Biomedical subjects

C A Orengo

Publications and source records attributed to C A Orengo.

At least 19 recordsLinked to original sources

PubMed2001

Evolution of function in protein superfamilies, from a structural perspective.

The recent growth in protein databases has revealed the functional diversity of many protein superfamilies. We have assessed the functional variation of homologous enzyme superfamilies containing two or more enzymes, as defined by the CATH protein structure classification, by way of the Enzyme Commission (EC) scheme. Combining sequence and structure information to identify relatives, the majority of superfamilies display variation in enzyme function, with 25 % of superfamilies in the PDB having members of different enzyme types. We determined the extent of functional similarity at different levels of sequence identity for 486,000 homologous pairs (enzyme/enzyme and enzyme/non-enzyme), with structural and sequence relatives included. For single and multi-domain proteins, variation in EC number is rare above 40 % sequence identity, and above 30 %, the first three digits may be predicted with an accuracy of at least 90 %. For more distantly related proteins sharing less than 30 % sequence identity, functional variation is significant, and below this threshold, structural data are essential for understanding the molecular basis of observed functional differences. To explore the mechanisms for generating functional diversity during evolution, we have studied in detail 31 diverse structural enzyme superfamilies for which structural data are available. A large number of variations and peculiarities are observed, at the atomic level through to gross structural rearrangements. Almost all superfamilies exhibit functional diversity generated by local sequence variation and domain shuffling. Commonly, substrate specificity is diverse across a superfamily, whilst the reaction chemistry is maintained. In many superfamilies, the position of catalytic residues may vary despite playing equivalent functional roles in related proteins. The implications of functional diversity within supefamilies for the structural genomics projects are discussed. More detailed information on these superfamilies is available at http://www.biochem.ucl.ac.uk/bsm/FAM-EC/.

Binding Sites↗

PubMed2001

VIDA: a virus database system for the organization of animal virus genome open reading frames.

VIDA is a new virus database that organizes open reading frames (ORFs) from partial and complete genomic sequences from animal viruses. Currently VIDA includes all sequences from GenBank for Herpesviridae, Coronaviridae and Arteriviridae. The ORFs are organized into homologous protein families, which are identified on the basis of sequence similarity relationships. Conserved sequence regions of potential functional importance are identified and can be retrieved as sequence alignments. We use a controlled taxonomical and functional classification for all the proteins and protein families in the database. When available, protein structures that are related to the families have also been included. The database is available for online search and sequence information retrieval at http://www.biochem.ucl.ac.uk/bsm/virus_database/ VIDA.html.

Animals↗

PubMed2001

A rapid classification protocol for the CATH Domain Database to support structural genomics.

In order to support the structural genomic initiatives, both by rapidly classifying newly determined structures and by suggesting suitable targets for structure determination, we have recently developed several new protocols for classifying structures in the CATH domain database (http://www.biochem.ucl.ac.uk/bsm/cath). These aim to increase the speed of classification of new structures using fast algorithms for structure comparison (GRATH) and to improve the sensitivity in recognising distant structural relatives by incorporating sequence information from relatives in the genomes (DomainFinder). In order to ensure the integrity of the database given the expected increase in data, the CATH Protein Family Database (CATH-PFDB), which currently includes 25,320 structural domains and a further 160,000 sequence relatives has now been installed in a relational ORACLE database. This was essential for developing more rigorous validation procedures and for allowing efficient querying of the database, particularly for genome analysis. The associated Dictionary of Homologous Superfamilies [Bray,J.E., Todd,A.E., Pearl,F.M.G., Thornton,J.M. and Orengo,C.A. (2000) Protein Eng., 13, 153-165], which provides multiple structural alignments and functional information to assist in assigning new relatives, has also been expanded recently and now includes information for 903 homologous superfamilies. In order to improve coverage of known structures, preliminary classification levels are now provided for new structures at interim stages in the classification protocol. Since a large proportion of new structures can be rapidly classified using profile-based sequence analysis [e.g. PSI-BLAST: Altschul,S.F., Madden,T.L., Schaffer,A.A., Zhang,J., Zhang,Z., Miller,W. and Lipman,D.J. (1997) Nucleic Acids Res., 25, 3389-3402], this provides preliminary classification for easily recognisable homologues, which in the latest release of CATH (version 1.7) represented nearly three-quarters of the non-identical structures.

Computational Biology↗

PubMed2001

Tolerability and effectiveness of atypical antipsychotics in male geriatric inpatients.

