Hedgehog partial agonism drives warburg-lie metabolism in muscle and brown fat

Diabetes, obesity, and cancer affect upward of 15% of the world’s population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca2+-Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of “selective partial agonists,” capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes.

Portrait of a charismatic leader : putting Bob Brown in context

Australia has a long record of charismatic political leaders and Bob Brown is perhaps the most notable recent example, but unlike other leaders of this style he has demonstrated remarkable political skill.

Tyk2 and Stat3 regulate brown adipose tissue differentiation and obesity

Mice lacking the Jak tyrosine kinase member Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT). Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high-fat diet and in obese humans. Expression of Tyk2 or the constitutively active form of the transcription factor Stat3 (CAStat3) restores differentiation in Tyk2−/− brown preadipocytes. Furthermore, Tyk2−/− mice expressing CAStat3 transgene in BAT also show improved BAT development, normal levels of insulin, and significantly lower body weights. Stat3 binds to PRDM16, a master regulator of BAT differentiation, and enhances the stability of PRDM16 protein. These results define Tyk2 and Stat3 as critical determinants of brown fat lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans.

Comparisons of seismic rock slope stability assessments between the Hoek-Brown and Mohr-Coulomb failure criteria

Current investigations have shown that earthquakes can trigger significant damages of equipment, property infrastructure and environment. This is a persistent cause of economic loss for any country, especially for the loss of life. The conventional method for slope stability design is to utilize limit equilibrium method (LEM) in conjunction with the pseudo-static (PS) approach. However, the LEM has a significant drawback which is to determine the slip surface before factor of safety calculation. The numerical upper and lower bound limit analysis method employed in this paper can avoid this limitation. In this study, the presented slope stability evaluations considering earthquake effects based on the finite difference method will be discussed and compared with the results from the numerical limit analysis methods.

Reading in brown paper : Beckett's budget and the sensationalist press in interwar Sydney

This article addresses the audience reception of sensationalist newspapers in interwar Australia through a case study of Sydney weekly Beckett's Budget. During a libel trial brought against Beckett's in 1928, readers came to its defence and their testimony reveals overlaps between reading and political allegiances: reading Beckett's equated with voting Labor. While histories of sensationalist media in Australia have rightly emphasised illicit sexuality and public outcry, connections between sensationalism and working-class political movements remain on the margins of academic interest. Responding to the question 'Do you read Beckett's?' readers' evidence at the trial constitutes an audience response and invites debate over the ways gender and class could inform political engagement in the 1920s. Viewing Beckett's Budget outside of 'brown paper' and beyond the sensationalist genre reveals a shift in Australian political culture as party strategists embraced a broader electorate, using Beckett's Budget to tap into the culture and concerns of interwar society.

The functional significance of ventilation frequency, and its relationship to oxygen demand in the resting brown long-eared bat, Plecotus auritus

Mean oxygen consumption and simultaneous ventilation frequency of nine non-reproductive brown long-eared bats (body mass 8.53–13.33 g) were measured on 159 occasions. Ambient (chamber) temperature at which the measurements were made ranged from 10.8 to 41.1°C. Apneic ventilation occurred in 22 of the 59 measurements made when mean oxygen consumption was less than 0.5 ml·min-1. No records of apneic ventilation were obtained when it was over 0.5 ml·min-1. The relationship between ventilation frequency and mean oxygen consumption depended on whether ventilation was apneic or non-apneic. When ventilation was non-apneic the relationship was positive and log-linear. When ventilation was apneic the relationship was log-log. Within the thermoneutral zone ventilation frequency was not significantly different from that predicted from allometric equations for a terrestrial mammal of equivalent body mass, but was significantly greater than that predicted for a bird. A reduction in the amount of oxygen consumed per breath occurred at ambient temperatures above the upper critical temperature (39°C).

A colourful addition to the spider fauna of Victoria : the peacock spider Maratus splendens (Rainbow, 1896) (Araneae: Salticidae)

Jumping spiders belonging to the endemic Australian genus Maratus are popularly referred to as peacock spiders, so called for the remarkable courtship displays of the often brightly coloured males. Several Maratus splendens were found in Buldah State Forest, East Gippsland in 2011 and 2013, representing the first records of this species from Victoria. Until recently, this species was known only from around Sydney. While a degree of caution should be exercised whenever implying possible new distributional records based on single localities, it is considered most likely that this discovery represents a genuine expansion in the known range of Maratus splendens. Details are also provided for a previously unpublished record from the central coast of New South Wales.

MicroRNA profiling in brown adipose tissue and muscle-derived CD34+ cells

 The major findings established a mouse brown adipose tissue (BAT)-enriched miRNA profile conserved in human BAT and predicted to target genes potentially involved in growth and development. The present results also identified a human skeletal muscle-derived CD34+ cell population with the capacity to differentiate into brown adipocytes in vitro. These CD34+ expressed common miRNAs to mouse and human BAT. Finally these findings show an up-regulation of 4 miRNAs in human adult skeletal muscle following cold exposure. These miRNAs were also present in mouse and human BAT as well as in CD34+ brown adipocytes.

In-situ synthesis of gold nanoparticles for multifunctionalization of silk fabrics

A simple in-situ synthesis route for gold nanoparticles (NPs) was developed to realize multifunctions for silk fabrics. The gold NPs were prepared in a heated solution containing white silk fabric samples. The silk fabrics were colored red and brown by the gold NPs because of their localized surface plasmon resonance (LSPR) property. Gold nanospheres on silk were obtained at a low gold content, and gold nanoplates were synthesized as the gold content increased. The silk fabrics treated with gold NPs showed good light fastness. Moreover, the gold NPs endowed silk fabrics with strong antibacterial activity, excellent UV protection property and enhanced thermal conductivity. © 2013 Elsevier Ltd. All rights reserved.

Validation of the Italian version of the Yale-Brown Obsessive Compulsive Scale-Second Edition (Y-BOCS-II) in a clinical sample

OBJECTIVE: The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) is the most widely accepted measure of obsessive-compulsive disorder (OCD) symptom severity. Recently, the scale has been revised into a second edition (Y-BOCS-II) in order to improve its measurement properties. The present study aimed to evaluate the psychometric properties of the Italian version of the Y-BOCS-II Severity Scale (SS) in a large clinical sample. METHOD: The original version of the Y-BOCS-II was translated into Italian, which involved forward and back-translation procedures. The Italian Y-BOCS-II-SS was administered to one hundred twenty-five treatment-seeking adults with OCD, together with the original Y-BOCS-SS and a battery of self-report measures assessing OCD symptom severity and depressive and anxious symptomology. The factor structure, internal consistency, temporal stability, and construct validity were investigated on the whole sample, while inter-rater and test-retest reliability were assessed on a subsample of participants. RESULTS: Factor analyses revealed a two-factor structure different from those of the original scale, comprising (1) symptom severity; and (2) interference from symptoms. Internal consistency, test-retest reliability over a 2-week period and inter-rater reliability were satisfactory. The Y-BOCS-II-SS also showed excellent construct validity (and better than the Y-BOCS-SS), with good convergent and discriminant validity when assessed against other OCD symptom measures and measures of depression, anxiety and worry. CONCLUSIONS: These findings suggest that the Italian version of the Y-BOCS-II-SS retains the adequate psychometric properties of the original and that it can be confidently used as an assessment tool of OCD symptoms in both clinical and research settings.