Probabilistic annotation of protein sequences based on functional classifications

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background One of the most evident achievements of bioinformatics is the development of methods that transfer biological knowledge from characterised proteins to uncharacterised sequences. This mode of protein function assignment is mostly based on the detection of sequence similarity and the premise that functional properties are conserved during evolution. Most automatic approaches developed to date rely on the identification of clusters of homologous proteins and the mapping of new proteins onto these clusters, which are expected to share functional characteristics. Results Here, we inverse the logic of this process, by considering the mapping of sequences directly to a functional classification instead of mapping functions to a sequence clustering. In this mode, the starting point is a database of labelled proteins according to a functional classification scheme, and the subsequent use of sequence similarity allows defining the membership of new proteins to these functional classes. In this framework, we define the Correspondence Indicators as measures of relationship between sequence and function and further formulate two Bayesian approaches to estimate the probability for a sequence of unknown function to belong to a functional class. This approach allows the parametrisation of different sequence search strategies and provides a direct measure of annotation error rates. We validate this approach with a database of enzymes labelled by their corresponding four-digit EC numbers and analyse specific cases. Conclusion The performance of this method is significantly higher than the simple strategy consisting in transferring the annotation from the highest scoring BLAST match and is expected to find applications in automated functional annotation pipelines.Published versio

Interacting multivalent molecules: affinity and valence impact the extent and symmetry of phase separation

Self-assembly by phase separation is emerging as a powerful and ubiquitous mechanism to organize and compartmentalize biomolecules in cells. Most of the proteins involved in phase separation have a fixed number of binding sites, i.e., fixed multivalency. Therefore, extending theories of phase separation to multivalent components with a fixed number of binding sites is an important challenge. In this work, we develop a simple lattice model for a three-component system composed of two multivalent proteins and the solvent. We show that interaction strength as well as valency of the protein components determine the extent of phase separation, whereas valency alone determines the symmetry of the phase diagram. Our theoretical predictions agree with experimental results on a synthetic system of proteins with tunable interaction strength and valency

The self-assembly and evolution of homomeric protein complexes

We introduce a simple "patchy particle" model to study the thermodynamics and dynamics of self-assembly of homomeric protein complexes. Our calculations allow us to rationalize recent results for dihedral complexes. Namely, why evolution of such complexes naturally takes the system into a region of interaction space where (i) the evolutionarily newer interactions are weaker, (ii) subcomplexes involving the stronger interactions are observed to be thermodynamically stable on destabilization of the protein-protein interactions and (iii) the self-assembly dynamics are hierarchical with these same subcomplexes acting as kinetic intermediates.Comment: 4 pages, 4 figure

Co-production outcomes for urban equality: Learning from different trajectories of citizens' involvement in urban change

The involvement of citizens and communities in processes that affect their lives and livelihoods through co-production methods has gained currency in recent years as a method to deliver place-based action capable of advancing the Sustainable Development Goals. Co-production represents a promising approach that addresses criticisms leveraged against community-oriented and participatory planning approaches. In this paper, we investigate the potential of co-production methods to advance different dimensions of urban equality in urban environments, including progress towards equitable distribution of resources and services, the reciprocal recognition of communities and institutions, the access to political and decision-making processes, and the recognition of multiple forms of knowledge and perspectives. First, the paper reviews what is unique about co-production as a method in urban development planning. Co-production is distinct because it focuses on delivering a shared outcome. In doing so, it challenges epistemic injustices. Second, the paper presents a collective assessment of the outcomes of co-production practices in six different cities. The comparative analysis of these experiences shows that multiple co-production practices can help to establish long-term, adaptable partnerships to deliver urban equality. However, such a process requires constant adjustment and trade-offs to achieve equality gains in different domains. For that reason, the transformative impacts of co-production are not always measurable, even when its role in social change is evident

PDB-wide identification of biological assemblies from conserved quaternary structure geometry

International audienceProtein structures are key to understanding bio-molecular mechanisms and diseases, yet their interpretation is hampered by limited knowledge of their biologically relevant quaternary structures (QSs). A critical challenge in obtaining QSs from crystallographic data is to distinguish biological interfaces from crystal packing contacts. We tackled this challenge with two strategies for aligning and comparing QS states, both across homologs (QSalign), and across data repositories (QSbio). QS conservation across homologs was a remarkably strong predictor of biological relevance and allowed annotating of >80,000 biological QS states. QS conservation across methods enabled us to create a meta-predictor, QSbio, from which we inferred confidence estimates for >110,000 assemblies in the Protein Data Bank, which approach the accuracy of manual curation. Based on the dataset obtained, we analyzed interaction interfaces among pairs of structurally conserved QSs. This revealed a striking plasticity of interfaces, which can maintain a similar interaction geometry through widely different chemical properties

Urogenital dysfunction in male patients with Charcot-Marie-Tooth: a systematic review

