Biomedical subjects

Brian Marsden

Publications and source records attributed to Brian Marsden.

4 recordsLinked to original sources

PubMed2024

Development of methodology to support molecular endotype discovery from synovial fluid of individuals with knee osteoarthritis: The STEpUP OA consortium.

OBJECTIVES: To develop a protocol for largescale analysis of synovial fluid proteins, for the identification of biological networks associated with subtypes of osteoarthritis. METHODS: Synovial Fluid To detect molecular Endotypes by Unbiased Proteomics in Osteoarthritis (STEpUP OA) is an international consortium utilising clinical data (capturing pain, radiographic severity and demographic features) and knee synovial fluid from 17 participating cohorts. 1746 samples from 1650 individuals comprising OA, joint injury, healthy and inflammatory arthritis controls, divided into discovery (n = 1045) and replication (n = 701) datasets, were analysed by SomaScan Discovery Plex V4.1 (>7000 SOMAmers/proteins). An optimised approach to standardisation was developed. Technical confounders and batch-effects were identified and adjusted for. Poorly performing SOMAmers and samples were excluded. Variance in the data was determined by principal component (PC) analysis. RESULTS: A synovial fluid standardised protocol was optimised that had good reliability (<20% co-efficient of variation for >80% of SOMAmers in pooled samples) and overall good correlation with immunoassay. 1720 samples and >6290 SOMAmers met inclusion criteria. 48% of data variance (PC1) was strongly correlated with individual SOMAmer signal intensities, particularly with low abundance proteins (median correlation coefficient 0.70), and was enriched for nuclear and non-secreted proteins. We concluded that this component was predominantly intracellular proteins, and could be adjusted for using an 'intracellular protein score' (IPS). PC2 (7% variance) was attributable to processing batch and was batch-corrected by ComBat. Lesser effects were attributed to other technical confounders. Data visualisation revealed clustering of injury and OA cases in overlapping but distinguishable areas of high-dimensional proteomic space. CONCLUSIONS: We have developed a robust method for analysing synovial fluid protein, creating a molecular and clinical dataset of unprecedented scale to explore potential patient subtypes and the molecular pathogenesis of OA. Such methodology underpins the development of new approaches to tackle this disease which remains a huge societal challenge.

Humans↗

PubMed2006

Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases.

Protein tyrosine phosphatases PTPN5, PTPRR and PTPN7 comprise a family of phosphatases that specifically inactivate MAPKs (mitogen-activated protein kinases). We have determined high-resolution structures of all of the human family members, screened them against a library of 24000 compounds and identified two classes of inhibitors, cyclopenta[c]quinolinecarboxylic acids and 2,5-dimethylpyrrolyl benzoic acids. Comparative structural analysis revealed significant differences within this conserved family that could be explored for the design of selective inhibitors. PTPN5 crystallized, in two distinct crystal forms, with a sulphate ion in close proximity to the active site and the WPD (Trp-Pro-Asp) loop in a unique conformation, not seen in other PTPs, ending in a 3(10)-helix. In the PTPN7 structure, the WPD loop was in the closed conformation and part of the KIM (kinase-interaction motif) was visible, which forms an N-terminal aliphatic helix with the phosphorylation site Thr66 in an accessible position. The WPD loop of PTPRR was open; however, in contrast with the structure of its mouse homologue, PTPSL, a salt bridge between the conserved lysine and aspartate residues, which has been postulated to confer a more rigid loop structure, thereby modulating activity in PTPSL, does not form in PTPRR. One of the identified inhibitor scaffolds, cyclopenta[c]quinoline, was docked successfully into PTPRR, suggesting several possibilities for hit expansion. The determined structures together with the established SAR (structure-activity relationship) propose new avenues for the development of selective inhibitors that may have therapeutic potential for treating neurodegenerative diseases in the case of PTPRR or acute myeloblastic leukaemia targeting PTPN7.

Amino Acid Sequence↗

PubMed2004

SAD--a normalized structural alignment database: improving sequence-structure alignments.

MOTIVATION: We present a structural alignment database that is specifically targeted for use in derivation and optimization of sequence-structure alignment algorithms for homology modeling. We have paid attention to ensure that fold-space is properly sampled, that the structures involved in alignments are of significant resolution (better than 2.5 A) and the alignments are accurate and reliable. RESULTS: Alignments have been taken from the HOMSTRAD, BAliBASE and SCOP-based Gerstein databases along with alignments generated by a global structural alignment method described here. In order to discriminate between equivalent alignments from these different sources, we have developed a novel scoring function, Contact Alignment Quality score, which evaluates trial alignments by their statistical significance combined with their ability to reproduce conserved three-dimensional residue contacts. The resulting non-redundant, unbiased database contains 1927 alignments from across fold-space with high-resolution structures and a wide range of sequence identities. AVAILABILITY: The database can be interactively queried either over the web at http://abagyan.scripps.edu/lab/web/sad/show.cgi or by using MySQL, and is also available to download over the web.

Algorithms↗

PubMed2002

The binary Kuiper-belt object 1998 WW31.

The recent discovery of a binary asteroid during a spacecraft fly-by generated keen interest, because the orbital parameters of binaries can provide measures of the masses, and mutual eclipses could allow us to determine individual sizes and bulk densities. Several binary near-Earth, main-belt and Trojan asteroids have subsequently been discovered. The Kuiper belt-the region of space extending from Neptune (at 30 astronomical units) to well over 100 AU and believed to be the source of new short-period comets-has become a fascinating new window onto the formation of our Solar System since the first member object, not counting Pluto, was discovered in 1992 (ref. 13). Here we report that the Kuiper-belt object 1998 WW31 is binary with a highly eccentric orbit (eccentricity e approximately 0.8) and a long period (about 570 days), very different from the Pluto/Charon system, which was hitherto the only previously known binary in the Kuiper belt. Assuming a density in the range of 1 to 2 g cm-3, the albedo of the binary components is between 0.05 and 0.08, close to the value of 0.04 generally assumed for Kuiper-belt objects.

Journal Article↗