The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends.

Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo protein folding and preventing amyloid formation. Chaperones of the Hsp70 family can further disaggregate otherwise irreversible aggregate species such as α-synuclein fibrils, which accumulate in Parkinson's disease. However, the mechanisms and kinetics of this key functionality are only partially understood. Here, we combine microfluidic measurements with chemical kinetics to study α-synuclein disaggregation. We show that Hsc70 together with its co-chaperones DnaJB1 and Apg2 can completely reverse α-synuclein aggregation back to its soluble monomeric state. This reaction proceeds through first-order kinetics where monomer units are removed directly from the fibril ends with little contribution from intermediate fibril fragmentation steps. These findings extend our mechanistic understanding of the role of chaperones in the suppression of amyloid proliferation and in aggregate clearance, and inform on possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies

The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends

Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo protein folding and preventing amyloid formation. Chaperones of the Hsp70 family can further disaggregate otherwise irreversible aggregate species such as alpha-synuclein fibrils, which accumulate in Parkinson's disease. However, the mechanisms and kinetics of this key functionality are only partially understood. Here, we combine microfluidic measurements with chemical kinetics to study alpha-synuclein disaggregation. We show that Hsc70 together with its co-chaperones DnaJB1 and Apg2 can completely reverse alpha-synuclein aggregation back to its soluble monomeric state. This reaction proceeds through first-order kinetics where monomer units are removed directly from the fibril ends with little contribution from intermediate fibril fragmentation steps. These findings extend our mechanistic understanding of the role of chaperones in the suppression of amyloid proliferation and in aggregate clearance, and inform on possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies. Molecular chaperones from the Hsp70 family can break up protein aggregates, including amyloids. Here, the authors utilize microfluidic diffusional sizing to assess the mechanism of alpha-synuclein (alpha S) disaggregation by the Hsc70-DnaJB1-Apg2 system, and show that single alpha S molecules are removed directly from the fibril ends

Remediation of charged organic pollutants—binding motifs for highly efficient water cleaning with nanoparticles

AbstractMany charged organic molecules behave as persistent and hazardous pollutants with harmful effects on human health and ecosystems. They are widely distributed related to their charged molecular structure that provides water solubility. In order to track the fate and behavior of such pollutants, charged dyes with specific absorption in the visible spectra serve as convenient model compounds. We provide a platform of smart adsorbers that efficiently remediate positively and negatively charged dyes (crystal violet and Amaranth) from water. Metal oxide nanoparticles serve as a core with an intrinsically large surface area. The surface potential was tuned towards positive or negative by decorating the cores with self‐assembled monolayers of dedicated long‐chained phosphonic acid derivatives. Selective remediation of the dyes was obtained with corresponding oppositely charged core‐shell nanoparticles. Mixed dye solution can be cleaned by a cascade approach or by applying both particle systems simultaneously. The removal efficiency was determined as a function of particle concentration via UV‐spectroscopy. The results of remediation experiments at different pH values and using superparamagnetic iron oxide nanoparticle cores lead to a simple process with recycling capability.</jats:p

Future Exoplanet Research: Science Questions and How to Address Them

Started approximately in the late 1980s, exoplanetology has up to now unveiled the main gross bulk characteristics of planets and planetary systems. In the future it will benefit from more and more large telescopes and advanced space missions. These instruments will dramatically improve their performance in terms of photometric precision, detection speed, multipixel imaging, high-resolution spectroscopy, allowing to go much deeper in the knowledge of planets. Here we outline some science questions which should go beyond these standard improvements and how to address them. Our prejudice is that one is never too speculative: experience shows that the speculative predictions initially not accepted by the community have been confirmed several years later (like spectrophotometry of transits or circumbinary planets).Comment: Invited review, accepte

Summary of 2006 to 2010 FPMU Measurements of International Space Station Frame Potential Variations

