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Macrophage S1PR1 signaling alters angiogenesis and lymphangiogenesis during skin inflammation
(2019)
The bioactive lipid sphingosine-1-phosphate (S1P), along with its receptors, modulates lymphocyte trafficking and immune responses to regulate skin inflammation. Macrophages are important in the pathogenesis of psoriasiform skin inflammation and express various S1P receptors. How they respond to S1P in skin inflammation remains unknown. We show that myeloid specific S1P receptor 1 (S1PR1) deletion enhances early inflammation in a mouse model of imiquimod-induced psoriasis, without altering the immune cell infiltrate. Mechanistically, myeloid S1PR1 deletion altered the formation of IL-1β, VEGF-A, and VEGF-C, and their receptors’ expression in psoriatic skin, which subsequently lead to reciprocal regulation of neoangiogenesis and neolymphangiogenesis. Experimental findings were corroborated in human clinical datasets and in knockout macrophages in vitro. Increased blood vessel but reduced lymph vessel density may explain the exacerbated inflammatory phenotype in conditional knockout mice. These findings assign a novel role to macrophage S1PR1 and provide a rationale for therapeutically targeting local S1P during skin inflammation.
The website Sci-Hub enables users to download PDF versions of scholarly articles, including many articles that are paywalled at their journal’s site. Sci-Hub has grown rapidly since its creation in 2011, but the extent of its coverage has been unclear. Here we report that, as of March 2017, Sci-Hub’s database contains 68.9% of the 81.6 million scholarly articles registered with Crossref and 85.1% of articles published in toll access journals. We find that coverage varies by discipline and publisher, and that Sci-Hub preferentially covers popular, paywalled content. For toll access articles, we find that Sci-Hub provides greater coverage than the University of Pennsylvania, a major research university in the United States. Green open access to toll access articles via licit services, on the other hand, remains quite limited. Our interactive browser at https://greenelab.github.io/scihub allows users to explore these findings in more detail. For the first time, nearly all scholarly literature is available gratis to anyone with an Internet connection, suggesting the toll access business model may become unsustainable.
Background: The aim of this study was to assess the knowledge and attitudes towards pregnancy-related issues of Zika virus (ZIKV) infection among general practitioners (GPs), a frontline healthcare worker group, in Indonesia.
Methods: A cross-sectional, online survey assessing knowledge and attitudes towards ZIKV infection on multiple-item scales was sent to GPs in the Sumatra and Java islands of Indonesia. The associations between independent factors and either knowledge or attitude were assessed with logistic regressions. The correlation and association between knowledge and attitude were estimated.
Results: We included 457 (53.7%) out of 850 responses in the analysis. Among these, 304 (66.5%) and 111 (24.2%) respondents had a good knowledge and attitude, respectively. No demographic, workplace, professional development, or experiential characteristics related to ZIKV infection were associated with knowledge. In the multivariate analysis, only contact experience was associated with attitude. There was a significant, positive correlation between knowledge and attitude scores.
Conclusions: Although knowledge of pregnancy-related complications of ZIKV infection is relatively high among GPs in Indonesia, more than 75% of them had a poor attitude towards pregnancy-related issues of Zika. Strategies for enhancing the capacity of GPs to develop positive attitudes and respond to ZIKV infection are needed.
Parabens and sorbic acid are commonly used as food preservatives due to their antimicrobial effect. However, their use in foods for infants and young children is not permitted in the European Union. Previous studies found these compounds in some gel-filled baby teethers, whereby parabens, which are well-known as endocrine disruptors, were identified in the polymer-based chewing surface consisting of ethylene-vinyl acetate (EVA). To assess the exposure of infants and young children to these products, the application of parabens in teethers should be thoroughly investigated. Therefore, the present study aimed to apply a representative migration test procedure combined with an accurate analytical method to examine gel-filled baby teethers without elaborate sample preparation, high costs, and long processing times. Accordingly, solid-phase extraction (SPE), in combination with a stable isotope dilution assay (SIDA) and subsequent gas chromatography–mass spectrometry (GC–MS) for analysis of methyl-, ethyl-, and n-propylparaben (MeP, EtP, and n-PrP), was found to be well-suited, with recoveries ranging from 93 to 99%. The study compared the release of these parabens from intact teether surfaces into water and saliva simulant under real-life conditions, with total amounts of detected parabens found to be in the range of 101–162 µg 100 mL−1 and 57–148 µg 100 mL−1, respectively. Furthermore, as a worst-case scenario, the release into water was examined using a long-term migration study.
