β-hairpin-mediated formation of structurally distinct multimers of neurotoxic prion peptides

Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109–122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109–122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109–122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106–126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

WordCloud: a Cytoscape plugin to create a visual semantic summary of networks

<p>Abstract</p> <p>Background</p> <p>When biological networks are studied, it is common to look for clusters, i.e. sets of nodes that are highly inter-connected. To understand the biological meaning of a cluster, the user usually has to sift through many textual annotations that are associated with biological entities.</p> <p>Findings</p> <p>The WordCloud Cytoscape plugin generates a visual summary of these annotations by displaying them as a tag cloud, where more frequent words are displayed using a larger font size. Word co-occurrence in a phrase can be visualized by arranging words in clusters or as a network.</p> <p>Conclusions</p> <p>WordCloud provides a concise visual summary of annotations which is helpful for network analysis and interpretation. WordCloud is freely available at <url>http://baderlab.org/Software/WordCloudPlugin</url></p

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

Cancer is nowadays recognised as a genetic and epigenetic disease. Much effort has been devoted in the last 30 years to the elucidation of the ‘classical' oncogenes and tumour-suppressor genes involved in malignant cell transformation. However, since the acceptance that major disruption of DNA methylation, histone modification and chromatin compartments are a common hallmark of human cancer, epigenetics has come to the fore in cancer research. One piece is still missing from the story: are the epigenetic genes themselves driving forces on the road to tumorigenesis? We are in the early stages of finding the answer, and the data are beginning to appear: knockout mice defective in DNA methyltransferases, methyl-CpG-binding proteins and histone methyltransferases strongly affect the risk of cancer onset; somatic mutations, homozygous deletions and methylation-associated silencing of histone acetyltransferases, histone methyltransferases and chromatin remodelling factors are being found in human tumours; and the first cancer-prone families arising from germline mutations in epigenetic genes, such as hSNF5/INI1, have been described. Even more importantly, all these ‘new' oncogenes and tumour-suppressor genes provide novel molecular targets for designed therapies, and the first DNA-demethylating agents and inhibitors of histone deacetylases are reaching the bedside of patients with haematological malignancies

Giant pedunculated hepatocellular carcinoma with hemangioma mimicking intestinal obstruction

<p>Abstract</p> <p>Background</p> <p>Pedunculated hepatocellular carcinoma (P-HCC) has rarely been reported and is characteristically large and encapsulated. Only sporadic cases have been published, in which P-HCC was combined with other liver tumors (mostly benign), making the diagnosis difficult.</p> <p>Case presentation</p> <p>We report a patient who was admitted to our hospital with clinical features of intestinal obstruction and a palpable mass in the right iliac fossa. Ultrasound, computed tomography and magnetic resonance imaging demonstrated an encapsulated mass of unclear origin and characteristics of liver hemangioma. Laboratory tests revealed elevated α-fetoprotein (> 800 ng/ml) and cancer antigen 125 (> 51.2 U/ml). With a possible diagnosis of giant liver hemangioma, we proceeded to surgery. During surgery, a giant pedunculated tumor was discovered on the inferior surface of the right lobe of the liver, hanging free in the right abdominal cavity towards the right iliac fossa. The macroscopic appearance of the tumor was compatible with liver hemangioma. Tumor resection was performed at a safe distance, including the pedicle. The rest of the liver appeared normal. Histopathological examination revealed grade II and III HCC (according to Edmondson-Steiner's classification) with nodular configuration, central necrosis, and infiltration of the capsule. Underneath the tumor capsule, residual tissue of a cavernous hemangioma was recognized. The resection margins were free of neoplastic tissue.</p> <p>Conclusion</p> <p>This rare presentation of a giant P-HCC combined with a hemangioma with features of intestinal obstruction confirmed the diagnostic difficulties of similar cases, and required prompt surgical treatment. Therefore, patients benefit from surgical resection because both the capsule and the pedicle prevent vascular invasion, therefore improving prognosis.</p