Electric potential variations on the International Space Station (ISS) structure in low Earth orbit are dominated by contributions from interactions of the United States (US) 160 volt solar arrays with the relatively high density, low temperature plasma environment and inductive potentials generated by motion of the large vehicle across the Earth?s magnetic field. The Floating Potential Measurement Unit (FPMU) instrument suite comprising two Langmuir probes, a plasma impedance probe, and a floating potential probe was deployed in August 2006 for use in characterizing variations in ISS potential, the state of the ionosphere along the ISS orbit and its effect on ISS charging, evaluating effects of payloads and visiting vehicles, and for supporting ISS plasma hazard assessments. This presentation summarizes observations of ISS frame potential variations obtained from the FPMU from deployment in 2006 through the current time. We first describe ISS potential variations due to current collection by solar arrays in the day time sector of the orbit including eclipse exit and entry charging events, potential variations due to plasma environment variations in the equatorial anomaly, and visiting vehicles docked to the ISS structure. Next, we discuss potential variations due to inductive electric fields generated by motion of the vehicle across the geomagnetic field and the effects of external electric fields in the ionosphere. Examples of night time potential variations at high latitudes and their possible relationship to auroral charging are described and, finally, we demonstrate effects on the ISS potential due to European Space Agency and US plasma contactor devices

Temporal Accumulation and Decision Processes in the Duration Bisection Task Revealed by Contingent Negative Variation

The duration bisection paradigm is a classic task used to examine how humans and other animals perceive time. Typically, participants first learn short and long anchor durations and are subsequently asked to classify probe durations as closer to the short or long anchor duration. However, the specific representations of time and the decision rules applied in this task remain the subject of debate. For example, researchers have questioned whether participants actually use representations of the short and long anchor durations in the decision process rather than merely a response threshold that is derived from those anchor durations. Electroencephalographic (EEG) measures, like the contingent negative variation (CNV), can provide information about the perceptual and cognitive processes that occur between the onset of the timing stimulus and the motor response. The CNV has been implicated as an electrophysiological marker of interval timing processes such as temporal accumulation, representation of the target duration, and the decision that the target duration has been attained. We used the CNV to investigate which durations are involved in the bisection categorization decision. The CNV increased in amplitude up to the value of the short anchor, remained at a constant level until about the geometric mean (GM) of the short and long anchors, and then began to resolve. These results suggest that the short anchor and the GM of the short and long anchors are critical target durations used in the bisection categorization decision process. In addition, larger mean N1P2 amplitude differences were associated with larger amplitude CNVs, which may reflect the participant’s precision in initiating timing on each trial across a test session. Overall, the results demonstrate the value of using scalp-recorded EEG to address basic questions about interval timing

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial.

BACKGROUND: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer. METHODS: The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus gemcitabine (vandetanib group) or placebo plus gemcitabine (placebo group) according to pre-generated sequences produced on the principle of randomly permuted blocks with variable block sizes of two and four. Patients were stratified at randomisation by disease stage and ECOG performance status. All patients received gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion, weekly, for 7 weeks followed by a 1-week break, followed by a cycle of 3 weeks of treatment with a 1-week break, until disease progression, and either oral vandetanib 300 mg per day once daily or matching placebo. Patients and investigators were masked to treatment assignment. The primary outcome measure was overall survival (defined as the difference in time between randomisation and death from any cause or the censor date) in the intention-to-treat population. This trial has been completed and the final results are reported. The study is registered at EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Patients were screened and enrolled between Oct 24, 2011, and Oct 7, 2013. Of 381 patients screened, 142 eligible patients were randomly assigned to treatment (72 to the vandetanib group and 70 to the placebo group). At database lock on July 15, 2015, at a median follow-up of 24·9 months (IQR 24·3 to not attainable), 131 patients had died: 70 (97%) of 72 in the vandetanib group and 61 (87%) of 70 in the placebo group. The median overall survival was 8·83 months (95% CI 7·11-11·58) in the vandetanib group and 8·95 months (6·55-11·74) in the placebo group (hazard ratio 1·21, 80·8% CI 0·95-1·53; log rank χ(2)1df 1·1, p=0·303). The most common grade 3-4 adverse events were neutropenia (35 [49%] of 72 patients in the vandetanib group vs 22 [31%] of 70 in the placebo group), thrombocytopenia (20 [28%] vs 16 [23%]), hypertension (nine [13%] vs 11 [16%]), leucopenia (12 [17%] vs 13 [19%]), and fatigue (17 [24%] vs 15 [21%]). No treatment-related deaths occurred during the study. INTERPRETATION: The addition of vandetanib to gemcitabine monotherapy did not improve overall survival in advanced pancreatic cancer. Tyrosine kinase inhibitors might still have potential in the treatment of pancreatic cancer but further development requires the identification of biomarkers to specifically identify responsive cancer subtypes. FUNDING: Cancer Research UK and AstraZeneca