The generation of toxic oligomers during the aggregation of the amyloid-β (Aβ) peptide Aβ42 into amyloid fibrils and plaques has emerged as a central feature of the onset and progression of ...Alzheimer’s disease, but the molecular pathways that control pathological aggregation have proved challenging to identify. Here, we use a combination of kinetic studies, selective radiolabeling experiments, and cell viability assays to detect directly the rates of formation of both fibrils and oligomers and the resulting cytotoxic effects. Our results show that once a small but critical concentration of amyloid fibrils has accumulated, the toxic oligomeric species are predominantly formed from monomeric peptide molecules through a fibril-catalyzed secondary nucleation reaction, rather than through a classical mechanism of homogeneous primary nucleation. This catalytic mechanism couples together the growth of insoluble amyloid fibrils and the generation of diffusible oligomeric aggregates that are implicated as neurotoxic agents in Alzheimer’s disease. These results reveal that the aggregation of Aβ42 is promoted by a positive feedback loop that originates from the interactions between the monomeric and fibrillar forms of this peptide. Our findings bring together the main molecular species implicated in the Aβ aggregation cascade and suggest that perturbation of the secondary nucleation pathway identified in this study could be an effective strategy to control the proliferation of neurotoxic Aβ42 oligomers.
The
Interface Region Imaging Spectrograph
(IRIS) small explorer spacecraft provides simultaneous spectra and images of the photosphere, chromosphere, transition region, and corona with 0.33 – ...0.4 arcsec spatial resolution, two-second temporal resolution, and 1 km s
−1
velocity resolution over a field-of-view of up to 175 arcsec × 175 arcsec. IRIS was launched into a Sun-synchronous orbit on 27 June 2013 using a Pegasus-XL rocket and consists of a 19-cm UV telescope that feeds a slit-based dual-bandpass imaging spectrograph. IRIS obtains spectra in passbands from 1332 – 1358 Å, 1389 – 1407 Å, and 2783 – 2834 Å, including bright spectral lines formed in the chromosphere (Mg
ii
h 2803 Å and Mg
ii
k 2796 Å) and transition region (C
ii
1334/1335 Å and Si
iv
1394/1403 Å). Slit-jaw images in four different passbands (C
ii
1330, Si
iv
1400, Mg
ii
k 2796, and Mg
ii
wing 2830 Å) can be taken simultaneously with spectral rasters that sample regions up to 130 arcsec × 175 arcsec at a variety of spatial samplings (from 0.33 arcsec and up). IRIS is sensitive to emission from plasma at temperatures between 5000 K and 10 MK and will advance our understanding of the flow of mass and energy through an
interface region
, formed by the chromosphere and transition region, between the photosphere and corona. This highly structured and dynamic region not only acts as the conduit of all mass and energy feeding into the corona and solar wind, it also requires an order of magnitude more energy to heat than the corona and solar wind combined. The IRIS investigation includes a strong numerical modeling component based on advanced radiative–MHD codes to facilitate interpretation of observations of this complex region. Approximately eight Gbytes of data (after compression) are acquired by IRIS each day and made available for unrestricted use within a few days of the observation.
The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a ...randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF
) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.
This systematic review evaluated the evidence comparing patient-important outcomes in spinal or epidural vs general anaesthesia for total hip and total knee arthroplasty.
MEDLINE, Ovid EMBASE, EBSCO ...CINAHL, Thomson Reuters Web of Science, and the Cochrane Central Register of Controlled Trials from inception until March 2015 were searched. Eligible randomized controlled trials or prospective comparative studies investigating mortality, major morbidity, and patient-experience outcomes directly comparing neuraxial (spinal or epidural) with general anaesthesia for total hip arthroplasty, total knee arthroplasty, or both were included. Independent reviewers working in duplicate extracted study characteristics, validity, and outcomes data. Meta-analysis was conducted using the random-effects model.
