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A protein–protein interface between a peptide-recognition domain (Fyn-SH3) and catechol O -methyltransferase (COMT) is computationally designed to generate a highly selective peptide-modifying system. Detailed mechanistic analysis sets a gold standard for studying the complex kinetic properties of designer fusion proteins.

Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme A-/- and to a lesser extent granzyme K-/-, but not granzyme B-/-, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme A-/- mice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy. ClinicalTrials.gov NCT00281294.

Predikin is a system for making predictions about protein kinase specificity. It was declared the \"best performer\" in the protein kinase section of the Peptide Recognition Domain specificity prediction category of the recent DREAM4 challenge (an independent test using unpublished data). In this article we discuss some recent improvements to the Predikin web server--including a more streamlined approach to substrate-to-kinase predictions and whole-proteome predictions--and give an analysis of Predikin's performance in the DREAM4 challenge. We also evaluate these improvements using a data set of yeast kinases that have been experimentally characterised, and we discuss the usefulness of Frobenius distance in assessing the predictive power of position weight matrices.

Chromosome arm aneuploidies (CAAs) are pervasive in cancers. However, how they affect cancer development, prognosis and treatment remains largely unknown. Here, we analyse CAA profiles of 23,427 tumours, identifying aspects of tumour evolution including probable orders in which CAAs occur and CAAs predicting tissue-specific metastasis. Both haematological and solid cancers initially gain chromosome arms, while only solid cancers subsequently preferentially lose multiple arms. 72 CAAs and 88 synergistically co-occurring CAA pairs multivariately predict good or poor survival for 58% of 6977 patients, with negligible impact of whole-genome doubling. Additionally, machine learning identifies 31 CAAs that robustly alter response to 56 chemotherapeutic drugs across cell lines representing 17 cancer types. We also uncover 1024 potential synthetic lethal pharmacogenomic interactions. Notably, in predicting drug response, CAAs substantially outperform  mutations and focal deletions/amplifications combined. Thus, CAAs predict cancer prognosis, shape tumour evolution, metastasis and drug response, and may advance precision oncology. Chromosome arm-level aneuploidies (CAAs) are frequently observed in cancer. Here, the authors analyse CAA landscapes across different tumour types, relating these chromosome arm gains and losses to tumour evolution, metastasis, patient survival and response to a range of anti-cancer therapies.

Advances in genomic technology have enabled a greater understanding of the genetics of common immune-mediated diseases such as ankylosing spondylitis (AS), inflammatory bowel disease (IBD) and psoriasis. The substantial overlap in genetically identified pathogenic pathways has been demonstrated between these diseases. However, to date, gene discovery approaches have only mapped a minority of the heritability of these common diseases, and most disease-associated variants have been found to be non-coding, suggesting mechanisms of disease-association through transcriptional regulatory effects. Epigenetics is a major interface between genetic and environmental modifiers of disease and strongly influence transcription. DNA methylation is a well-characterised epigenetic mechanism, and a highly stable epigenetic marker, that is implicated in disease pathogenesis. DNA methylation is an under-investigated area in immune-mediated diseases, and many studies in the field are affected by experimental design limitations, related to study design, technical limitations of the methylation typing methods employed, and statistical issues. This has resulted in both sparsity of investigations into disease-related changes in DNA methylation, a paucity of robust findings, and difficulties comparing studies in the same disease. In this review, we cover the basics of DNA methylation establishment and control, and the methods used to examine it. We examine the current state of DNA methylation studies in AS, IBD and psoriasis; the limitations of previous studies; and the best practices for DNA methylation studies. The purpose of this review is to assist with proper experimental design and consistency of approach in future studies to enable a better understanding of the functional role of DNA methylation in immune-mediated disease.

YqhD, an E. coli alcohol/aldehyde oxidoreductase, is an enzyme able to produce valuable bio-renewable fuels and fine chemicals from a broad range of starting materials. Herein, we report the first computational solution-phase structure-dynamics analysis of YqhD, shedding light on the effect of oxidized and reduced NADP/H cofactor binding on the conformational dynamics of the biocatalyst using molecular dynamics (MD) simulations. The cofactor oxidation states mainly influence the interdomain cleft region conformations of the YqhD monomers, involved in intricate cofactor binding and release. The ensemble of NADPH-bound monomers has a narrower average interdomain space resulting in more hydrogen bonds and rigid cofactor binding. NADP-bound YqhD fluctuates between open and closed conformations, while it was observed that NADPH-bound YqhD had slower opening/closing dynamics of the cofactor-binding cleft. In the light of enzyme kinetics and structural data, simulation findings have led us to postulate that the frequently sampled open conformation of the cofactor binding cleft with NADP leads to the more facile release of NADP while increased closed conformation sampling during NADPH binding enhances cofactor binding affinity and the aldehyde reductase activity of the enzyme.

