Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) complexes promoting prosurvival and inflammatory signaling. RIPK1 also ...directly regulates caspase-8-mediated apoptosis or, if caspase-8 activity is blocked, RIPK3-MLKL-dependent necroptosis. We show that C57BL/6 Ripk1−/− mice die at birth of systemic inflammation that was not transferable by the hematopoietic compartment. However, Ripk1−/− progenitors failed to engraft lethally irradiated hosts properly. Blocking TNF reversed this defect in emergency hematopoiesis but, surprisingly, Tnfr1 deficiency did not prevent inflammation in Ripk1−/− neonates. Deletion of Ripk3 or Mlkl, but not Casp8, prevented extracellular release of the necroptotic DAMP, IL-33, and reduced Myd88-dependent inflammation. Reduced inflammation in the Ripk1−/−Ripk3−/−, Ripk1−/−Mlkl−/−, and Ripk1−/−Myd88−/− mice prevented neonatal lethality, but only Ripk1−/−Ripk3−/−Casp8−/− mice survived past weaning. These results reveal a key function for RIPK1 in inhibiting necroptosis and, thereby, a role in limiting, not only promoting, inflammation.
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•RIPK1 delivers a TNF-dependent survival signal to HSC entering the bone marrow•RIPK1 can inhibit RIPK3/MLKL necroptosis•RIPK3/MLKL-dependent necroptosis causes IL-33 release in Ripk1−/− mice•Lethal, necroptosis-induced, systemic inflammation in Ripk1−/− mice is Myd88 dependent
Ripk1 deficiency induces RIPK3/MLKL-dependent necroptosis, triggers IL-33 release, and causes Myd88-dependent systemic inflammation and perinatal death. These phenotypes could be rescued by deletion of Ripk3 and Casp8, revealing a key function for RIPK1 in inhibiting necroptosis and limiting inflammation.
Testing, Adjusting and Balancing (TAB) is a process utilized for heating, ventilating, and air-conditioning (HVAC) and related systems to optimize system performance and prove that design intent has ...been met. Equipment selection, improper and proper use of TAB instrumentation, system layout for testing and maintenance access, document review strategies, defining meaningful and useful TAB data, incorporating new industry product technologies, and project scheduling issues are all common challenges that a TAB provider encounters. This article offers solutions and ideas to help overcome these challenges, for the benefit of the design professional, construction team, commissioning provider and ultimately the building owner.
RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive ...inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3-caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1β inflammatory responses independent of MLKL and necroptotic cell death.
We begin with the history of aquaporin zero (AQP0), the most prevalent membrane protein in the eye lens, from the early days when AQP0 was a protein of unknown function known as Major Intrinsic ...Protein 26. We progress through its joining the aquaporin family as a water channel in its own right and discuss how regulation of its water permeability by pH and calcium came to be discovered experimentally and linked to lens homeostasis and development. We review the development of molecular dynamics (MD) simulations of lipid bilayers and membrane proteins, including aquaporins, with an emphasis on simulation studies that have elucidated the mechanisms of water conduction, selectivity, and proton exclusion by aquaporins in general. We also review experimental and theoretical progress toward understanding why mammalian AQP0 has a lower water permeability than other aquaporins and the evolution of our present understanding of how its water permeability is regulated by pH and calcium. Finally, we discuss how MD simulations have elucidated the nature of lipid interactions with AQP0.
Massive discs around low-mass stars Haworth, Thomas J; Cadman, James; Meru, Farzana ...
Monthly notices of the Royal Astronomical Society,
05/2020, Letnik:
494, Številka:
3
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
We use a suite of smoothed particle hydrodynamic simulations to investigate the susceptibility of protoplanetary discs to the effects of self-gravity as a function of star–disc properties. ...We also include passive irradiation from the host star using different models for the stellar luminosities. The critical disc-to-star mass ratio for axisymmetry (for which we produce criteria) increases significantly for low-mass stars. This could have important consequences for increasing the potential mass reservoir in a proto Trappist-1 system, since even the efficient Ormel et al. formation model will be influenced by processes like external photoevaporation, which can rapidly and dramatically deplete the dust reservoir. The aforementioned scaling of the critical Md/M* for axisymmetry occurs in part because the Toomre Q parameter has a linear dependence on surface density (which promotes instability) and only an $M_*^{1/2}$ dependence on shear (which reduces instability), but also occurs because, for a given Md/M*, the thermal evolution depends on the host star mass. The early phase stellar irradiation of the disc (for which the luminosity is much higher than at the zero age main sequence, particularly at low stellar masses) can also play a key role in significantly reducing the role of self-gravity, meaning that even solar mass stars could support axisymmetric discs a factor two higher in mass than usually considered possible. We apply our criteria to the DSHARP discs with spirals, finding that self-gravity can explain the observed spirals so long as the discs are optically thick to the host star irradiation.
