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Introduction: Healthcare workers (HCWs) are exposed to bloodborne pathogens (e.g., contaminated devices). In the healthcare environment, needlestick injuries (NSI) represent a major risk factor in the transmission of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Medical students are at risk of occupational exposure to bloodborne viruses following needlestick injuries during medical education. Reporting of needlestick injuries is an important step for initiating early prophylaxis or treatment. In the case of a bloodborne infection, pursuant to insure law could result in a claim. The objective of the present study was to describe occupational blood exposure of medical students through needlestick injuries.
Methods: Sixth-year medical students were invited to complete an anonymous questionnaire.
Results: In our study, 58.8% (n=183/311) of medical students recalled at least one needlestick injury during their studies. Overall, 284 needlestick injuries were reported. Only 38.3% of medical students reported all NSI to the appropriate hospital personnel. The main reason (54.0%) for not reporting NSI was being ashamed of having an NSI.
Conclusions: Occupational exposure to blood is a common problem among medical students. Efforts are required to ensure greater awareness among medical students about the risk of bloodborne pathogens. Proper training in procedures and how to act in case of injury should be offered to reduce the number of needlestick injuries.
Risk transfer with CDOs
(2008)
Modern bank management comprises both classical lending business and transfer of asset risk to capital markets through securitization. Sound knowledge of the risks involved in securitization transactions is a prerequisite for solid risk management. This paper aims to resolve a part of the opaqueness surrounding credit-risk allocation to tranches that represent claims of different seniority on a reference portfolio. In particular, this paper analyzes the allocation of credit risk to different tranches of a CDO transaction when the underlying asset returns are driven by a common macro factor and an idiosyncratic component. Junior and senior tranches are found to be nearly orthogonal, motivating a search for the whereabout of systematic risk in CDO transactions. We propose a metric for capturing the allocation of systematic risk to tranches. First, in contrast to a widely-held claim, we show that (extreme) tail risk in standard CDO transactions is held by all tranches. While junior tranches take on all types of systematic risk, senior tranches take on almost no non-tail risk. This is in stark contrast to an untranched bond portfolio of the same rating quality, which on average suffers substantial losses for all realizations of the macro factor. Second, given tranching, a shock to the risk of the underlying asset portfolio (e.g. a rise in asset correlation or in mean portfolio loss) has the strongest impact, in relative terms, on the exposure of senior tranche CDO-investors. Our findings can be used to explain major stylized facts observed in credit markets.
Risk transfer with CDOs
(2008)
Modern bank management comprises both classical lending business and transfer of asset risk to capital markets through securitization. Sound knowledge of the risks involved in securitization transactions is a prerequisite for solid risk management. This paper aims to resolve a part of the opaqueness surrounding credit-risk allocation to tranches that represent claims of different seniority on a reference portfolio. In particular, this paper analyzes the allocation of credit risk to different tranches of a CDO transaction when the underlying asset returns are driven by a common macro factor and an idiosyncratic component. Junior and senior tranches are found to be nearly orthogonal, motivating a search for the where about of systematic risk in CDO transactions. We propose a metric for capturing the allocation of systematic risk to tranches. First, in contrast to a widely-held claim, we show that (extreme) tail risk in standard CDO transactions is held by all tranches. While junior tranches take on all types of systematic risk, senior tranches take on almost no non-tail risk. This is in stark contrast to an untranched bond portfolio of the same rating quality, which on average suffers substantial losses for all realizations of the macro factor. Second, given tranching, a shock to the risk of the underlying asset portfolio (e.g. a rise in asset correlation or in mean portfolio loss) has the strongest impact, in relative terms, on the exposure of senior tranche CDO-investors. Our findings can be used to explain major stylized facts observed in credit markets.
