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Impact of epicardial adipose tissue on myocardial function and structure in patients with severe aortic valve stenosis
No full textAbstract Aims Epicardial adipose tissue (EAT) is closely associated with the development of heart failure and adverse myocardial remodelling. In patients with severe aortic valve stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR), increased EAT has been identified as a predictor of adverse outcomes; however, the underlying pathophysiological mechanisms remain unclear. This study aims to explore the effects of increased EAT volumes on myocardial remodelling and dysfunction in patients with severe AS. Methods and results One hundred thirty‐seven patients with severe AS (median age 80 years, 62% male) underwent cardiac magnetic resonance imaging (CMR) prior to TAVR. Myocardial volumes and function as well as EAT volumes were quantified from CMR acquisitions. The cohort was dichotomised at the median EAT volume. Patients with increased EAT volumes above the median (≥46.5 mL/m 2 ) showed impaired left atrial (LA) reservoir strain (Es) as a distinct functional feature compared with patients with lower EAT volumes (11.8% [7.6–16.7] vs. 15.0% [10.9–19.1], P = 0.011), while left ventricular (LV) morphology and function (all P ≥ 0.216), right atrial and ventricular morphology and function (all P ≥ 0.090), as well as tissue characteristics (all ≥ 0.229) were similar between both groups. In a subgroup analysis of the four types of severe AS, the difference was most prominent in patients with low ejection fraction high‐gradient AS. In multivariable regression analyses, EAT was independently associated with impaired LA Es, irrespective of co‐morbidities, ventricular function, tissue characteristics and functional characteristics of AS. Conclusions In patients with severe AS, increased EAT volume is independently associated with impaired LA function but not with other features of biventricular morphology, function or tissue composition. The incremental deterioration of LA function, in addition to the afterload imposed by AS in these patients, could increase vulnerability to heart failure and may require consideration as a therapeutic target beyond TAVR
Absorption cross sections of CHF3 (HFC-23) in synthetic air at 296 K
No full texthttp://dx.doi.org/10.13039/100014132 European Metrology Programme for Innovation and Researchhttp://dx.doi.org/10.13039/100010661 Horizon 2020 Framework Programmehttp://dx.doi.org/10.13039/100014013 UK Research and Innovatio
Developing a Spatiotemporal Repository of Extreme Heat and Cold Exposure in the United States for Precision Public Health Research
No full textCorrection: Identification of AAV variants with improved transduction of human vascular endothelial cells by screening AAV capsid libraries in non-human primates
No full textNeuronal THY1 Signaling Maintains Astrocytes in a Quiescent State
No full textABSTRACT THY1 is a cell surface protein of mature neurons. Although the Thy1 promoter is widely used as a neuron‐specific promoter for transgenic expression, the role of the endogenous THY1 protein in the brain remains largely unknown. As THY1 receptors are expressed on astrocytes, THY1 may mediate signaling between both cell types. We therefore investigated the role of THY1 signaling in neuron‐astrocyte communication using a full as well as a neuron‐specific Thy1 ‐knockout mouse model. Compared to wild‐type mice, aged individuals of both strains exhibited an increased expression of a subset of astrocyte activation‐associated genes, such as glial fibrillary acidic protein ( Gfap ), vimentin ( Vim ), and tenascin C ( Tnc ), whereas others appeared unaffected. Importantly, a cortical injury caused a permanent astrocytic activation in mice with neuronal Thy1 deletion, reflected by persistent high GFAP expression. The THY1‐associated modulation of gene expression was confirmed in primary astrocytes cultured with or without recombinant THY1. Moreover, functional assays indicate that THY1 inhibits astrocyte proliferation while promoting apoptosis. Interaction of neuronal THY1 with ITGB1 on astrocytes was identified to be responsible for the THY1‐mediated control of astrocyte activation. These data strongly suggest that THY1‐bearing neurons keep astrocytes in a quiescent state. Consequently, a depletion of THY1 supports the development of a partially activated astrocyte phenotype characterized by increased expression of intermediate filaments, increased proliferative capacity, and reduced cell death. Our findings demonstrate that neuronal THY1 is a still unrecognized novel regulator in the communication between astrocytes and neurons involved in the maintenance and restoration of tissue homeostasis in the brain.Deutsche Forschungsgemeinschaft https://doi.org/10.13039/50110000165
Keimzelltumoren des Hodens: Klassifikation, Schnellschnittdiagnostik, Sentinel-Lymphknoten-Biopsie und biologische Sonderformen
