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Background & Aims: Renal function assessed by creatinine is a key prognostic factor in cirrhotic patients. However, creatinine is influenced by several factors, rendering interpretation difficult in some situations. This is especially important in early stages of renal dysfunction where renal impairment might not be accompanied by an increase in creatinine. Other parameters, such as cystatin C (CysC) and beta‐trace protein (BTP), have been evaluated to fill this gap. However, none of these studies have considered the role of the patient's sex. The present study analysed CysC and BTP to evaluate their prognostic value and differentiate them according to sex.
Patients and methods: CysC and BTP were measured in 173 transjugular intrahepatic portosystemic shunt (TIPS)‐patients from the NEPTUN‐STUDY(NCT03628807) and analysed their relationship with mortality and sex. Propensity score for age, MELD, etiology and TIPS indication was used.
Results_ Cystatin C and BTP showed excellent correlations with creatinine values at baseline and follow‐up. CysC was an independent predictor of overall mortality (HR = 1.66(1.33‐2.06)) with an AUC of 0.75 and identified a cut‐off of 1.55 mg/L in the whole cohort. Interestingly, CysC was significantly lower in females, also after propensity score matching. In males, the only independent predictor was the creatinine level (HR = 1.54(1.25‐1.58)), while in females CysC levels independently predicted mortality (HR = 3.17(1.34‐7.52)).
Conclusion: This study demonstrates for the first time that in TIPS‐patients creatinine predicts mortality in males better than in females, whereas CysC is a better predictor of mortality in females. These results may influence future clinical decisions on therapeutic options for example, allocation for liver transplantation in TIPS‐patients.
Background and Aims: Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes. It is involved in pathogenesis of several inflammatory diseases. Hepatic MCP-1 is a readout of macrophage activation. While inflammation is a major driver of liver disease progression, the origin and role of circulating MCP-1 as a biomarker remains unclear.
Methods: Hepatic CC-chemokine ligand 2 (CCL2) expression and F4/80 staining for Kupffer cells were measured and correlated in a mouse model of chronic liver disease (inhalative CCl4 for 7 weeks). Next, hepatic RNA levels of CCL2 were measured in explanted livers of 39 patients after transplantation and correlated with severity of disease. Changes in MCP-1 were further evaluated in a rat model of experimental cirrhosis and acute-on-chronic liver failure (ACLF). Finally, we analyzed portal and hepatic vein levels of MCP-1 in patients receiving transjugular intrahepatic portosystemic shunt insertion for complications of portal hypertension.
Results: In this mouse model of fibrotic hepatitis, hepatic expression of CCL2 (P = 0.009) and the amount of F4/80 positive cells in the liver (P < 0.001) significantly increased after induction of hepatitis by CCl4 compared to control animals. Moreover, strong correlation of hepatic CCL2 expression and F4/80 positive cells were seen (P = 0.023). Furthermore, in human liver explants, hepatic transcription levels of CCL2 correlated with the MELD score of the patients, and thus disease severity (P = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma (P = 0.028) and correlation of hepatic CCL2 expression (R = 0.69, P = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte CCL2 expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein (P = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed (P = 0.018). Further, in the presence of ACLF, portal and hepatic vein levels of MCP-1 were significantly higher compared to patients without ACLF (both P = 0.039).
Conclusion: Circulating levels of MCP-1 mainly derive from the injured liver and are associated with severity of liver disease. Therefore, liver macrophages contribute significantly to disease progression. Circulating MCP-1 may reflect the extent of hepatic macrophage activation.
Recent developments in typology which put the notions of linguistic function and operation into the focus of interest and establish them as the ultimate base on which languages are comparable prove fruitful for contrastive linguistics. The functional approach is illustrated in a contrastive analysis of Persian and German relative clauses. In a sketch of the theory of the relative clause, four grammatical functions to be fulfilled by relative constructions are deduced, and the two languages are compared with respect to the various ways in which they realize them. Learning problems can thus be predicted with greater confidence, be explained more satisfactorily, and be remedied more efficiently, because they are seen as learner's attempts to transfer, beside the underlying functions and operations, which the languages do have in common, the techniques of their realization, which they do not have in common.
Das hier vorgestellte Schlagwortkatalogsystem ist die Zusammenfassung diverser Vorarbeiten, die, teilweise in Verbindung mit Seminaren, Übungen und dem Kölner Universalienprojekt, in den vergangenen Semestern am Institut für Sprachwissenschaft der Universität Köln durchgeführt wurden, um Methoden einer effizienten wissenschaftlichen Dokumentation zu erarbeiten und zu erproben. Vor etwa einem Jahr wurde mit dem Aufbau eines entsprechenden Schlagwortkatalogs begonnen, für dessen Benutzer dieses Papier erstellt worden ist. Wir glauben jedoch, auch demjenigen, der nicht mit unserem Kölner Katalog arbeitet, Anregungen zur Verarbeitung wissenschaftlicher Information geben zu können.
Das achte der von Schumann unter dem Namen "Dichterliebe" zusammengefaßten und vertonten Heine-Gedichte – "Und wüßten's die Blumen, die kleinen" – soll im folgenden einer Teilanalyse unterzogen werden. Wenn damit auch ein kleiner Beitrag zu dem im Rahmen einer semiotischen Theorie zu behandelnden allgemeinen Problem der Systembeziehungen zwischen Sprache und Musik geleistet werden soll, indem einer solchen Theorie in einer empirischen Untersuchung voranalysiertes Material zur Verfügung gestellt wird, so steht im Mittelpunkt des Interesses doch bloß jenes Lied für sich. Dies bedingt eine Verlagerung des Gesichtspunktes, unter dem das genannte Problem gesehen wird, vom System auf die Struktur, im Hjelmslev'schen Sinne. Die strukturellen Eigenschaften von Heines Gedicht werden verglichen mit denen von Schumanns Vertonung, es werden Beziehungen zwischen dem textuellen und dem musikalischen Ablauf aufgedeckt.
