A History of the Askin Government 1965-1975

This dissertation is a comprehensive evaluation of the Askin Government from 1965-1975. The thesis of the dissertation is that Askin's contribution as leader was crucial to the electoral success and longevity of the Liberal Country Party Coalition Government. As the study progressed it became clear that Askin's leadership was underpinned by his temperament and tactics. It is illustrated that Askin's successful leadership was based on his adherence to the proven political tactics often attributed to Machiavelli. His temperament also assisted his leadership aspirations and this is explained by using David Kersey's Temperament Sorter as a framework. The discrepancy between the body of political history in NSW on Labor governments and Liberal governments is addressed. There are two significant novelties presented in this dissertation. This is the first substantial study of Askin's leadership and the coalition government. After Askin's death in 1981 his Premiership was shrouded in corruption allegations that took on mythical proportions and became received wisdom. The corruption myth is dispelled by demonstrating that it was founded on unsubstantiated allegations

Identification of a novel class of nicotinic receptor antagonists - Dimeric conotoxins VxXIIA, VxXIIB, and VxXIIC from Conus vexillum

The venoms of predatory marine snails ( Conus spp.) contain diverse mixtures of peptide toxins with high potency and selectivity for a variety of voltage-gated and ligand-gated ion channels. Here we describe the chemical and functional characterization of three novel conotoxins, alpha D-VxXIIA, alpha D-VxXIIB, and alpha D-VxXIIC, purified from the venom of Conus vexillum. Each toxin was observed as an similar to 11-kDa protein by LC/MS, size exclusion chromatography, and SDS-PAGE. After reduction, the peptide sequences were determined by Edman degradation chemistry and tandem MS. Combining the sequence data together with LC/MS and NMR data revealed that in solution these toxins are pseudo-homodimers of paired 47-50-residue peptides. The toxin subunitsexhibited a novel arrangement of 10 conserved cystine residues, and additional post-translational modifications contributed heterogeneity to the proteins. Binding assays and two-electrode voltage clamp analyses showed that alpha D-VxXIIA, alpha D-VxXIIB, and alpha D-VxXIIC are potent inhibitors of nicotinic acetylcholine receptors (nAChRs) with selectivity for alpha 7 and alpha 2 containing neuronal nAChR subtypes. These dimeric conotoxins represent a fifth and highly divergent structural class of conotoxins targeting nAChRs

Isolation and Structure-Activity of -Conotoxin TIIIA, A Potent Inhibitor of Tetrodotoxin-Sensitive Voltage-Gated Sodium Channels

ABSTRACT -Conotoxins are three-loop peptides produced by cone snails to inhibit voltage-gated sodium channels during prey capture. Using polymerase chain reaction techniques, we identified a gene sequence from the venom duct of Conus tulipa encoding a new -conotoxin-TIIIA (TIIIA). A 125 I-TIIIA binding assay was established to isolate native TIIIA from the crude venom of Conus striatus. The isolated peptide had three post-translational modifications, including two hydroxyproline residues and C-terminal amidation, and Ͻ35% homology to other -conotoxins. TIIIA potently displaced [ 3 H]saxitoxin and 125 I-TIIIA from rat brain (Na v 1.2) and skeletal muscle (Na v 1.4) membranes. Alanine and glutamine scans of TIIIA revealed several residues, including Arg14, that were critical for high-affinity binding to tetrodotoxin (TTX)-sensitive Na ϩ channels. We were surprised to find that [E15A]TIIIA had a 10-fold higher affinity than TIIIA for TTX-sensitive sodium channels (IC 50 , 15 vs. 148 pM at rat brain membrane). TIIIA was selective for Na v 1.2 and -1.4 over Na v 1.3, -1.5, -1.7, and -1.8 expressed in Xenopus laevis oocytes and had no effect on rat dorsal root ganglion neuron Na ϩ current

Measurement invariance of the moral vitalism scale across 28 cultural groups

Moral vitalism refers to a tendency to view good and evil as actual forces that can influence people and events. The Moral Vitalism Scale had been designed to assess moral vitalism in a brief survey form. Previous studies established the reliability and validity of the scale in US-American and Australian samples. In this study, the cross-cultural comparability of the scale was tested across 28 different cultural groups worldwide through measurement invariance tests. A series of exact invariance tests marginally supported partial metric invariance, however, an approximate invariance approach provided evidence of partial scalar invariance for a 5-item measure. The established level of measurement invariance allows for comparisons of latent means across cultures. We conclude that the brief measure of moral vitalism is invariant across 28 cultures and can be used to estimate levels of moral vitalism with the same precision across very different cultural settings.Peer reviewe

AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity

Neuronal nAChRs are a diverse family of pentameric ion channels with wide distribution throughout cells of the nervous and immune systems. However, the role of specific subtypes in normal and pathological states remains poorly understood due to the lack of selective probes. Here, we used a binding assay based on acetylcholine-binding protein (AChBP), a homolog of the nicotinic acetylcholine ligand-binding domain, to discover a novel α-conotoxin (α-TxIA) in the venom of Conus textile. α-TxIA bound with high affinity to AChBPs from different species and selectively targeted the α3β2 nAChR subtype. A co-crystal structure of Ac-AChBP with the enhanced potency analog TxIA(A10L), revealed a 20° backbone tilt compared to other AChBP–conotoxin complexes. This reorientation was coordinated by a key salt bridge formed between Arg5 (TxIA) and Asp195 (Ac-AChBP). Mutagenesis studies, biochemical assays and electrophysiological recordings directly correlated the interactions observed in the co-crystal structure to binding affinity at AChBP and different nAChR subtypes. Together, these results establish a new pharmacophore for the design of novel subtype-selective ligands with therapeutic potential in nAChR-related diseases

Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes

omega -Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new omega -conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared with other omega -conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA-D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies, omega -conotoxins CVID and MVIIA had similar potencies to inhibit current through central (alpha (1B-d)) and peripheral (alpha (1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat beta (3) in Xenopus oocytes, However, the potency of CVID and MVIIA increased when alpha (1B-d) and alpha (1B-b) were expressed in the absence of rat beta (3), an effect most pronounced for CVID at alpha (1B-d) (up to 540-fold) and least pronounced for MVIIA at alpha (1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. H-1 NMR studies reveal that CMD possesses a combination of unique structural features, including two hydrogen bonds that stabilize loop 2 and place loop 2 proximal to loop 4, creating a globular surface that is rigid and well defined

Ontogeny and thermogenic role for sternal fat in female sheep

Brown adipose tissue acting through a unique uncoupling protein (UCP1) has a critical role in preventing hypothermia in new-born sheep but is then considered to rapidly disappear during postnatal life. The extent to which the anatomical location of fat influences postnatal development and thermogenic function, particularly following feeding, in adulthood, are not known and were both examined in our study. Changes in gene expression of functionally important pathways (i.e. thermogenesis, development, adipogenesis and metabolism) were compared between sternal and retroperitoneal fat depots together with a representative skeletal muscle over the first month of postnatal life, coincident with the loss of brown fat and accumulation of white fat. In adult sheep, implanted temperature probes were used to characterise the thermogenic response of fat and muscle to feeding and the effects of reduced or increased adiposity. UCP1 was more abundant within sternal than retroperitoneal fat and was only retained in the sternal depot of adults. Distinct differences in the abundance of gene pathway markers were apparent between tissues, with sternal fat exhibiting some similarities with muscle that were not apparent in the retroperitoneal depot. In adults, the post-prandial rise in temperature was greater and more prolonged in sternal than retroperitoneal fat and muscle, a difference that was maintained with altered adiposity. In conclusion, sternal adipose tissue retains UCP1 into adulthood when it shows a greater thermogenic response to feeding than muscle and retroperitoneal fat. Sternal fat may be more amenable to targeted interventions that promote thermogenesis in large mammals

Social mindfulness predicts concern for nature and immigrants across 36 nations

People cooperate every day in ways that range from largescale contributions that mitigate climate change to simple actions such as leaving another individual with choice – known as social mindfulness. It is not yet clear whether and how these complex and more simple forms of cooperation relate. Prior work has found that countries with individuals who made more socially mindful choices were linked to a higher country environmental performance – a proxy for complex cooperation. Here we replicated this initial finding in 41 samples around the world, demonstrating the robustness of the association between social mindfulness and environmental performance, and substantially built on it to show this relationship extended to a wide range of complex cooperative indices, tied closely to many current societal issues. We found that greater social mindfulness expressed by an individual was related to living in countries with more social capital, more community participation and reduced prejudice towards immigrants. Our findings speak to the symbiotic relationship between simple and more complex forms of cooperation in societies

Isolation, structure, and activity of GID, a novel alpha 4/7-conotoxin with an extended N-terminal sequence

Using assay-directed fractionation of Conus geographus crude venom, we isolated a-conotoxin GID, which acts selectively at neuronal nicotinic acetylcholine receptors (nAChRs). Unlike other neuronally selective alpha-conotoxins, alpha-GID has a four amino acid N-terminal tail, gamma-carboxyglutamate (Gla), and hydroxyproline (0) residues, and lacks an amidated C terminus. GID inhibits alpha7 and alpha3beta2 nAChRs with IC50 values of 5 and 3 nm, respectively and is at least 1000-fold less potent at the alpha1beta1gammadelta, alpha3beta4, and alpha4beta4 combinations. GID also potently inhibits the alpha4beta2 subtype (IC50 of 150 nm). Deletion of the N-terminal sequence (GIDDelta1-4) significantly decreased activity at the alpha4beta2 nAChR but hardly affected potency at alpha3beta2 and alpha7 nAChRs, despite enhancing the off-rates at these receptors. In contrast, Arg(12) contributed to alpha4beta2 and alpha7 activity but not to alpha3beta2 activity. The three-dimensional structure of GID is well defined over residues 4-19 with a similar motif to other a-conotoxins. However, despite its influence on activity, the tail appears to be disordered in solution. Comparison of GID with other alpha4/7-conotoxins which possess an NN(P/O) motif in loop II, revealed a correlation between increasing length of the aliphatic side-chain in position 10 (equivalent to 13 in GID) and greater alpha7 versus alpha3beta2 selectivity

A 32-society investigation of the influence of perceived economic inequality on social class stereotyping

International audienceThere is a growing body of work suggesting that social class stereotypes are amplified when people perceive higher levels of economic inequality-that is, the wealthy are perceived as more competent and assertive and the poor as more incompetent and unassertive. The present study tested this prediction in 32 societies and also examines the role of wealth-based categorization in explaining this relationship. We found that people who perceived higher economic inequality were indeed more likely to consider wealth as a meaningful basis for categorization. Unexpectedly, however, higher levels of perceived inequality were associated with perceiving the wealthy as less competent and assertive and the poor as more competent and assertive. Unpacking this further, exploratory analyses showed that the observed tendency to stereotype the wealthy negatively only emerged in societies with lower social mobility and democracy and higher corruption. This points to the importance of understanding how socio-structural features that co-occur with economic inequality may shape perceptions of the wealthy and the poor