No full textZusammenfassung Die Keimzelltumoren (KZT) sind die häufigsten Neoplasien im Hoden und lassen sich in Abhängigkeit vom Manifestationsalter, der Molekularbiologie und der Histomorphologie in Typ-I-, Typ-II- und Typ-III-Tumoren einteilen. Insgesamt gibt es dabei 6 histologische Subtypen, die unterschiedlich innerhalb dieser 3 Gruppen verteilt sind: Seminome, embryonale Karzinome, Chorionkarzinome, Dottersacktumoren, Teratome und spermatozytäre Tumoren. Am häufigsten sind die malignen Typ-II-KZT, die primär meist durch eine radikale Orchiektomie therapiert werden. In Fällen kleiner Tumoren, bei denen z.B. aufgrund negativer Serumtumormarker unklar ist, ob ein maligner oder benigner Hodentumor (z.B. Epidermiszyste, Keimstranggonadenstromatumor, Adenomatoidtumor, andere testikuläre Adnextumoren) vorliegt, kann zunächst eine Enukleation mit anschließender Schnellschnittuntersuchung erfolgen, da für benigne Tumoren eine hodenerhaltende Tumorresektion ausreicht. Die genaue Einteilung der KZT erfolgt dann histopathologisch durch die morphologischen Charakteristika der KZT-Subtypen und kann unter gewissen Umständen durch immunhistochemische Analysen ergänzt werden. Bei der Untersuchung von Resektaten aus Metastasen (z.B. retroperitoneale Lymphknoten) können auch biologische Sonderformen, wie eine somatische Malignität oder das sogenannte „Growing-Teratoma“-Syndrom detektiert werden. Sollten histomorphologisch Anteile der typischen KZT-Subtypen in somatischen Malignitäten fehlen, kann der KZT-Ursprung molekularpathologisch durch Nachweis des Isochromosoms 12p oder einer Vermehrung chromosomalen Materials auf Chromosom 12 bestätigt werden
The behavior flexibility rating scales: systematic-narrative review of psychometric properties and clinical applications
No full textAggregation-Dependent Epitope Sequence and Modification Fingerprints of Anti-Aβ Antibodies
No full textAbstract A hallmark of Alzheimer’s disease (AD), the most common form of dementia, is the progressive accumulation of amyloid-beta (Aβ) peptides across distinct brain regions. Anti-Aβ antibodies (Aβ-Abs) targeting specific Aβ variants are essential tools for AD research, diagnostics, and therapy. The monoclonal antibodies Aducanumab, Lecanemab, and Donanemab have recently been approved as the first disease-modifying treatments for early AD, highlighting the clinical importance of their exact binding profiles. In this study, we systematically characterized the binding and modification requirements of 20 Aβ-Abs, including biosimilars of Aducanumab, Lecanemab, and Donanemab, across monomeric, oligomeric, and aggregated Aβ forms. Array-based analysis of 20,000 modified Aβ peptides defined binding epitopes at single-residue resolution and revealed the impact of sequence variation, including familial AD mutations, as well as diverse post-translational modifications (PTMs). Notably, genetic variants such as H6R impaired binding of therapeutic Aβ-Abs like Aducanumab. Donanemab showed strong preference for pyroglutamate-modified AβpE3–10, while Lecanemab and Aducanumab exhibited aggregation- and sequence-context-dependent binding requirements. Comparison of peptide binding profiles with binding of full-length and aggregated Aβ via immunoprecipitation-mass spectrometry, capillary immunoassays, Western blotting, and immunohistochemistry on AD brain tissue revealed distinct aggregation-dependent binding behaviours. The valency- and context-dependence of Aducanumab binding, together with its preference for Ser8-phosphorylated Aβ, supports a dimerization-mediated binding mechanism. For Lecanemab, our data suggest that additional structural contributions beyond the minimal N-terminal epitope are required for binding to aggregated Aβ, which remain to be fully resolved. Together, this work provides the most comprehensive dataset to date on aggregation-dependent sequence and modification selectivity of Aβ-Abs. By integrating mutational, PTM, and aggregation contexts in a unified experimental framework, we establish a resource that enables rational selection of antibodies for research and diagnostic applications, and offers mechanistic insights that may inform the design and optimization of future therapeutic antibodies in AD
Active particles in moving traps: Minimum work protocols and information efficiency of work extraction
No full textWe revisit the elementary problem of moving a particle in a harmonic trap in finite time with minimal work cost and extend it to the case of an active particle. By comparing the Gaussian case of an Active Ornstein-Uhlenbeck particle and the non-Gaussian run-and-tumble particle, we establish general principles for thermodynamically optimal control of active matter beyond specific models. We show that the open-loop optimal protocols, which do not incorporate system-state information, are identical to those of passive particles but result in larger work fluctuations due to activity. In contrast, closed-loop (or feedback) control with a single (initial) measurement changes the optimal protocol and reduces the average work relative to the open-loop control for small enough measurement errors. Minimum work is achieved by particles with finite persistence time. As an application, we propose an active information engine which extracts work from self-propulsion. This periodic engine achieves higher information efficiency with run-and-tumble particles than with active Ornstein-Uhlenbeck particles. Complementing a companion paper that gives only the main results [Garcia-Millan , companion paper, ], here we provide a full account of our theoretical calculations and simulation results. We include derivations of optimal protocols, work variance, impact of measurement uncertainty, and information-acquisition costs.Engineering and Physical Sciences Research Council http://dx.doi.org/10.13039/501100000266H2020 Marie Skłodowska-Curie Actions http://dx.doi.org/10.13039/100010665UK Research and Innovation http://dx.doi.org/10.13039/100014013Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/50110000165