Host–parasite systems have intricately coupled life cycles, but each interactor can respond differently to changes in environmental variables like temperature. Although vital to predicting how ...parasitism will respond to climate change, thermal responses of both host and parasite in key traits affecting infection dynamics have rarely been quantified. Through temperature-controlled experiments on an ectothermic host–parasite system, we demonstrate an offset in the thermal optima for survival of infected and uninfected hosts and parasite production. We combine experimentally derived thermal performance curves with field data on seasonal host abundance and parasite prevalence to parameterize an epidemiological model and forecast the dynamical responses to plausible future climate-warming scenarios. In warming scenarios within the coastal southeastern United States, the model predicts sharp declines in parasite prevalence, with local parasite extinction occurring with as little as 2 °C warming. The northern portion of the parasite’s current range could experience local increases in transmission, but assuming no thermal adaptation of the parasite, we find no evidence that the parasite will expand its range northward under warming. This work exemplifies that some host populations may experience reduced parasitism in a warming world and highlights the need to measure host and parasite thermal performance to predict infection responses to climate change.
Over millions of years, vertebrate species populated vast environments spanning the globe. Among the most challenging habitats encountered were those with limited availability of oxygen, yet many ...animal and human populations inhabit and perform life cycle functions and/or daily activities in varying degrees of hypoxia today. Of particular interest are species that inhabit high-altitude niches, which experience chronic hypobaric hypoxia throughout their lives. Physiological and molecular aspects of adaptation to hypoxia have long been the focus of high-altitude populations and, within the past decade, genomic information has become increasingly accessible. These data provide an opportunity to search for common genetic signatures of selection across uniquely informative populations and thereby augment our understanding of the mechanisms underlying adaptations to hypoxia. In this review, we synthesize the available genomic findings across hypoxia-tolerant species to provide a comprehensive view of putatively hypoxia-adaptive genes and pathways. In many cases, adaptive signatures across species converge on the same genetic pathways or on genes themselves i.e., the hypoxia inducible factor (HIF) pathway). However, specific variants thought to underlie function are distinct between species and populations, and, in most cases, the precise functional role of these genomic differences remains unknown. Efforts to standardize these findings and explore relationships between genotype and phenotype will provide important clues into the evolutionary and mechanistic bases of physiological adaptations to environmental hypoxia.
RIPK1 is an essential downstream component of many pattern recognition and death receptors. RIPK1 can promote the activation of caspase-8 induced apoptosis and RIPK3-MLKL-mediated necroptosis, ...however, during development RIPK1 limits both forms of cell death. Accordingly, Ripk1
mice present with systemic cell death and consequent multi-organ inflammation, which is driven through the activation of both FADD-caspase-8 and RIPK3-MLKL signaling pathways causing perinatal lethality. TRADD is a death domain (DD) containing molecule that mediates signaling downstream of TNFR1 and the TLRs. Following the disassembly of the upstream receptor complexes either RIPK1 or TRADD can form a complex with FADD-caspase-8-cFLIP, via DD-DD interactions with FADD, facilitating the activation of caspase-8. We show that genetic deletion of Ripk1 licenses TRADD to complex with FADD-caspase-8 and activates caspase-8 during development. Deletion of Tradd provided no survival advantage to Ripk1
animals and yet was sufficient to reduce the systemic cell death and inflammation, rescue the intestinal and thymic histopathologies, reduce cleaved caspases in most tissues and rescue the anemia observed in Ripk1
neonates. Furthermore, deletion of Ripk3 is sufficient to rescue the neonatal lethality of Ripk1
Tradd
animals and delays but does not completely prevent early mortality. Although Ripk3 deletion provides a significant survival advantage, Ripk1
Tradd
Ripk3
animals die between 22 and 49 days, are runty compared to littermate controls and present with splenomegaly. These findings reveal a new mechanism by which RIPK1 limits apoptosis through blocking TRADD recruitment to FADD and preventing aberrant activation of caspase-8.
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