Cytochrome P450 epoxygenases of the 2C family (CYP2C) are highly expressed in the endothelium and metabolize arachidonic acid to different regioisomers of epoxyeicosatrienoic acids (EET). They have a number of roles in the regulation of vascular tone and homeostasis by activating different signal transduction pathways and have recently been reported to be involved in proliferation and angiogenesis. However, the exact mechanisms by which epoxygenases regulate angiogenesis are still unclear. Therefore, the initial aim of the present study was to characterize the relevance of major signalling molecules that are involved in angiogenesis and to investigate possible signalling pathways involved. Initially the effect of CYP2C9 overexpression on expression levels of EphB4, a tyrosine kinase that plays a role in a number of developmental processes, was investigated. EphB4 protein expression was increased in CYP2C9 overexpressing cells without any effects on expression levels of its ligand ephrinB2. To clarify whether EphB4 is a critical determinant of CYP2C9-induced angiogenesis, endothelial cell sprouting was assessed using a collagen gel-based in vitro angiogenesis assay. Following transfection with EphB4 antisense or scrambled oligonucleotides, capillary-like structures were clearly present after 24 hours in cells overexpressing CYP2C9, while EphB4 downregulation abolished CYP2C9-induced sprouting. In addition stimulation of human umbilical vein endothelial cells with VEGF resulted in an increase in CYP2C expression and a subsequent increase of 11,12-EET production; an effect that was abolished by the CYP epoxygenases inhibitor MSPPOH as well as when cells were infected with a dominant negative mutant of AMPK. In vivo 11,12-EET treatment increased EphB4 expression in mesenteric arteries as well as in Matrigel plugs; an effect that was abolished when plugs were impregnated at the same time with small interfering RNA (siRNA) for EphB4. Furthermore, impregnation of Matrigel plugs with VEGF resulted in endothelial cell and smooth muscle cell recruitment into a Matrigel plug and this effect was mediated by CYP2C9-derived EETs as it was prevented by 14,15-EEZE. When infiltration of EET impregnated plugs with endothelial cells and pericytes/smooth muscle cells in vivo was compared to the effects seen in VEGF treated plugs, it was apparent that only EET treatment resulted in the formation of tube like structures that were covered by smooth muscle cells. Therefore, the final aim of the study was to further define the consequences of EET signalling in vivo as well as to characterize its physiological relevance. This hypothesis could be assessed by isolectin injection through the tail-vein where isolectin was taken up only by the EET-impregnated plug. Moreover ultrasound measurements revealed accumulation of contrast agent in EET impregnated plugs compared to control plugs. Taken together our findings emphasize that CYP2C plays a crucial role in the vessel formation process by modulating the effects mediated by two important control elements of the angiogenic response, namely VEGF and EphB4. CYP2C-derived EETs not only participate as second messengers in the angiogenic response, but have the potential to influence much more than angiogenesis by enhancing smooth muscle cell/pericyte recruitment to endothelial cell tubes to promote vascular maturation.
Prion diseases or transmissible spongiform encephalopathies (TSEs) are rare neurological disorders that may be of genetic or infectious origin, but most frequently occur sporadically in humans. Their outcome is invariably fatal. The infectious agent has been defined as prion (from proteinaceous infectious only) in 1992 by Stanley B. Prusiner and represent mainly, if not solely, an abnormal, protease-resistant isoform (PrPSc) of a cellular protein, the prion protein or PrPC. According to the “protein only” hypothesis, the prion is devoid of informational nucleic acids and consists of an “infectious” protein that is capable of converting the normal host protein PrPC into a likeness of itself. TSEs can be distinguished from other neurodegenerative diseases because of their infectivity and transmission capability. The only organ system in which severe histopathological damage can be demonstrated as a consequence of infection with prions is the nervous system. The communal lesions are neuronal loss, spongiosis and astrogliosis, accompanied by an intra- and extracellular accumulation of PrPSc, occasionally in form of amyloid plaques. Even if a strong activation of microglia and astrocytes occurs, no immunological response is usually detectable as consequence of prion infection. Despite the considerable attention for its involvement in TSEs, the physiological role of the cellular, nonpathogenic isoform of PrPC, has not yet been determined. In the last years, several putative cellular functions