Using Easton's 1965 definition that politics is the "authoritative allocation of values for a society" (8), this study examines values as expressed through the educational policies for the citizenry ...of the state. This study seeks to provide a frame work for understanding and setting forth generalizations about the way values (i.e. educational policy choices) are authoritatively allocated in the Texas State Legislature. This case study (Yin, 1989) of legislator value preferences and voting behavior within Texas educational policy culture is both descriptive and explanatory. It describes legislators' voting patterns and formulates explanatory generalizations about why the legislators vote the way they do. The primary data collection instruments are survey instruments administered to legislators and content analysis of legislation passed by the Texas State Legislature. The study employs qualitative and quantitative analysis techniques. The data have been coded and displayed to provide valid results and communication of a practical analysis (Miles & Huberman, 1984). The study found that the selected legislators claimed a preference for the individual value of efficiency. The least favored individual value was equity. Analysis of the bills relating to educational policy passed by this session (72nd Regular Session) confirmed that the legislators voted in accord with their stated preferences. This study's significance is twofold. First, it contributes to the development of theoretical generalizations and refines a framework for analyzing political culture and legislator voting behavior. Second, school administrators, state policymakers and the like can gain insights that will be useful in influencing the development of educational policies.
Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting ...heterotrimeric G protein Gi. Activation of CB1-Gi signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of Gi activation by CB1. Here, we present the structure of the CB1-Gi signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities. The structure illustrates how FUB stabilizes the receptor in an active state to facilitate nucleotide exchange in Gi. The results compose the structural framework to explain CB1 activation by different classes of ligands and provide insights into the G protein coupling and selectivity mechanisms adopted by the receptor.
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•3 Å cryo-EM structure of the CB1-Gi complex bound to potent agonist MDMB-Fubinaca•MDMB-Fubinaca locks “toggle switch” residues F2003.36/W3566.48 in active conformation•Quantum mechanics calculations reveal the mechanism for the high affinity of Fubinaca•Molecular dynamic simulations reveal a path for ligand entry between TM1 and TM7
Looking at how a toxic, synthetic ligand locks cannabinoid receptor 1 into a signaling conformation points to ways to understand and modulate receptor activity.
Abstract
Aims
Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic ...diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension.
Methods and results
C57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25–40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206+ (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, Na+, and albuminuria (each by 20–25%). None of the above parameters were altered by MCC950 in normotensive mice.
Conclusion
MCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy.
The functional divergence of duplicate genes (ohnologues) retained from whole genome duplication (WGD) is thought to promote evolutionary diversification. However, species radiation and phenotypic ...diversification are often temporally separated from WGD. Salmonid fish, whose ancestor underwent WGD by autotetraploidization ~95 million years ago, fit such a 'time-lag' model of post-WGD radiation, which occurred alongside a major delay in the rediploidization process. Here we propose a model, 'lineage-specific ohnologue resolution' (LORe), to address the consequences of delayed rediploidization. Under LORe, speciation precedes rediploidization, allowing independent ohnologue divergence in sister lineages sharing an ancestral WGD event.
Using cross-species sequence capture, phylogenomics and genome-wide analyses of ohnologue expression divergence, we demonstrate the major impact of LORe on salmonid evolution. One-quarter of each salmonid genome, harbouring at least 4550 ohnologues, has evolved under LORe, with rediploidization and functional divergence occurring on multiple independent occasions >50 million years post-WGD. We demonstrate the existence and regulatory divergence of many LORe ohnologues with functions in lineage-specific physiological adaptations that potentially facilitated salmonid species radiation. We show that LORe ohnologues are enriched for different functions than 'older' ohnologues that began diverging in the salmonid ancestor.
LORe has unappreciated significance as a nested component of post-WGD divergence that impacts the functional properties of genes, whilst providing ohnologues available solely for lineage-specific adaptation. Under LORe, which is predicted following many WGD events, the functional outcomes of WGD need not appear 'explosively', but can arise gradually over tens of millions of years, promoting lineage-specific diversification regimes under prevailing ecological pressures.
A portable, molecularly imprinted polymer (MIP)-based microneedle (MN) sensor for the electrochemical detection of imidacloprid (IDP) has been demonstrated. The MN sensor was fabricated via ...layer-by-layer (LbL) in-tube coating using a carbon nanotube (CNT)/cellulose nanocrystal (CNC) composite, and an IDP-imprinted polyaniline layer co-polymerized with imidazole-functionalized CNCs (PANI-co-CNC-Im) as the biomimetic receptor film. The sensor, termed MIP@CNT/CNC MN, was analyzed using both cyclic voltammetry (CV) and differential pulse voltammetry (DPV) and showed excellent electrochemical performance for the detection of IDP. The CV detection range for IDP was 2.0-99 µM, with limits of detection (LOD) of 0.35 µM, while the DPV detection range was 0.20-92 µM with an LOD of 0.06 µM. Additionally, the MIP@CNT/CNC MN sensor showed excellent reusability and could be used up to nine times with a 1.4 % relative standard deviation (% RSD) between uses. Lastly, the MIP@CNT/CNC MN sensor successfully demonstrated the quantification of IDP in a honey sample.
Background and Purpose
Inflammasomes are multimeric complexes that facilitate caspase‐1‐mediated processing of the pro‐inflammatory cytokines IL‐1β and IL‐18. Clinical hypertension is associated with ...renal inflammation and elevated circulating levels of IL‐1β and IL‐18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces BP, markers of renal inflammation and fibrosis.
