Biology subjects

Anderson, D.

Publications and source records attributed to Anderson, D..

39 records · Page 3Linked to original sources

bioRxiv2019

Alpha-Actinin-1 promotes activity of the L-type Ca2+ Channel CaV1.2

The L-type Ca2+ channel CaV1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of -actinin to the IQ motif of CaV1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi-functional mechanism that restricts CaV1.2 activity to its target sites. We solved separate NMR structures of the IQ motif (residues 1646-1664) bound to -actinin-1 and to apo-calmodulin (apoCaM). The CaV1.2 K1647A and Y1649A mutations, which impair -actinin-1 but not apoCaM binding, but not the F1658A and K1662E mutations, which impair apoCaM but not -actinin-1 binding, decreased single channel open probability, gating charge movement, and its coupling to channel opening. Thus, -actinin recruits CaV1.2 to defined surface regions and simultaneously boosts its open probability so that CaV1.2 is mostly active when appropriately localized.

molecular biology↗

bioRxiv2018

Rewiring of Th-memory-associated gene co-expression networks underlie immunotherapy-induced changes in symptom expression in mite-sensitised atopics

BackgroundMultiple regulatory mechanisms have been identified employing conventional hypothesis-driven approaches as contributing to allergen-specific immunotherapy outcomes, but understanding of how these integrate to maintain immunological homeostasis is incomplete. ObjectiveTo explore the potential for unbiased systems-level gene co-expression network analysis to advance understanding of immunotherapy mechanisms. MethodsWe profiled genome-wide allergen-specific Th-memory responses prospectively across 24mths of subcutaneous immunotherapy (SCIT) in 25 rhinitics, documenting changes in immunoinflammatory pathways and associated co-expression networks and their relationships to symptom scores to 36mths. ResultsPrior to immunotherapy, mite-specific Th-memory response networks involved multiple discrete co-expression modules including those related to Th2-, Type1-IFN-, Inflammation-, and FOXP3/IL2-associated signalling. A signature comprising 109 genes correlated with symptom scores, and these mapped to cytokine signalling/T-cell activation-associated pathways, with upstream drivers including hallmark Th1/Th2-and inflammation-associated genes. Reanalysis after 3.5mths SCIT updosing detected minimal changes to pathway/upstream regulator profiles despite 32.5% reduction in symptoms, however network analysis revealed underlying merging of FOXP3/IL2-with Inflammation-and Th2-associated modules. By 12mths on SCIT, symptoms had reduced by 41% without further significant changes to pathway/upstream regulator or network profiles. Continuing SCIT to 24mths stabilised symptoms at 47% of baseline, accompanied by upregulation of the Type1-IFN-associated network module and its merging into the Th2/FOXP3/IL2/Inflammation module. ConclusionsSCIT stimulates progressive integration of Th-memory-associated Th2-,FOXP3/IL2-, Inflammation-, and Type1-IFN-signalling subnetworks, forming a single highly integrated co-expression network module, maximising potential for stable homeostatic control of allergen-specific Th2 responses via cross-regulation. Th2-anatogonistic Type1-IFN signalling may play a key role in stabilising clinical effects of SCIT. Clinical ImplicationStabilisation of the clinical effectiveness of SCIT involves recruitment of Th2-antagonistic Type 1 IFN-dependent signalling into the overall gene co-expression network underlying the allergen-specific Th-memory response, and this does not occur until the 2nd year of treatment. Capsule summarySCIT-induced rewiring of the gene network governing allergen-specific Th2-memory, as opposed to selective upregulation of genes associated with regulatory functions, underlies the clinical effectiveness of immunotherapy.

immunology↗

bioRxiv2018

Deconvoluting Virome-Wide Antiviral Antibody Profiling Data

The ability to comprehensively characterize exposures and immune responses to viral infections will be critical to better understanding human health and disease. We previously described the VirScan system, a phage-display based technology for profiling antibody binding to a comprehensive library of peptides designed to represent the human virome. The previous VirScan analytical approach did not fully account for disproportionate representation of viruses in the library or for antibody cross-reactivity among sequences shared by related viruses. Here we present the AntiViral Antibody Response Deconvolution Algorithm ( AVARDA), a multi-module software package for analyzing VirScan datasets. AVARDA provides a probabilistic assessment of infection at species-level resolution by considering alignment of all library peptides to each other and to all human viruses. We employed AVARDA to analyze VirScan data from a cohort of encephalitis patients with either known viral infections or undiagnosed etiologies. By comparing acute and convalescent sera, AVARDA successfully confirmed or detected antibody responses to human herpesviruses 1, 3, 4, 5, and 6, thereby improving the rate of diagnosing viral encephalitis in this cohort by 62.5%. We further assessed AVARDAs utility in the setting of an epidemiological study, demonstrating its ability to determine infections acquired in a child followed prospectively from infancy. We consider ways in which AVARDAs conceptual framework may be further developed in the future and describe how its analyses may be extended beyond investigations of viral infection. AVARDA, in combination with VirScan and other pan-pathogen serological techniques, is likely to find broad utility in the epidemiology and diagnosis of infectious diseases.

bioinformatics↗