SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals.

SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein (S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.

ELIXIR-UK role in bioinformatics training at the national level and across ELIXIR.

ELIXIR-UK is the UK node of ELIXIR, the European infrastructure for life science data. Since its foundation in 2014, ELIXIR-UK has played a leading role in training both within the UK and in the ELIXIR Training Platform, which coordinates and delivers training across all ELIXIR members. ELIXIR-UK contributes to the Training Platform's coordination and supports the development of training to address key skill gaps amongst UK scientists. As part of this work it acts as a conduit for nationally-important bioinformatics training resources to promote their activities to the ELIXIR community. ELIXIR-UK also leads ELIXIR's flagship Training Portal, TeSS, which collects information about a diverse range of training and makes it easily accessible to the community. ELIXIR-UK also works with others to provide key digital skills training, partnering with the Software Sustainability Institute to provide Software Carpentry training to the ELIXIR community and to establish the Data Carpentry initiative, and taking a lead role amongst national stakeholders to deliver the StaTS project - a coordinated effort to drive engagement with training in statistics.

Systematic computational prediction of protein interaction networks.

Determining the network of physical protein associations is an important first step in developing mechanistic evidence for elucidating biological pathways. Despite rapid advances in the field of high throughput experiments to determine protein interactions, the majority of associations remain unknown. Here we describe computational methods for significantly expanding protein association networks. We describe methods for integrating multiple independent sources of evidence to obtain higher quality predictions and we compare the major publicly available resources available for experimentalists to use.

FFPred: an integrated feature-based function prediction server for vertebrate proteomes.

One of the challenges of the post-genomic era is to provide accurate function annotations for large volumes of data resulting from genome sequencing projects. Most function prediction servers utilize methods that transfer existing database annotations between orthologous sequences. In contrast, there are few methods that are independent of homology and can annotate distant and orphan protein sequences. The FFPred server adopts a machine-learning approach to perform function prediction in protein feature space using feature characteristics predicted from amino acid sequence. The features are scanned against a library of support vector machines representing over 300 Gene Ontology (GO) classes and probabilistic confidence scores returned for each annotation term. The GO term library has been modelled on human protein annotations; however, benchmark performance testing showed robust performance across higher eukaryotes. FFPred offers important advantages over traditional function prediction servers in its ability to annotate distant homologues and orphan protein sequences, and achieves greater coverage and classification accuracy than other feature-based prediction servers. A user may upload an amino acid and receive annotation predictions via email. Feature information is provided as easy to interpret graphics displayed on the sequence of interest, allowing for back-interpretation of the associations between features and function classes.

The CATH database: an extended protein family resource for structural and functional genomics.

The CATH database of protein domain structures (http://www.biochem.ucl.ac.uk/bsm/cath_new) currently contains 34 287 domain structures classified into 1383 superfamilies and 3285 sequence families. Each structural family is expanded with domain sequence relatives recruited from GenBank using a variety of efficient sequence search protocols and reliable thresholds. This extended resource, known as the CATH-protein family database (CATH-PFDB) contains a total of 310 000 domain sequences classified into 26 812 sequence families. New sequence search protocols have been designed, based on these intermediate sequence libraries, to allow more regular updating of the classification. Further developments include the adaptation of a recently developed method for rapid structure comparison, based on secondary structure matching, for domain boundary assignment. The philosophy behind CATHEDRAL is the recognition of recurrent folds already classified in CATH. Benchmarking of CATHEDRAL, using manually validated domain assignments, demonstrated that 43% of domains boundaries could be completely automatically assigned. This is an improvement on a previous consensus approach for which only 10-20% of domains could be reliably processed in a completely automated fashion. Since domain boundary assignment is a significant bottleneck in the classification of new structures, CATHEDRAL will also help to increase the frequency of CATH updates.

Measuring aggression in older adults: a latent variable modeling approach.

This cross-sectional measurement study demonstrates a technique for combining information from several aggression scales into one aggression score using latent variable modeling. Participants included male patients (n = 49) with a DSM-IV diagnosis of dementia at The Veterans Affairs Medical Center Outpatient Geriatric Psychiatry Clinic. Data from seven aggression scales were used to indicate the latent aggression variable. Results provided evidence that a unidimensional latent variable model of aggression adequately represented the data. Reliability of the aggression latent variable was estimated as 0.90, whereas reliability of the separate scales estimated with this sample were less than 0.84. Our findings suggest that combining multiple scales into one aggression score using latent variable modeling results in comprehensive and reliable aggression scores that offer researchers several advantages over current methods for measuring aggression.

Review: what can structural classifications reveal about protein evolution?

In this article we present a review of the methods used for comparing and classifying protein structures. We discuss the hierarchies and populations of fold groups and evolutionary families in some of the major classifications and we consider some of the problems confronting any general analyses of structural evolution in protein families. We also review some more recent analyses that have expanded these classifications by identifying sequence relatives in the genomes and thereby reveal interesting trends in fold usage and recurrence.

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.

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.

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/.

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.

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.

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.

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.

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.

Functional impairment in COPD patients: the impact of anxiety and depression.

The authors examined the relationship between functional status and comorbid anxiety and depression and the relationship between utilization of health care resources and psychopathology in elderly patients with chronic obstructive pulmonary disease (COPD). Elderly male veterans (N = 43) with COPD completed anxiety, depression, and functional status measures. The authors constructed regression models to explore the contribution of COPD severity, medical burden, depression, and anxiety to the dependent variables of functional impairment and health care utilization. Anxiety and depression contributed significantly to the overall variance in functional status of COPD patients, over and above medical burden and COPD severity, as measured by the 8 scales of the Medical Outcomes Study (MOS) 36-item Short Form Health Survey. Surprisingly, medical burden and COPD severity did not contribute significantly to overall variance in functional status. Few patients were receiving any treatment for anxiety or depression.

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.

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.

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.