A look at how solution processing can help reduce the cost of inorganic solar cell technologies is presented. The article also examines the development of inorganic solution precursors and deposition ...tehccniques.
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IJS, KILJ, NUK, PNG, UL, UM
Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains ...poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells.
Macroautophagy, a major pathway for organelle and protein turnover, has been implicated in the neurodegeneration of Alzheimer's disease (AD). The basis for the profuse accumulation of autophagic ...vacuoles (AVs) in affected neurons of the AD brain, however, is unknown. In this study, we show that constitutive macroautophagy in primary cortical neurons is highly efficient, because newly formed autophagosomes are rapidly cleared by fusion with lysosomes, accounting for their scarcity in the healthy brain. Even after macroautophagy is strongly induced by suppressing mTOR (mammalian target of rapamycin) kinase activity with rapamycin or nutrient deprivation, active cathepsin-positive autolysosomes rather than LC3-II-positive autophagosomes predominate, implying efficient autophagosome clearance in healthy neurons. In contrast, selectively impeding late steps in macroautophagy by inhibiting cathepsin-mediated proteolysis within autolysosomes with cysteine- and aspartyl-protease inhibitors caused a marked accumulation of electron-dense double-membrane-limited AVs, containing cathepsin D and incompletely degraded LC3-II in perikarya and neurites. Similar structures accumulated in large numbers when fusion of autophagosomes with lysosomes was slowed by disrupting their transport on microtubules with vinblastine. Finally, we find that the autophagic vacuoles accumulating after protease inhibition or prolonged vinblastine treatment strongly resembled AVs that collect in dystrophic neurites in the AD brain and in an AD mouse model. We conclude that macroautophagy is constitutively active and highly efficient in healthy neurons and that the autophagic pathology observed in AD most likely arises from impaired clearance of AVs rather than strong autophagy induction alone. Therapeutic modulation of autophagy in AD may, therefore, require targeting late steps in the autophagic pathway.
Although the terms ‘health’ and ‘healthy’ are often applied to marine ecosystems and communicate information about holistic condition (e.g. as required by the Ecosystem Approach), their meaning is ...unclear. Ecosystems have been understood in various ways, from non-interacting populations of species to complex integrated systems. Health has been seen as a metaphor, an indicator that aggregates over system components, or a non-localized emergent system property. After a review, we define good ecosystem health as: ‘the condition of a system that is self-maintaining, vigorous, resilient to externally imposed pressures, and able to sustain services to humans. It contains healthy organisms and populations, and adequate functional diversity and functional response diversity. All expected trophic levels are present and well interconnected, and there is good spatial connectivity amongst subsystems.’ We equate this condition with good ecological or environmental status, e.g. as referred to by recent EU Directives. Resilience is central to health, but difficult to measure directly. Ecosystems under anthropogenic pressure are at risk of losing resilience, and thus of suffering regime shifts and loss of services. For monitoring whole ecosystems, we propose an approach based on ‘trajectories in ecosystem state space’, illustrated with time-series from the northwestern North Sea. Change is visualized as Euclidian distance from an arbitrary reference state. Variability about a trend in distance is used as a proxy for inverse resilience. We identify the need for institutional support for long time-series to underpin this approach, and for research to establish state space co-ordinates for systems in good health.
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BFBNIB, NUK, PNG, UL, UM, UPUK
It has been shown that treatment with miglustat (Zavesca, N‐butyldeoxynojirimycin, OGT 918) improves key clinical features of type I Gaucher disease after 1 year of treatment. This study reports ...longer‐term efficacy and safety data. Patients who had completed 12 months of treatment with open‐label miglustat (100‐300 mg three times daily) were enrolled to continue with therapy in an extension study. Data are presented up to month 36. Liver and spleen volumes measured by CT or MRI were scheduled every 6 months. Biochemical and haematological parameters, including chitotriosidase activity (a sensitive marker of Gaucher disease activity) were monitored every 3 months. Safety data were also collected every 3 months. Eighteen of 22 eligible patients at four centres entered the extension phase and 14 of these completed 36 months of treatment with miglustat. After 36 months, there were statistically significant improvements in all major efficacy endpoints. Liver and spleen organ volumes were reduced by 18% and 30%, respectively. In patients whose haemoglobin value had been below 11.5 g/dl at baseline, mean haemoglobin increased progressively from baseline by 0.55 g/dl at month 12 (NS), 1.28 g/dl at month 24 (p=0.007), and 1.30 g/dl at month 36 (p=0.013). The mean platelet count at month 36 increased from baseline by 22×109/L. No new cases of peripheral neuropathy occurred since previously reported. Diarrhoea and weight loss, which were frequently reported during the initial 12‐month study, decreased in magnitude and prevalence during the second and third years. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. In conclusion, miglustat was increasingly effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UL, UM, UPUK, VKSCE, ZAGLJ
Lysosomal storage diseases are inborn errors of metabolism, the hallmark of which is the accumulation, or storage, of macromolecules in the late endocytic system. They are monogenic disorders that ...occur at a collective frequency of 1 in 5,000 live births and are caused by inherited defects in genes that mainly encode lysosomal proteins, most commonly lysosomal enzymes. A subgroup of these diseases involves the lysosomal storage of glycosphingolipids. Through our understanding of the genetics, biochemistry and, more recently, cellular aspects of sphingolipid storage disorders, we have gained insights into fundamental aspects of cell biology that would otherwise have remained opaque. In addition, study of these disorders has led to significant progress in the development of therapies, several of which are now in routine clinical use. Emerging mechanistic links with more common diseases suggest we need to rethink our current concept of disease boundaries.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this ambitious book, Kevin M. F. Platt focuses on a cruel paradox central to Russian history: that the price of progress has so often been the traumatic suffering of society at the hands of the ...state. The reigns of Ivan IV (the Terrible) and Peter the Great are the most vivid exemplars of this phenomenon in the pre-Soviet period. Both rulers have been alternately lionized for great achievements and despised for the extraordinary violence of their reigns. In many accounts, the balance of praise and condemnation remains unresolved; often the violence is simply repressed.