have been attributed to PrPC: its localization in “lipid rafts” is consistent with a possible role in cell adhesion, transmembrane signalling or as a recognition molecule. Furthermore, PrPC has been implicated in protection against oxidative stress, copper metabolism, apoptosis, cell proliferation and in the regeneration of blood precursors stem cells in the adult. It has also been shown that PrPC interacts with the neuronal cell adhesion molecule NCAM, promoting neurite outgrowth. However, both the PrPC-mediated effects and the role of PrPC-dependent pathways on neuronal differentiation are still not elucidated. First objective of this Ph.D thesis was the establishment of a novel in vitro cellular model for the study of the role of PrPC in neuronal differentiation and neurite outgrowth. Furthermore, an additional goal of this project was the indentification of the PrPC domains responsible for the induction of neuronal differentiation. A novel PrPC-depleted cell line (PrP0/0 ML) was derived from murine primary PrP-knockout neuronal cells by SV40 large T antigen-mediated immortalization. A temperature sensitive form of this oncogenic protein was used, allowing a temperature-mediated regulation of its expression. This cell line was then characterised for its growth potential, for the expression of specific cellular markers and for its ability to differentiate. It was found that, under culture conditions promoting the expression of the temperature-sensitive SV40 large T antigen, the cells expressed nestin, a specific marker of neuronal precursor cells. Therefore, the PrP0/0 ML cell line was identified as a potential neuronal stem cell line. In fact, under nonpermissive culture conditions when the expression of the temperature-sensitive SV40 large T antigen is downregulated, the PrP0/0 ML cells differentiated into neurons. Noteworthy, maintenance of the cells in conditions that promote cell differentiation induced a progressive reduction in the expression levels of nestin, an event that strongly correlated with the appearance of the specific neuronal markers MAP-2b and NeuN. In order to investigate the role of PrPC in the process of neuronal differentiation, the PrP0/0 ML cells were then reconstituted for the expression of either the full-length PrP or a N-terminal truncated PrPC form (PrPdel32-134). The differentiation potential of both reconstituted cell lines under nonpermissive culture conditions was then compared with that of the parenteral PrP0/0 ML cells. This in vitro study clearly highlights that PrPC expression in the PrP0/0 ML cell line accelerates neuronal differentiation and that the N-terminal domain of the prion protein is not necessary for this PrP-mediated function. Prion diseases like BSE, vCJK, Kuru and the majority of iatrogenic cases of CJK are caused by a peripheral infection. Infectious prions accumulate in the central and peripheral nervous system as well as in extracerebral tissues, such as the secondary lymphoid organs and muscles. The prion pathogenesis is a dynamic process which can be defined temporary and spatially in different phases: i) infection and peripheral replication, ii) neuroinvasion, transport of prions from the periphery to the central nervous system (CNS), and iii) neurodegeneration. In the last years, progresses in the elucidation of the peripheral prion pathogenesis were achieved. The identification of the cell types involved in the lymphoreticular prion replication phase and the recognition of the role of the peripheral nervous system in the process of prion spread from the periphery to the CNS have elucidated some of the cellular mechanisms that are involved in prion uptake, replication and propagation. However, relatively little information is available about the mechanism(s) underlying intercellular prion transfer and tissue-to tissue prion spread. Microvesicles (MVs) are submicron vesicles (0,03-1 microm.) with a single membrane and are shed from most eukaryotic cells undergoing activation or apoptosis. The segregation of specific proteins is followed by blebbing of the membrane surface, leading to the formation of MVs and their release in the extracellular environment. MVs can be also secreted upon fusion of multivesicular endosomes with the plasma membrane (exosomes). The secretion of MVs is the result of a complex cellular process involving changes in the metabolism of lipids and proteins. The functional role of MVs is still largely unknown. However, there is evidence showing that they are important modulators of cell-to-cell communication, participate in a variety of intracellular adhesion processes and are able to induce cellular response(s). The release of PrPC and infectious PrPSc by prion infected epithelial, neuroglial and neuronal cells in association with exosomes has recently been highlighted. Furthermore, it has been shown that exosomes can propagate prion