The class B2 of GPCRs known as adhesion G protein-coupled receptors (aGPCRs) has come under increasing academic and nonacademic research focus over the past decade due to their physiological importance as mechano-sensors in cell-cell and cell-matrix contexts. A major advance in understanding signal transduction of aGPCRs was achieved by the identification of the so-called Stachel sequence, which acts as an intramolecular agonist at the interface between the N terminus (Nt) and the seven-transmembrane helix domain (7TMD). Distinct extracellular signals received by the Nt are integrated at the Stachel into structural changes of the 7TMD towards an active state conformation. Until recently, little information was available on how the activation process of aGPCRs is realized at the molecular level. In the past three years several structures of the 7TMD plus the Stachel in complex with G proteins have been determined, which provide new insights into the architecture and molecular function of this receptor class. Herein, we review this structural information to extract common and distinct aGPCR features with particular focus on the Stachel binding site within the 7TMD. Our analysis extends the current view of aGPCR activation and exposes similarities and differences not only between diverse aGPCR members, but also compared to other GPCR classes.
Weniger anzeigenThe recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2.
Weniger anzeigenDigital data have become a valuable resource for autocratic governments seeking to influence societal behaviours. The rise of social credit systems in China has garnered a great deal of attention, with some even referring to them as ‘Orwellian’ surveillance systems. This study expands on previous research that has found surprisingly high levels of acceptance of social credit systems in China to the Southeast Asian region. Through an online opinion survey conducted in Thailand, Indonesia, Malaysia and the Philippines, we discovered that citizens in these countries exhibit higher acceptance rates of social credit systems than opposition rates, although lower than those observed in China. Moreover, we find that acceptance rates would decline significantly if the technologies supporting these systems originated from China. By introducing an external technology acceptance model, we provide an explanation for these findings based on citizens' attitudes towards their domestic situation and their perceptions of China's potential benefits to their countries. Interestingly, most of the ‘China Threat’ perceptions do not translate into opposition against Chinese social credit system technologies, except for military risks. Instead, citizens' negative views are primarily influenced by specific technology-related risks. These findings contribute to the existing literature on the acceptance of government-run social credit systems and public perception in the context of international relations.
Weniger anzeigenIn der Bestandsaufnahme werden der gegenwärtige Stand und die Möglichkeiten der personenbezogenen Genomsequenzierung und ihr Nutzen für die Erforschung von seltenen Erkrankungen und Krebserkrankungen erörtert sowie einige wichtige sich aus der Genomforschung ergebende ethische und rechtliche Fragen diskutiert.
Although mobile social networking sites have successfully penetrated into individual’s various aspects of everyday lives, few empirical studies have investigated important antecedents of civic involvement in the WeChat context from a network capital perspective. The principal aims of the research are to systematically explore the underlying associations between mobile social media use, network heterogeneity, network capital, and civic participation among young people. The data was collected in an online survey of 1,208 young people in mainland China. Structural equation modeling analysis was carried out to examine the corresponding hypotheses. Findings revealed that informational WeChat use could positively impact young people’s network heterogeneity, which subsequently contributes to increased degrees of civic involvement. Additionally, the results demonstrated that network heterogeneity and network capital on WeChat are positively associated with civic involvement. Furthermore, network heterogeneity and network capital could mediate the association between WeChat use for information and individual’s civic activities. These obtained outcomes underlined the vital role of mobile social media communication in facilitating democratic engagement of young citizens in contemporary mobile media-saturated society.
