A point mutation in the AF-2 domain of thyroid hormone receptor alpha1 expressed after CRE mediated recombination partially recapitulates hypothyroidism.

Thyroid hormones act directly on transcription by binding to TRα1, TRβ1, TRβ2 nuclear receptors, regulating many aspects of post-natal development and homeostasis. To precisely analyze the implication of the widely expressed TRα1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TRα1 coding sequence, which is expressed only after CRE/loxP mediated DNA recombination. The amino-acid change prevents interaction between TRα1 and histone acetyltransferase coactivators and the release of corepressors. Early expression of this dominant-negative receptor deeply affects post-natal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TRβ1 and TRβ2 are predominantly expressed. Both respective abundance and intrinsic properties of TRα1 and TRβ1/2 seems to govern specificity of action

Evidence for electronically-driven ferroelectricity in the family of strongly correlated dimerized BEDT-TTF molecular conductors

By applying measurements of the dielectric constants and relative length changes to the dimerized molecular conductor $\kappa$-(BEDT-TTF)$_2$Hg(SCN)$_2$Cl, we provide evidence for order-disorder type electronic ferroelectricity which is driven by charge order within the (BEDT-TTF)$_2$ dimers and stabilized by a coupling to the anions. According to our density functional theory calculations, this material is characterized by a moderate strength of dimerization. This system thus bridges the gap between strongly dimerized materials, often approximated as dimer-Mott systems at 1/2 filling, and non- or weakly dimerized systems at 1/4 filling exhibiting charge order. Our results indicate that intra-dimer charge degrees of freedom are of particular importance in correlated $\kappa$-(BEDT-TTF)$_2$X salts and can create novel states, such as electronically-driven multiferroicity or charge-order-induced quasi-1D spin liquids.Comment: 6 pages, 4 figures + Supplementary Information (8 pages, 8 figures

Exploring the Usability of the German COVID-19 Contact Tracing App in a Combined Eye Tracking and Retrospective Think Aloud Study

In the course of the corona virus (COVID-19) pandemic, many digital solutions for mobile devices (e.g., apps) were presented in order to provide additional resources supporting the control of the pandemic. Contact tracing apps (i.e., identify persons who may have been in contact with a COVID-19 infected) constitute one of the most popular as well as promising solutions. However, as a prerequisite for an effective application, such apps highly depend on being used by large numbers of the population. Consequently, it is important that these apps offer a high usability for everyone. We therefore conducted an exploratory study to learn more about the usability of the German COVID-19 contact tracing app Corona-Warn-App (CWA). More specifically, N = 15 participants assessed the CWA, relying on a combined eye tracking and retrospective think aloud approach. The results indicate, on the one hand, that the CWA leaves a promising impression for pandemic control, as essential functions are easily recognized. However, on the other hand, issues were revealed (e.g., privacy policy) that could be addressed in future updates more properly

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor a-chain (IL-7Ra) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Ra extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency

Optimization of pneumatic vacuum generators – heading for energy-efficient handling processes

In current production systems, automation and handling of workpieces is often solved by use of vacuum technology. Most production systems use vacuum ejectors which generate vacuum from compressed air by means of the Venturi effect. However, producing vacuum with compressed air is significantly less efficient than using other principles. To minimize the energy costs of pneumatic vacuum generation or to make full use of the energy available, it is important that the inner contour of the nozzle is shaped precisely to suit the specific application - also the system\'s flow conduction needs to be optimal and the flow losses have to be minimized. This paper presents a method for optimally designing pneumatic vacuum generators and producing them economically even at very low lot sizes in order to keep the operation costs low and address other concerns (such as noise emissions) as well

Lepton Mass Hierarchy and Neutrino Oscillations

Starting from the symmetry of lepton flavor democracy, we propose and discuss a simple pattern for the mass generation and flavor mixing of the charged leptons and neutrinos. The three neutrino masses are nearly degenerate, and the flavor mixing angles can be calculated. The observed deficit of solar and atmospheric neutrinos can be interpreted as a consequence of the near degeneracy and large oscillations of $\nu_e$, $\nu_{\mu}$ and $\nu_{\tau}$ in the vacuum. Our {\it Ansatz} can also accommodate the cosmological requirement for hot dark matter and the current data on neutrinoless $\beta\beta$-decay.Comment: LaTex 9 page

Deletion of the Ca2+-activated potassium (BK) alpha-subunit but not the BK-beta-1-subunit leads to progressive hearing loss

The large conductance voltage- and Ca2+-activated potassium (BK) channel has been suggested to play an important role in the signal transduction process of cochlear inner hair cells. BK channels have been shown to be composed of the pore-forming alpha-subunit coexpressed with the auxiliary beta-1-subunit. Analyzing the hearing function and cochlear phenotype of BK channel alpha-(BKalpha–/–) and beta-1-subunit (BKbeta-1–/–) knockout mice, we demonstrate normal hearing function and cochlear structure of BKbeta-1–/– mice. During the first 4 postnatal weeks also, BKalpha–/– mice most surprisingly did not show any obvious hearing deficits. High-frequency hearing loss developed in BKalpha–/– mice only from ca. 8 weeks postnatally onward and was accompanied by a lack of distortion product otoacoustic emissions, suggesting outer hair cell (OHC) dysfunction. Hearing loss was linked to a loss of the KCNQ4 potassium channel in membranes of OHCs in the basal and midbasal cochlear turn, preceding hair cell degeneration and leading to a similar phenotype as elicited by pharmacologic blockade of KCNQ4 channels. Although the actual link between BK gene deletion, loss of KCNQ4 in OHCs, and OHC degeneration requires further investigation, data already suggest human BK-coding slo1 gene mutation as a susceptibility factor for progressive deafness, similar to KCNQ4 potassium channel mutations. © 2004, The National Academy of Sciences. Freely available online through the PNAS open access option

Semi-automatic tumor segmentation of rectal cancer based on functional magnetic resonance imaging

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