Inhibiting the NLRP3 Inflammasome

Inflammasomes are protein complexes which are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18. The inflammasome most studied in sterile inflammation and non-communicable disease is the NLRP3 inflammasome. Upon activation by diverse pathogen or disease associated signals, NLRP3 nucleates the oligomerization of an adaptor protein ASC forming a platform (the inflammasome) for the recruitment and activation of the protease caspase-1. Active caspase-1 catalyzes the processing and release of IL-1β and IL-18, and via cleavage of the pore forming protein gasdermin D can drive pyroptotic cell death. This review focuses on the structural basis and mechanism for NLRP3 inflammasome signaling in the context of drug design, providing chemical structures, activities, and clinical potential of direct inflammasome inhibitors. A cryo-EM structure of NLRP3 bound to NEK7 protein provides structural insight and aids in the discovery of novel NLRP3 inhibitors utilizing ligand-based or structure-based approaches

Community Foundations: Egypt

This paper deals with community foundations in Egyp

Deep electronic states in ion-implanted Si

In this paper we present an overview of the deep states present after ion-implantation by various species into n-type silicon, measured by Deep Level Transient Spectroscopy (DLTS) and high resolution Laplace DLTS (LDLTS). Both point and small extended defects are found, prior to any anneal, which can therefore be the precursors to more detrimental defects such as end of range loops. We show that the ion mass is linked to the concentrations of defects that are observed, and the presence of small interstitial clusters directly after ion implantation is established by comparing their behaviour with that of electrically active stacking faults. Finally, future applications of the LDLTS technique to ion-implanted regions in Si-based devices are outlined.</p

Evaluation of ‘Shisha No Thanks’ – a co-design social marketing campaign on the harms of waterpipe smoking

Waterpipe (shisha) is becoming increasingly popular worldwide, particularly among young people; and in some countries, it is one of the few forms of tobacco use that is increasing. While there is a growing body of evidence of the harms of waterpipe smoke, there is a scarcity of research of interventions to address this form of tobacco consumption

Behavioral states may be associated with distinct spatial patterns in electrocorticogram

To determine if behavioral states are associated with unique spatial electrocorticographic (ECoG) patterns, we obtained recordings with a microgrid electrode array applied to the cortical surface of a human subject. The array was constructed with the intent of extracting maximal spatial information by optimizing interelectrode distances. A 34-year-old patient with intractable epilepsy underwent intracranial ECoG monitoring after standard methods failed to reveal localization of seizures. During the 8-day period of invasive recording, in addition to standard clinical electrodes a square 1 × 1 cm microgrid array with 64 electrodes (1.25 mm separation) was placed on the right inferior temporal gyrus. Careful review of video recordings identified four extended naturalistic behaviors: reading, conversing on the telephone, looking at photographs, and face-to-face interactions. ECoG activity recorded with the microgrid that corresponded to these behaviors was collected and ECoG spatial patterns were analyzed. During periods of ECoG selected for analysis, no electrographic seizures or epileptiform patterns were present. Moments of maximal spatial variance are shown to cluster by behavior. Comparisons between conditions using a permutation test reveal significantly different spatial patterns for each behavior. We conclude that ECoG recordings obtained on the cortical surface with optimal high spatial frequency resolution reveal distinct local spatial patterns that reflect different behavioral states, and we predict that similar patterns will be found in many if not most cortical areas on which a microgrid is placed

Treatment outcomes of patients on Second-line Antiretroviral Therapy in resource-limited settings: A Systematic Review and Meta-Analysis

A growing proportion of patients on antiretroviral therapy in resource-limited settings have switched to second-line regimens. We carried out a systematic review in order to summarize reported rates and reasons for virological failure among people on second-line therapy in resource-limited settings

Application of ¹⁴C analyses to source apportionment of carbonaceous PM_2.5 in the UK