Weniger anzeigenThe US-Dollar (USD) holds a paramount position in the hierarchy of the International Monetary System (IMS). The significance of this currency has experienced a remarkable surge, leading to non-US banking systems to adopt new strategies for integrating themselves into the USD funding structure. Consequently, non-US banks have turned to new financial instruments and institutions to hedge their balance sheets effectively. While previous research has primarily focused on the Eurodollar market and FX swaps, the role of US banks in providing USD funding liquidity to these markets and instruments has been curtailed due to post-GFC regulations. This funding gap has been filled by US prime MMFs. Therefore, this paper investigates the emerging global dimension of unsecured funding liquidity provided by prime MMFs through wholesale funding instruments, namely commercial papers (CPs) and certificates of deposit (CDs), to the European and Japanese banking systems. Moreover, it examines the implications of this unsecured funding for JPY/USD and EUR/USD FX swaps markets. The paper argues that rates associated with CPs and CDs have become pivotal indicators of liquidity conditions in the offshore USD system. Disruptions in these markets can result in significant vulnerabilities in FX swaps markets, as evidenced during the pandemic crisis. Only through the Fed’s backstop strategy, implemented via swap lines and the Money Market Mutual Fund Liquidity Facility (MMLF), have the liquidity conditions of prime MMFs improved, yielding favorable outcomes for non-US banks.
Weniger anzeigenBased on indirect evidence, increased mucosal translocation of gut-derived microbial macromolecules has been proposed as an important pathomechanism in HIV infection. Here, we quantified macromolecule translocation across intestinal mucosa from treatment-naive HIV-infected patients, HIV-infected patients treated by combination antiretroviral therapy, and HIV-negative controls and analyzed the translocation pathways involved. Macromolecule permeability was quantified by FITC-Dextran 4000 (FD4) and horseradish peroxidase (HRP) flux measurements. Translocation pathways were addressed using cold inhibition experiments. Tight junction proteins were characterized by immunoblotting. Epithelial apoptosis was quantified and translocation pathways were further characterized by flux studies in T84 cell monolayers using inducers and inhibitors of apoptosis and endocytosis. In duodenal mucosa of untreated but not treated HIV-infected patients, FD4 and HRP permeabilities were more than a 4-fold increase compared to the HIV-negative controls. Duodenal macromolecule permeability was partially temperature-dependent and associated with epithelial apoptosis without altered expression of the analyzed tight junction proteins. In T84 monolayers, apoptosis induction increased, and both apoptosis and endocytosis inhibitors reduced macromolecule permeability. Using quantitative analysis, we demonstrate the increased macromolecule permeability of the intestinal mucosa in untreated HIV-infected patients. Combining structural and mechanistic studies, we identified two pathways of increased macromolecule translocation in HIV infection: transcytosis and passage through apoptotic leaks.
Weniger anzeigenThe essential trace elements copper, selenium and zinc are of relevance for immunity and immune response to vaccination. In this longitudinal study, adult healthcare workers (n = 126) received two doses of an mRNA vaccine (BNT162b2), and longitudinal serum samples were prepared. Vaccine-induced antibodies and their neutralizing activity were analyzed, and the trace elements copper, zinc, and selenium along with the copper transporter ceruloplasmin were measured. Subjects with combined deficiency of copper and zinc, i.e. both in the lowest tertiles at baseline, displayed particularly low antibody titers at three (Double Q1: 13 AU/mL vs. not double Q1: 29 AU/mL) and six (Double Q1: 200 AU/mL vs. not double Q1: 425 AU/mL) weeks after vaccination (p < 0.05). The results indicate the potential importance of an adequate trace element status of copper and zinc for raising a strong vaccine-induced SARS-CoV-2 antibody response, and highlights the importance of considering combined micronutrient insufficiencies, as single deficiencies may synergize.
Weniger anzeigenChronic Fatigue Syndrome (CFS) presents with symptoms of hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, thyroid hormone (TH) profiles of elevated thyrotropin and low thyroxine (T4) are not consistently observed. Recently, autoantibodies to the Se transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto's thyroiditis and shown to impair selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS, and associate with reduced selenoprotein expression and impaired TH deiodination.