Despite the popularity of direct democracy in recent decades, research on the actual output effects of popular decision-making is rare. This is especially true with regard to equality, where there are at least three major research gaps: 1) a lack of cross-national analyses; 2) insufficient investigation of the differential effects of different direct democratic instruments on equality; and 3) a failure to distinguish between different aspects of equality, i.e., socioeconomic, legal and political equality. This article takes a first step to tackle these shortcomings by looking at all national referenda in European democracies between 1990 and 2015, differentiating between mandatory, bottom-up and top-down referenda. We find that a large majority of successful direct democratic bills—regardless of which instrument is employed—are not related to equality issues. Of the remaining ones, there are generally more successful pro-equality bills than contra-equality ones, but the differences are rather marginal. Mandatory referenda tend to produce pro-equality outputs, but no clear patterns emerge for bottom-up and top-down referenda. Our results offer interesting, preliminary insights to the current debate on direct democracy, pointing to the conclusion that popular decision-making via any type of direct democratic instrument is neither curse nor blessing with regard to equality. Instead, it is necessary to look at other factors such as context conditions or possible indirect effects in order to get a clearer picture of the impacts of direct democracy on equality.
Zielsetzung: Ziel dieser Arbeit war es, den Einfluss des neuen, rauschoptimierten virtuell monoenergetischen Rekonstruktionsalgorithmus (VMI+) von abdominellen Dual-Energy CT (DECT) Aufnahmen bei Patienten mit gastrointestinalem Stromatumor (GIST) hinsichtlich der objektiven und subjektiven Bildqualität zu evaluieren sowie die Vorteile dessen im Vergleich zu den bislang verwendeten Algorithmen aufzuzeigen.
Material und Methoden: 45 DECT Datensätze von 21 Patienten mit GIST (12 Männer und 9 Frauen, durchschnittliches Alter: 63.4 ± 9.2 Jahre) wurden sowohl mit einem linear gemischten Algorithmus (M_0.6), mit dem traditionellen virtuell monoenergetischen Algorithmus (VMI) als auch mit dem rauschoptimierten VMI+ Algorithmus in 10 keV Intervallen von 40 bis 100 keV rekonstruiert. Zur objektiven Berechnung des Signal-zu-Rausch Verhältnisses („signal-to-noise ratio“=SNR) sowie des Kontrast-zu-Rausch Verhältnisses („contrast-to-noiseratio“=CNR) wurde die Signalabschwächung der GIST-Läsionen und abdomineller Metastasen in den drei Rekonstruktionsvarianten in Hounsfield Units (HU) gemessen. Die Beurteilung der subjektiven allgemeinen Bildqualität, der Abgrenzbarkeit der Läsionen, der Bildschärfe sowie des Bildrauschens im jeweiligen Rekonstruktionsalgorithmus wurde von drei Radiologen unter Verwendung von Likert-Skalen durchgeführt.
Ergebnisse: Die objektive Bildqualität wies die höchsten Werte in den 40 keV VMI+ Serien auf (SNR: 11.0 ± 4.7; CNR: 9.0 ± 4.1) und war somit signifikant besser als die M_0.6 Serie (SNR: 7.5 ± 2.8; CNR: 5.5 ± 2.7) und alle VMI Serien (bei allen P < 0.001). Bezüglich der subjektiven Bildqualität und der Bildschärfe wurden die 60 keV VMI+ Rekonstruktionen bevorzugt (Median: 5; P ≤ 0.008). Die subjektive Einschätzung bezüglich der Abgrenzbarkeit der GIST Läsionen erzielte die besten Werte in den 40 keV und 50 keV VMI+ Rekonstruktionen (beide Mediane: 4). Das Bildrauschen wurde in den 90 keV und 100 keV VMI und VMI+ Rekonstruktionen als am geringsten beurteilt (alle Mediane: 5).