Aims Purposes of this study were to describe lower urinary tract symptoms (LUTS) and related urodynamic patterns in patients with hereditary spastic paraplegia (HSP), and to characterize LUTS management and associated uronephrological complications. Methods We retrospectively reviewed medical files of HSP patients, consecutively followed in our Physical and Rehabilitation Medicine Department between 1999 and 2016. Clinical, urodynamic, and radiological data were collected and analyzed. Different treatments which have been prescribed and uronephrological complications were also recorded. Patients with other neurological or urological diseases were excluded. Results Thirty-three patients with HSP were included. Mean duration of follow-up was 8.1 ± 5 years, mean age 62 ± 14 years, and 70% were men. The most frequent LUTS was urgency and voiding dysfunction (both 69.7%). Incontinence and retention with a significant postvoid residue above 100 mL accounted for 66.7% and 57.6% of initial symptoms respectively. Neurogenic detrusor overactivity was diagnosed in 80.7% of patients. Two-thirds of our cohort were treated with anticholinergics and 9.1% required intradetrusor botulinum-toxin injections. Only 27.3% of patients performed clean intermittent self-catheterization. Febrile urinary tract infections (21.2%), urolithiasis (15,1%), hydronephrosis (6%), and chronic renal failure (9.1%) were found. Conclusion Given their high prevalence and the risk of uronephrological complications, LUTS should be systematically assessed in HSP patients. The systematic screening of urological dysfunction in this population would improve its management, decrease the incidence of uronephrological complications, and increase the quality of life

Artificial insemination in felids

Artificial insemination in the domestic cat and in wild felids has several indications. In the cat, it may replace natural reproduction when matings are unsuccessful or difficult, and it may help to perform geographical exchanges of semen and therefore enhance genetic improvement. In wild felids, it plays a complementary role inside conservation programs. However, its use is complex. First, oestrus and ovulation have to be induced. This is most often obtained using gonadotrophins, which unfortunately may induce undesirable effects, like ovarian hyperstimulation. In males, the semen is generally collected by electro-ejaculation. It may be frozen. However, teratospermia, which is the production of numerous spermatozoa showing morphological abnormalities, is a specific problem affecting felids. Intrauterine inseminations give better results. For a long period, laparoscopy was recommended in felids to perform intrauterine inseminations. Recently, new techniques consisting of catheterizing the cervix through a vaginal access have been developed in the cat as in some wild felids species. Altogether, the rate of success of artificial insemination in felids remains moderate.L'insémination artificielle chez le chat domestique et les félidés sauvages répond à plusieurs indications. Chez le chat, elle peut notamment permettre d'aider la reproduction lorsque l'accouplement ne se produit pas ou difficilement et de favoriser les échanges géographiques de semence et donc un brassage et une meilleure sélection génétiques. Chez les félins sauvages, elle joue un rôle complémentaire au sein des programmes de conservation. Son utilisation est cependant complexe. L'oestrus et l'ovulation sont le plus souvent induits par l'emploi de gonadotropines qui possèdent cependant des effets indésirables, notamment un risque d'hyperstimulation ovarienne. La semence des mâles est généralement récoltée par électro-éjaculation. Elle peut être congelée. Néanmoins, un problème spécifique aux félins tient à la tératospermie, c'est-à-dire la production de nombreux spermatozoïdes porteurs d'anomalies morphologiques. L'insémination artificielle donne de meilleurs résultats lorsque la semence est déposée par voie intra-utérine. Pendant longtemps, la laparoscopie a été la technique de référence, mais récemment, des techniques de cathétérisme du col utérin par voie vaginale ont été mises au point, aussi bien chez le chat que chez certains félidés sauvages. Les résultats de l'insémination artificielle chez les félidés restent moyens (souvent moins de 50 % de gestations obtenues)

In Vivo Turnover of Tau and APP Metabolites in the Brains of Wild-Type and Tg2576 Mice: Greater Stability of sAPP in the β-Amyloid Depositing Mice

The metabolism of the amyloid precursor protein (APP) and tau are central to the pathobiology of Alzheimer's disease (AD). We have examined the in vivo turnover of APP, secreted APP (sAPP), Aβ and tau in the wild-type and Tg2576 mouse brain using cycloheximide to block protein synthesis. In spite of overexpression of APP in the Tg2576 mouse, APP is rapidly degraded, similar to the rapid turnover of the endogenous protein in the wild-type mouse. sAPP is cleared from the brain more slowly, particularly in the Tg2576 model where the half-life of both the endogenous murine and transgene-derived human sAPP is nearly doubled compared to wild-type mice. The important Aβ degrading enzymes neprilysin and IDE were found to be highly stable in the brain, and soluble Aβ40 and Aβ42 levels in both wild-type and Tg2576 mice rapidly declined following the depletion of APP. The cytoskeletal-associated protein tau was found to be highly stable in both wild-type and Tg2576 mice. Our findings unexpectedly show that of these various AD-relevant protein metabolites, sAPP turnover in the brain is the most different when comparing a wild-type mouse and a β-amyloid depositing, APP overexpressing transgenic model. Given the neurotrophic roles attributed to sAPP, the enhanced stability of sAPP in the β-amyloid depositing Tg2576 mice may represent a neuroprotective response