Dissection of a novel molecular determinant mediating Golgi to trans-Golgi network transition

Two major functions of the Golgi apparatus (GA) are formation of complex glycans and sorting of proteins destined for various subcellular compartments or secretion. To fulfill these tasks proper localization of the accessory proteins within the different sub-compartments of the GA is crucial. Here we investigate structural determinants mediating transition of the two glycosyltransferases β-1,4- galactosyltransferase 1 (gal-T1) and the α-1,3-fucosyltransferase 6 (fuc-T6) from the trans-Golgi cisterna to the trans-Golgi network (TGN). Upon treatment with the ionophore monensin both glycosyltransferases are found in TGN-derived swollen vesicles, as determined by confocal fluorescence microscopy and density gradient fractionation. Both enzymes carry a signal consisting of the amino acids E₅P₆ in gal-T1 and D₂P₃ in fuc-T6 necessary for the transition of these glycosyltransferases from the trans-Golgi cisterna to the TGN, but not for their steady state localization in the trans-Golgi cisterna. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Received 30 July 2008; received after revision 17 September 2008; accepted 29 September 2008     

Explaining Atomic Spectra within Classical Physics: 1897-1913

In this paper we analyse the approach to interpreting atomic spectra in the framework of classical physics from the discovery of the electron in 1897 to Bohr's atomic model of 1913. Taken as a whole, efforts in this direction are part of a remarkable intellectual endeavour in which the classical theoretical framework seems to have been exploited to its full potential. By demonstrating the limits and weaknesses of classical physics in solving the problem of spectral emissions, these attempts opened the way to a complete break from traditional thought and the introduction of the new quantum ideas.     

The effect of anesthetics on the basal secretion of immunoreactive growth hormone in rats]

The authors investigated basal levels of plasma immunoreactive growth-hormone in the rat (R-GH) after administration of 3 different anesthetic drugs: urethan, chloral hydrate and gamma-hdroxy-butyrate (GHB). Lowest R-GH concentrations (5 +/- 3 ng/ml) are observed after urethan; they are significantly higher (15 +/- 4 ng/ml) after chloral hydrate but this anesthetic also causes hyperglycemia (210 +/- 30 mg/100 ml). Normal blood glucose levels are observed under GHB narco-analgesia which elicits a clear-cut R-GH secretory episode (70 +/- 5 ng/ml); basal values (12 +/- 3 ng/ml) are maintained for several hours thereafter.     

Interactions between contractile and regulatory proteins of the myofibril

Zusammenfassung Die Regulationseiweisse (Tropomyo sin und Troponinkomplex), welche die Wechselwirkung der kontraktilen Eiweisse in der Myofibrille steuern, zeigen eine spezifische und unspezifische Bindung an den Actomyosinkomplex. Die spezifisch gebundene Menge der Regulationseiweisse beträgt nur etwa 1/100 derjenigen von Actomyosin, genügt aber trotzdem, um die Steuerung der Mg-ATPase und damit der Muskelkontraktion durch Ca²⁺ zu gewährleisten.     

Shedding light on mitophagy in neurons: what is the evidence for PINK1/Parkin mitophagy in vivo?

Neurons are highly specialised cells with a large bioenergetic demand, and so require a healthy mitochondrial network to function effectively. This network is compromised in many neurological disorders, in which damaged mitochondria accumulate. Dysfunctional mitochondria can be removed via an organelle-specific autophagic pathway, a process known as mitophagy. The canonical mitophagy pathway is dependent on the actions of PINK1 (PTEN-induced putative kinase 1) and Parkin and has been well studied in immortalised cells and cultured neurons. However, evidence for a role of this mitophagy pathway in the brain is still limited, and studies suggest that there may be important differences in how neurons respond to mitochondrial damage in vitro and in vivo. Here, we first describe the evidence for a functional PINK1/Parkin mitophagy pathway in neurons, and review how this pathway is affected in disease models. We then critically evaluate the literature by comparing findings from in vitro models and more recent in vivo studies in flies and mice. The emerging picture implicates that alternative mitophagy pathways operate in neurons in vivo. New mouse models that employ fluorescent biosensors to monitor mitophagy in vivo will be instrumental to understand the relative role of the different clearance pathways in the brain under physiological and pathological conditions.     

Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.