Determination of the radiocarbon (&lt;sup&gt;14&lt;/sup&gt;C) content of airborne particulate matter yields insight into the proportion of the carbonaceous material derived from fossil and contemporary carbon sources. Daily samples of PM&lt;sub&gt;2.5&lt;/sub&gt; were collected by high-volume sampler at an urban background site in Birmingham, UK, and the fraction of &lt;sup&gt;14&lt;/sup&gt;C in both the total carbon, and in the organic and elemental carbon fractions, determined by two-stage combustion to CO&lt;sub&gt;2&lt;/sub&gt;, graphitisation and quantification by accelerator mass spectrometry. OC and EC content was also determined by Sunset Analyzer. The mean fraction contemporary TC in the PM&lt;sub&gt;2.5&lt;/sub&gt; samples was 0.50 (range 0.27–0.66, n = 26). There was no seasonality to the data, but there was a positive trend between fraction contemporary TC and magnitude of SOC/TC ratio and for the high values of these two parameters to be associated with air-mass back trajectories arriving in Birmingham from over land. Using a five-compartment mass balance model on fraction contemporary carbon in OC and EC, the following average source apportionment for the TC in these PM&lt;sub&gt;2.5&lt;/sub&gt; samples was derived: 27% fossil EC; 20% fossil OC; 2% biomass EC; 10% biomass OC; and 41% biogenic OC. The latter category will comprise, in addition to BVOC-derived SOC, other non-combustion contemporary carbon sources such as biological particles, vegetative detritus, humic material and tyre wear. The proportion of total PM&lt;sub&gt;2.5&lt;/sub&gt; at this location estimated to derive from BVOC-derived secondary organic aerosol was 9–29%. The findings from this work are consistent with those from elsewhere in Europe and support the conclusion of a significant and ubiquitous contribution from non-fossil biogenic sources to the carbon in terrestrial aerosol

A record-linkage study of the development of hepatocellular carcinoma in persons with hepatitis C infection in Scotland

We investigated trends in first time hospital admissions and deaths attributable to hepatocellular carcinoma (HCC) in a large population based cohort of 22 073 individuals diagnosed with hepatitis C viral (HCV) infection through laboratory testing in Scotland in 1991 2006. We identified new cases of HCC through record linkage to the national inpatient hospital discharge database and deaths registry. A total of 172 persons diagnosed with HCV were admitted to hospital or died with first time mention of HCC. Hepatocellular carcinoma incidence increased between 1996 and 2006 (average annual change of 6.1, 95% confidence interval (CI):0.9 11.6%, P¼0.021). The adjusted relative risk of HCC was greater for males (hazard ratio¼2.7, 95% CI: 1.7 4.2), for those aged 60 years or older (hazard ratio ¼2.7, 95% CI: 1.9 4.1) compared with 50 59 years, and for those with a previous alcohol related hospital admission (hazard ratio¼2.5, 95% CI: 1.7 3.7). The risk of individuals diagnosed with HCV developing HCC was greatlyincreased compared with the general Scottish population (standardised incidence ratio¼127, 95% CI: 102 156). Owing to the advancing age of the Scottish HCV diagnosed population, the annual number of HCC cases is projected to increase, with a consequent increasing burden on the public healthcare system

Racial and ethnic disparities in access to liver transplantation

Access to liver transplantation is reportedly inequitable for racial/ethnic minorities, but inadequate adjustments for geography and disease progression preclude any meaningful conclusions. We aimed to evaluate the association between candidate race/ethnicity and liver transplant rates after thorough adjustments for these factors and to determine how uniform racial/ethnic disparities were across Model for End-Stage Liver Disease (MELD) scores. Chronic end-stage liver disease candidates initially wait-listed between February 28, 2002 and February 27, 2007 were identified from Scientific Registry for Transplant Recipients data. The primary outcome was deceased donor liver transplantation (DDLT); the primary exposure covariate was race/ethnicity (white, African American, Hispanic, Asian, and other). Cox regression was used to estimate the covariate-adjusted DDLT rates by race/ethnicity, which were stratified by the donation service area and MELD score. With averaging across all MELD scores, African Americans, Asians, and others had similar adjusted DDLT rates in comparison with whites. However, Hispanics had an 8% lower DDLT rate versus whites [hazard ratio (HR) = 0.92, P = 0.011]. The disparity among Hispanics was concentrated among patients with MELD scores < 20, with HR = 0.84 ( P = 0.021) for MELD scores of 6 to 14 and HR = 0.85 ( P = 0.009) for MELD scores of 15 to 19. Asians with MELD scores < 15 had a 24% higher DDLT rate with respect to whites (HR = 1.24, P = 0.024). However, Asians with MELD scores of 30 to 40 had a 46% lower DDLT rate (HR = 0.54, P = 0.004). In conclusion, although African Americans did not have significantly different DDLT rates in comparison with similar white candidates, race/ethnicity-based disparities were prominent among subgroups of Hispanic and Asian candidates. By precluding the survival benefit of liver transplantation, this inequity may lead to excess mortality for minority candidates. Liver Transpl 16:1033–1040, 2010. © 2010 AASLD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78074/1/22108_ftp.pd