Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice

Brain type carnosinase in dementia: a pilot study

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Comparative effects of whey and casein proteins on satiety in overweight and obese individuals: A randomized controlled trial

Background/Objective: Dairy protein seems to reduce appetite by increasing satiety and delaying the return of hunger and subsequently lowering energy intake compared with fat or carbohydrate. The aim of this study was to compare the effect of whey with that of casein proteins on satiety in overweight/obese individuals. Methods/Subjects: This was a randomized, parallel-design 12-week-long study. Seventy subjects with a body mass index between 25 and 40 kg/m2 and aged 18–65 years were randomized into one of three supplement groups: glucose control (n=25), casein (n=20) or whey (n=25) protein. Before commencing the study, at weeks 6 and 12 of the treatment, a Visual Analogue Scale (VAS) was used to measure subjective sensations of appetite before lunch and before dinner. Results: Rating for VAS (mm) at 6 and 12 weeks showed significantly higher satiety in the whey group compared with the casein (P=0.017 and P=0.025, respectively) or control (P=0.024 and P=0.032, respectively) groups when measured before lunch. Similarly, at 6 and 12 weeks, the score for fullness was also significantly higher in the whey group compared with both casein (P=0.038 and P=0.022, respectively) and control (P=0.020 and P=0.030, respectively) groups. However, these short-term effects on satiety from dairy whey proteins did not have any long-term effects on energy intake or body weight over 12 weeks compared with casein. Conclusions: Collectively, whey protein supplementation appears to have a positive and acute postprandial effect on satiety and fullness compared with casein and carbohydrate supplementation in overweight and obese individuals

3D field phase-space control in tokamak plasmas

A small relaxation of the axisymmetric magnetic field of a tokamak into a non-axisymmetric three-dimensional (3D) configuration can be effective to control magnetohydrodynamic instabilities, such as edge-localized modes. However, a major challenge to the concept of 3D tokamaks is that there are virtually unlimited possible choices for a 3D magnetic field, and most of them will only destabilize or degrade plasmas by symmetry breaking. Here, we demonstrate the phase-space visualization of the full 3D field-operating windows of a tokamak, which allows us to predict which configurations will maintain high confinement without magnetohydrodynamic instabilities in an entire region of plasmas. We test our approach at the Korean Superconducting Tokamak Advanced Research (KSTAR) facility, whose 3D coils with many degrees of freedom in the coil space make it unique for this purpose. Our experiments show that only a small subset of coil configurations can accomplish edge-localized mode suppression without terminating the discharge with core magnetohydrodynamic instabilities, as predicted by the perturbative 3D expansion of plasma equilibrium and the optimizing principle of local resonance. The prediction provided excellent guidance, implying that our method can substantially improve the efficiency and fidelity of the 3D optimization process in tokamaks