Schlussfolgerung: Niedrigenergetische VMI+ Rekonstruktionen erhöhen signifikant das Signal-zu-Rausch Verhältnis sowie das Kontrast-zu-Rausch Verhältnis verglichen mit den traditionellen VMI Rekonstruktionen und der linear gemischten M_0.6 Bildserie und verbessern sowohl die objektive als auch die subjektive Bildqualität abdomineller DECT Aufnahmen bei Patienten mit GIST signifikant.
Astrocytes are increasingly perceived as active partners in physiological brain function and behaviour. The structural correlations of the glia–synaptic interaction are the peripheral astrocyte processes (PAPs), where ezrin and radixin, the two astrocytic members of the ezrin-radixin-moesin (ERM) family of proteins are preferentially localised. While the molecular mechanisms of ERM (in)activation appear universal, at least in mammalian cells, and have been studied in great detail, the actual ezrin and radixin kinases, phosphatases and binding partners appear cell type specific and may be multiplexed within a cell. In astrocytes, ezrin is involved in process motility, which can be stimulated by the neurotransmitter glutamate, through activation of the glial metabotropic glutamate receptors (mGluRs) 3 or 5. However, it has remained open how this mGluR stimulus is transduced to ezrin activation. Knowing upstream signals of ezrin activation, ezrin kinase(s), and membrane-bound binding partners of ezrin in astrocytes might open new approaches to the glial role in brain function. Ezrin has also been implicated in invasive behaviour of astrocytomas, and glial activation. Here, we review data pertaining to potential molecular interaction partners of ezrin in astrocytes, with a focus on PKC and GRK2, and in gliomas and other diseases, to stimulate further research on their potential roles in glia-synaptic physiology and pathology.
Purpose: To determine whether machine learning assisted-texture analysis of multi-energy virtual monochromatic image (VMI) datasets from dual-energy CT (DECT) can be used to differentiate metastatic head and neck squamous cell carcinoma (HNSCC) lymph nodes from lymphoma, inflammatory, or normal lymph nodes.
Materials and methods: A retrospective evaluation of 412 cervical nodes from 5 different patient groups (50 patients in total) having undergone DECT of the neck between 2013 and 2015 was performed: (1) HNSCC with pathology proven metastatic adenopathy, (2) HNSCC with pathology proven benign nodes (controls for (1)), (3) lymphoma, (4) inflammatory, and (5) normal nodes (controls for (3) and (4)). Texture analysis was performed with TexRAD® software using two independent sets of contours to assess the impact of inter-rater variation. Two machine learning algorithms (Random Forests (RF) and Gradient Boosting Machine (GBM)) were used with independent training and testing sets and determination of accuracy, sensitivity, specificity, PPV, NPV, and AUC.
Results: In the independent testing (prediction) sets, the accuracy for distinguishing different groups of pathologic nodes or normal nodes ranged between 80 and 95%. The models generated using texture data extracted from the independent contour sets had substantial to almost perfect agreement. The accuracy, sensitivity, specificity, PPV, and NPV for correctly classifying a lymph node as malignant (i.e. metastatic HNSCC or lymphoma) versus benign were 92%, 91%, 93%, 95%, 87%, respectively.
Conclusion: Machine learning assisted-DECT texture analysis can help distinguish different nodal pathology and normal nodes with a high accuracy.
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.
Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.
