Probing the Mechanisms of Fibril Formation Using Lattice Models

Using exhaustive Monte Carlo simulations we study the kinetics and mechanism of fibril formation using lattice models as a function of temperature and the number of chains. While these models are, at best, caricatures of peptides, we show that a number of generic features thought to govern fibril assembly are present in the toy model. The monomer, which contains eight beads made from three letters (hydrophobic, polar, and charged), adopts a compact conformation in the native state. The kinetics of fibril assembly occurs in three distinct stages. In each stage there is a cascade of events that transforms the monomers and oligomers to ordered structures. In the first "burst" stage highly mobile oligomers of varying sizes form. The conversion to the aggregation-prone conformation occurs within the oligomers during the second stage. As time progresses, a dominant cluster emerges that contains a majority of the chains. In the final stage, the aggregation-prone conformation particles serve as a template onto which smaller oligomers or monomers can dock and undergo conversion to fibril structures. The overall time for growth in the latter stages is well described by the Lifshitz-Slyazov growth kinetics for crystallization from super-saturated solutions.Comment: 27 pages, 6 figure

Accuracy of computerized tomography in determining hepatic tumor size in patients receiving liver transplantation or resection

Computerized tomography (CT) of liver is used in oncologic practice for staging tumors, evaluating response to treatment, and screening patients for hepatic resection. Because of the impact of CT liver scan on major treatment decisions, it is important to assess its accuracy. Patients undergoing liver transplantation or resection provide a unique opportunity to test the accuracy of hepatic-imaging techniques by comparison of finding of preoperative CT scan with those at gross pathologic examination of resected specimens. Forty-one patients who had partial hepatic resection (34 patients) or liver transplantation (eight patients) for malignant (30 patients) or benign (11 patients) tumors were evaluable. Eight (47%) of 17 patients with primary malignant liver tumors, four (31%) of 13 patients with metastatic liver tumors, and two (20%) of 10 patients with benign liver tumors had tumor nodules in resected specimens that were not apparent on preoperative CT studies. These nodules varied in size from 0.1 to 1.6 cm. While 11 of 14 of these nodules were 1.0 cm. These results suggest that conventional CT alone may be insufficient to accurately determine the presence or absence of liver metastases, extent of liver involvement, or response of hepatic metastases to treatment

Structure of the unphosphorylated STAT5a dimer

STAT proteins have the function of signaling from the cell membrane into the nucleus, where they regulate gene transcription. Latent mammalian STAT proteins can form dimers in the cytoplasm even before receptor-mediated activation by specific tyrosine phosphorylation. Here we describe the 3.21-angstrom crystal structure of an unphosphorylated STAT5a homodimer lacking the N-terminal domain as well as the C-terminal transactivation domain. The overall structure of this fragment is very similar to phosphorylated STATs. However, important differences exist in the dimerization mode. Although the interface between phosphorylated STATs is mediated by their Src-homology 2 domains, the unphosphorylated STAT5a fragment dimerizes in a completely different manner via interactions between their beta-barrel and four-helix bundle domains. The STAT4 N-terminal domain dimer can be docked onto this STAT5a core fragment dimer based on shape and charge complementarities. The separation of the dimeric arrangement, taking place upon activation and nuclear translocation of STAT5a, is demonstrated by fluorescence resonance energy transfer experiments in living cells

