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.

Exercise-induced muscle glucose uptake in mice with graded, muscle-specific GLUT-4 deletion

To investigate the importance of the glucose transporter GLUT-4 for muscle glucose uptake during exercise, transgenic mice with skeletal muscle GLUT-4 expression approximately 30–60% of normal (CON) and approximately 5–10% of normal (KO) were generated using the Cre/Lox system and compared with wild-type (WT) mice during approximately 40 min of treadmill running (KO: 37.7 ± 1.3 min; WT: 40 min; CON: 40 min, P = 0.18). In WT and CON animals, exercise resulted in an overall increase in muscle glucose uptake. More specifically, glucose uptake was increased in red gastrocnemius of WT mice and in the soleus and red gastrocnemius of CON mice. In contrast, the exercise-induced increase in muscle glucose uptake in all muscles was completely abolished in KO mice. Muscle glucose uptake increased during exercise in both red and white quadriceps of WT mice, while the small increases in CON mice were not statistically significant. In KO mice, there was no change at all in quadriceps muscle glucose uptake. No differences in muscle glycogen use during exercise were observed between any of the groups. However, there was a significant increase in plasma glucose levels after exercise in KO mice. The results of this study demonstrated that a reduction in skeletal muscle GLUT-4 expression to approximately 10% of normal levels completely abolished the exercise-induced increase in muscle glucose uptake.

Mechanical behaviour of functionally graded carbon nanofibre/phenolic nanocomposites: numerical modelling and experimental validation

In this study, a finite element-based model was developed to investigate the mechanical behaviour of functionally graded carbon nanofibre (CNF)/phenolic nanocomposites. Four functionally graded nanocomposites (FGNs), a non-graded nanocomposite (NGN), and a pure phenolic with the same geometry and total carbon nanofibre content were designed and fabricated. Flexural tests were conducted to validate the proposed finite element model. Close agreement was obtained between experimental results and numerical predictions. The results showed that flexural modulus can be improved about 45% by controlling the CNF content across the thickness of the samples.

Bending behaviour of step-wise graded carbon nanofiber/polymer nanocomposites

In this study, a finite element-based model was developed to investigate the mechanical behavior of step-wise graded carbon nanofibre/phenolic nanocomposites. Four step-wise graded nanocomposites (FGNs), a non-graded nanocomposite (NGN), and a pure phenolic with the same geometry and total carbon nanofiber content were designed, fabricated and analyzed. Flexural tests were conducted to validate the finite element model. Close agreement was obtained between experimental results and numerical predictions. The results showed that flexural modulus was highly influenced by the compositional gradients.

Lying idiots: reality television & lie to me

This article addresses perhaps the key question for Television Studies: Who does television think you are? It argues that Reality Television answers this question by producing its viewers as, in the Classical Greek sense, idiots (meaning private and ignorant persons). Idiots are the perfect target for the advertising dollar that supports commercial television production. As Reg Grundy observes, Reality Television is anything but reality. With its tight framings of reality, it paradoxically operates to sever the viewing self from reality—from the “truth” of life. Lie to Me is the type of television we are left with after the demise of Reality Television. Lie to Me makes us self-conscious, in the strongest sense, and thus sustains the mission of Reality Television. By dragging the notion of reality into its self-serving fictions, it puts the viewer into the dangerous position of being unable to lie to television. If Reality Television constrained reality to falsity, Lie to Me implicates the viewer in the zone where falsity transforms into reality. Lastly, this article enquires into the possibilities, in today’s television ecology, for a mode of TV citizenship that would counter the abject viewing position of the consumerist idiot.

Fabrication, characterization and modelling of functionally graded nanocomposites

This research introduced the innovative concept of controlling the composition in nanocomposites for optimizing the mechanical performance; as well as tailoring the thermal and electrical properties for multi-functional applications. It led to the development of novel lighter stronger materials for use in engineering applications such as automotive body and mining equipment.

A history of the lie of innocence: sons who become orphans

This thesis deals with a history of the lie of innocence, its inception in biblical representation and its development in literary representations from the eighteenth century to contemporary times. The aim is to disclose the way the lie functioned across time both in Christian societies and in the secular ones in their wake.

Suicidal ideation and physical illness: Does the link lie with depression?

Objective
Medical illness is a risk factor for suicidality; however, disorder-specific risks are not well-known and these relationships are often explained by major depressive disorder (MDD). We aimed to investigate the relationship between suicidal ideation, MDD and medical illnesses in an age-stratified, population-based sample of men participating in the Geelong Osteoporosis Study.

Methods
Suicidal ideation and medical conditions were self-reported. Medical conditions were confirmed by medical records, medication use or clinical data where possible. MDD was determined using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition.

Results
Of the 907 men, 8.5% reported suicidal ideation. Thyroid disorders (OR 3.85, 95%CI 1.2–12.1), syncope and seizures (OR 1.96, 95%CI 1.1–3.5), liver disorders (OR 3.53, 95%CI 1.1–11.8; younger men only) and alcoholism (OR 2.15, 95%CI 1.1–4.4) were associated with increased odds of suicidal ideation, independent of age and MDD. Major vascular events doubled the odds of suicidal ideation but this was explained by MDD. No association was evident with high medical burden, musculoskeletal disease, metabolic factors, gastrointestinal disorders, headaches, cardiovascular disease, COPD, cancer and psoriasis.

Conclusion
Health care professionals should focus on identification, assessment and management of suicidal ideation in the medically ill in patients both with and without MDD.

Sliding wear behavior of plasma sprayed Fe3Al–Al2O3 graded coatings

Fe3Al–Al2O3 double-layer coatings (DC), Fe3Al-Fe3Al/50%Al2O3–Al2O3 triple-layer coatings (TC) and Fe3Al-Al2O3 graded coatings (GC) were produced from a series of Fe3Al/Al2O3 composite powders with different compositions on low carbon steel substrate using PLAXAIR plasma spraying equipment. Friction behaviors and wear resistance of the three kinds of coatings have been investigated under different loads. Tests were carried out using an MRH-3 standard machine, in lineal contact sliding under dry condition against hardmetal, at a sliding velocity of about 1.57 ms−1. Wear rates under different loads were measured and the friction coefficients were recorded. SEM analysis was carried out to identify the wear mechanisms. The results show that the GC has higher wear-resistance than DC and TC. The tribological characteristics of graded coating were different along the depth of the coatings, and the surface of coatings with pure Al2O3 does not show the best wear resistance. The wear rate and friction coefficients were also different under different loads. The failure types of plasma-sprayed Fe3Al-Al2O3 graded coatings in lineal contact were: loosening of ceramic particles, crack nucleation and propagation, brittle fracture, plastic deformation, and adhesive wear.

A study on mechanical behavior of functionally-graded carbon nanotube-reinforced nanocomposites

In this study, we are focusing on the investigation of the effects of gradient patterns on mechanical behavior of functionally-graded carbon nanotube-reinforced nanocomposites and considering typical beams made of such nanocomposites. Both analytic and finite element-based numerical models were developed. Analytic model was developed based on the first-order shear deformation and Timoshenko beam theories meanwhile finite element models were developed using Abaqus in conjunction with user-defined subroutines for defining the continuously gradient material properties for different gradient patterns. Position-dependent elastic modulus equations for four continuously graded patterns were studied. A nongraded pattern was used for benchmarking with the same geometry and total carbon nanotube (CNT) contents. For validation and verification, the results on both deflection and stress of these nanocomposite beams were analyzed, which clearly showed high influence from gradient patterns on these mechanical behaviors of such beams.