Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils

Several lines of evidence indicate that prefibrillar assemblies of amyloid-{beta} (A{beta}) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of A{beta} fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in A{beta} peptides and stabilizes the self-assembly of seeding-competent, {beta}-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic A{beta} oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by A{beta} oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells

Bronchoscopy-Derived Correlates of Lung Injury following Inhalational Injuries: A Prospective Observational Study

Background: Acute lung injury (ALI) is a major factor determining morbidity following burns and inhalational injury. In experimental models, factors potentially contributing to ALI risk include inhalation of toxins directly causing cell damage; inflammation; and infection. However, few studies have been done in humans. Methods: We carried out a prospective observational study of patients admitted to the NC Jaycees Burn Center who were intubated and on mechanical ventilation for burns and suspected inhalational injury. Subjects were enrolled over an 8-month period and followed till discharge or death. Serial bronchial washings from clinically-indicated bronchoscopies were collected and analyzed for markers of cell injury and inflammation. These markers were compared with clinical markers of ALI. Results: Forty-three consecutive patients were studied, with a spectrum of burn and inhalation injury severity. Visible soot at initial bronchoscopy and gram negative bacteria in the lower respiratory tract were associated with ALI in univariate analyses. Subsequent multivariate analysis also controlled for % body surface area burns, infection, and inhalation severity. Elevated IL-10 and reduced IL-12p70 in bronchial washings were statistically significantly associated with ALI. Conclusions: Independently of several factors including initial inhalational injury severity, infection, and extent of surface burns, high early levels of IL-10 and low levels of IL-12p70 in the central airways are associated with ALI in patients intubated after acute burn/inhalation injury. Lower airway secretions can be collected serially in critically ill burn/inhalation injury patients and may yield important clues to specific pathophysiologic pathways

Detection of interstellar E-1-cyano-1,3-butadiene in GOTHAM observations of TMC-1

Interstellar matter and star formationStars and planetary system

Low-mass pre--main-sequence stars in the Magellanic Clouds

[Abridged] The stellar Initial Mass Function (IMF) suggests that sub-solar stars form in very large numbers. Most attractive places for catching low-mass star formation in the act are young stellar clusters and associations, still (half-)embedded in star-forming regions. The low-mass stars in such regions are still in their pre--main-sequence (PMS) evolutionary phase. The peculiar nature of these objects and the contamination of their samples by the evolved populations of the Galactic disk impose demanding observational techniques for the detection of complete numbers of PMS stars in the Milky Way. The Magellanic Clouds, the companion galaxies to our own, demonstrate an exceptional star formation activity. The low extinction and stellar field contamination in star-forming regions of these galaxies imply a more efficient detection of low-mass PMS stars than in the Milky Way, but their distance from us make the application of special detection techniques unfeasible. Nonetheless, imaging with the Hubble Space Telescope yield the discovery of solar and sub-solar PMS stars in the Magellanic Clouds from photometry alone. Unprecedented numbers of such objects are identified as the low-mass stellar content of their star-forming regions, changing completely our picture of young stellar systems outside the Milky Way, and extending the extragalactic stellar IMF below the persisting threshold of a few solar masses. This review presents the recent developments in the investigation of PMS stars in the Magellanic Clouds, with special focus on the limitations by single-epoch photometry that can only be circumvented by the detailed study of the observable behavior of these stars in the color-magnitude diagram. The achieved characterization of the low-mass PMS stars in the Magellanic Clouds allowed thus a more comprehensive understanding of the star formation process in our neighboring galaxies.Comment: Review paper, 26 pages (in LaTeX style for Springer journals), 4 figures. Accepted for publication in Space Science Review

On the origin and evolution of the material in 67P/Churyumov-Gerasimenko

International audiencePrimitive objects like comets hold important information on the material that formed our solar system. Several comets have been visited by spacecraft and many more have been observed through Earth- and space-based telescopes. Still our understanding remains limited. Molecular abundances in comets have been shown to be similar to interstellar ices and thus indicate that common processes and conditions were involved in their formation. The samples returned by the Stardust mission to comet Wild 2 showed that the bulk refractory material was processed by high temperatures in the vicinity of the early sun. The recent Rosetta mission acquired a wealth of new data on the composition of comet 67P/Churyumov-Gerasimenko (hereafter 67P/C-G) and complemented earlier observations of other comets. The isotopic, elemental, and molecular abundances of the volatile, semi-volatile, and refractory phases brought many new insights into the origin and processing of the incorporated material. The emerging picture after Rosetta is that at least part of the volatile material was formed before the solar system and that cometary nuclei agglomerated over a wide range of heliocentric distances, different from where they are found today. Deviations from bulk solar system abundances indicate that the material was not fully homogenized at the location of comet formation, despite the radial mixing implied by the Stardust results. Post-formation evolution of the material might play an important role, which further complicates the picture. This paper discusses these major findings of the Rosetta mission with respect to the origin of the material and puts them in the context of what we know from other comets and solar system objects

Detection of two interstellar polycyclic aromatic hydrocarbons via spectral matched filtering

International audienceUnidentified infrared emission bands are ubiquitous in many astronomical sources. These bands are widely, if not unanimously, attributed to collective emissions from polycyclic aromatic hydrocarbon (PAH) molecules, yet no single species of this class has been identified in space. Using spectral matched filtering of radio data from the Green Bank Telescope, we detected two nitrile-group-functionalized PAHs, 1- and 2-cyanonaphthalene, in the interstellar medium. Both bicyclic ring molecules were observed in the TMC-1 molecular cloud. In this paper, we discuss potential in situ gas-phase PAH formation pathways from smaller organic precursor molecules. © 2021 American Association for the Advancement of Science. All rights reserved