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short online survey completed by 121 specialist physicians determined that the primary factor that influences treatment decision-making is efficacy, and that a wide range of non-invasive techniques are used to diagnose NASH, while confirmatory liver biopsy is not performed by all physicians despite guideline recommendations. © 2020 Novartis Pharma AG.Store operated calcium (Ca2+) entry is an important homeostatic mechanism in cells, whereby the release of Ca2+ from intracellular endoplasmic reticulum stores triggers the activation of a Ca2+ influx pathway. Mediated by Orai1, this Ca2+ influx has specific and essential roles in biological processes as diverse as lactation to immunity. Although pharmacological inhibitors of this Ca2+ influx mechanism have helped to define the role of store operated Ca2+ entry in many cellular events, the lack of isoform specific modulators and activators of Orai1 has limited our full understanding of these processes. Here we report the identification and synthesis of an Orai1 activity enhancer that concurrently potentiated Orai1 Ca2+ -dependent inactivation (CDI). This unique enhancer of Orai1 had only a modest effect on Orai3 with weak inhibitory effects at high concentrations in intact MCF-7 breast cancer cells. The Orai1 enhancer heightened vascular smooth muscle cell migration induced by platelet-derived growth factor and the unique store operated Ca2+ entry pathway present in skeletal muscle cells. These studies show that IA65 is an exemplar for the translation and development of Orai isoform selective agents. The ability of IA65 to activate CDI demonstrates that agents can be developed that can enhance Orai1-mediated Ca2+ influx but avoid the cytotoxicity associated with sustained Orai1 activation. IA65 and/or future analogues with similar Orai1 and CDI activating properties could be fine tuners of physiological processes important in specific disease states, such as cellular migration and immune cell function.Cyclical renewal of integumentary organs, including hair, feathers, and teeth occurs throughout an organism's lifetime. Transition from the resting to the initiation stage is critical for each cycle, but the mechanism remains largely unknown. Humans have two sets of dentitions-deciduous and permanent-and tooth replacement occurs only once. Prior to eruption of the permanent tooth (PT), the successional dental lamina (SDL) of the PT can be detected as early as the embryonic stage, even though it then takes about 6-12 years for the SDL to develop to late bell stage. Little is known about the mechanism by which resting SDL transitions into the initiation stage inside the mandible. As a large mammal, the miniature pig, which is also a diphyodont, was a suitable model for our recent study (EMBO J (2020)39 e102374). Using this model, we found that the SDL of PT did not begin the transition into the bud stage until the deciduous tooth (DT) began to erupt. Copyright © 2020 Wu and Wang.In Saccharomyces cerevisiae, the absence of Pif1 helicase induces the instability of G4-containing CEB1 minisatellite during leading strand but not lagging strand replication. We report that RPA and Pif1 cooperate to maintain CEB1 stability when the G4 forming strand is either on the leading or lagging strand templates. At the leading strand, RPA acts in the same pathway as Pif1 to maintain CEB1 stability. Consistent with this result, RPA co-precipitates with Pif1. This association between Pif1 and RPA is affected by the rfa1-D228Y mutation that lowers the affinity of RPA in particular for G-rich single-stranded DNA. At the lagging strand, in contrast to pif1Δ, the rfa1-D228Y mutation strongly increases the frequency of CEB1 rearrangements. We explain that Pif1 is dispensable at the lagging strand DNA by the ability of RPA by itself to prevent formation of stable G-rich secondary structures during lagging strand synthesis. Remarkably, overexpression of Pif1 rescues the instability of CEB1 at the lagging strand in the rfa1-D228Y mutant indicating that Pif1 can also act at the lagging strand. We show that the effects of the rfa1-D228Y (rpa1-D223Y in fission yeast) are conserved in Schizosaccharomyces pombe. Finally, we report that RNase H1 interacts in a DNA-dependent manner with RPA in budding yeast, however overexpression of RNase H1 does not rescue CEB1 instability observed in pif1Δ and rfa1-D228Y mutants. Collectively these results add new insights about the general role of RPA in preventing formation of DNA secondary structures and in coordinating the action of factors aimed at resolving them. Copyright © 2020 Maestroni et al.Living cells regulate key cellular processes by spatial organisation of catalytically active proteins in higher-order signalling complexes. These act as organising centres to facilitate proximity-induced activation and inhibition of multiple intrinsically weakly associating signalling components, which makes elucidation of the underlying protein-protein interactions challenging. Here we show that DNA origami nanostructures provide a programmable molecular platform for the systematic analysis of signalling proteins by engineering a synthetic DNA origami-based version of the apoptosome, a multi-protein complex that regulates apoptosis by co-localizing multiple caspase-9 monomers. Tethering of both wildtype and inactive caspase-9 variants to a DNA origami platform demonstrates that enzymatic activity is induced by proximity-driven dimerization with half-of-sites reactivity, and additionally, reveals a multivalent activity enhancement in oligomers of three and four enzymes. Our results offer fundamental insights in caspase-9 activity regulation and demonstrate that DNA origami-based protein assembly platforms have the potential to inform the function of other multi-enzyme complexes involved in inflammation, innate immunity and cell death.Background Rheumatoid arthritis is the most common type of inflammatory arthritis affecting about 1% of the population. With the advent of disease-modifying anti-rheumatic drugs the disease can be well controlled in many cases. Patients, however, are prone to developing infectious complications. K-975 In rare cases, these can mimic a flare of the underlying itself. Case presentation We report the case of a 45-year-old female patient with a history of seronegative rheumatoid arthritis (RA) who presented with swelling and tenderness of the third metacarpophalangeal joint of the right hand. A flare of her RA was suspected based on clinical and ultrasound findings which showed a tenosynovitis with intense power doppler activity. Her steroid dose was increased but the clinical response to glucocorticoid therapy was very limited. Subsequently, she developed skin manifestations of 'swimmer's granuloma' over the next 2 weeks after first presentation. Finally, a diagnosis of a Mycobacterium marinum infection was established with the help of tissue biopsy and culture, and the patient received appropriate antibiotic treatment with the desired effect.