infectivity both in vitro and in vivo, suggesting that PrPSc-bearing exosomes may provide a mechanism for intercellular transmission of infectious prions in addition to cell-to-cell contact. Second objective of this Ph.D thesis was to determine the possible role of plasma membrane-derived microvesicles in the propagation and transmission of prions. The release of MVs was first studied in different murine neuronal cell lines. Here it is shown for the first time that neurons also shed plasma membrane derived MVs, in addition to exosomes. Immunoelectron microscopy and immunoblot analyses clearly demonstrated the presence of PrPC on the membrane of MVs released from PrPC-expressing cells. Characterization of lipid rafts components in MVs highlighted the presence of the ganglioside GM2, the tyrosine kinase p59Fyn, flotillin-2 and the neuronal protein GAP-43. In order to investigate whether MVs are involved in the intercellular transmission of prions, MVs were first isolated from two prion infected murine neuronal cell lines, namely the Neuro-2a PK1 and the N2a58 cells, and then used for in vitro and in vivo infection assays. Immunoblot analyses after proteinase K treatment demonstrated the association of PrPSc with the secreted MVs. The PrPSc-bearing MVs were then used to perform infection experiments on noninfected cells. By the use of cell blot assay, a method that allows the detection of PrPSc-amplification and -accumulation in cultured cells, the kinetic of prion infection in the de novo infected cells was followed. Noteworthy, it was found that PrPSc-bearing MVs were capable to transmit prions in vitro and to stably infect the recipient cells. In order to investigate the role of MVs in the transmission of infectivity in vivo, PrPSc-bearing MVs as well as MVs isolated from noninfected cells (as negative control) were injected intracerebrally in PrPC-overexpressing indicator mice (tga20). The development of clinical disease was followed in a time-dependent manner. Clinical symptoms could be observed only in the group of indicator mice inoculated with the PrPSc-bearing MVs, which then succumbed to desease. These findings clearly demonstrated that MVs are biological carriers of both PrPSc and prion infectivity. MVs could therefore participate in vivo in the processes of intercellular prion transmission and propagation.
The growth of blood vessels is crucial for organ growth in the embryo and repair of wounded tissues in the adult. An imbalance in this process contributes to numerous malignant, inflammatory, ischemic, infectious and immune disorders (Ferrara et al., 2003). Postnatal neovascularization occurs through the recruitment of progenitor cells and angiogenesis. Integrins are heterodimeric cell surface molecules and are the main receptors for extracellular matrix proteins. Regulation of integrin activation is crucial during embryonic development and during adult life. Dysregulation of integrin activity leads to severe diseases. In this study, we have demonstrated that Rap1, a small GTPase regulating integrin activity, and its GEF Epac1 are expressed in both EPC and endothelial cells. Moreover, the pharmacological activator of Epac activates the small GTPase Rap1 in progenitor cells. In parallel the angiogenic growth factors VEGF and bFGF activate Rap1 in endothelial cells. In addition, the regulation of Rap1 activity in EPC and in endothelial cells plays an important role in the regulation of migration and adhesion to matrix proteins, by regulating the activity of different integrins, a mechanism known as integrin inside‐out signaling. Furthermore, regulation of Rap1 activity affects probably indirectly through outside‐in signaling of integrins the activity of several and crucial proteins such PKB/Akt and focal adhesion kinase in endothelial cells. In line with these results, we have demonstrated that Rap1 activity affect angiogenesis, homing of EPC to ischemic tissues and thereby postnatal neovascularization. The understanding how Rap1 regulates integrin activity in endothelial cells is still not completely clear, for example we have demonstrated that the known effectors of Rap1 mediating the increase of integrin activity in T and B cells, such as RAPL and RIAM are, respectively, either not increasing integrin activity or not expressed in endothelial cells. We aim to find the effector of Rap1 promoting integrin activity in endothelial cells and how RAPL regulates integrin functions and angiogenesis. Moreover data from us and others using genetic models and generation of Rap1a or Rap1b deficient mice or deficient for Rap1a and Rap1b led to embryonic lethality suggesting that Rap1 is a key node protein during embryonic development. The development of conditionnal Rap1a/b endothelial/pericytes restricted deficient mice will help us to decipher more precisely the role of Rap1 during vascular development and angiogenesis.
