Search

Vascular endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in diseases such as cancer and retinopathies. Inhibitors of Src cytoplasmic tyrosine kinase have been applied to suppress VE-cadherin tyrosine phosphorylation and prevent excessive leakage, edema and high interstitial pressure. Here we show that the Src-related Yes tyrosine kinase, rather than Src, is localized at endothelial cell (EC) junctions where it becomes activated in a flow-dependent manner. EC-specific Yes1 deletion suppresses VE-cadherin phosphorylation and arrests VE-cadherin at EC junctions. This is accompanied by loss of EC collective migration and exaggerated agonist-induced macromolecular leakage. Overexpression of Yes1 causes ectopic VE-cadherin phosphorylation, while vascular leakage is unaffected. In contrast, in EC-specific Src deficiency, VE-cadherin internalization is maintained and leakage is suppressed. In conclusion, Yes-mediated phosphorylation regulates constitutive VE-cadherin turnover, thereby maintaining endothelial junction plasticity and vascular integrity.

Emerging concepts of developmental vascular remodelling recently identified that selectively labelled sprouting tip cells and/or venous endothelial cells (ECs) accumulate in developing arteries, suggesting directional migration of specific ECs drive artery formation. However, a general population analysis and detailed quantitative investigation of migratory mechanisms is so far lacking. Here, we developed a universally applicable quantitative approach and a computational model allowing to track and simulate stochastically labelled EC populations irrespective of labelling density and origin. Dynamic mapping of EC distributions in a bespoke coordinate system revealed how ECs move during the most active remodelling phases in the mouse retina. Simulation and parameter sensitivity analysis illustrated that the population shift from veins to arteries cannot be explained by random walk, but best fits to a tuneable dual force-field between shear-force induced directionality against blood flow, and hypoxia mediated VEGF-gradients. High migration rates require only weak flow-migration coupling, whereas low migration rates require strong coupling to the flow direction. Functional analysis identified Cdc42 as the critical mediator of overall population movement from veins to arteries, yet with surprising heterogeneity suggesting the existence of distinct cell populations. This new quantitative understanding will enable future tailored intervention and tuning of the remodelling process.

Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient-derived GBM stem cell cultures and combined single-cell RNA sequencing of GAM-GBM co-cultures and real-timein vivomonitoring of GAM-GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM-induced GAM polarization and the ability to attract and activate GAMs – features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock-out experiments in zebrafish subsequently identifiedLGALS1as a primary regulator of immunosuppression. Overall, our work highlights that GAM-GBM interactions can be studied in a clinically relevant way using co-cultures and avatar models, while offering new opportunities to identify promising immune-modulating targets.

Prior work has yielded contradicting evidence regarding the age at which children consistently and correctly categorize things as living or non-living. The present study tested children’s animacy judgments about robots with a Naïve Biology task. In the Naïve Biology task, 3- and 5-year-olds were asked if robots, animals, or artifacts possessed mechanical or biological internal parts. To gauge how much children anthropomorphize robots in comparison to animals and artifacts, children also responded to a set of interview questions. To examine the role of morphology, two robots were used: a humanoid robot (Nao) and a non-humanoid robot (Dash). To investigate the role of dynamic characteristics, children saw one robot behave in a goal-directed manner (i.e., moving towards a ball) and one robot exhibit non-goal-directed behavior (i.e., moving away from a ball). Children of both age groups correctly attributed biological insides to the animal and mechanical insides to the artifact. However, 3-year-olds seemed confused about what belonged inside both robots and assigned biological and mechanical insides equally. In contrast, 5-year-olds correctly assigned mechanical insides to both robots, regardless of the robot’s morphology or goal-directedness. Regarding the Animacy Interview, 3-year-olds performed at chance level when asked about the animacy of robots, animals, and artifacts. In contrast, 5-year-olds correctly attributed animacy to animals and accurately refrained from anthropomorphizing artifacts and the non-humanoid robot Dash. However, 5-year-olds performed at chance for Nao, suggesting they may be confused about the psychological properties of a human-looking robot. Taken together, these findings reveal a developmental transition during the preschool years in the attribution of biological and psychological properties to social robot.

In the target article, Clark and Fischer argue that little is known about children's perceptions of social robots. By reviewing the existing literature we demonstrate that infants and young children interact with robots in the same ways they do with other social agents. Importantly, we conclude children's understanding that robots are artifacts (e.g., not alive) develops gradually during the preschool years.