Actin cytoskeleton dynamics is essential for proper nervous system development and function. A conserved set of neuronal-specific microexons influences multiple aspects of neurobiology; however, their roles in regulating the actin cytoskeleton are unknown. Here, we study a microexon in DAAM1, a formin-homology-2 (FH2) domain protein involved in actin reorganization. Microexon inclusion extends the linker region of the DAAM1 FH2 domain, altering actin polymerization. Genomic deletion of the microexon leads to neuritogenesis defects and increased calcium influx in differentiated neurons. Mice with this deletion exhibit postsynaptic defects, fewer immature dendritic spines, impaired long-term potentiation, and deficits in memory formation. These phenotypes are associated with increased RHOA/ROCK signaling, which regulates actin-cytoskeleton dynamics, and are partially rescued by treatment with a ROCK inhibitor. This study highlights the role of a conserved neuronal microexon in regulating actin dynamics and cognitive functioning. Actin is crucial for nervous system function yet the role of microexons in its modulation is unclear. Here, the authors show that a microexon in DAAM1 has a role in actin dynamics, neuronal function and memory formation in mice.

Carbon sequestration in deep underground saline aquifers holds significant promise for reducing atmospheric carbon dioxide emissions (CO2). However, challenges remain in predicting the long term migration of injected CO2. Addressing these challenges requires an understanding of pore-scale transport of CO2 within existing brine-filled geological reservoirs. Studies on the transport of fluids through geological porous media have predominantly focused on oil-bearing formations such as sandstone. However, few studies have considered pore-scale transport within limestone and other carbonate formations, which are found in potential storage sites. In this work, high-resolution micro-Computed Tomography (microCT) was used to obtain pore-scale structural information of two model carbonates: Indiana Limestone and Pink Dolomite. A modified watershed algorithm was applied to extract pore network from the reconstructed microCT volumetric images of rock samples and compile a list of pore-scale characteristics from the extracted networks. These include statistical distributions of pore size and radius, pore-pore separation, throat radius, and network coordination. Finally, invasion percolation algorithms were applied to determine saturation-pressure curves for the rock samples. The statistical distributions were comparable to literature values for the Indiana Limestone. This served as validation for the network extraction approach for Pink Dolomite, which has not been considered previously. Based on the connectivity and the pore-pore separation, formations such as Pink Dolomite may present suitable storage sites for carbon storage. The pore structural distributions and saturation curves obtained in this study can be used to inform core- and reservoir-scale modeling and experimental studies of sequestration feasibility. La séquestration du carbone dans les aquifères salins profonds souterrains est très prometteuse pour la réduction des émissions de dioxyde de carbone (CO2) dans l’atmosphère. Cependant, des problèmes demeurent dans la prédiction de la migration à long terme du CO2 injecté. Relever ces défis nécessite une compréhension du transport de CO2 à l’échelle du pore dans des réservoirs géologiques existants remplis de saumure. Les études sur le transport des fluides en milieu poreux géologique ont principalement porté sur les formations oléagineuses telles que le grès. Cependant, peu d’études ont examiné les transports à l’échelle du pore dans le calcaire et d’autres formations carbonatées, qui se trouvent dans des sites de stockage potentiels. Dans ce travail, la micro-tomographie (microCT) à haute résolution a été utilisée pour obtenir de l’information structurale à l’échelle du pore de deux exemples de formations carbonatées : Indiana limestone et Pink dolomite. Un algorithme watershed a été appliqué pour extraire les réseaux de pores des microCT images volumétriques reconstruits des spécimens de roche et de compiler une liste de caractéristiques pores des réseaux extraits. Il s’agit notamment de distributions statistiques de la taille et du rayon des pores, la séparation entres pores, le rayon des gorges, et la coordination du réseau. Enfin, des invasions de percolation ont été appliquées pour déterminer les courbes de saturation pression pour les exemples de roches. Les distributions statistiques sont comparables aux valeurs de la littérature pour l’Indiana limestone. Cela a servi de validation de l’approche d’extraction de réseau pour Pink dolomite, qui n’a pas été précédemment examinés. Basées sur la connectivité et la séparation entre pores, les formations Aelles que Pink dolomite peuvent présenter des sites de stockage appropriés pour le stockage du CO2. Les distributions de structure des pores et des courbes de saturation obtenus dans cette étude peuvent être utilisées pour informer noyau et modélisation à l’échelle du réservoir et les études expérimentales de la faisabilité de la séquestration.