32 research outputs found
Dissecting the Specificity of Protein-Protein Interaction in Bacterial Two-Component Signaling: Orphans and Crosstalks
Predictive understanding of the myriads of signal transduction pathways in a
cell is an outstanding challenge of systems biology. Such pathways are
primarily mediated by specific but transient protein-protein interactions,
which are difficult to study experimentally. In this study, we dissect the
specificity of protein-protein interactions governing two-component signaling
(TCS) systems ubiquitously used in bacteria. Exploiting the large number of
sequenced bacterial genomes and an operon structure which packages many pairs
of interacting TCS proteins together, we developed a computational approach to
extract a molecular interaction code capturing the preferences of a small but
critical number of directly interacting residue pairs. This code is found to
reflect physical interaction mechanisms, with the strongest signal coming from
charged amino acids. It is used to predict the specificity of TCS interaction:
Our results compare favorably to most available experimental results, including
the prediction of 7 (out of 8 known) interaction partners of orphan signaling
proteins in Caulobacter crescentus. Surveying among the available bacterial
genomes, our results suggest 15~25% of the TCS proteins could participate in
out-of-operon "crosstalks". Additionally, we predict clusters of crosstalking
candidates, expanding from the anecdotally known examples in model organisms.
The tools and results presented here can be used to guide experimental studies
towards a system-level understanding of two-component signaling.Comment: Supplementary information available on
http://www.plosone.org/article/info:doi/10.1371/journal.pone.001972
Direct-coupling analysis of residue co-evolution captures native contacts across many protein families
The similarity in the three-dimensional structures of homologous proteins
imposes strong constraints on their sequence variability. It has long been
suggested that the resulting correlations among amino acid compositions at
different sequence positions can be exploited to infer spatial contacts within
the tertiary protein structure. Crucial to this inference is the ability to
disentangle direct and indirect correlations, as accomplished by the recently
introduced Direct Coupling Analysis (DCA) (Weigt et al. (2009) Proc Natl Acad
Sci 106:67). Here we develop a computationally efficient implementation of DCA,
which allows us to evaluate the accuracy of contact prediction by DCA for a
large number of protein domains, based purely on sequence information. DCA is
shown to yield a large number of correctly predicted contacts, recapitulating
the global structure of the contact map for the majority of the protein domains
examined. Furthermore, our analysis captures clear signals beyond intra- domain
residue contacts, arising, e.g., from alternative protein conformations,
ligand- mediated residue couplings, and inter-domain interactions in protein
oligomers. Our findings suggest that contacts predicted by DCA can be used as a
reliable guide to facilitate computational predictions of alternative protein
conformations, protein complex formation, and even the de novo prediction of
protein domain structures, provided the existence of a large number of
homologous sequences which are being rapidly made available due to advances in
genome sequencing.Comment: 28 pages, 7 figures, to appear in PNA
Concurrent Oral 1 - Therapy of rheumatic disease: OP4. Effectiveness of Rituximab in Rheumatoid Arthritis: Results from the British Society for Rheumatology Biologics Register (BSRBR)
Background: Rituximab (RTX) in combination with methotrexate (MTX) has been licensed since 2006 for the management of severe active rheumatoid arthritis (RA) in patients who have failed at least one anti-tumour necrosis factor (anti-TNF) therapy. Published clinical trials have demonstrated the efficacy of RTX in improving both clinical symptoms and patients' physical function. This study aimed to assess the effectiveness of RTX in RA patients treated in routine clinical practice by examining clinical and patient reported outcomes six months after receiving a first course of RTX. Methods: The analysis involved 550 RA patients registered with the BSRBR, who were starting RTX and were followed up for at least 6 months. Change in Disease Activity Score (DAS28) and European League Against Rheumatism (EULAR) response were used to assess the clinical response while change in Health Assessment Questionnaire (HAQ) score was used to assess the physical function of the patients 6 months after starting RTX. The change in DAS28 and HAQ was compared between seronegative and seropositive patients and anti-TNF naïve patients versus anti-TNF failures. The response was also compared between patients receiving RTX in combination with MTX, other non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) or no nbDMARDs. Results: The mean (s.d.) age of the cohort was 59 (12) years and 78% of the patients were females. The patients had a mean (s.d.) of 15 (10) years of disease duration. 16% were biologic naïve while 84% were anti-TNF failures. 32% of the patients were seronegative and 68% were seropositive. The mean (95% CI) DAS28 at baseline was 6.2 (6.1, 6.3) which decreased to 4.8 (4.7, 4.9) at 6 months of follow up. 16% were EULAR good responders, 43% were moderate responders and 41% were non responders. The mean (95% CI) change in HAQ was −0.1 (−0.2, −0.1) (Table 1). The mean change in DAS28 was similar in seropositive and seronegative patients (p = 0.18) while the anti-TNF naïve patients showed a greater reduction in DAS28 scores than anti-TNF failures (p = 0.05). Patients receiving RTX in combination with MTX showed similar changes in DAS28 and HAQ compared to patients receiving RTX alone or with other nbDMARDs. Conclusions: RTX has proven to be effective in the routine clinical practice. Anti-TNF naïve patients seem to benefit more from RTX treatment than anti-TNF failures. Disclosure statement: The authors have declared no conflicts of interes
BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis
Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes
Beyond equilibrium climate sensitivity
ISSN:1752-0908ISSN:1752-089