The atypical antipsychotics are gradually becoming the mainstay of treatment for psychosis in the elderly. The present study examines the effectiveness and tolerability of risperidone and olanzapine treatment in 34 matched male patients admitted to a VA Medical Center geriatric inpatient unit. The Positive and Negative Syndrome Scale for Schizophrenia (PANSS), the Cohen-Mansfield Agitation Inventory (CMAI), the Rating Scale for Side-Effects, the Extra-Pyramidal Rating Scale, and the Mini-Mental State Examination were administered at admission and discharge. T-tests at admission and discharge across groups indicate that the patients as a whole were performing significantly better following their stay on the CMAI (t(30)=4.31, p=0.000), the GAF (t(31)=9.73, p=0.000), the PANSS total score (t(29)=3.82, p=0.001), and the positive symptom portion of the PANSS (t(28)=4.29, p=0.000). No significant differences were detected between the two groups with regard to length of hospitalization, or reduction in scores on the PANSS, or CMAI, however the daily cost of risperidone was 1/3 as much as olanzapine (p=0.00). The two treatments were comparable in the elderly men evaluated in this study.

Aged↗

PubMed2001

Contribution of PTSD/POW history to behavioral disturbances in dementia.

As many World War II and Korean Conflict veterans suffering from posttraumatic stress disorder (PTSD) grow older, increasing numbers will be diagnosed with dementia. We retrospectively analyzed patients with dementia, comparing the behavioral disturbances of those with PTSD to those without PTSD. We hypothesized that due to the additive effect of the neurobiological and behavioral changes associated with PTSD and dementia, the dementia with PTSD group would show more agitation and disinhibition than the dementia without PTSD group. Sixteen patients with diagnoses of dementia and PTSD were matched on age and Mini-Mental States Examination (MMSE) scores to 16 patients with dementia without PTSD. Demographic characteristics, co-morbid diagnoses, global Assessment of Functioning (GAF), Cohen-Mansfield Agitation Inventory (CMAI), and paranoid items of Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale for Schizophrenia (PANSS) were assessed. The patients with diagnoses of dementia with PTSD did not differ significantly in their clinical presentation, hospital course, and condition at discharge from patients with dementia without PTSD. Chi-square analysis showed that significantly more subjects in the PTSD group were prescribed anti-depressants compared to the non-PTSD group. Interestingly, within the PTSD group, the subgroup of patients who were former prisoners of war had a significantly higher mean score for paranoia and significantly less verbal agitation. This pilot study reveals that a diagnosis of PTSD alone is not sufficient to influence behavior in veterans with dementia; however, we also present provocative results that patients with more severe trauma (POW) do have changes in their behavior.

Aged↗

PubMed2001

One session cognitive behavioural therapy for elderly patients with chronic obstructive pulmonary disease.

BACKGROUND: We hypothesized that compared to an educational intervention, a single 2 h session of cognitive behavioural therapy (CBT), with 6-week follow-up, would reduce anxiety and depression, improve physical and mental functioning, and lead to a better quality of life and greater satisfaction with treatment in older patients with chronic obstructive pulmonary disease (COPD). METHODS: Fifty-six subjects were recruited from a large, urban, academically affiliated Veterans Affairs (VA) Hospital, a non-profit private hospital, and a local newspaper, for a single blind randomized controlled clinical trial. One 2 h session of group CBT was designed to reduce symptoms of anxiety, with specific components including relaxation training, cognitive interventions, and graduated practice, followed by homework and weekly calls for 6 weeks. This was compared to a group that received 2 h of COPD education, followed by weekly calls. Pre- and post-intervention subjects in both groups were administered SF-36, Geriatric Depression Scale, Beck Anxiety Inventory, 6 min walk test, and the FEV-1. Following the intervention, both groups completed the Client Satisfaction Questionnaire. RESULTS: When compared with a group that received education about COPD, 2 h CBT group showed decreased depression and anxiety. Contrary to our hypothesis, despite the decrease in depression and anxiety, there was no change in the physical functioning of the patients. CONCLUSIONS: Twenty to 40% of patients with COPD have high levels of anxiety and depression. Our study finds that as little as 2 h of CBT administered in a group setting is able to reduce these anxious and depressive symptoms.

Aged↗

PubMed2001

Genomewide function conservation and phylogeny in the Herpesviridae.

The Herpesviridae are a large group of well-characterized double-stranded DNA viruses for which many complete genome sequences have been determined. We have extracted protein sequences from all predicted open reading frames of 19 herpesvirus genomes. Sequence comparison and protein sequence clustering methods have been used to construct herpesvirus protein homologous families. This resulted in 1692 proteins being clustered into 243 multiprotein families and 196 singleton proteins. Predicted functions were assigned to each homologous family based on genome annotation and published data and each family classified into seven broad functional groups. Phylogenetic profiles were constructed for each herpesvirus from the homologous protein families and used to determine conserved functions and genomewide phylogenetic trees. These trees agreed with molecular-sequence-derived trees and allowed greater insight into the phylogeny of ungulate and murine gammaherpesviruses.