Experimental Approach
Wild‐type and inflammasome‐deficient ASC−/− mice were uninephrectomized and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomized but received a placebo pellet and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real‐time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry.
Key Results
1K/DOCA/salt‐induced hypertension in mice was associated with increased renal mRNA expression of inflammasome subunits NLRP3, ASC and pro‐caspase‐1, and the cytokine, pro‐IL‐1β, as well as protein levels of active caspase‐1 and mature IL‐1β. Following treatment with 1K/DOCA/salt, ASC−/− mice displayed blunted pressor responses and were also protected from increases in renal expression of IL‐6, IL‐17A, CCL2, ICAM‐1 and VCAM‐1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt‐treated mice.
Conclusions and Implications
Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt treatment are dependent on inflammasome activity, highlighting the inflammasome/IL‐1β pathway as a potential therapeutic target in hypertension.
Linked Articles
This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4
Personality research is a growing field in political behavior, but most research to date is confined to democracies. We expand the scope to Russia, an authoritarian regime, and find that the impact ...of personality is substantial but different from the existing literature. We find that agreeableness, a personality trait associated with a desire to maintain positive relations with others that is usually peripheral to politics, becomes the single most important and consistent trait affecting attitudes. This perspective helps us to understand why individuals who are socioeconomically and demographically similar can have quite different attitudes to the regime. Our analysis also helps us to understand the mechanisms through which personality works and how it shapes attitudes to such important elements as religion and state propaganda. Our findings suggest a new, and empirically testable, mechanism behind situations in which regimes rapidly dissolve, including revolutions.
This study presents a novel approach to the detection of epinephrine, lactate, and cortisol biomarkers in human sweat using molecularly-imprinted polymers (MIP) embedded screen printed carbon ...electrode (SPCE) sensors. The epinephrine and lactate MIP SPCE sensors were fabricated by epinephrine or lactate-imprinted polyaniline co-polymerized with 3-aminophenylboronic acid and gold nanoparticles (PANI-co-PBA/AuNP) selective membrane on a commercial SPCE. The cortisol sensor was comprised of a cortisol-imprinted poly(glycidyl methacryate-co-ethylene glycol dimethacrylate) (poly (GMA-co-EGDMA)@AuNP selective membrane deposited on a SPCE. Both cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were used as modes of analysis for the MIP SPCE sensors. All sensors exhibited a rapid (∼1 min) and selective response to the epinephrine, lactate, and cortisol target analytes, with excellent precision between scans for both CV and DPV analysis modes. For CV, the LOD for epinephrine, lactate, and cortisol was 8.2 nM, 13 mM, and 0.042 μM, respectively. The LOD for DPV were 0.60 nM, 2.2 mM, and 0.025 μM for epinephrine, lactate, and cortisol, respectively. The MIP SPCE sensor platforms were further validated through the successful quantification of epinephrine, lactate, and cortisol in human sweat.
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•MIP based screen printed carbon electrode (SPCE) sensors for multianalytes detection in sweat.•MIP-SPCE sensors exhibited rapid and selective response to epinephrine, lactate, and cortisol.•MIP-SPCE sensor effectively quantified epinephrine, lactate, and cortisol in sweat.•MIP SPCE show great promise as point-of-need (PON) sensors for sweat analytics.
This article demonstrates an array of inexpensive molecularly imprinted microneedle platforms for the multiplexed electrochemical detection of pH, epinephrine, dopamine, and lactate biomarkers in ...human sweat. The multiplexed sensors were fabricated via layer-by-layer (LbL) assembly on a polydimethylsiloxane (PDMS) microneedle platform coated with a conductive PDMS/carbon nanotube (CNT)/cellulose nanocrystal (CNC) composite (PDMS/CNT/CNC@PDMS). The pH sensor was comprised of a pH-responsive polyaniline (PANI)/CNT/CNC/silver nanoparticle (AgNP) composite layer. The epinephrine, dopamine, and lactate sensors consisted of an additional epinephrine, dopamine, or lactate-imprinted PANI-co-3-aminophenylboronic acid (PBA)/gold nanoparticle (AuNP) layer atop the PANI/CNT/CNC/AgNP composite layer. Each sensor rapidly (∼2 min) and selectively responded to their target analytes, with excellent precision between scans. The limits of detection (LOD) for the epinephrine, dopamine, and lactate sensors were 0.0007 ± 0.0002 μM, 2.11 ± 0.05 nM, and 0.07 ± 0.07 mM, respectively. The pH sensor accurately responded to a pH range of 4.25–10. The applicability of the sensor platforms were successfully verified through quantification of pH, epinephrine, dopamine, and lactate in a human sweat sample, showing promise for use as a wearable, point of need (PON) sensor for sweat analytics.
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•This article demonstrates a molecularly imprinted microneedle sensors for multiplex electrochemical detection of pH, epinephrine, dopamine, and lactate in human sweat.•Each multiplex sensor rapidly (∼2 min) and selectively responded to the four target analytes with excellent precision and low limits of detection.•The practical applicability of the multiplex sensors was successfully verified via quantification of pH, epinephrine, dopamine, and lactate in real human sweat.•The sensors show great promise for use as point of need (PON) wearable sensor sweat sensor analytics.
Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome ...and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity.
GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined.
GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects.
Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.
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