We included 29 studies involving 10 488 patients. Compared with general anaesthesia, neuraxial anaesthesia significantly reduced length of stay (weighted mean difference −0.40 days; 95% confidence interval −0.76 to −0.03; P+0.03; I2 73%; 12 studies). No statistically significant differences were found between neuraxial and general anaesthesia for mortality, surgical duration, surgical site or chest infections, nerve palsies, postoperative nausea and vomiting, or thromboembolic disease when antithrombotic prophylaxis was used. Subgroup analyses failed to find statistically significant interactions (P>0.05) based on risk of bias, type of surgery, or type of neuraxial anaesthesia.
Neuraxial anaesthesia for total hip or total knee arthroplasty, or both appears equally effective without increased morbidity when compared with general anaesthesia. There is limited quantitative evidence to suggest that neuraxial anaesthesia is associated with improved perioperative outcomes. Future investigations should compare intermediate and long-term outcome differences to better inform anaesthesiologists, surgeons, and patients on importance of anaesthetic selection.
The Sun Earth Connection Coronal and Heliospheric Investigation (SECCHI) is a five telescope package, which has been developed for the Solar Terrestrial Relation Observatory (STEREO) mission by the ...Naval Research Laboratory (USA), the Lockheed Solar and Astrophysics Laboratory (USA), the Goddard Space Flight Center (USA), the University of Birmingham (UK), the Rutherford Appleton Laboratory (UK), the Max Planck Institute for Solar System Research (Germany), the Centre Spatiale de Leige (Belgium), the Institut d’Optique (France) and the Institut d’Astrophysique Spatiale (France). SECCHI comprises five telescopes, which together image the solar corona from the solar disk to beyond 1 AU. These telescopes are: an extreme ultraviolet imager (EUVI: 1–1.7 R
⊙
), two traditional Lyot coronagraphs (COR1: 1.5–4 R
⊙
and COR2: 2.5–15 R
⊙
) and two new designs of heliospheric imagers (HI-1: 15–84 R
⊙
and HI-2: 66–318 R
⊙
). All the instruments use 2048×2048 pixel CCD arrays in a backside-in mode. The EUVI backside surface has been specially processed for EUV sensitivity, while the others have an anti-reflection coating applied. A multi-tasking operating system, running on a PowerPC CPU, receives commands from the spacecraft, controls the instrument operations, acquires the images and compresses them for downlink through the main science channel (at compression factors typically up to 20×) and also through a low bandwidth channel to be used for space weather forecasting (at compression factors up to 200×). An image compression factor of about 10× enable the collection of images at the rate of about one every 2–3 minutes. Identical instruments, except for different sizes of occulters, are included on the STEREO-A and STEREO-B spacecraft.
The crucial early stages of amyloid growth, in which normally soluble proteins are converted into fibrillar nanostructures, are challenging to study using conventional techniques yet are critical to ...the protein aggregation phenomena implicated in many common pathologies. As with all nucleation and growth phenomena, it is difficult to track individual nuclei in traditional macroscopic experiments, which probe the overall temporal evolution of the sample, but do not yield detailed information on the primary nucleation step as they mix independent stochastic events into an ensemble measurement. To overcome this limitation, we have developed microdroplet assays enabling us to detect single primary nucleation events and to monitor their subsequent spatial as well as temporal evolution, both of which we find to be determined by secondary nucleation phenomena. By deforming the droplets to high aspect ratio, we visualize in real-time propagating waves of protein assembly emanating from discrete primary nucleation sites. We show that, in contrast to classical gelation phenomena, the primary nucleation step is characterized by a striking dependence on system size, and the filamentous protein self-assembly process involves a highly nonuniform spatial distribution of aggregates. These findings deviate markedly from the current picture of amyloid growth and uncover a general driving force, originating from confinement, which, together with biological quality control mechanisms, helps proteins remain soluble and therefore functional in nature.