Hypoxic pulmonary vasoconstriction (HPV) redistributes pulmonary blood flow from areas of low oxygen partial pressure to areas of normal or relativity high oxygen availability, thus optimising the matching of perfusion to ventilation and preventing arterial hypoxemia. Generalised alveolar hypoxia results in a sustained increase in pulmonary artery pressure which in turn leads to structural changes in the walls of the pulmonary vasculature (pulmonary vascular remodelling). Recent findings have indicated a role for cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) in hypoxia-induced pulmonary vasoconstriction. Given that the intracellular concentration of EETs is determined by the soluble epoxide hydrolase (sEH), which metabolises EETs to their less active dihydroxyeicosatrienoic acids (DHETs), we assessed the influence of the sEH and EETs on pulmonary artery pressure, acute and chronic HPV, and pulmonary vascular remodelling in the mouse lung. In isolated lungs from wild-type mice, acute HPV was significantly increased by sEH inhibition, an effect abolished by pre-treatment with CYP epoxygenase inhibitors and the EET antagonist 14,15-EEZE. The acute hypoxia-induced vasoconstriction and EET production were greater in lungs from sEH-/- mice than from wild-type mice and sEH inhibition had no further effect on HPV in lungs from the former animals, while MSPPOH (CYP epoxygenase inhibitor) and 14,15-EEZE decreased the response. Exogenous application of 11,12-EET increased pulmonary artery pressure in a concentration-dependent manner and enhanced acute HPV in wild-type lungs, while 14,15-EET and 11,12-DHET were without significant effect on pulmonary artery pressure. 5-HT2A receptor antagonism or Rho kinase inhibition shifted the EET concentration-response curve to the right and abrogated the EET- and sEH inhibition-induced potentiation of acute hypoxic vasoconstriction. In lungs from wild-type and sEH-/- mice, hypoxic preconditioning (hypoxic ventilation for 10 minutes) enhanced the 5-HT response. 1-Adamantyl-3-cyclohexylurea (ACU), a sEH inhibitor, further amplified the hypoxia-induced 5-HT-hypersensitivity in wild-type mice. However, after hypoxic preconditioning, the sEH-/- lungs displayed a striking leftward shift in the 5-HT response. 11,12-EET can activate TRPC6 channels in endothelial cells by eliciting its translocation to the plasma membrane, more specifically to membrane domains enriched with the caveolae marker caveolin-1. This effect was also observed in rat pulmonary artery smooth muscle cells overexpressing the channel. Exposure of the latter cells to acute hypoxia also stimulated the intracellular translocation of TRPC6 to caveolae, an effect that was sensitive to the EET antagonist. The EET-induced translocation of TRPC6 channels was prevented by a 5-HT2A receptor antagonist but not by a Rho kinase inhibitor. Moreover, while acute hypoxia and 11,12-EET increased pulmonary pressure in lungs from TRPC6+/- mice, lungs from TRPC6-/- mice did not respond to either stimuli. These results indicate that the sEH and CYP-derived EETs are involved in acute HPV and that EET-induced pulmonary contraction under normoxic and hypoxic conditions involves a TRPC6 channel, a 5-HT2A receptor-dependent pathway and Rho kinase activation. In the second part of the study the role of the sEH in the development of pulmonary hypertension and vascular remodelling induced in mice by exposure to hypoxia (10% O2) for 21 days was analysed. In wild-type mice, chronic hypoxia decreased the pulmonary expression/activity of the sEH, induced right heart hypertrophy and erythropoiesis, and increased the number of partially and fully muscularised pulmonary resistance arteries (by 3-fold). Moreover, in HEK 293 cells, hypoxia (1% O2 up to 24 h) decreased sEH promoter activity by 50%. In isolated lungs, pre-exposure to chronic hypoxia significantly increased baseline perfusion pressures