Animals↗

PubMed2001

Outcomes of decreased length of hospital stay among geriatric patients with dementia.

This study examined the outcomes associated with shortening hospital stays for geriatric inpatients with dementia at a Veterans Administration medical center. Thirty-three patients who were admitted after January 1997, when the hospital decided to reduce patients' lengths of stay, were matched with 33 patients who were admitted before January 1997. Despite significant differences in lengths of stay, no differences were found between the groups on measures of agitation or overall functioning. Despite significantly shorter stays since January 1997, the results of our study indicate that the cognitive and emotional status of patients discharged since that time are equivalent to those of patients discharged after longer hospital stays.

Aged↗

PubMed2000

Assigning genomic sequences to CATH.

We report the latest release (version 1.6) of the CATH protein domains database (http://www.biochem.ucl. ac.uk/bsm/cath ). This is a hierarchical classification of 18 577 domains into evolutionary families and structural groupings. We have identified 1028 homo-logous superfamilies in which the proteins have both structural, and sequence or functional similarity. These can be further clustered into 672 fold groups and 35 distinct architectures. Recent developments of the database include the generation of 3D templates for recognising structural relatives in each fold group, which has led to significant improvements in the speed and accuracy of updating the database and also means that less manual validation is required. We also report the establishment of the CATH-PFDB (Protein Family Database), which associates 1D sequences with the 3D homologous superfamilies. Sequences showing identifiable homology to entries in CATH have been extracted from GenBank using PSI-BLAST. A CATH-PSIBLAST server has been established, which allows you to scan a new sequence against the database. The CATH Dictionary of Homologous Superfamilies (DHS), which contains validated multiple structural alignments annotated with consensus functional information for evolutionary protein superfamilies, has been updated to include annotations associated with sequence relatives identified in GenBank. The DHS is a powerful tool for considering the variation of functional properties within a given CATH superfamily and in deciding what functional properties may be reliably inherited by a newly identified relative.

Amino Acid Sequence↗

PubMed2000

From structure to function: approaches and limitations.

This review presents a summary of current approaches to extract functional information from structural data on proteins and their complexes. While structural homologs may reveal possible biochemical functions (which may be hidden at the sequence level), elucidating the exact biological role of a protein in vivo will only be possible by including other results, such as data on expression and localization.

Binding Sites↗

PubMed2000

Using the CATH domain database to assign structures and functions to the genome sequences.

The CATH database of protein structures contains approximately 18000 domains organized according to their (C)lass, (A)rchitecture, (T)opology and (H)omologous superfamily. Relationships between evolutionary related structures (homologues) within the database have been used to test the sensitivity of various sequence search methods in order to identify relatives in Genbank and other sequence databases. Subsequent application of the most sensitive and efficient algorithms, gapped blast and the profile based method, Position Specific Iterated Basic Local Alignment Tool (PSI-BLAST), could be used to assign structural data to between 22 and 36 % of microbial genomes in order to improve functional annotation and enhance understanding of biological mechanism. However, on a cautionary note, an analysis of functional conservation within fold groups and homologous superfamilies in the CATH database, revealed that whilst function was conserved in nearly 55% of enzyme families, function had diverged considerably, in some highly populated families. In these families, functional properties should be inherited far more cautiously and the probable effects of substitutions in key functional residues carefully assessed.

Algorithms↗

PubMed2000

The CATH Dictionary of Homologous Superfamilies (DHS): a consensus approach for identifying distant structural homologues.

A consensus approach has been developed for identifying distant structural homologues. This is based on the CATH Dictionary of Homologous Superfamilies (DHS), a database of validated multiple structural alignments annotated with consensus functional information for evolutionary protein superfamilies (URL: http://www. biochem.ucl.ac.uk/bsm/dhs). Multiple structural alignments have been generated for 362 well-populated superfamilies in the CATH structural domain database and annotated with secondary structure, physicochemical properties, functional sequence patterns and protein-ligand interaction data. Consensus functional information for each superfamily includes descriptions and keywords extracted from SWISS-PROT and the ENZYME database. The Dictionary provides a powerful resource to validate, examine and visualize key structural and functional features of each homologous superfamily. The value of the DHS, for assessing functional variability and identifying distant evolutionary relationships, is illustrated using the pyridoxal-5'-phosphate (PLP) binding aspartate aminotransferase superfamily. The DHS also provides a tool for examining sequence-structure relationships for proteins within each fold group.