At the end of last year, I designed an inquiry about the present state of linguistic typology in the form of a questionnaire. It was an attempt to cover the whole field by formulating the questions which seemed most relevant to it. This questionnaire is reproduced, without modifications, following this preface. In the first days of this year, it was sent to 33 linguists who I know are working in the field. The purpose was to form, on the basis of responses received, a picture of convergences and divergences among trends of present-day linguistic typology. The idea was also to get an objective basis for my report on "The present state of linguistic typology", to be delivered at the XIII. International Congress of Linguistics at Tokyo, 1982.
I shall use the precise term 'interlinear morphemic translation (IMT) to designate the object of this study. [...] An IMT is a translation of a text in a language L1 to a string of elements taken from L2 where, ideally, each morpheme of the L1 text is rendered by a morpheme of L2 or a configuration of symbols representing its meaning and where the sequence of the units of the translation corresponds to the sequence of the morphemes which they render. [...] An IMT is needed whenever it is essential that the reader grasp the grammatical structure of the L1 text but is presumed to be so unfamiliar with L1 that he will not be able to do so merely with the aid of a normal translation and the context in which the text is cited. [...] The primary aim of an IMT is to make the grammatical structure of the L1 text transparent. The textual fluency of the IMT by standards of the L2 grammar is a subordinate aim at best.
Cephalization is a major innovation of animal evolution and implies a synchronization of nervous system, mouth, and foregut polarization to align alimentary tract and sensomotoric system for effective foraging. However, the underlying integration of morphogenetic programs is poorly understood. Here, we show that invagination of neuroectoderm through de novo polarization and apical constriction creates the mouth opening in the Caenorhabditis elegans embryo. Simultaneously, all 18 juxta-oral sensory organ dendritic tips become symmetrically positioned around the mouth: While the two bilaterally symmetric amphid sensilla endings are towed to the mouth opening, labial and cephalic sensilla become positioned independently. Dendrite towing is enabled by the pre-polarized sensory amphid pores intercalating into the leading edge of the anteriorly migrating epidermal sheet, while apical constriction-mediated cell–cell re-arrangements mediate positioning of all other sensory organs. These two processes can be separated by gradual inactivation of the 26S proteasome activator, RPN-6.1. Moreover, RPN- 6.1 also shows a dose-dependent requirement for maintenance of coordinated apical polarization of other organs with apical lumen, the pharynx, and the intestine. Thus, our data unveil integration of morphogenetic programs during the coordination of alimentary tract and sensory organ formation and suggest that this process requires tight control of ubiquitin-dependent protein degradation.
Yeast large ribosomal subunit (LSU) precursors are subject to substantial changes in protein composition during their maturation due to coordinated transient interactions with a large number of ribosome biogenesis factors and due to the assembly of ribosomal proteins. These compositional changes go along with stepwise processing of LSU rRNA precursors and with specific rRNA folding events, as revealed by recent cryo-electron microscopy analyses of late nuclear and cytoplasmic LSU precursors. Here we aimed to analyze changes in the spatial rRNA surrounding of selected ribosomal proteins during yeast LSU maturation. For this we combined a recently developed tethered tertiary structure probing approach with both targeted and high throughput readout strategies. Several structural features of late LSU precursors were faithfully detected by this procedure. In addition, the obtained data let us suggest that early rRNA precursor processing events are accompanied by a global transition from a flexible to a spatially restricted rRNA conformation. For intermediate LSU precursors a number of structural hallmarks could be addressed which include the fold of the internal transcribed spacer between 5.8S rRNA and 25S rRNA, the orientation of the central protuberance and the spatial organization of the interface between LSU rRNA domains I and III.
Selfish genetic elements that act as post-segregation distorters cause lethality in non-carrier individuals after fertilization. Two post-segregation distorters have been previously identified in Caenorhabditis elegans, the peel-1/zeel-1 and the sup-35/pha-1 elements. These elements seem to act as modification-rescue systems, also called toxin/antidote pairs. Here we show that the maternal-effect toxin/zygotic antidote pair sup-35/pha-1 is required for proper expression of apical junction (AJ) components in epithelia and that sup-35 toxicity increases when pathways that establish and maintain basal epithelial characteristics, die-1, elt-1, lin-26, and vab-10, are compromised. We demonstrate that pha-1(e2123) embryos, which lack the antidote, are defective in epidermal morphogenesis and frequently fail to elongate. Moreover, seam cells are frequently misshaped and mispositioned and cell bond tension is reduced in pha-1(e2123) embryos, suggesting altered tissue material properties in the epidermis. Several aspects of this phenotype can also be induced in wild-type embryos by exerting mechanical stress through uniaxial loading. Seam cell shape, tissue mechanics, and elongation can be restored in pha-1(e2123) embryos if expression of the AJ molecule DLG-1/Discs large is reduced. Thus, our experiments suggest that maternal-effect toxicity disrupts proper development of the epidermis which involves distinct transcriptional regulators and AJ components.