In this paper, we investigated whether Canadian preschoolers prefer to learn from a competent robot over an incompetent human using the classic trust paradigm (Koenig & Harris, 2004). An adapted naive biology task was also administered to assess children’s perception of robots. In Study 1, 3-year-olds and 5-year-olds were presented with two informants; A social, humanoid robot (Nao) who labeled familiar objects correctly, while a human informant labeled them incorrectly. Both informants then labeled unfamiliar objects with novel labels. It was found that 3-year-old children equally endorsed the labels provided by the robot and the human, but 5-year-old children learned significantly more from the competent robot. Interestingly, 5-year-olds endorsed Nao’s labels even though they accurately categorized the robot as having mechanical insides. In contrast, 3-year-old children associated Nao with biological or mechanical insides equally. In Study 2, new samples of 3-year-olds and 5-year-olds were tested to determine whether the human-like appearance of the robot informant impacted children’s trust judgments. The procedure was identical to that of Study 1, except that a non-humanoid robot, Cozmo, replaced Nao. It was found that 3-year-old children still trusted the robot and the human equally and that 5-year-olds preferred to learn new labels from the robot, suggesting that the robot’s morphology does not play a key role in their selective trust strategies. It is concluded that by 5 years of age, preschoolers show a robust sensitivity to epistemic characteristics (e.g., competency), but that younger children’s decisions are equally driven by the animacy of the informant.

Vascular Endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in progression of diseases such as cancer and eye diseases. Inhibitors of SRC cytoplasmic tyrosine kinase have been applied to suppress tyrosine phosphorylation of VE-cadherin and thereby to prevent excessive leakage, edema and high interstitial pressure. We show that the SRC-related YES tyrosine kinase rather than SRC, is localized at endothelial cell (EC) junctions. EC-specific YES deletion suppresses VE-cadherin phosphorylation, and arrests VE-cadherin at EC junctions. This is accompanied by loss of EC collective migration, and exaggerated agonist-induced macromolecular leakage, while extravasation of monocytes is suppressed. Overexpression of Yes causes ectopic VE-cadherin phosphorylation while vascular leakage is unaffected. In contrast, in EC-specific Src-deficient mice, VE-cadherin internalization is maintained and leakage is suppressed. In conclusion, YES-mediated VE-cadherin phosphorylation regulates its constitutive turnover, required for endothelial junction plasticity and vascular integrity.

Optical-resolution photoacoustic microscopy (OR-PAM) combines high spatial resolution and strong absorption-based contrast in tissue, which has enabled structural and spectroscopic imaging of endogenous chromophores, primarily hemoglobin. This makes OR-PAM an important tool for preclinical vascular research. Conventional piezoelectric ultrasound transducers often need to be placed far away from the signal source due to their opacity, which results in reduced acoustic sensitivity. Optical ultrasound sensors are an alternative as their transparency allows them to be positioned close to the sample for minimal source-detector distances. In this work, a backward-mode OR-PAM system based on a planar Fabry-Pérot ultrasound sensor and coaxially aligned excitation and interrogation beams was developed. Two 3D imaging modes, using raster-scanning for enhanced image quality or continuous-scanning for fast imaging, were implemented and tested on a leaf skeleton phantom. In fast imaging mode, a scan-rate of 100,000 A-lines/s could be achieved. In raster-scanning mode, 3D images of a zebrafish embryo were acquired in vivo. The transparency of the FP sensor in the visible and near-infrared wavelength region makes it potentially suitable for combined functional and molecular imaging using OR-PAM and multi-photon fluorescence microscopy.

In diesem Erfahrungsbericht stellt eine Alumna der Hochschule für Angewandte Wissenschaften Hamburg ihren Einstieg in das Berufsleben nach dem Studium dar. Sie berichtet über den Bewerbungsprozess, die damit einhergehenden Gedanken und Einflussfaktoren. Zudem schildert sie ihre Eindrücke und Erlebnisse der ersten Monate im neuen Beruf und welche Herausforderungen ihr dabei begegneten.

