Since the end of the Cold War, more and more countries feature political regimes that are neither liberal democracies nor closed authoritarian systems. Most research on these hybrid regimes focuses ...on how elites manipulate elections to stay in office, but in places as diverse as Bolivia, Georgia, Kyrgyzstan, Serbia, Thailand, Ukraine and Venezuela, protest in the streets has been at least as important as elections in bringing about political change. The Politics of Protest in Hybrid Regimes builds on previously unpublished data and extensive fieldwork in Russia to show how one high-profile hybrid regime manages political competition in the workplace and in the streets. More generally, the book develops a theory of how the nature of organizations in society, state strategies for mobilizing supporters, and elite competition shape political protest in hybrid regimes.
Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 ...pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation.
We present the results of a new search for galaxies at redshift z ≃ 9 in the first two Hubble Frontier Fields with completed HST WFC3/IR and ACS imaging. To ensure robust photometric redshift ...solutions, and to minimize incompleteness, we confine our search to objects with H
160 < 28.6 (AB mag), consider only image regions with an rms noise σ160 > 30 mag (within a 0.5-arcsec diameter aperture), and insist on detections in both H
160 and J
140. The result is a survey covering an effective area (after accounting for magnification) of 10.9 arcmin2, which yields 12 galaxies at 8.4 < z < 9.5. Within the Abell-2744 cluster and parallel fields, we confirm the three brightest objects reported by Ishigaki et al., but recover only one of the four z > 8.4 sources reported by Zheng et al. In the MACSJ0416.1−240 cluster field, we report five objects, and explain why each of these eluded detection or classification as z ≃ 9 galaxies in the published searches of the shallower CLASH data. Finally, we uncover four z ≃ 9 galaxies from the MACSJ0416.1−240 parallel field. Based on the published magnification maps, we find that only one of these 12 galaxies is likely boosted by more than a factor of 2 by gravitational lensing. Consequently, we are able to perform a fairly straightforward reanalysis of the normalization of the z ≃ 9 UV galaxy luminosity function as explored previously in the HUDF12 programme. We conclude that the new data strengthen the evidence for a continued smooth decline in UV luminosity density (and hence star formation rate density) from z ≃ 8 to 9, contrary to recent reports of a marked drop-off at these redshifts. This provides further support for the scenario in which early galaxy evolution is sufficiently extended to explain cosmic reionization.
Target identification is a high-priority, albeit challenging, aspect of drug discovery. Diazirine-based photoaffinity probes (PAPs) can facilitate the process by covalently capturing transient ...molecular interactions. This can help identify target proteins and map the ligand’s interactome. Diazirine probes have even been incorporated by cellular machinery into proteins. Embarking on the synthesis of customized PAPs, containing either an aliphatic or trifluoromethyl phenyl diazirine, can be a considerable endeavor, particularly for medicinal chemists and chemical biologists new to the field. This review takes a synthetic focus, aiming to summarize available routes, propose new avenues, and illuminate recent advances in diazirine synthesis. Select examples of diazirine photoaffinity labeling applications have been included throughout to provide instructive definition of the advantages and limitations of the technology while simultaneously highlighting how these reagents can be applied in a practical sense.
Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of ...classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an “alternative inflammasome” that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K+ efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans.
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•LPS by itself triggers IL-1β secretion in human, but not in murine monocytes•Human monocytes activate an alternative inflammasome in response to LPS•This proceeds independently of K+ efflux, pyroptosome formation, and pyroptosis•Alternative but not classical inflammasome signals via TLR4-TRIF-RIPK1-FADD-CASP8
How human monocytes secrete processed IL-1β upon LPS challenge is unknown. Hornung and colleagues report that LPS triggers an alternative NLRP3 inflammasome pathway in human monocytes. Unlike classical NLRP3 inflammasome signaling, alternative inflammasome activation proceeds independently of potassium efflux, pyroptosome formation, and pyroptosis, while it engages TLR4-TRIF-RIPK1-FADD-CASP8 upstream of NLRP3.
There are a significant number of natural product (NP) drugs in development. We review the 100 NP and NP-derived compounds and 33 Antibody Drug Conjugates (ADCs) with a NP-derived cytotoxic component ...being evaluated in clinical trials or in registration at the end of 2013. 38 of these compounds and 33 ADCs are being investigated as potential oncology treatments, 26 as anti-infectives, 19 for the treatment of cardiovascular and metabolic diseases, 11 for inflammatory and related diseases and 6 for neurology. There was a spread of the NP and NP-derived compounds through the different development phases (17 in phase I, 52 in phase II, 23 in phase III and 8 NDA and/or MAA filed), while there were 23 ADCs in phase I and 10 in phase II. 50 of these 100 compounds were either NPs or semi-synthetic (SS) NPs, which indicated the original NP still plays an important role. NP and NP-derived compounds for which clinical trials have been halted or discontinued since 2008 are listed in the Supplementary Information. The 25 NP and NP-derived drugs launched since 2008 are also reviewed, and late stage development candidates and new NP drug pharmacophores analysed. The short term prospect for new NP and NP-derived drug approvals is bright, with 31 compounds in phase III or in registration, which should ensure a steady stream of approvals for at least the next five years. However, there could be future issues for new drug types as only five new drug pharmacophores discovered in the last 15 years are currently being evaluated in clinical trials. The next few years will be critical for NP-driven lead discovery, and a concerted effort is required to identify new biologically active pharmacophores and to progress these and existing compounds through pre-clinical drug development into clinical trials.