Se status and SELENOP-aAb prevalence was compared by combining European CFS patients (n = 167) and healthy controls (n = 545) from different sources. The biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP showed linear correlations across the samples without reaching saturation, indicative of Se deficiency. SELENOP-aAb prevalence was 9.6-15.6% in CFS versus 0.9-2.0% in controls, depending on cut-off for positivity. The linear correlation between Se and GPx3 activity was absent in SELENOP-aAb positive patients, suggesting impaired Se supply of kidney. A subgroup of paired control (n = 119) and CSF (n = 111) patients had been characterized for TH and biochemical parameters before. Within this subgroup, SELENOP-aAb positive patients displayed particularly low deiodinase activity (SPINA-GD index), free T3 levels, total T3 to total T4 (TT3/TT4) and free T3 to free T4 (FT3/FT4) ratios. In 24 h urine, iodine concentrations were significantly lower in SELENOP-aAb positive than in SELENOP-aAb negative patients or controls (median (IQR); 43.2 (16.0) vs. 58.9 (45.2) vs. 89.0 (54.9) & mu;g/L). The data indicate that SELENOP-aAb associate with low deiodination rate and reduced activation of TH to active T3.
We conclude that a subset of CFS patients express SELENOP-aAb that disturb Se transport and reduce sele-noprotein expression in target tissues. Hereby, TH activation decreases as an acquired condition not reflected by thyrotropin and T4 in blood. This hypothesis opens new diagnostic and therapeutic options for SELENOP-aAb positive CFS, but requires clinical evidence from intervention trials.
Weniger anzeigenBackground: Left ventricular global longitudinal strain (LV GLS) is a superior predictor of adverse cardiac events in patients with myocardial infarction and heart failure. We investigated the ability of morphological features of infarcted myocardium to detect acute left ventricular (LV) dysfunction and predict LV functional recovery after three months in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods: Sixty-six STEMI patients were included in the C-reactive protein (CRP) apheresis in Acute Myocardial Infarction Study (CAMI-1). LV ejection fraction (LVEF), LV GLS, LV global circumferential strain (LV GCS), infarct size (IS), area-at-risk (AAR), and myocardial salvage index (MSI) were assessed by CMR 5 ± 3 days (baseline) and 12 ± 2 weeks after (follow-up) the diagnosis of first acute STEMI. Results: Significant changes in myocardial injury parameters were identified after 12 weeks of STEMI diagnosis. IS decreased from 23.59 ± 11.69% at baseline to 18.29 ± 8.32% at follow-up (p < 0.001). AAR and MVO also significantly reduced after 12 weeks. At baseline, there were reasonably moderate correlations between IS and LVEF (r = −0.479, p < 0.001), LV GLS (r = 0.441, p < 0.001) and LV GCS (r = 0.396, p = 0.001) as well as between AAR and LVEF (r = −0.430, p = 0.003), LV GLS (r = 0.501, p < 0.001) and weak with LV GCS (r = 0.342, p = 0.020). At follow-up, only MSI and change in LV GCS over time showed a weak but significant correlation (r = −0.347, p = 0.021). Patients with larger AAR at baseline improved more in LVEF (p = 0.019) and LV GLS (p = 0.020) but not in LV GCS. Conclusion: The CMR tissue characteristics of myocardial injury correlate with the magnitude of LV dysfunction during the acute stage of STEMI. AAR predicts improvement in LVEF and LV GLS, while MSI is a sensitive marker of LV GCS recovery at three months follow-up after STEMI.
Weniger anzeigenPercutaneous left atrial appendage closure (LAAC) has emerged as a non-pharmacological alternative for stroke prevention in patients with atrial fibrillation (AF) not suitable for anticoagulation therapy. Real-world data on peri-procedural outcomes are limited. The aim of this study was to analyze outcomes of peri-procedural safety and healthcare resource utilization in 11,240 adult patients undergoing LAAC in the United States between 2016 and 2019. Primary outcomes (safety) were in-hospital ischemic stroke or systemic embolism (SE), pericardial effusion (PE), major bleeding, device embolization and mortality. Secondary outcomes (resource utilization) were adverse discharge disposition, hospital length of stay (LOS) and costs. Logistic and Poisson regression models were used to analyze outcomes by adjusting for 10 confounders. SE decreased by 97% between 2016 and 2019 [95% Confidence Interval (CI) 0-0.24] (p = 0.003), while a trend to lower numbers of other peri-procedural complications was determined. In-hospital mortality (0.14%) remained stable. Hospital LOS decreased by 17% (0.78-0.87, p < 0.001) and adverse discharge rate by 41% (95% CI 0.41-0.86, p = 0.005) between 2016 and 2019, while hospital costs did not significantly change (p = 0.2). Female patients had a higher risk of PE (OR 2.86 [95% CI 2.41-6.39]) and SE (OR 5.0 [95% CI 1.28-43.6]) while multi-morbid patients had higher risks of major bleeding (p < 0.001) and mortality (p = 0.031), longer hospital LOS (p < 0.001) and increased treatment costs (p = 0.073). Significant differences in all outcomes were observed between male and female patients across US regions. In conclusion, LAAC has become a safer and more efficient procedure. Significant sex differences existed across US regions. Careful considerations should be taken when performing LAAC in female and comorbid patients.
