Necroptosis, pyroptosis and apoptosis: an intricate game of cell death

Cell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity. In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially. Different modalities of what has become known as \u27programmed cell death\u27 have been described, and some key players in these processes have been identified. We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death. These studies have highlighted the complex mechanisms tipping the balance between different cell fates. Here, we summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis, highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole

Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation

Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1beta and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K (+) efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca (2+) fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation

Fluorescent markers of the microtubule cytoskeleton in Zymoseptoria tritici

AbstractThe microtubule cytoskeleton supports vital processes in fungal cells, including hyphal growth and mitosis. Consequently, it is a target for fungicides, such as benomyl. The use of fluorescent fusion proteins to illuminate microtubules and microtubule-associated proteins has led to a break-through in our understanding of their dynamics and function in fungal cells. Here, we introduce fluorescent markers to visualize microtubules and accessory proteins in the wheat pathogen Zymoseptoria tritici. We fused enhanced green-fluorescent protein to α-tubulin (ZtTub2), to ZtPeb1, a homologue of the mammalian plus-end binding protein EB1, and to ZtGrc1, a component of the minus-end located γ-tubulin ring complex, involved in the nucleation of microtubules. In vivo observation confirms the localization and dynamic behaviour of all three markers. These marker proteins are useful tools for understanding the organization and importance of the microtubule cytoskeleton in Z. tritici

Model Reduction for Multiscale Lithium-Ion Battery Simulation

In this contribution we are concerned with efficient model reduction for multiscale problems arising in lithium-ion battery modeling with spatially resolved porous electrodes. We present new results on the application of the reduced basis method to the resulting instationary 3D battery model that involves strong non-linearities due to Buttler-Volmer kinetics. Empirical operator interpolation is used to efficiently deal with this issue. Furthermore, we present the localized reduced basis multiscale method for parabolic problems applied to a thermal model of batteries with resolved porous electrodes. Numerical experiments are given that demonstrate the reduction capabilities of the presented approaches for these real world applications

Largest Lyapunov Exponent for Many Particle Systems at Low Densities

The largest Lyapunov exponent $\lambda^+$ for a dilute gas with short range interactions in equilibrium is studied by a mapping to a clock model, in which every particle carries a watch, with a discrete time that is advanced at collisions. This model has a propagating front solution with a speed that determines $\lambda^+$, for which we find a density dependence as predicted by Krylov, but with a larger prefactor. Simulations for the clock model and for hard sphere and hard disk systems confirm these results and are in excellent mutual agreement. They show a slow convergence of $\lambda^+$ with increasing particle number, in good agreement with a prediction by Brunet and Derrida.Comment: 4 pages, RevTeX, 2 Figures (encapsulated postscript). Submitted to Phys. Rev. Let

Vertical migration, feeding and colouration in the mesopelagic shrimp Sergestes arcticus

Intraspecific variation in vertical distribution, timing of vertical migration, and colouration of the mesopelagic shrimp Sergestes arcticus were studied in the >400 m deep part of Masfjorden, Norway. Very few individuals were caught in the upper strata during daytime, and larger individuals occurred deeper during the day than smaller ones. Vertical migration was prominent and no overall trend of increasing length with depth was found at night. Small individuals arrived in the upper layers earlier than larger ones. Animal colouration assessed by digital photography revealed significant variance in individual redness. Depth of capture was the most important factor explaining colouration, with increasing degree of redness with depth. Assessing the gut fullness of the transparent shrimps provided a rapid way of estimating feeding activity and showed that feeding took place mainly at night

Chaotic Properties of Dilute Two and Three Dimensional Random Lorentz Gases II: Open Systems

We calculate the spectrum of Lyapunov exponents for a point particle moving in a random array of fixed hard disk or hard sphere scatterers, i.e. the disordered Lorentz gas, in a generic nonequilibrium situation. In a large system which is finite in at least some directions, and with absorbing boundary conditions, the moving particle escapes the system with probability one. However, there is a set of zero Lebesgue measure of initial phase points for the moving particle, such that escape never occurs. Typically, this set of points forms a fractal repeller, and the Lyapunov spectrum is calculated here for trajectories on this repeller. For this calculation, we need the solution of the recently introduced extended Boltzmann equation for the nonequilibrium distribution of the radius of curvature matrix and the solution of the standard Boltzmann equation. The escape-rate formalism then gives an explicit result for the Kolmogorov Sinai entropy on the repeller.Comment: submitted to Phys Rev

