Smac Mimetics and TNFalpha: A Dangerous Liaison?

Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. It has been thought that small-molecule mimetics of Smac, an endogenous IAP antagonist, might potentiate apoptosis in cancer cells by promoting caspase activation. However, three recent papers, two in Cell (Vince et al., 2007; Varfolomeev et al., 2007) and one in Cancer Cell (Petersen et al., 2007), now report that Smac mimetics primarily kill cancer cells via a different mechanism, the induction of autoubiquitination and degradation of cIAPs, which culminates in TNFalpha-mediated cell death

Superadiabatic dynamical density functional study of Brownian hard-spheres in time-dependent external potentials

Superadiabatic dynamical density functional theory (superadiabatic-DDFT), a first-principles approach based on the inhomogeneous two-body correlation functions, is employed to investigate the response of interacting Brownian particles to time-dependent external driving. Predictions for the superadiabatic dynamics of the one-body density are made directly from the underlying interparticle interactions, without need for either adjustable fit parameters or simulation input. The external potentials we investigate have been chosen to probe distinct aspects of structural relaxation in dense, strongly interacting liquid states. Nonequilibrium density profiles predicted by the superadiabatic theory are compared with those obtained from both adiabatic DDFT and event-driven Brownian dynamics simulation. Our findings show that superadiabatic-DDFT accurately predicts the time-evolution of the one-body density

Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex

Proteins of the death domain (DD) superfamily mediate assembly of oligomeric signaling complexes for the activation of caspases and kinases via unknown mechanisms. Here we report the crystal structure of the PIDD DD and RAIDD DD complex, which forms the core of the caspase-2-activating complex PIDDosome. Although RAIDD DD and PIDD DD are monomers, they assemble into a complex that comprises seven RAIDD DDs and five PIDD DDs. Despite the use of an asymmetric assembly mechanism, all DDs in the complex are in quasi-equivalent environments. The structure provided eight unique asymmetric interfaces, which can be classified into three types. These three types of interactions together cover a majority of the DD surface. Mutagenesis on almost all interfaces leads to disruption of the assembly, resulting in defective caspase-2 activation. The three types of interactions may represent most, if not all, modes of interactions in the DD superfamily for assembling complexes of different stoichiometry

Mean-Field Theory of Inhomogeneous Fluids

The Barker-Henderson perturbation theory is a bedrock of liquid-state physics, providing quantitative predictions for the bulk thermodynamic properties of realistic model systems. However, this successful method has not been exploited for the study of inhomogeneous systems. We develop and implement a first-principles 'Barker-Henderson density functional', thus providing a robust and quantitatively accurate theory for classical fluids in external fields. Numerical results are presented for the hard-core Yukawa model in three dimensions. Our predictions for the density around a fixed test particle and between planar walls are in very good agreement with simulation data. The density profiles for the free liquid vapour interface show the expected oscillatory decay into the bulk liquid as the temperature is reduced towards the triple point, but with an amplitude much smaller than that predicted by the standard mean-field density functional

ER stress activates the NLRP3 inflammasome via an UPR-independent pathway

Uncontrolled endoplasmic reticulum (ER) stress responses are proposed to contribute to the pathology of chronic inflammatory diseases such as type 2 diabetes or atherosclerosis. However, the connection between ER stress and inflammation remains largely unexplored. Here, we show that ER stress causes activation of the NLRP3 inflammasome, with subsequent release of the pro-inflammatory cytokine interleukin-1β. This ER-triggered proinflammatory signal shares the same requirement for reactive oxygen species production and potassium efflux compared with other known NLRP3 inflammasome activators, but is independent of the classical unfolded protein response (UPR). We thus propose that the NLRP3 inflammasome senses and responds to ER stress downstream of a previously uncharacterized ER stress response signaling pathway distinct from the UPR, thus providing mechanistic insight to the link between ER stress and chronic inflammatory diseases

Quantifying the Energetics and Length Scales of Carbon Segregation to Fe Symmetric Tilt Grain Boundaries Using Atomistic Simulations

Segregation of impurities to grain boundaries plays an important role in both the stability and macroscopic behavior of polycrystalline materials. The research objective in this work is to better characterize the energetics and length scales involved with the process of solute and impurity segregation to grain boundaries. Molecular dynamics simulations are used to calculate the segregation energies for carbon within multiple grain boundary sites over a database of 125 symmetric tilt grain boundaries in Fe. The simulation results show that the majority of atomic sites near the grain boundary have segregation energies lower than in the bulk. Moreover, depending on the boundary, the segregation energies approach the bulk value approximately 5-12 \AA\ away from the center of the grain boundary, providing an energetic length scale for carbon segregation. A subsequent data reduction and statistical representation of this dataset provides critical information such as about the mean segregation energy and the associated energy distributions for carbon atoms as a function of distance from the grain boundary, which quantitatively informs higher scale models with energetics and length scales necessary for capturing the segregation behavior of impurities in Fe. The significance of this research is the development of a methodology capable of ascertaining segregation energies over a wide range of grain boundary character (typical of that observed in polycrystalline materials), which herein has been applied to carbon segregation in a specific class of grain boundaries in iron

Molecular epidemiology of tuberculosis in the Somali region, eastern Ethiopia

Background: Tuberculosis (TB) is one of the leading causes of morbidity and mortality in low-income countries like Ethiopia. However, because of the limited laboratory infrastructure there is a shortage of comprehensive data on the genotypes of clinical isolates of Mycobacterium tuberculosis (M. tuberculosis) complex (MTBC) in peripheral regions of Ethiopia. The objective of this study was to characterize MTBC isolates in the Somali region of eastern Ethiopia. Methods: A cross-sectional study was conducted in three health institutions between October 2018 and December 2019 in the capital of Somali region. A total of 323 MTBC isolates (249 from pulmonary TB and 74 from extrapulmonary TB) were analyzed using regions of difference 9 (RD 9)-based polymerase chain reaction (PCR) and spoligotyping. Results: Of the 323 MTBC isolates, 99.7% (95% CI: 99.1-100%) were M. tuberculosis while the remaining one isolate was M. bovis based on RD 9-based PCR. Spoligotyping identified 71 spoligotype patterns; 61 shared types and 10 orphans. A majority of the isolates were grouped in shared types while the remaining grouped in orphans. The M. tuberculosis lineages identified in this study were lineage 1, 2, 3, 4, and 7 with the percentages of 7.4, 2.2, 28.2, 60.4, and 0.6%, respectively. Most (87.9%) of the isolates were classified in clustered spoligotypes while the remaining 12.1% isolates were singletons. The predominant clustered spoligotypes identified were SIT 149, SIT 21, SIT 26, SIT 53, and SIT 52, each consisting of 17.6, 13.3, 8.4, 7.4, and 5%, respectively. Lineage 3 and lineage 4, as well as the age group (15-24), were associated significantly with clustering. Conclusion: The MTBC isolated from TB patients in Somali region were highly diverse, with considerable spoligotype clustering which suggests active TB transmission. In addition, the Beijing spoligotype was isolated in relatively higher frequency than the frequencies of its isolation from the other regions of Ethiopia warranting the attention of the TB Control Program of the Somali region