Amino Acid Sequence↗

PubMed2000

Guardianship applications for elderly patients: why do they fail?

Variables associated with successful completion of guardianship applications for elderly patients were identified. Thirteen patients for whom applications were approved were compared with 26 whose applications did not reach the court. Patients for whom the process was successful scored significantly higher on the anergia-depression subscale of the Brief Psychiatric Rating Scale and had significantly more medical conditions in the past year. A survey of next of kin revealed that the process had a much better chance of success when the unit social worker made the guardianship recommendation and when family members were given more information about the taxing and time-consuming process of obtaining guardianship.

Aged↗

PubMed2000

Nonalcohol-related use disorders in geropsychiatric patients.

The authors determined the prevalence and demographic features of drug use disorders in a database of 565 veteran geropsychiatric inpatients. Twenty-four patients (4%) were diagnosed with nonalcoholic substance use disorders, including 18 (3%) with prescription drug use disorders and 6 (1%) with illegal drug use disorders. The patients diagnosed with prescription drug use disorders were predominantly Caucasian, whereas those diagnosed with illegal substance use disorders were predominantly African American. No other significant demographic differences were noted. Nonalcohol substance use disorders represent an unappreciated problem in psychiatrically hospitalized older adults, with illegal substance use disorders making up a larger than expected proportion of this group.

Adult↗

PubMed2000

Behavioral disturbances in geropsychiatric inpatients across dementia types.

The objective of this study was to compare differences in behavioral, psychiatric, and cognitive status among geropsychiatric inpatients with Alzheimer's, vascular, alcohol-induced, and mixed dementia. Participants included 150 patients with dementia consecutively admitted to an acute geropsychiatric inpatient unit. Measures included the Mini-Mental State Examination, Cohen-Mansfield Agitation Inventory, Cumulative Illness Rating Scale, Basic and Independent Activities of Daily Living, Positive and Negative Syndrome Scale for Schizophrenia, and the Initiation/Perseveration subscale of the Dementia Rating Scale. No significant differences existed in the character or severity of agitation among patients with Alzheimer's, vascular, alcohol-related and mixed dementia. Interestingly, patients with vascular dementia compared to patients with other dementias admitted for behavioral disturbances were less cognitively impaired and more medically burdened.

Aged↗

PubMed1999

Protein folds, functions and evolution.

The evolution of proteins and their functions is reviewed from a structural perspective in the light of the current database. Protein domain families segregate unequally between the three major classes, the 32 different architectures and almost 700 folds observed to date. We find that the number of new topologies is still increasing, although 25 new structures are now determined for each new topology. The corresponding analysis and classification of function is only just beginning, fuelled by the genome data. The structural data revealed unexpected conservations and divergence of function both within and between families. The next five years will see the compilation of a definitive dictionary of protein families and their related functions, based on structural data which reveals relationships hidden at the sequence level. Such information will provide the foundation to build a better understanding of the molecular basis of biological complexity and hopefully to facilitate rational molecular design.

Animals↗

PubMed1999

Correlation of observed fold frequency with the occurrence of local structural motifs.

It is well known that some protein folds (superfolds) occur very frequently. We show that compared to other folds, most superfold structures have a higher proportion of their alpha-helical or beta-strand residues in one of three basic units of supersecondary structure (alpha-hairpin, beta-hairpin or betaalphabeta-unit). Furthermore, by taking into consideration two more complex motifs, the four-stranded Greek-key (beta4) and the betaalpha-Greek key (betaalphabetabeta), we demonstrate that the remaining superfold structures contain many of these higher order units of three-dimensional packing. The implications of these results for folding are discussed.

Models, Molecular↗

PubMed1999

The CATH Database provides insights into protein structure/function relationships.

We report the latest release (version 1.4) of the CATH protein domains database (http://www.biochem.ucl.ac.uk/bsm/cath). This is a hierarchical classification of 13 359 protein domain structures into evolutionary families and structural groupings. We currently identify 827 homologous families in which the proteins have both structual similarity and sequence and/or functional similarity. These can be further clustered into 593 fold groups and 32 distinct architectures. Using our structural classification and associated data on protein functions, stored in the database (EC identifiers, SWISS-PROT keywords and information from the Enzyme database and literature) we have been able to analyse the correlation between the 3D structure and function. More than 96% of folds in the PDB are associated with a single homologous family. However, within the superfolds, three or more different functions are observed. Considering enzyme functions, more than 95% of clearly homologous families exhibit either single or closely related functions, as demonstrated by the EC identifiers of their relatives. Our analysis supports the view that determining structures, for example as part of a 'structural genomics' initiative, will make a major contribution to interpreting genome data.

Algorithms↗