The ryanodine receptor is a channel is of key importance in heart muscle contraction and is the target for hundreds of disease mutations that cause arrhythmia. Circulating adrenaline ultimately leads to the activation of kinases (PKA, CaMKII) that can phosphorylate the ryanodine receptor. This then facilitates its opening, such that calcium ions are released more readily. In this study, the authors determined the high-resolution crystal structures of the PKA kinase bound to its interaction domain in the ryanodine receptor channel.
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As a surgeon scientist, Dr. Alan So’s interest in research is to meld both bench side research and clinical research. In this paper, he found that, given the prevalence of sonic hedgehog pathway overexpression in cancers and in bladder cancer specifically, GLI inhibition with antisense oligonucleotides is a promising new treatment modality for urothelial carcinoma.
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Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype (“stemness”) on the immunological properties of cancer has not been systematically explored. Using gene-expression–based metrics, we evaluated the association of stemness with immune cell infiltration and genomic, transcriptomic, and…
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In Escherichia coli, the peptidoglycan crosslinking reaction to form the cell wall is primarily carried out by penicillin-binding proteins that catalyse D,D-transpeptidase activity. However, an alternate crosslinking mechanism involving the L,D-transpeptidase YcbB can lead to bypass of D,D-transpeptidation and beta-lactam resistance. Due to the important roles YcbB can undertake during stress and infectious conditions, it is a promising target for the development of novel and specific antibacterial therapies.
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Ibrutinib (IB) is an oral Bruton’s tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human…
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Previous work from this group has suggested that the structure of lipid nanoparticles (LNPs) contained inverted micelles that protect the siRNA More recent data suggested this is not the case. This publication provides further evidence to overturn the existing paradigm of LNP formation and provides insight into particle formation through a series of events involving the fusion of precursor particles as a result of neutralising the pH.
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Rationale: Diesel exhaust (DE), an established model of traffic-related air pollution, contributes significantly to the global burden of asthma and may augment the effects of allergen inhalation. Newer diesel particulate-filtering technologies may increase NO2 emissions, raising questions regarding their effectiveness in reducing harm from associated engine output. Objectives: To assess the effects of diesel exhaust and allergen co-exposure on lung function,…
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Single-cell transcriptomics provides an opportunity to characterize cell-type-specific transcriptional networks, intercellular signaling pathways and cellular diversity with unprecedented resolution by profiling thousands of cells in a single experiment. However, owing to the unique statistical properties of scRNA-seq data, the optimal measures of association for identifying gene-gene and cell-cell relationships from single-cell transcriptomics remain unclear. Here, we conducted a large-scale evaluation…
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The spliceosome has been implicated in genome maintenance for decades. Recently, a surge in discoveries in cancer has suggested that the oncogenic mechanism of spliceosomal defects may involve defective genome stability. The action of the core spliceosome prevents R-loop accumulation, and regulates the expression of genome stability factors. At the same time, specific spliceosomal components have non-canonical functions in genome…
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This the most detailed study to date describing differences between human genomes. The findings are astounding: an average of 818,054 small insertions and deletions (genomic alterations that each affected less than 50 bases of DNA) and 27,622 SVs (genomic alterations that affected 50 bases or more of DNA) were identified per genome. Remarkably, an average of 156 polymorphic inversions were identified per...
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