2014 ISS Potable Water Characterization and Continuation of the DMSD Chronicle

During 2014 the crews from Expeditions 38-41 were resident on the International Space Station (ISS). In addition to the U.S. potable water reclaimed from humidity condensate and urine, the other water supplies available for their use were Russian potable water reclaimed from condensate and Russian ground-supplied potable water. Beginning in June of 2014, and for the fourth time since 2010, the product water from the U.S. Water Processor Assembly (WPA) experienced a rise in the total organic carbon (TOC) level due to organic contaminants breaking through the water treatment process. Results from ground analyses of ISS archival water samples returned on Soyuz 38 confirmed that dimethylsilanediol (DMSD) was once again the contaminant responsible for the rise. With this confirmation in hand and based upon the low toxicity of DMSD, a waiver was approved to allow the crew to continue to consume the water after the TOC level exceeded the U.S. Segment limit of 3 mg/L. Several weeks after the WPA multifiltration beds were replaced, as anticipated based upon experience from previous rises, the TOC levels returned to below the method detection limit of the onboard TOC analyzer (TOCA). This paper presents and discusses the chemical analysis results for the ISS archival potable water samples returned in 2014 and analyzed by the Johnson Space Center's Toxicology and Environmental Chemistry laboratory. These results showed compliance with ISS potable water quality standards and indicated that the potable water supplies were acceptable for crew consumption. Although DMSD levels were at times elevated they remained well below the 35 mg/L health limit, so continued consumption of the U.S potable water was considered a low risk to crew health and safety. Excellent agreement between inflight and archival sample TOC data confirmed that the TOCA performed optimally and it continued to serve as a vital tool for monitoring organic breakthrough and planning remediation action

Revertant fibres and dystrophin traces in Duchenne muscular dystrophy: Implication for clinical trials

Duchenne muscular dystrophy (DMD) is characterised by the absence of dystrophin in muscle biopsies, although residual dystrophin can be present, either as dystrophin-positive (revertant) fibres or traces. As restoration of dystrophin expression is the end point of clinical trials, such residual dystrophin is a key factor in recruitment of patients and may also confound the analysis of dystrophin restoration in treated patients, if, as previously observed in the mdx mouse, revertant fibres increase with age. In 62% of the diagnostic biopsies reports of 65 DMD patients studied, traces or revertants were recorded with no correlation between traces or revertants, the patients' performance, or corticosteroids response. In nine of these patients, there was no increase in traces or revertants in biopsies taken a mean of 8.23 years (5.8-10.4 years) after the original diagnostic biopsy. This information should help in the design and execution of clinical trials focused on dystrophin restoration strategies. (C) 2010 Elsevier B.V. All rights reserved

Fractal Analysis of Protein Potential Energy Landscapes

The fractal properties of the total potential energy V as a function of time t are studied for a number of systems, including realistic models of proteins (PPT, BPTI and myoglobin). The fractal dimension of V(t), characterized by the exponent \gamma, is almost independent of temperature and increases with time, more slowly the larger the protein. Perhaps the most striking observation of this study is the apparent universality of the fractal dimension, which depends only weakly on the type of molecular system. We explain this behavior by assuming that fractality is caused by a self-generated dynamical noise, a consequence of intermode coupling due to anharmonicity. Global topological features of the potential energy landscape are found to have little effect on the observed fractal behavior.Comment: 17 pages, single spaced, including 12 figure

International Space Station Potable Water Characterization for 2013

In this post-construction, operational phase of International Space Station (ISS) with an ever-increasing emphasis on its use as a test-bed for future exploration missions, the ISS crews continue to rely on water reclamation systems for the majority of their water needs. The onboard water supplies include U.S. Segment potable water from humidity condensate and urine, Russian Segment potable water from condensate, and ground-supplied potable water, as reserve. In 2013, the cargo returned on the Soyuz 32-35 flights included archival potable water samples collected from Expeditions 34-37. The former Water and Food Analytical Laboratory (now Toxicology and Evironmental Chemistry Laboratory) at the NASA Johnson Space Center continued its long-standing role of performing chemical analyses on ISS return water samples to verify compliance with potable water quality specifications. This paper presents and discusses the analytical results for potable water samples returned from Expeditions 34-37, including a comparison to ISS quality standards. During the summer of 2013, the U.S. Segment potable water experienced a third temporary rise and fall in total organic carbon (TOC) content, as the result of organic contamination breaking through the water system's treatment process. Analytical results for the Expedition 36 archival samples returned on Soyuz 34 confirmed that dimethylsilanediol was once again the responsible contaminant, just as it was for the previous comparable TOC rises in 2010 and 2012. Discussion herein includes the use of the in-flight total organic carbon analyzer (TOCA) as a key monitoring tool for tracking these TOC rises and scheduling appropriate remediation