Neuropathic pain is a debilitating and commonly treatment-refractory condition requiring novel therapeutic options. Accumulating preclinical studies indicate that the potassium channel Slack (KNa1.1) contributes to the processing of neuropathic pain, and that Slack activators, when injected into mice, ameliorate pain-related hypersensitivity. However, whether Slack activation might reduce neuropathic pain in humans remains elusive. Here, we evaluated the tolerability and analgesic efficacy of loxapine, a first-generation antipsychotic drug and Slack activator, in neuropathic pain patients. We aimed to treat 12 patients with chronic chemotherapy-induced, treatment-refractory neuropathic pain (pain severity ≥ 4 units on an 11-point numerical rating scale) in a monocentric, open label, proof-of-principle study. Patients received loxapine orally as add-on analgesic in a dose-escalating manner (four treatment episodes for 14 days, daily dose: 20, 30, 40, or 60 mg loxapine) depending on tolerability and analgesic efficacy. Patient-reported outcomes of pain intensity and/or relief were recorded daily. After enrolling four patients, this study was prematurely terminated due to adverse events typically occurring with first-generation antipsychotic drugs that were reported by all patients. In two patients receiving loxapine for at least two treatment episodes, a clinically relevant analgesic effect was found at a daily dose of 20–30 mg of loxapine. Another two patients tolerated loxapine only for a few days. Together, our data further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy. However, loxapine is no valid treatment option for painful polyneuropathy due to profound dopamine and histamine receptor-related side effects.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02820519.
Der DNA-Translokator von T. thermophilus HB27, ebenso wie Typ-IV-Pili (T4P), sind Multiproteinkomplexe, die die Membranen und das Periplasma durchspannen. Sie sind ähnlich aufgebaut und enthalten identische Proteine. Der DNA-Translokator vermittelt Transport von DNA in das Zellinnere während der natürlichen Transformation. T4P sind filamentöse Zellorganellen, die an der inneren Membran assembliert werden und bis zu mehrere Mikrometer aus der Zelle hinausragen. Sie dienen der Anhaftung und Fortbewegung der Zellen auf Oberflächen.
Das Ziel dieser Arbeit war es, die Funktionen einzelner Komponenten der Komplexe und ihrer Proteindomänen bei der natürlichen Transformation, der T4P-Assemblierung und den durch T4P vermittelten Funktionen Adhäsion und „twitching motility“ aufzuklären.
Es sind neun Proteine bekannt, die eine duale Rolle als Komponenten des DNA-Translokators und des T4P spielen. Eines dieser Proteine ist die Assemblierungs-ATPase PilF, die Hexamere bildet. Diese cytoplasmatischen ATPase-Komplexe stellen die Energie für die Assemblierung der T4P bereit, ebenso wie für die Aufnahme freier DNA. Es ist jedoch bisher nicht geklärt, wie die durch PilF bereitgestellte Energie auf die anderen Komponenten des DNA-Translokators/T4P übertragen wird.
In dieser Arbeit konnte gezeigt werden, dass PilF an das cytoplasmatische Protein PilM des T4P und DNA-Translokators bindet. Zudem konnten Proteinkomplexe bestehend aus den Proteinen PilM, PilN und PilO heterolog produziert und aus Zellmembranen koisoliert werden. PilF interagierte mit diesen PilMNO-Komplexen via PilM. Diese Interaktionen führt zur Stimulierung der ATPase-Aktivität von PilF. Dies deutet an, dass PilM ein Kupplungsprotein ist, welches die Assemblierungs-ATPase PilF physisch und funktionell mit dem T4P/DNA-Translokator über den PilMNO-Komplex verbindet.
Neben PilF standen Präpiline von T. thermophilus im Fokus dieser Arbeit. Präpiline sind Vorläuferproteine, die zu Pilinen prozessiert werden und als solche dann die Untereinheiten der Pilus-Strukturen bilden.
Zusammenfassend konnten die Rollen einzelner Präpilin-ähnlicher Proteine bei T4P-assoziierten Funktionen geklärt werden und es konnten erste Analysen zur Charakterisierung des weitestgehend unbekannten Proteins ComZ durchgeführt werden. Desweiteren liefert diese Arbeit Hinweise darauf, dass die membranassoziierten Proteine PilM, PilN und PilO Kupplungsproteine sind, die PilF mit den periplasmatischen Komponenten des T4P/DNA-Translokators verbinden und dadurch die ATPase-Aktivität von PilF stimulieren. Die Rollen einzelner Proteindomänen von PilF und PilM bei der Protein-Protein-Interaktion und der Bindung von Liganden wurden aufgeklärt, sowie ihre Funktionen bei den T4P-vermittelten Funktionen und der natürlichen Transformation.