Chaotic Properties of Dilute Two and Three Dimensional Random Lorentz Gases I: Equilibrium Systems

We compute the Lyapunov spectrum and the Kolmogorov-Sinai entropy for a moving particle placed in a dilute, random array of hard disk or hard sphere scatterers - i.e. the dilute Lorentz gas model. This is carried out in two ways: First we use simple kinetic theory arguments to compute the Lyapunov spectrum for both two and three dimensional systems. In order to provide a method that can easily be generalized to non-uniform systems we then use a method based upon extensions of the Lorentz-Boltzmann (LB) equation to include variables that characterize the chaotic behavior of the system. The extended LB equations depend upon the number of dimensions and on whether one is computing positive or negative Lyapunov exponents. In the latter case the extended LB equation is closely related to an "anti-Lorentz-Boltzmann equation" where the collision operator has the opposite sign from the ordinary LB equation. Finally we compare our results with computer simulations of Dellago and Posch and find very good agreement.Comment: 48 pages, 3 ps fig

Foresight Review on Design for Safety

This review explores how a culture of design for safety can enhance the safety of the world around us. Design for safety goes beyond legislation, regulations and standards. These all play an important role for established products and services but their limited scope often leads to missed opportunities to enhance safety by taking a broader perspective. Design is applied to both mature industries (which have many years of experience and a good understanding of risks and how to reduce them) and emerging industries (that use new technologies requiring new ways of controlling risk which may not yet be known or understood). An example of an emerging risk is the internet that is enabling rapid innovation of new products which generate data. This data is widely shared across the internet and the risks associated with this are as yet not fully understood by the public. A design for safety culture takes a holistic approach to understanding the influences that affect safety. Such influences are varied and take into account the broader environment within which design operates, including complex interactions, behaviour and culture. It goes beyond traditional design methods and focuses on the goal of a safer design. Implementing design for safety requires an understanding of the challenges and the methods to address them. It needs multidisciplinary teams that bring together people with the relevant skills to understand the challenges and a collaborative approach of ‘designing with’ rather than the more traditional approach of ‘designing for’. This can be achieved through an international diverse community that works together to identify and share best practices

Novel approaches for the serodiagnosis of louse-borne relapsing fever

Louse-borne relapsing fever (LBRF) caused by B. recurrentis is a poverty-related and neglected infectious disease with an endemic focus in the Horn of Africa. Re-emergence of the disease occurred in Europe during the refugee crisis in 2015 and sporadic outbreaks were frequently reported in Eastern Africa where poor settings lack affordable diagnostics. Currently, there are no validated in vitro assays available for the serodiagnosis of LBRF. The aim of this study was to develop novel and reliable immunoassays by investigating clinically suspected and culture-confirmed serum samples from LBRF patients and a broad panel of serum samples from patients with other spirochetal, bacterial, and parasitic diseases. We identified two immunoreactive antigens (complement-inhibiting protein CihC and the glycerophosphodiester phosphodiesterase GlpQ of B. recurrentis) as the most promising target candidates leading to the evaluation of two immunoassays (line immunoblot and ELISA) for IgM and IgG. To optimize the IgM immunoassay, we conducted a bioinformatic approach to localize the relevant immunogenic regions within CihC. By utilizing a N-terminal CihC fragment, the sensitivity and specificity of both immunoassays (CihC and GlpQ) were high (IgM: sensitivity 100%, specificity of 89.9%, IgG: sensitivity 100%, specificity 99.2%). In conclusion, our findings indicate the diagnostic potential of CihC and GlpQ as valuable markers for the serodiagnosis of LBRF even at early time points of infection. Here, we provide strong evidence for the utilization of these immunoassays as reliable tools in clinical practice