Death Is Coming and the Clot Thickens, as Pyroptosis Feeds the Fire.

Pyroptotic cell death during endotoxemia causes death via unknown mechanisms. In this issue of Immunity, Wu et al. (2019) show that T3SS rod proteins or LPS induces inflammasome activation, macrophage pyroptosis, and accompanying tissue factor release, directly connecting inflammation to coagulation.The Cambridge NIHR Biomedical Research Centre

Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease.

Cytokines activate or inhibit immune cell behavior and are thus integral to all immune responses. IL-1α and IL-1β are powerful apical cytokines that instigate multiple downstream processes to affect both innate and adaptive immunity. Multiple studies show that IL-1β is typically activated in macrophages after inflammasome sensing of infection or danger, leading to caspase-1 processing of IL-1β and its release. However, many alternative mechanisms activate IL-1α and IL-1β in atypical cell types, and IL-1 function is also important for homeostatic processes that maintain a physiological state. This review focuses on the less studied, yet arguably more interesting biology of IL-1. We detail the production by, and effects of IL-1 on specific innate and adaptive immune cells, report how IL-1 is required for barrier function at multiple sites, and discuss how perturbation of IL-1 pathways can drive disease. Thus, although IL-1 is primarily studied for driving inflammation after release from macrophages, it is clear that it has a multifaceted role that extends far beyond this, with various unconventional effects of IL-1 vital for health. However, much is still unknown, and a detailed understanding of cell-type and context-dependent actions of IL-1 is required to truly understand this enigmatic cytokine, and safely deploy therapeutics for the betterment of human health

Helical frontier orbitals of conjugated linear molecules

Compounds containing allenes, cumulenes and oligoynes (polyalkynes) have attracted attention for both their conformation and reactivity. Whilst the textbook molecular orbital description explains the general electronic and molecular structure of the cumulenes, there are anomalies in both the crystal structures and cycloaddition products involving oligoynes and allenes; the understanding of these molecules is incomplete. Through a computational study we elucidate that the frontier orbitals of the allene and oligoyne families are extended helices. These orbitals are the linear analogue to the Möbius aromatic systems, which also display non-linear π interactions. The axial chirality found in allenes and oligoynes is intimately related to the topology of the frontier orbitals, and has implications for predictions of cycloaddition pathways, structure stability and spectroscopy

Interleukin-1α Activity in Necrotic Endothelial Cells Is Controlled by Caspase-1 Cleavage of Interleukin-1 Receptor-2: IMPLICATIONS FOR ALLOGRAFT REJECTION.

Inflammation is a key instigator of the immune responses that drive atherosclerosis and allograft rejection. IL-1α, a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from endothelial cells (ECs) damaged during transplant drives allograft rejection. However, IL-1α requires cleavage for full cytokine activity, and what controls cleavage in necrotic ECs is currently unknown. We find that ECs have very low levels of IL-1α activity upon necrosis. However, TNFα or IL-1 induces significant levels of active IL-1α in EC necrotic lysates without alteration in protein levels. Increased activity requires cleavage of IL-1α by calpain to the more active mature form. Immunofluorescence and proximity ligation assays show that IL-1α associates with interleukin-1 receptor-2, and this association is decreased by TNFα or IL-1 and requires caspase activity. Thus, TNFα or IL-1 treatment of ECs leads to caspase proteolytic activity that cleaves interleukin-1 receptor-2, allowing IL-1α dissociation and subsequent processing by calpain. Importantly, ECs could be primed by IL-1α from adjacent damaged VSMCs, and necrotic ECs could activate neighboring normal ECs and VSMCs, causing them to release inflammatory cytokines and up-regulate adhesion molecules, thus amplifying inflammation. These data unravel the molecular mechanisms and interplay between damaged ECs and VSMCs that lead to activation of IL-1α and, thus, initiation of adaptive responses that cause graft rejection.This study was supported by British Heart Foundation Grants FS/09/005/26845, FS/13/3/30038 and FS/11/77/29327 (MCHC) & RG/13/14/30314 (MRB); the BHF Cambridge CRE; and the NIHR Cambridge BRC.This is the final version of the article. It first appeared from ASBMB via http://dx.doi.org/10.1074/jbc.M115.66791