Platt explores historical and cultural representations of the two rulers from the early nineteenth century to the present, as they shaped and served the changing dictates of Russian political life. Throughout, he shows how past representations exerted pressure on subsequent attempts to evaluate these liminal figures. In ever-changing and often counterposed treatments of the two, Russians have debated the relationship between greatness and terror in Russian political practice, while wrestling with the fact that the nation's collective selfhood has seemingly been forged only through shared, often self-inflicted trauma. Platt investigates the work of all the major historians, from Karamzin to the present, who wrote on Ivan and Peter. Yet he casts his net widely, and "historians" of the two tsars include poets, novelists, composers, and painters, giants of the opera stage, Party hacks, filmmakers, and Stalin himself. To this day the contradictory legacies of Ivan and Peter burden any attempt to come to terms with the nature of political power-past, present, future-in Russia.
In this ambitious book, Kevin M. F. Platt focuses on a cruel paradox central to Russian history: that the price of progress has so often been the traumatic suffering of society at the hands of the state. The reigns of Ivan IV (the Terrible) and Peter the Great are the most vivid exemplars of this phenomenon in the pre-Soviet period. Both rulers have been alternately lionized for great achievements and despised for the extraordinary violence of their reigns. In many accounts, the balance of praise and condemnation remains unresolved; often the violence is simply repressed.
Platt explores historical and cultural representations of the two rulers from the early nineteenth century to the present, as they shaped and served the changing dictates of Russian political life. Throughout, he shows how past representations exerted pressure on subsequent attempts to evaluate these liminal figures. In ever-changing and often counterposed treatments of the two, Russians have debated the relationship between greatness and terror in Russian political practice, while wrestling with the fact that the nation's collective selfhood has seemingly been forged only through shared, often self-inflicted trauma. Platt investigates the work of all the major historians, from Karamzin to the present, who wrote on Ivan and Peter. Yet he casts his net widely, and "historians" of the two tsars include poets, novelists, composers, and painters, giants of the opera stage, Party hacks, filmmakers, and Stalin himself. To this day the contradictory legacies of Ivan and Peter burden any attempt to come to terms with the nature of political power-past, present, future-in Russia.
Dogs with epilepsy are among the commonest neurological patients in veterinary practice and therefore have historically attracted much attention with regard to definitions, clinical approach and ...management. A number of classification proposals for canine epilepsy have been published during the years reflecting always in parts the current proposals coming from the human epilepsy organisation the International League Against Epilepsy (ILAE). It has however not been possible to gain agreed consensus, "a common language", for the classification and terminology used between veterinary and human neurologists and neuroscientists, practitioners, neuropharmacologists and neuropathologists. This has led to an unfortunate situation where different veterinary publications and textbook chapters on epilepsy merely reflect individual author preferences with respect to terminology, which can be confusing to the readers and influence the definition and diagnosis of epilepsy in first line practice and research studies.In this document the International Veterinary Epilepsy Task Force (IVETF) discusses current understanding of canine epilepsy and presents our 2015 proposal for terminology and classification of epilepsy and epileptic seizures. We propose a classification system which reflects new thoughts from the human ILAE but also roots in former well accepted terminology. We think that this classification system can be used by all stakeholders.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Since the discovery of lysosomes more than 70 years ago, much has been learned about the functions of these organelles. Lysosomes were regarded as exclusively degradative organelles, but more recent ...research has shown that they play essential roles in several other cellular functions, such as nutrient sensing, intracellular signalling and metabolism. Methodological advances played a key part in generating our current knowledge about the biology of this multifaceted organelle. In this review, we cover current methods used to analyze lysosome morphology, positioning, motility and function. We highlight the principles behind these methods, the methodological strategies and their advantages and limitations. To extract accurate information and avoid misinterpretations, we discuss the best strategies to identify lysosomes and assess their characteristics and functions. With this review, we aim to stimulate an increase in the quantity and quality of research on lysosomes and further ground‐breaking discoveries on an organelle that continues to surprise and excite cell biologists.
Lysosomes play essential roles beyond their well‐known degradative function, including nutrient sensing, intracellular signalling and metabolism. To better understand these functions, it is essential to employ the best methodological approaches and know their advantages and limitations. Here, we review current methods used to analyze lysosome morphology, positioning, motility and function. The proper use of these methods will allow new discoveries to be made about this fascinating organelle.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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