection. Lack of association.

We tested the hypothesis that intracranial aneurysm develops because of viral infection that produces arterial damage, and that aneurysmal rupture is related to viral infection. The following viral agents were studied: influenza A, influenza B, and respiratory syncytial viral titers, by the indirect immunofluorescence method, in 29 patients and 29 controls; herpes simplex virus titers, by immunofluorescence, in 31 patients and 31 controls; rubella viral titers (Rubazyme test), in 34 patients and 34 controls; and influenza A and B viral titers, by the complement fixation method, in 54 patients and 54 controls. Patients were selected on the basis of documented aneurysmal subarachnoid hemorrhage. Analysis, with derivation of the chi 2 method, to compare titer levels in patients and controls for each specific viral titer did not reveal positive correlations between the viral titers and aneurysmal subarachnoid hemorrhage.

Echovirus polymyositis in patients with hypogammaglobulinemia. Failure of high-dose intravenous gammaglobulin therapy and review of the literature.

A 29-year-old man with X-linked hypogammaglobulinemia was treated with prednisone and methotrexate for polymyositis. Subsequently, it was established that disseminated echovirus 11 infection was causing the polymyositis. Treatment with large doses of intravenous gammaglobulin did not result in improvement. Viral cultures of blood, urine, and cerebrospinal fluid gave positive results throughout treatment and at postmortem examination. Multiple cultures of other tissues, including muscle, also gave positive results at postmortem examination. Severity of infection and treatment with prednisone and methotrexate prior to referral, diagnosis, and gammaglobulin treatment may explain the lack of response. A review of 23 cases of echovirus infection in patients with hypogammaglobulinemia revealed that the infection in these patients may cause meningoencephalitis or a polymyositis-like syndrome or both. Treatment with immunosuppressive agents, the standard therapy for polymyositis, is contraindicated, and intravenous or intraventricular gammaglobulin or both may be helpful.

Positional statistical significance in sequence alignment.

Beginning with the concept of near-optimal sequence alignments, we can assign a probability that each element in one sequence is paired in an alignment with each element in another sequence. This involves a sum over the set of all possible pairwise alignments. The method employs a designed hidden Markov model (HMM) and the rigorous forward and forward-backward algorithms of Rabiner. The approach can use any standard sequence-element-to-element probabilistic similarity measures and affine gap penalty functions. This allows the positional alignment statistical significance to be obtained as a function of such variables. A measure of the probabilistic relationship between any single sequence and a set of sequences can be directly obtained. In addition, the employed HMM with the Viterbi algorithm provides a simple link to the standard dynamic programming optimal alignment algorithms.

A biologically consistent model for comparing molecular phylogenies.

In the framework of the problem of combining different gene trees into a unique species phylogeny, a model for duplication/speciation/loss events along the evolutionary tree is introduced. The model is employed for embedding a phylogeny tree into another one via the so-called duplication/speciation principle requiring that the gene duplicated evolves in such a way that any of the contemporary species involved bears only one of the gene copies diverged. The number of biologically meaningful elements in the embedding result (duplications, losses, information gaps) is considered a (asymmetric) dissimilarity measure between the trees. The model duplication concept is compared with that one defined previously in terms of a mapping procedure for the trees. A graph-theoretic reformulation of the measure is derived.

Performance of threading scoring functions designed using new optimization method.

We present a new procedure for optimization of a threading scoring function. A scoring function is usually formulated in terms of the structural environment states that describe the protein fold model. We propose a method for the optimal selection of those structural environment states that naturally follows from the probabilistic description of the threading problem and is done prior to threading experiments. We demonstrate the selection of the optimal structural environment states for the solvent exposure of the amino acid position, and present the results of threading experiments performed using scoring functions designed with and without the optimization of the structural environment states. These results confirm that the optimal scoring function predicts the sequence-to-structure alignments most accurately. Threading experiments performed with 15 optimally designed scoring functions show that the correlation coefficient between the information content of the amino acid distribution that determines the scoring function and the accuracy of the optimal sequence-to-structure alignment is 0.94.