Weniger anzeigenBackground: Selenium is essential for expression and proper function of a set of redox active selenoproteins implicated in aging-relevant diseases, e.g. type 2 diabetes mellitus (T2D) and hypertension. However, data in cohorts of older adults, particularly with respect to different Se biomarkers and sex-specific analyses are sparse.
Objective: To assess associations of serum Se and selenoprotein P (SELENOP) concentrations with T2D and hypertension in a cohort of older females and males.
Methods: This study included 1500 participants from the Berlin Aging Study II. Diagnosis of T2D was made in case of antidiabetic medication, self-reported T2D, or laboratory parameters. Diagnosis of hypertension was based on self-report, blood pressure measurement, or anti-hypertensive medication. Se was measured by spectroscopy, and SELENOP by ELISA. Multiple adjusted regression models quantified dose-dependent associations.
Results: Participants had a median(IQR) age of 68 (65,71) years, and 767 (51%) were women. 191 (13%) participants had T2D and 1126 (75%) had hypertension. Se and SELENOP correlated significantly (r = 0.59, p < 0.001), and were elevated in those with self-reported Se supplementation. Serum Se and SELENOP were not associated with T2D in the whole cohort. In men, SELENOP was positively associated with T2D, OR (95%CI) for one mg/L increase in SELENOP was 1.22 (1.00,1.48). Se was non-linearly associated with hypertension, comparing to the lowest quartile (Q1), and participants with higher Se levels (Q3) had a lower OR (95%CI) of 0.66 (0.45,0.96), which was specific for men. SELENOP positively associated with hypertension, and OR (95%CI) per one mg/L increase was 1.15 (1.01,1.32).
Conclusions: The data suggest a sex-specific interrelationship of Se status with T2D and hypertension, with apparent biomarker-specific associations.
Weniger anzeigenThe activation of the mineralocorticoid (MR) and glucocorticoid (GR) receptors on peripheral sensory neurons seems to modify pain perception through both direct non-genomic and indirect genomic pathways. These distinct subpopulations of sensory neurons are not known for peripheral human nerves. Therefore, we examined MR and GR on subpopulations of sensory neurons in sectioned human and rat peripheral nerves. Real-time PCR (RT-PCR) and double immunofluorescence confocal analysis of MR and GR with the neuronal markers PGP9.5, neurofilament 200 (NF200), and the potential pain signaling molecules CGRP, Nav1.8, and TRPV1 were performed in human and rat nerve tissue. We evaluated mechanical hyperalgesia after intrathecal administration of GR and MR agonists. We isolated MR- and GR-specific mRNA from human peripheral nerves using RT-PCR. Our double immunofluorescence analysis showed that the majority of GR colocalized with NF200 positive, myelinated, mechanoreceptive A-fibers and, to a lesser extent, with peripheral peptidergic CGRP-immunoreactive sensory nerve fibers in humans and rats. However, the majority of MR colocalized with CGRP in rat as well as human nerve tissue. Importantly, there was an abundant colocalization of MR with the pain signaling molecules TRPV1, CGRP, and Nav1.8 in human as well as rat nerve tissue. The intrathecal application of the GR agonist reduced, and intrathecal administration of an MR agonist increased, mechanical hyperalgesia in rats. Altogether, these findings support a translational approach in mammals that aims to explain the modulation of sensory information through MR and GR activation. Our findings show a significant overlap between humans and rats in MR and GR expression in peripheral sensory neurons.
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