A current paradigm proposes that mitochondrial damage is a critical determinant of NLRP3 inflammasome activation. Here, we genetically assess whether mitochondrial signalling represents a unified ...mechanism to explain how NLRP3 is activated by divergent stimuli. Neither co‐deletion of the essential executioners of mitochondrial apoptosis BAK and BAX, nor removal of the mitochondrial permeability transition pore component cyclophilin D, nor loss of the mitophagy regulator Parkin, nor deficiency in MAVS affects NLRP3 inflammasome function. In contrast, caspase‐8, a caspase essential for death‐receptor‐mediated apoptosis, is required for efficient Toll‐like‐receptor‐induced inflammasome priming and cytokine production. Collectively, these results demonstrate that mitochondrial apoptosis is not required for NLRP3 activation, and highlight an important non‐apoptotic role for caspase‐8 in regulating inflammasome activation and pro‐inflammatory cytokine levels.
Synopsis
Mitochondria are believed to have an important role in NLRP3 activation. Using 14 strains of knockout mice, this study finds no evidence for the involvement of mitochondrial damage in NLRP3 function, but shows that caspase‐8 is needed for inflammasome priming.
The essential mitochondrial apoptosis executioners, BAX and BAK are not required for NLRP3 activation.
Genetic deletion of the mitochondrial permeability transition pore component cyclophilin D, the mitochondrial anti‐viral signalling protein (MAVS) or the mitophagy regulator Parkin does not impact on NLRP3 activity.
Caspase‐8 expression is required for efficient inflammasome priming and Toll‐like‐receptor‐induced cytokine production.
Mitochondria are believed to have an important role in NLRP3 activation. Using 14 strains of knockout mice, this study finds no evidence for the involvement of mitochondrial damage in NLRP3 function, but shows that caspase‐8 is needed for inflammasome priming.
•Community-based extension relies on social relationships with farmers to increase the trust in and effectiveness of extension activities.•We find that, much like in social relationships, personality ...characteristics may influence who benefits from community-based extension programs.•More extraverted farmers were more likely to discuss bean farming with a larger proportion of farmers in their villages.•More sociable farmers were also more likely to benefit from the distribution of trial packs of improved bean seed.
Community-based extension relies on social relationships with farmers to increase the trust in and effectiveness of extension activities. Personality traits play an important role in social outcomes. We develop a conceptual model which shows that farmer personality can influence the likelihood of being aware of and incorporating information from community-based extension activities. We then examine this heterogeneity empirically leveraging a previously implemented randomized control trial and a dataset of Big Six personality traits (agency, agreeableness, openness to experience, neuroticism, extraversion, and conscientiousness) for bean farmers in the Mbeya Region of Tanzania. We find that more extraverted farmers residing in villages where community extension agents were randomly selected to distribute trial packs of improved bean seed along with a demonstration plot comparison (rather than a demonstration plot comparison alone) were more likely to adopt the improved bean varieties. These farmers were also more likely to discuss bean farming with a larger proportion of farmers in their villages, indicating that the benefits of the trial pack treatment may have been greater for more sociable farmers. Our findings suggest that community-based extension effectiveness may be increased by considering the role of personality in the quality and quantity of farmers’ interactions within their communities.
For most Americans, the savings and loan industry is defined by the fraud, ineptitude and failures of the 1980s. However, these events overshadow a long history in which thrifts played a key role in ...helping thousands of households buy homes. First appearing in the 1830s savings and loans, then known as building and loans, encourage their working-class members to adhere to the principles of thrift and mutual co-operation as a way to achieve the 'American Dream' of home ownership. This book traces the development of this industry from its origins as a movement of a loosely affiliated collection of institutions into a major element of America's financial markets. It also analyses how diverse groups of Americans, including women, ethnic Americans and African Americans, used thrifts to improve their lives and elevate their positions in society. Finally the overall historical perspective sheds new light on the events of the 1980s and analyses the efforts to rehabilitate the industry in the 1990s.
Crohn's disease (CD) is a chronic inflammatory intestinal disorder associated with intestinal dysbiosis. Diet modulates the intestinal microbiome and therefore has a therapeutic potential. The aim of ...this study is to determine the potential efficacy of three versions of the specific carbohydrate diet (SCD) in active Crohn's Disease.
18 patients with mild/moderate CD (PCDAI 15-45) aged 7 to 18 years were enrolled. Patients were randomized to either SCD, modified SCD(MSCD) or whole foods (WF) diet. Patients were evaluated at baseline, 2, 4, 8 and 12 weeks. PCDAI, inflammatory labs and multi-omics evaluations were assessed.
Mean age was 14.3 ± 2.9 years. At week 12, all participants (n = 10) who completed the study achieved clinical remission. The C-reactive protein decreased from 1.3 ± 0.7 at enrollment to 0.9 ± 0.5 at 12 weeks in the SCD group. In the MSCD group, the CRP decreased from 1.6 ± 1.1 at enrollment to 0.7 ± 0.1 at 12 weeks. In the WF group, the CRP decreased from 3.9 ± 4.3 at enrollment to 1.6 ± 1.3 at 12 weeks. In addition, the microbiome composition shifted in all patients across the study period. While the nature of the changes was largely patient specific, the predicted metabolic mode of the organisms increasing and decreasing in activity was consistent across patients.
This study emphasizes the impact of diet in CD. Each diet had a positive effect on symptoms and inflammatory burden; the more exclusionary diets were associated with a better resolution of inflammation.
