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Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Background While there is enough convincing evidence in childhood acute lymphoblastic leukemia (ALL), the data on the pre-natal origin in childhood acute myeloid leukemia (AML) are less comprehensive. Our study aimed to screen Guthrie cards (neonatal blood spots) of non-infant childhood AML and ALL patients for the presence of their respective leukemic markers. Methods We analysed Guthrie cards of 12 ALL patients aged 2–6 years using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements (n = 15) and/or intronic breakpoints of TEL/AML1 fusion gene (n = 3). In AML patients (n = 13, age 1–14 years) PML/RARalpha (n = 4), CBFbeta/MYH11 (n = 3), AML1/ETO (n = 2), MLL/AF6 (n = 1), MLL/AF9 (n = 1) and MLL/AF10 (n = 1) fusion genes and/or internal tandem duplication of FLT3 gene (FLT3/ITD) (n = 2) were used as clonotypic markers. Assay sensitivity determined using serial dilutions of patient DNA into the DNA of a healthy donor allowed us to detect the pre-leukemic clone in Guthrie card providing 1–3 positive cells were present in the neonatal blood spot. Results In 3 patients with ALL (25%) we reproducibly detected their leukemic markers (Ig/TCR n = 2; TEL/AML1 n = 1) in the Guthrie card. We did not find patient-specific molecular markers in any patient with AML. Conclusion In the largest cohort examined so far we used identical approach for the backtracking of non-infant childhood ALL and AML. Our data suggest that either the prenatal origin of AML is less frequent or the load of pre-leukemic cells is significantly lower at birth in AML compared to ALL cases.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
Non-standard errors
(2021)
In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in sample estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: non-standard errors. To study them, we let 164 teams test six hypotheses on the same sample. We find that non-standard errors are sizeable, on par with standard errors. Their size (i) co-varies only weakly with team merits, reproducibility, or peer rating, (ii) declines significantly after peer-feedback, and (iii) is underestimated by participants.
Nicht zuletzt durch die Entwicklung und Verbreitung der sogenannten Neuen Medien ist das Thema 'Medialität' im gesamten Bereich der Geistes- und Kulturwissenschaften virulent geworden. Im Rahmen der aktuellen Diskurse um den Begriff des Mediums ist zu beobachten, daß dieser Ausdruck häufig unterschiedslos auf so verschiedene Referenzobjekte wie Internet, Fernsehen, Printmedien, Computer, Schrift, Bilder, Schallwellen u. v. a. bezogen wird. Das Medium orale Sprache gerät dabei sonderbarerweise häufig aus dem Blickfeld. - Warum ist dies so?
Woher kommt das neuerwachte Interesse an Sprachrichtigkeit? Woher kommt die ausgeprägte sprachliche Unsicherheit, die auch bei vielen hochgebildeten Menschen den Wunsch entstehen lässt, von Sprachpflegern über ihr Ureigenstes, nämlich ihre Muttersprache, belehrt zu werden? Obwohl Antworten auf diese Fragen letztlich spekulativ bleiben, wage ich doch die These, dass eine Ursache hierfür die Rechtschreibreform ist, die von einem Großteil der Bevölkerung nach wie vor nicht angenommen wird, die insgesamt weder zur Vereinfachung noch zu einer höheren Einheitlichkeit geführt hat; die aber andererseits ein öffentliches Nachdenken und Diskutieren über Sprachrichtigkeit in Gang setzte. – Jedenfalls ist die Verunsicherung ein Faktum, das von Linguisten nicht ignoriert werden sollte.
Ausgangspunkt: Die Kritik am "Zwei-Welten-Modell": Die grundlegende linguistische Unterscheidung zwischen "Sprache" und "Sprechen" ist im Rahmen der neueren Debatten um Sprachmedialität wieder verstärkt thematisiert und kritisiert worden. Lässt sich dieses schulbildende, in der Linguistik geradezu eherne Begriffspaar überhaupt noch sinnvollerweise aufrechterhalten? Oder muss es mindestens umdefiniert, vielleicht sogar gänzlich verworfen werden? Hat sich insbesondere die auf Chomsky zurückgehende Unterscheidung von Sprachkompetenz und -performanz nicht von selbst ad absurdum geführt, nachdem der linguistische Kognitivismus chomskyscher Provenienz Sprache als lebendiges Phänomen, als Medium menschlicher Kommunikation, vollständig aus dem Blick verloren hat? Führt nicht schon die scheinbar harmlose linguistische Differenzierung zwischen einer Sprachregel und ihrer Anwendung zu einer irreführenden und unangemessenen Verdinglichung von Sprache? ...
Ziel des vorliegenden Aufsatzes ist es, zu einer neuerlichen Diskussion der Begriffe 'Medium' und 'Kommunikation' in der Linguistik beizutragen. Dabei versuche ich insbesondere, den philosophisch-kulturwissenschaftlichen Diskurs, in welchem die Themen 'Medialität' und 'Perfonnanz' seit längerer Zeit intensiv diskutiert werden, zu dem in der Angewandten Linguistik geläufigen Modell der Kommunikationsformen in Beziehung zu setzen und Möglichkeiten einer Verbindung dieser beiden Diskurse zumindest anzudeuten. Der Aufsatz gliedert sich in vier Abschnitte: Zunächst werden einige geläufige Mediendefinitionen vorgestellt. Im zweiten Kapitel stelle ich dann die Frage 'Ist Kommunikation ein Transportvorgang?', um auf dieser Grundlage im dritten Kapitel eine alternative Medienkonzeption vorzustellen. Im letzten Kapitel wird dieser Medienbegriff dann sowohl vom Begriff des Zeichensystems, als auch von dem der Kommunikationsform abgegrenzt.
The medium of (oral) language is mostly disregarded (or overlooked) in contemporary media theories. This "ignoring of language" in media studies is often accompanied by an inadequate transport model of communication, and it converges with an "ignoring of mediality" in mentalistic theories of language. In the present article it will be argued that this misleading opposition of language and media can only be overcome if one already regards oral language, not just written language, as a medium of the human mind. In my argumentation I fall back on Wittgenstein’s conception of language games to try to show how Wittgenstein’s ideas can help us to clear up the problem of the mediality of language and also to show to what extent the mentalistic conception of Chomskyan provenance cannot be adequate to the phenomenon of language.