Mass Transfer, Transiting Stream and Magnetopause in Close-in Exoplanetary Systems with Applications to WASP-12

We study mass transfer by Roche lobe overflow in close-in exoplanetary systems. The planet's atmospheric gas passes through the inner Lagrangian point and flows along a narrow stream, accelerating to 100-200\kms velocity before forming an accretion disk. We show that the cylinder-shaped accretion stream can have an area (projected in the plane of the sky) comparable to that of the planet and a significant optical depth to spectral line absorption. Such a "transiting cylinder" may produce an earlier ingress of the planet transit, as suggested by recent HST observations of the WASP-12 system. The asymmetric disk produced by the accretion stream may also lead to time-dependent obscuration of the star light and apparent earlier ingress. We also consider the interaction of the stellar wind with the planetary magnetosphere. Since the wind speed is subsonic/sub-Alfvenic and comparable to the orbital velocity of the planet, the head of the magnetopause lies eastward relative to the substellar line (the line joining the planet and the star). The gas around the magnetopause may, if sufficiently compressed, give rise to asymmetric ingress/egress during the planet transit, although more works are needed to evaluate this possibility.Comment: 6 pages with 2 figures. Accepted in ApJ. Small changes (add discussion on asymmetric disks

Cell surface IL-1α trafficking is specifically inhibited by interferon-γ, and associates with the membrane via IL-1R2 and GPI anchors.

IL-1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL-1α and IL-1β are translated as proforms that require cleavage for full cytokine activity and release, while IL-1α is reported to occur as an alternative plasma membrane-associated form on many cell types. However, the existence of cell surface IL-1α (csIL-1α) is contested, how IL-1α tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL-1α after ligation of TLRs. Pro-IL-1α tethers to the plasma membrane in part through IL-1R2 or via association with a glycosylphosphatidylinositol-anchored protein, and can be cleaved, activated, and released by proteases. csIL-1α requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN-γ, independent of expression level. We also reveal how prior csIL-1α detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent-associated secretory phenotype via csIL-1α, but rather via soluble IL-1α. We believe these data are important for determining the local or systemic context in which IL-1α can contribute to disease and/or physiological processes.Work was funded by British Heart Foundation Grants FS/13/3/30038, FS/18/19/33371 and RG/16/8/32388 to MCHC, the BHF Cambridge CRE RE/13/6/30180, and the Cambridge NIHR Biomedical Research Centr

Estimation of colorectal adenoma recurrence with dependent censoring

<p>Abstract</p> <p>Background</p> <p>Due to early colonoscopy for some participants, interval-censored observations can be introduced into the data of a colorectal polyp prevention trial. The censoring could be dependent of risk of recurrence if the reasons of having early colonoscopy are associated with recurrence. This can complicate estimation of the recurrence rate.</p> <p>Methods</p> <p>We propose to use midpoint imputation to convert interval-censored data problems to right censored data problems. To adjust for potential dependent censoring, we use information from auxiliary variables to define risk groups to perform the weighted Kaplan-Meier estimation to the midpoint imputed data. The risk groups are defined using two risk scores derived from two working proportional hazards models with the auxiliary variables as the covariates. One is for the recurrence time and the other is for the censoring time. The method described here is explored by simulation and illustrated with an example from a colorectal polyp prevention trial.</p> <p>Results</p> <p>We first show that midpoint imputation under an assumption of independent censoring will produce an unbiased estimate of recurrence rate at the end of the trial, which is often the main interest of a colorectal polyp prevention trial, and then show in simulations that the weighted Kaplan-Meier method using the information from auxiliary variables based on the midpoint imputed data can improve efficiency in a situation with independent censoring and reduce bias in a situation with dependent censoring compared to the conventional methods, while estimating the recurrence rate at the end of the trial.</p> <p>Conclusion</p> <p>The research in this paper uses midpoint imputation to handle interval-censored observations and then uses the information from auxiliary variables to adjust for dependent censoring by incorporating them into the weighted Kaplan-Meier estimation. This approach can handle a situation with multiple auxiliary variables by deriving two risk scores from two working PH models. Although the idea of this approach might appear simple, the results do show that the weighted Kaplan-Meier approach can gain efficiency and reduce bias due to dependent censoring.</p