Humans encode two inflammatory caspases that detect cytoplasmic LPS, caspase‐4 and caspase‐5. When activated, these trigger pyroptotic cell death and caspase‐1‐dependent IL‐1β production; however the ...mechanism underlying this process is not yet confirmed. We now show that a specific NLRP3 inhibitor, MCC950, prevents caspase‐4/5‐dependent IL‐1β production elicited by transfected LPS. Given that both caspase‐4 and caspase‐5 can detect cytoplasmic LPS, it is possible that these proteins exhibit some degree of redundancy. Therefore, we generated human monocytic cell lines in which caspase‐4 and caspase‐5 were genetically deleted either individually or together. We found that the deletion of caspase‐4 suppressed cell death and IL‐1β production following transfection of LPS into the cytoplasm, or in response to infection with Salmonella typhimurium. Although deletion of caspase‐5 did not confer protection against transfected LPS, cell death and IL‐1β production were reduced after infection with Salmonella. Furthermore, double deletion of caspase‐4 and caspase‐5 had a synergistic effect in the context of Salmonella infection. Our results identify the NLRP3 inflammasome as the specific platform for IL‐1β maturation, downstream of cytoplasmic LPS detection by caspase‐4/5. We also show that both caspase‐4 and caspase‐5 are functionally important for appropriate responses to intracellular Gram‐negative bacteria.
We present a new determination of the ultraviolet (UV) galaxy luminosity function (LF) at redshift z 7 and 8, and a first estimate at z 9. An accurate determination of the form and evolution of the ...galaxy LF during this era is of key importance for improving our knowledge of the earliest phases of galaxy evolution and the process of cosmic reionization. Our analysis exploits to the full the new, deepest Wide Field Camera 3/infrared imaging from our Hubble Space Telescope (HST) Ultra-Deep Field 2012 (UDF12) campaign, with dynamic range provided by including a new and consistent analysis of all appropriate, shallower/wider area HST survey data. Our new measurement of the evolving LF at z 7 to 8 is based on a final catalogue of 600 galaxies, and involves a step-wise maximum-likelihood determination based on the photometric redshift probability distribution for each object; this approach makes full use of the 11-band imaging now available in the Hubble Ultra-Deep Field (HUDF), including the new UDF12 F140W data, and the latest Spitzer IRAC imaging. The final result is a determination of the z 7 LF extending down to UV absolute magnitudes M
1500 = −16.75 (AB mag) and the z 8 LF down to M
1500 = −17.00. Fitting a Schechter function, we find M1500
* = −19.90+0.23
−0.28, log φ* = −2.96+0.18
−0.23 and a faint-end slope α = −1.90+0.14
−0.15 at z 7, and M1500* = −20.12+0.37
−0.48, log φ* = −3.35+0.28
−0.47 and α = −2.02+0.22
+0.23 at z 8. These results strengthen previous suggestions that the evolution at z > 7 appears more akin to 'density evolution' than the apparent 'luminosity evolution' seen at z 5 − 7. We also provide the first meaningful information on the LF at z 9, explore alternative extrapolations to higher redshifts, and consider the implications for the early evolution of UV luminosity density. Finally, we provide catalogues (including derived z
phot, M
1500 and photometry) for the most robust z ∼ 6.5-11.9 galaxies used in this analysis. We briefly discuss our results in the context of earlier work and the results derived from an independent analysis of the UDF12 data based on colour-colour selection.
A key debate in the new literature on authoritarianism concerns the role of institutions in general and legislatures in particular. While much of the literature accepts that authoritarian ...legislatures matter, there is little agreement as to why and how. In this article, we argue that a key function of authoritarian legislatures is to help leaders reduce social protest. In contrast to existing literature, which stresses the representative function of authoritarian legislatures, we argue that legislatures reduce social protest by providing rent-seeking opportunities to key opposition elites who, in return for access to these spoils, demobilize their supporters. We test this argument using original data on the distribution of leadership positions in 83 Russian regional legislatures and two new datasets on opposition protest in Russia. Our findings suggest that legislative cooptation may extend the lifespan of authoritarian regimes by helping to reduce antiregime protest.
MCC950 a potent, highly specific small molecule inhibitor of canonical and noncanonical activation of NLRP3 inflammasome has been evaluated in a multitude of NLRP3 driven inflammatory diseases. ...However, the effect of MCC950 on colonic inflammation has not yet been reported. In the present study we investigated the effect of MCC950 in a spontaneous chronic colitis mouse model Winnie, which mimics human ulcerative colitis. Oral administration of 40 mg/kg MCC950 commencing at Winnie week seven for three weeks significantly improved body weight gain, colon length, colon weight to body weight ratio, disease activity index and histopathological scores. MCC950 significantly suppressed release of proinflammatory cytokines IL-1β, IL-18, IL1-α, IFNγ, TNF-α, IL6, IL17, chemokine MIP1a and Nitric Oxide in colonic explants. Moreover, MCC950 resulted in a significant decrease of IL-1β release and activation of caspase-1 in colonic explants and macrophage cells isolated from Winnie. Complete inhibition with MCC950 in Winnie colonic explants shows, for the first time, the contribution of inflammatory effects resulting exclusively from canonical and noncanonical NLRP3 inflammasome activation in colitis. Taken together, our results illustrate the efficacy of MCC950 in the treatment of murine ulcerative colitis and provides avenue for a potential novel therapeutic agent for human inflammatory bowel diseases.
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