The self-assembly of α-synuclein is closely associated with Parkinson’s disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, ...dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson’s disease and related conditions.
ABSTRACT We describe a complete volume limited sample of nearby active galaxies selected by their 14-195 keV luminosity, and outline its rationale for studying the mechanisms regulating gas inflow ...and outflow. We also describe a complementary sample of inactive galaxies, selected to match the host galaxy properties. The active sample appears to have no bias in terms of active galactic nucleus (AGN) type, the only difference being the neutral absorbing column, which is two orders of magnitude greater for the Seyfert 2s. In the luminosity range spanned by the sample, -43.7, the optically obscured and X-ray absorbed fractions are 50%-65%. The similarity of these fractions to more distant spectroscopic AGN samples, although over a limited luminosity range, suggests that the torus does not strongly evolve with redshift. Our sample confirms that X-ray unabsorbed Seyfert 2s are rare, comprising not more than a few percent of the Seyfert 2 population. At higher luminosities, the optically obscured fraction decreases (as expected for the increasing dust sublimation radius), but the X-ray absorbed fraction changes little. We argue that the cold X-ray absorption in these Seyfert 1s can be accounted for by neutral gas in clouds that also contribute to the broad-line region (BLR) emission, and suggest that a geometrically thick neutral gas torus co-exists with the BLR and bridges the gap to the dusty torus.
Context:
Only approximately 85% of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can be explained by ...inactivating mutations in the androgen receptor (AR) gene.
Objective:
The objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls.
Design:
Quantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus.
Setting:
The study was conducted at a university hospital endocrine research laboratory.
Patients:
GFs from 169 individuals were studied encompassing control males (n = 68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n = 46).
Intervention(s):
There were no interventions.
Main Outcome Measure(s):
DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured.
Results:
The APOD assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff < 2.3-fold APOD-induction; 100% sensitivity, 93.3% specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling.
Conclusions:
AR mutation-positive AIS can be reliably identified by the APOD assay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance.
The use of Apolipoprotein D as a biomarker for androgen sensitivity identifies a new type of androgen insensitivity syndrome that is not associated with a mutation in the androgen receptor gene.
Background and aims. With the inclusion of gaming disorder in the ICD-11, diagnostic criteria were introduced for this relatively new disorder. These criteria may also be applied to other potential ...specific Internet-use disorders, which may be classified in ICD-11 as other disorders due to addictive behaviors, such as online buying-shopping disorder, online pornography-use disorder, social-networks-use disorder, and online gambling disorder. Due to the heterogeneity in existing instruments, we aimed to develop a consistent and economic measure of major types of (potential) specific Internet-use disorders based on ICD-11 criteria for gaming disorder. Methods. The new 11-item Assessment of Criteria for Specific Internet-use Disorders (ACSID-11) measures five behavioral addictions with the same set of items by following the principles of WHO’s ASSIST. The ACSID-11 was administered to active Internet users (N = 985) together with an adaptation of the Ten-Item Internet Gaming Disorder Test (IGDT-10) and screeners for mental health. We used Confirmatory Factor Analyses to analyze the factor structure of ACSID-11. Results. The assumed four-factorial structure was confirmed and was superior to the unidimensional solution. This applied to gaming disorder and to the other specific Internet-use disorders. ACSID-11 scores correlated with IGDT-10 as well as with the measures of psychological distress. Discussion and Conclusions. The ACSID-11 seems to be suitable for the consistent assessment of (potential) specific Internet-use disorders based on ICD-11 diagnostic criteria for gaming disorder. The ACSID-11 may be a useful and economic instrument for studying various behavioral addictions with the same items and improving comparability.
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.
Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth‐system processes. However, interlaboratory ...discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I‐CDES) values for Intercarb‐Carbon Dioxide Equilibrium Scale.
Key Points
The exclusive use of carbonate reference materials is a robust method for the standardization of clumped isotope measurements
Measurements using different acid temperatures, designs of preparation lines, and mass spectrometers are statistically indistinguishable
We propose new consensus values for a set of seven carbonate reference materials and updated guidelines to report clumped isotope measurements
The intestinal lamina propria (LP) contains a diverse array of mononuclear phagocyte (MNP) subsets, including conventional dendritic cells (cDC), monocytes and tissue-resident macrophages (mφ) that ...collectively play an essential role in mucosal homeostasis, infection and inflammation. In the current review we discuss the function of intestinal cDC and monocyte-derived MNP, highlighting how these subsets play several non-redundant roles in the regulation of intestinal immune responses. While much remains to be learnt, recent findings also underline how the various populations of MNP adapt to deal with the challenges specific to their environment. Understanding these processes should help target individual subsets for 'fine tuning' immunological responses within the intestine, a process that may be of relevance both for the treatment of inflammatory bowel disease (IBD) and for optimized vaccine design.
Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment ...options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.
We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.
Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval CI, 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.
In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).
The HITRAN2020 molecular spectroscopic database Gordon, I.E.; Rothman, L.S.; Hargreaves, R.J. ...
Journal of Quantitative Spectroscopy & Radiative Transfer/Journal of quantitative spectroscopy & radiative transfer,
01/2022, Volume:
277
Journal Article
Peer reviewed
Open access
•The HITRAN2020 molecular spectroscopic database and its validations are presented.•Extended line-by-line coverage to 55 molecules, with new isotopologues included.•Increased spectral and dynamic ...ranges for multiple molecules.•Quality and amount of spectral parameters (including sophisticated line shapes) is increased.•Updates to cross sections, CIA, software tools & auxiliary data also described.
The HITRAN database is a compilation of molecular spectroscopic parameters. It was established in the early 1970s and is used by various computer codes to predict and simulate the transmission and emission of light in gaseous media (with an emphasis on terrestrial and planetary atmospheres). The HITRAN compilation is composed of five major components: the line-by-line spectroscopic parameters required for high-resolution radiative-transfer codes, experimental infrared absorption cross-sections (for molecules where it is not yet feasible for representation in a line-by-line form), collision-induced absorption data, aerosol indices of refraction, and general tables (including partition sums) that apply globally to the data. This paper describes the contents of the 2020 quadrennial edition of HITRAN. The HITRAN2020 edition takes advantage of recent experimental and theoretical data that were meticulously validated, in particular, against laboratory and atmospheric spectra. The new edition replaces the previous HITRAN edition of 2016 (including its updates during the intervening years).
All five components of HITRAN have undergone major updates. In particular, the extent of the updates in the HITRAN2020 edition range from updating a few lines of specific molecules to complete replacements of the lists, and also the introduction of additional isotopologues and new (to HITRAN) molecules: SO, CH3F, GeH4, CS2, CH3I and NF3. Many new vibrational bands were added, extending the spectral coverage and completeness of the line lists. Also, the accuracy of the parameters for major atmospheric absorbers has been increased substantially, often featuring sub-percent uncertainties. Broadening parameters associated with the ambient pressure of water vapor were introduced to HITRAN for the first time and are now available for several molecules.
The HITRAN2020 edition continues to take advantage of the relational structure and efficient interface available at www.hitran.org and the HITRAN Application Programming Interface (HAPI). The functionality of both tools has been extended for the new edition.
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