The dismal outcome of gastric cancer patients highlights the need for diagnostic biomarkers and effective therapeutic targets, such as microRNAs. We sought to discover microRNAs involved in gastric ...cancer, and to elucidate their downstream target mechanisms. Both cultured gastric epithelial cells (HFE145 and NCI-N87) and primary human gastric tissues (31 non-neoplastic stomach (NS) and 25 gastric carcinomas (GC)) were studied. MicroRNA microarrays and quantitative RT-PCR were applied to discover and verify differentially expressed microRNAs. in vitro cell migration and invasion, cell proliferation, cell cycle and apoptosis assays were executed to elucidate biological effects of microRNA-192 and -215. Western blotting and luciferase assays were performed to confirm direct messenger RNA targeting by microRNA-192 and -215. MicroRNA microarray analyses revealed that 25 and 20 microRNAs were upregulated and downregulated in GC vs NS, respectively. Expression levels of both microRNA-192 and -215 were significantly higher in GC than in NS (P<0.05). Luciferase assays suggested that microRNA-215 inhibits activated leukocyte cell adhesion molecule (ALCAM) expression at the posttranscriptional level. In addition, expression levels of ALCAM were significantly lower in GC than in NS. Mimics and inhibitors, respectively, of microRNA-192 or -215 exerted no effect on cell cycle or apoptosis in the immortalized normal gastric cell line HFE145 or the gastric cancer cell line NCI-N87. However, mimics of microRNA-192 or -215 significantly increased growth rates in HFE145 cells, whereas inhibitors of microRNA-192 or -215 caused significant decreases in growth rates in NCI-N87 cells. ALCAM knockdown by an ALCAM-specific siRNA significantly increased cell growth in HFE145 cells. Both transfection of mimics of microRNA-192 or -215 and ALCAM knockdown by an ALCAM-specific siRNA significantly increased the migration of HFE145 cells. In conclusion, in gastric cancer, both microRNA-192 and -215 are overexpressed in vivo and exert cell growth and migration-promoting effects in vitro, thus representing potential microRNAs with a role in cancer in the human stomach.
Characterizing the sizes and interactions of macromolecules under native conditions is a challenging problem in many areas of molecular sciences, which fundamentally arises from the polydisperse ...nature of biomolecular mixtures. Here, we describe a microfluidic platform for diffusional sizing based on monitoring micron-scale mass transport simultaneously in space and time. We show that the global analysis of such combined space-time data enables the hydrodynamic radii of individual species within mixtures to be determined directly by deconvoluting average signals into the contributions from the individual species. We demonstrate that the ability to perform rapid noninvasive sizing allows this method to be used to characterize interactions between biomolecules under native conditions. We illustrate the potential of the technique by implementing a single-step quantitative immunoassay that operates on a time scale of seconds and detects specific interactions between biomolecules within complex mixtures.
Low bispectral index (BIS) and low mean arterial pressure (MAP) are associated with worse outcomes after surgery. We tested the hypothesis that a combination of these risk factors, a ‘double low’, is ...associated with death and major complications after cardiac surgery.
We used data from 8239 cardiac surgical patients from two US hospitals. The primary outcomes were 30-day mortality and a composite of in-hospital mortality and morbidity. We examined whether patients who had a case-averaged double low, defined as time-weighted average BIS and MAP (calculated over an entire case) below the sample mean but not in the reference group, had increased risk of the primary outcomes compared with patients whose BIS and/or MAP were at or higher than the sample mean. We also examined whether a prolonged cumulative duration of a concurrent double low (simultaneous low MAP and BIS) increased the risk of the primary outcomes.
Case-averaged double low was not associated with increased risk of 30-day mortality {odds ratio OR 1.73 95% confidence interval (CI) 0.94–3.18 vs reference; P=0.01} or the composite of in-hospital mortality and morbidity OR 1.47 (95% CI 0.98–2.20); P=0.01 after correction for multiple outcomes. A prolonged concurrent double low was associated with 30-day mortality OR 1.06 (95% CI 1.01–1.11) per 10-min increase; P=0.001 and the composite of in-hospital mortality and morbidity OR 1.04 (95% CI 1.01–1.07), P=0.004.
A prolonged concurrent double low, but not a case-averaged double low, was associated with higher morbidity and mortality after cardiac surgery.
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