In situ architecture of the ER–mitochondria encounter structure

The endoplasmic reticulum and mitochondria are main hubs of eukaryotic membrane biogenesis that rely on lipid exchange via membrane contact sites1,2,3, but the underpinning mechanisms remain poorly understood. In yeast, tethering and lipid transfer between the two organelles is mediated by the endoplasmic reticulum–mitochondria encounter structure (ERMES), a four-subunit complex of unresolved stoichiometry and architecture4,5,6. Here we determined the molecular organization of ERMES within Saccharomyces cerevisiae cells using integrative structural biology by combining quantitative live imaging, cryo-correlative microscopy, subtomogram averaging and molecular modelling. We found that ERMES assembles into approximately 25 discrete bridge-like complexes distributed irregularly across a contact site. Each bridge consists of three synaptotagmin-like mitochondrial lipid binding protein domains oriented in a zig-zag arrangement. Our molecular model of ERMES reveals a pathway for lipids. These findings resolve the in situ supramolecular architecture of a major inter-organelle lipid transfer machinery and provide a basis for the mechanistic understanding of lipid fluxes in eukaryotic cells.<br/

Mechanisms of Activation of LRRC8 Volume Regulated Anion Channels.

Volume regulated anion channels (VRACs) are ubiquitously expressed in all vertebrate cells. Despite many years of research, the fundamental mechanisms underlying VRAC activation are not understood. The recent molecular identification of the LRRC8 genes underlying VRAC revealed that VRACs are formed by a hexameric assembly of members of the LRRC8 gene family. Knowing the genes underlying VRACs allowed the discovery of novel VRAC functions into cell volume regulation, and first structure function studies revealed important insight in channel activation mechanisms. The determination of cryo-EM structures of homomeric LRRC8A and LRRC8D complexes provide a framework for a rational approach to investigate biophysical mechanisms. We discuss several recent advances within the structural framework, and we critically review the literature on the main mechanisms proposed to be involved in VRAC activation, including low intracellular ionic strength, membrane unfolding, oxidation, phosphorylation and G-protein coupling

Coupling Climate Conditions, Sediment Sources and Sediment Transport in an Alpine Basin

In a fluvial system, mountain basins control sediment export to the lowland rivers. Hence, analysis of erosion processes and sediment delivery patterns in mountain basins is a key factor for many applications such as land‐use management, hazard assessment and infrastructure design. Several studies have investigated the alterations triggered by recent climatic change on the hydrological regime, while only a few works have explored the consequences on fluvial sediment dynamics. Here, we combined and analyzed the quasi‐unique dataset of climatic conditions, landform response and sediment export produced, since 1986 in the Rio Cordon basin (5 km2, Eastern Italian Alps) to examine the sediment delivery processes occurring in the last 3 decades. The temperature, precipitation and fluvial sediment fluxes in the basin were analyzed using continuous measurement executed by a permanent monitoring station, while the evolution of sediment source areas was investigated using three sediment source inventories. The results showed that during the period 1986–1993 the sediment fluxes (339 Mg yr−1) reflected the stable trend of the climatic conditions. The period between the first and second source inventory (i.e. 1994–2006) was characterized by climatic fluctuations and by the occurrence of high magnitude floods. Nevertheless, a limited increase in the extent of sediment source areas was detected, suggesting that the increased sediment export (759 Mg yr−1) was mainly driven by in‐channel sediment supply. Notwithstanding the marked climate warming and the increased precipitation, a weak source area evolution and a reduction in sediment export (237 Mg yr−1) were observed during the period 2007–2015. In particular, the higher rainfall did not result in an intensification of flood events, stressing the absence of hillslope‐channel connectivity

Type I interferon-mediated autoinflammation due to DNase II deficiency

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans

Development and applications of a high-speed atomic force microscope for nanoscience

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

An evidence-based review of natalizumab therapy in the management of Crohn&amp;rsquo;s disease

Raja GR Edula, Michael F PiccoMayo Clinic, Jacksonville, Florida, USAAbstract: Treatment options for Crohn&amp;rsquo;s disease have evolved beyond the early goals of induction and remission and are now more focused on preventing complications by altering the natural history of the disease. The advent of biologic therapies has revolutionized the management of Crohn&amp;rsquo;s disease. Specifically, antibodies to tumor necrosis factor alpha induce rapid mucosal healing. This translates into improved patient outcomes. However, many patients will fail these and other therapies. Natalizumab is a new biologic agent that has been approved for the treatment of moderately to severely active Crohn&amp;rsquo;s disease in patients who have failed or are intolerant to immunosuppressants and/or tumor necrosis factor inhibitors. It is a selective adhesion molecule inhibitor to alpha-4 integrin resulting in inhibition of the migration of inflammatory cells across the endothelium. This unique mechanism of action has been shown to be effective in the treatment of Crohn&amp;rsquo;s disease, making it an important option for otherwise refractory patients. Its use has been limited to these refractory patients because of concerns about the development of complications, especially progressive multifocal leukoencephalopathy. In this review, evidence-based data on the indications, efficacy and safety of natalizumab will be presented and its role in the management of patients with Crohn&amp;rsquo;s disease will be defined.Keywords: Crohn&amp;rsquo;s disease, natalizumab, alpha-4 integri