Re-mention of an old neurodegenerative disease: Alzheimer’s disease

Alzheimer’s disease(AD),the most common form of neuropsychiatric disorder,is characterized by neuronal degeneration and inexorably progressing dementia,especially in the elderly population.With a rapidly aging population in both developed and developing countries,AD has emerged as one of the largest growing problems worldwide.Current drugs improve the symptoms of AD,but do not have any profound intervention to delay its onset.Thus,understanding the molecular mechanisms underlying the genes tied to AD will be crucial to the development of therapeutic targets.This review will summarize the aetiology,pathology,and the evidence for the genetic components in AD,discuss the proposed amyloid cascade and the following tau hyperphosphorylation hypothesises,oxidative stress mediated neuronal cell death,as well as the function of Retromer complex during the developing of AD.Our laboratory’s current research progress and the challenges that still remained will be also highlighted.     

High frequency of BRAF mutations in nevi

To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.     

Dissecting the genomic complexity underlying medulloblastoma

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.     

Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity

Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.     

Amylase secretion from rat parotid glands as dependent on co-operation between sympathetic and parasympathetic nerves

Summary A slow, long-lasting degeneration secretion from the parotid gland was brought about in anaesthetized rats by section of the auriculo-temporal nerve 16–19 h in advance. This parasympathetic background activity greatly increased the secretion of amylase elicited by sympathetic nerve stimulation.Supported by grants from the Swedish Medical Research Council (project nr 00539) to N.E. and from the Medical Faculty, University of Lund, to P.G.     

The Prussian Mining Official Alexander von Humboldt

From summer 1792 until spring 1797, Alexander von Humboldt was a mining official in the Franconian parts of Prussia. He visited mines, inspected smelting works, calculated budgets, wrote official reports, founded a mining school, performed technological experiments, and invented a miners’ lamp and respirator. At the same time he also participated in the Republic of Letters, corresponded with savants in all Europe, and was a member of the Leopoldine Carolinian Academy and the Berlin Gesellschaft Naturforschender Freunde. He collected minerals, made geognostic observations, performed chemical and physiological experiments, read the newest scientific journals, and prepared and published texts on mineralogy, geognosy, chemistry, botany and physiology. Humboldt did his scientific investigations alongside his administrative and technical work. This raises the question of whether there were fruitful interactions between Humboldt's technical-administrative work and (parts of) his natural inquiry. I argue that the mining official Humboldt was a late eighteenth-century figure of hybrid savant-technician. Mines and smelting works provided numerous opportunities for studies of nature. Humboldt systematically used inspection tours for mineralogical and geognostic observations. He transformed mines into chemical laboratories, and he transferred knowledge and material items from his natural inquiries in mines to academic institutions. The main objective of this paper is to illuminate the persona of savant-technician (or scientific-technological expert) along with Humboldt's mixed technological and scientific work during his term as mining official.     

Paper tools in experimental cultures

The paper studies various functions of Berzelian formulas in European organic chemistry prior to the mid-nineteenth century from a semiotic, historical and epistemological perspective. I argue that chemists applied Berzelian formulas as productive ‘paper tools’ for creating a chemical order in the ‘jungle’ of organic chemistry. Beginning in the late 1820s, chemists applied chemical formulas to build models of the binary constitution of organic compounds in analogy to inorganic compounds. Based on these formula models, they constructed new classifications of organic substances. They further applied Berzelian formulas in a twofold way to experimentally investigate organic chemical reactions: as tools which supplemented laboratory tools and as tools for constructing interpretive models of organic reactions. The scrutiny of chemists' performances with chemical formulas on paper also reveals a dialectic which contributed considerably to the formation of the new experimental culture of synthetic carbon chemistry that emerged between the late 1820s and the early 1840s. In an unintended and unforeseen way, the tools reacted back on the goals of their users and contributed to conceptual development and a shift of scientific objects and practices (‘substitution’) which transcended the originally intended chemical order.     

Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2

Feedback inhibition is a fundamental principle in signal transduction allowing rapid adaptation to different stimuli. In mammalian cells, the major feedback inhibitor for G-protein-coupled receptors (GPCR) is G-protein-coupled receptor kinase 2 (GRK-2), which phosphorylates activated receptors, uncouples them from G proteins and initiates their internalization. The functions of GRK-2 are indispensable and need to be tightly controlled. Dysregulation promotes disorders such as hypertension or heart failure. In our search for a control mechanism for this vital kinase, here we show that the Raf kinase inhibitor protein (RKIP) is a physiological inhibitor of GRK-2. After stimulation of GPCR, RKIP dissociates from its known target, Raf-1 (refs 6-8), to associate with GRK-2 and block its activity. This switch is triggered by protein kinase C (PKC)-dependent phosphorylation of the RKIP on serine 153. The data delineate a new principle in signal transduction: by activating PKC, the incoming receptor signal is enhanced both by removing an inhibitor from Raf-1 and by blocking receptor internalization. A physiological role for this mechanism is shown in cardiomyocytes in which the downregulation of RKIP restrains beta-adrenergic signalling and contractile activity.     

Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene

Deletion experiments have defined two stretches of DNA (genetic elements), lying close to the promoter for a human gene for metallothionein, that separately mediate the induction of the gene by heavy metal ions, particularly cadmium, and by glucocorticoid hormones. The element responsible for induction by cadmium is duplicated, yet a single copy is fully functional; the element responsible for induction by glucocorticoid hormones is coincident with the DNA-binding site for the glucocorticoid hormone receptor.