The intestinal extracellular matrix (ECM) helps maintain appropriate tissue barrier function and regulate host-microbial interactions. Chondroitin sulfate- and dermatan sulfate-glycosaminoglycans ...(CS/DS-GAGs) are integral components of the intestinal ECM, and alterations in CS/DS-GAGs have been shown to significantly influence biological functions. Although pathologic ECM remodeling is implicated in inflammatory bowel disease (IBD), it is unknown whether changes in the intestinal CS/DS-GAG composition are also linked to IBD in humans. Our aim was to characterize changes in the intestinal ECM CS/DS-GAG composition in intestinal biopsy samples from patients with IBD using mass spectrometry. We characterized intestinal CS/DS-GAGs in 69 pediatric and young adult patients (n = 13 control, n = 32 active IBD, n = 24 IBD in remission) and 6 adult patients. Here, we report that patients with active IBD exhibit a significant decrease in the relative abundance of CS/DS isomers associated with matrix stability (CS-A and DS) compared to controls, while isomers implicated in matrix instability and inflammation (CS-C and CS-E) were significantly increased. This imbalance of intestinal CS/DS isomers was restored among patients in clinical remission. Moreover, the abundance of pro-stabilizing CS/DS isomers negatively correlated with clinical disease activity scores, whereas both pro-inflammatory CS-C and CS-E content positively correlated with disease activity scores. Thus, pediatric patients with active IBD exhibited increased pro-inflammatory and decreased pro-stabilizing CS/DS isomer composition, and future studies are needed to determine whether changes in the CS/DS-GAG composition play a pathogenic role in IBD.
Scattered-site housing with Intensive Case Management (ICM) may be an appropriate and less-costly option for homeless adults with mental illness who do not require the treatment intensity of ...Assertive Community Treatment.
To examine the effect of scattered-site housing with ICM services on housing stability and generic quality of life among homeless adults with mental illness and moderate support needs for mental health services.
The At Home/Chez Soi project was an unblinded, randomized trial. From October 2009 to July 2011, participants (N = 1198) were recruited in 4 Canadian cities (Vancouver, Winnipeg, Toronto, and Montreal), randomized to the intervention group (n = 689) or usual care group (n = 509), and followed up for 24 months.
The intervention consisted of scattered-site housing (using rent supplements) and off-site ICM services. The usual care group had access to existing housing and support services in their communities.
The primary outcome was the percentage of days stably housed during the 24-month period following randomization. The secondary outcome was generic quality of life, assessed by a EuroQoL 5 Dimensions (EQ-5D) health questionnaire.
During the 24 months after randomization, the adjusted percentage of days stably housed was higher among the intervention group than the usual care group, although adjusted mean differences varied across sites. table: see text The mean change in EQ-5D score from baseline to 24 months among the intervention group was not statistically different from the usual care group (60.5 95%CI, 58.6 to 62.5 at baseline and 67.2 95%CI, 65.2 to 69.1 at 24 months for the intervention group vs 62.1 95% CI, 59.9 to 64.4 at baseline and 68.6 95%CI, 66.3 to 71.0 at 24 months for the usual care group, difference in mean changes, 0.10 95%CI, −2.92 to 3.13, P=.95).
Among homeless adults with mental illness in 4 Canadian cities, scattered site housing with ICM services compared with usual access to existing housing and community services resulted in increased housing stability over 24 months, but did not improve generic quality of life.
isrctn.org Identifier: ISRCTN42520374.
Infections by carbapenem-resistant Enterobacteriaceae are difficult to manage owing to broad antibiotic resistance profiles and because of the inability of clinically used β-lactamase inhibitors to ...counter the activity of metallo-β-lactamases often harbored by these pathogens. Of particular importance is New Delhi metallo-β-lactamase (NDM), which requires a di-nuclear zinc ion cluster for catalytic activity. Here, we compare the structures and functions of clinical NDM variants 1–17. The impact of NDM variants on structure is probed by comparing melting temperature and refolding efficiency and also by spectroscopy (UV-visible, 1H NMR, and EPR) of di-cobalt metalloforms. The impact of NDM variants on function is probed by determining the minimum inhibitory concentrations of various antibiotics, pre-steady–state and steady-state kinetics, inhibitor binding, and zinc dependence of resistance and activity. We observed only minor differences among the fully loaded di-zinc enzymes, but most NDM variants had more distinguishable selective advantages in experiments that mimicked zinc scarcity imposed by typical host defenses. Most NDM variants exhibited improved thermostability (up to ∼10 °C increased Tm) and improved zinc affinity (up to ∼10-fold decreased Kd, Zn2). We also provide first evidence that some NDM variants have evolved the ability to function as mono-zinc enzymes with high catalytic efficiency (NDM-15, ampicillin: kcat/Km = 5 × 106m−1 s−1). These findings reveal the molecular mechanisms that NDM variants have evolved to overcome the combined selective pressures of β-lactam antibiotics and zinc deprivation.
L-histidine decarboxylase and Tourette's syndrome Ercan-Sencicek, A Gulhan; Stillman, Althea A; Ghosh, Ananda K ...
Nature reviews. Neuroscience,
05/2010, Letnik:
362, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Tourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles ...have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.
The use of asymmetrical strokes is common in freestyle swimming because of breathing and strength laterality. In this study, the asymmetrical freestyle swimming performance of a male elite level ...swimmer who breathed every second arm stroke (unilaterally) was investigated. A laser body scan and multi-angle video footage of the athlete were used to generate a swimming biomechanical model. This model was then used in a Smoothed Particle Hydrodynamics (SPH) fluid simulation of swimming through a virtual pool. The results from this study enabled the kinematic asymmetry to be related to the consequential fluid dynamic asymmetry. The intra-cyclic fluctuations in the streamwise forces and speed were also examined. Hand angles of attack were compared along with the lift and drag contributions of the hands to generating the streamwise thrust. From this study, connections between asymmetry and the resultant swimming performance were identified.
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