Optical-resolution photoacoustic microscopy (PAM) has been shown to enable the acquisition of high resolution (μm) functional and anatomical images. For backward-mode operation, conventional piezoelectric ultrasound transducers need to be placed far away from the signal source due to their opacity and size. This can result in reduced acoustic sensitivity. Planar Fabry-Perot polymer film interferometer (FPI) sensors have the potential to overcome this limitation since they are transparent to the excitation wavelength, can be placed immediately adjacent to the signal source for high acoustic sensitivity, and offer a broadband frequency response (0 –50 MHz). In this study, we present a high frame rate, backward-mode OR-PAM system based on a planar FPI ultrasound sensor. A ns-pulsed laser provides excitation pulses (

Alternaria fungi are widely distributed saprophytes and plant pathogens. As pathogens, Alternaria fungi infect crops and vegetables and cause losses in the fields and during postharvest storage. While farmers suffer from declining yields, consumers are endangered by the formation of secondary metabolites, because some of these exhibit a pronounced toxicological potential. The evaluation of the toxicological capabilities is still ongoing and will contribute to a valid risk assessment. Additionally, data on the incidence and the quantity of Alternaria mycotoxins found in food products is necessary for dietary exposure evaluations. A sensitive LC-MS/MS method for the determination of the Alternaria mycotoxins alternariol (AOH), alternariol monomethylether (AME), tentoxin (TEN), altertoxin I (ATX I), alterperylenol (ALTP), and tenuazonic acid (TA) was developed. AOH, AME, and TA were quantified using stable-isotopically labeled standards. TEN, ATX I, and ALTP were determined using matrix matched calibration. The developed method was validated by using starch and fresh tomato matrix and resulted in limits of detection ranging from 0.05 to 1.25 μg/kg for starch (as a model for cereals) and from 0.01 to 1.36 μg/kg for fresh tomatoes. Limits of quantification were determined between 0.16 and 4.13 μg/kg for starch and between 0.02 and 5.56 μg/kg for tomatoes. Recoveries varied between 83 and 108% for starch and between 95 and 111% for tomatoes. Intra-day precisions were below 4% and inter-day precisions varied from 3 to 8% in both matrices. Various cereal based infant foods, jars containing vegetables and fruits as well as tomato products for infants were analyzed for Alternaria mycotoxin contamination (n = 25). TA was the most frequently determined mycotoxin and was detected in much higher contents than the other toxins. AME and TEN were quantified in many samples, but in low concentrations, whereas AOH, ATX I, and ALTP were determined rarely, among which AOH had higher concentration. Some infant food products were highly contaminated with Alternaria mycotoxins and the consumption of these individual products might pose a risk to the health of infants. However, when the mean or median is considered, no toxicological risk was obvious.

Der Name „Hartung“ ist der Technik entnommen und bezeichnet zunachst weiter nichts, als das manche Stoffe infolge von Zusatzen oder geeigneter Behandlung oder beiden vereint harter gemacht werden. Vornehmlich eine Erhohung des Erweichungspunktes ist oft wunschenswert; hier wird also „Hartung“ so verstanden, das der bei Naturprodukten haufig uber eine ganze Reihe von Temperaturgraden sich erstreckende Schmelzbereich verengert und nach oben verschoben wird. In diesem Sinne spricht man denn auch von einer Hartung bei Harzen, bei Pechen, Asphalten, fetten Olen usw. und versteht jeweils eine der Korperklasse angepaste Behandlung darunter, die das obengenannte Ziel zu erreichen sucht. Durch Erhitzen der verschiedensten Harze mit Metalloxyden fuhrt man diese in ihre hoher schmelzenden Metallsalze (Resinate) uber, durch Verkochen mit Glycerin, Phenol und ahnlichen in die Ester, durch Behandlung mit polymerisierend wirkenden Stoffen oder durch Destillation hartet man Peche, durch Sauerstoffeinwirkung Asphalte, durch Wasserstoffanlagerung fette Ole und Trane usw. Die Reihe liese sich noch erheblich verlangern, wenn man sie auch auf analoge Prozesse, die aber unter anderen Namen gelaufig sind ausdehnte.

Bei den fruheren Untersuchungen uber Zusammensetzung und Verhalten von Schellackreinharz war durchweg die Beobachtung benutzt worden, das Kalilauge von funffacher Normalitat die Harz-molekel zerlegt und von den einzelnen Komponenten die Aleuritinsaure in Form ihres Kaliumsalzes zur Abscheidung bringt. Bevor diese grundlegende Tatsache gefunden worden war, waren aber vielfach Versuche angestellt worden, die Einwirkung von schwacheren Alkalilaugen und Sauren klarzustellen. Die Ergebnisse waren jedoch widersprechend, da der Gedanke einer Hydrolyse des Schellacks nicht in Betracht gezogen wurde, das Harz vielmehr als ein einfacher Ester einer Harzsaure angesprochen wurde, wie es in den Arbeiten fruherer Forscher ja stets geschieht.