and potentiated the acute HPV. While an sEH inhibitor, ACU, potentiated acute HPV in lungs from mice maintained in normoxic conditions, it had no effect on HPV in lungs from mice exposed to hypoxia. The EET antagonist, 14,15-EEZE, abolished the sEH inhibitor-dependent increase in acute HPV in normoxic lungs and decreased HPV in chronic hypoxic lungs. Hypoxia-induced right heart hypertrophy and erythropoiesis were more pronounced in sEH-/- than in wild-type mice. Under normoxic and hypoxic conditions the muscularisation of resistance pulmonary arteries was greater in lungs from sEH-/- mice than in lungs from wild-type mice. sEH-/- mice also displayed an enhanced acute HPV, compared to that observed in wild-type mice and chronic exposure to hypoxia did not further potentiate acute HPV. However, in the presence of 14,15-EEZE responses returned to levels observed in normoxic lungs from wild-type animals. Furthermore, immunohistochemistry demonstrated an extensive expression of the sEH in the medial wall of pulmonary arteries from human donor lungs. Whereas sEH expression was not detectable in samples from pulmonary hypertension patients, indicating that the sEH is involved in hypoxia-induced pulmonary vascular remodelling and hypoxic pulmonary vasoconstriction. Taken together, the results presented in this thesis indicate that the expression/activity of the sEH is an important determinant of the magnitude of acute and chronic hypoxia-induced pulmonary vasoconstriction and pulmonary vascular remodelling by inactivating vasoconstrictor CYP-derived EETs. As sEH inhibitors are currently being developed for the treatment of human systemic hypertension, it should be noted that these compounds may even promote the development of pulmonary hypertension.
Rolf Paproth – 70 Jahre
(2008)
Wenn über den Elbe-Biber im Elb-Havel-Winkel im Land Sachsen-Anhalt gesprochen wird, so ist dies nicht möglich ohne den Namen Rolf Paproth zu nennen. Dieser engagierte Naturfreund und -schützer leistete einen sehr wichtigen Beitrag zur naturkundlichen Erforschung seiner Heimat. Sein 70. Geburtstag am 11.Oktober 2008 ist Anlass, diese Leistungen zu würdigen.
Rolle der NADPH-Oxidase in der Thrombin-induzierten Signaltransduktion in glatten Gefässmuskelzellen
(2008)
Die Pathogenese der Atherosklerose besteht aus einem komplexen Netzwerk, bei dem anhand der hier vorliegenden Daten die vaskuläre NADPH-Oxidase eine zentrale Rolle spielt. In der Vergangenheit wurde bereits gezeigt, dass die Aktivierung der NADPH-Oxidase durch zahlreiche Mediatoren (u.a. Wachstumsfaktoren wie PDGF, Angiotensinogen II und Thrombin) mit vermehrter Freisetzung von Sauerstoffradikalen erfolgt. Ein spezifischer Nachweis, inwieweit die vaskuläre NADPH-Oxidase dabei tatsächlich involviert ist, stand bisher aus. Durch den Einsatz spezifischer Methoden (neutralisierende Antikörper, Antisense Oligonukleotide), wodurch die Untereinheiten der NADPH-Oxidase, p22phox und p47phox, gehemmt wurden, konnte nachgewiesen werden, dass die NADPH-Oxidase die wichtigste Quelle der Sauerstoffradikalbildung darstellt. Durch den Einsatz von p22phox Antisense Oligonukleotide wurde gezeigt, dass es durch die Stimulation mit Thrombin zu einer vermehrten ROS-Produktion durch die p22phox-tragende NADPH-Oxidase mit erhöhter Aktivierung der p38 MAP-Kinase kommt. Des Weiteren wird die Expression des pro-atherogenen Chemokins MCP-1 bekannterweise durch Thrombin induziert. Auch hier konnte durch den Einsatz von p22phox Antisense-Oligonukleotide der p22phox-tragenden NADPH-Oxidase eine zentrale Rolle in der redoxmediierten Genexpression dieses Chemokins zugeschrieben werden. Fehlte die sich im inaktiven Zustand der Oxidase im Zytosol befindliche Untereinheit p47phox, wurde ebenfalls eine beeinträchtigte basale als auch Agonisten-induzierte ROSProduktion durch die NADPH-Oxidase beobachtet. Dabei scheint die Oxidase auch bei Fehlen von p47phox - im Gegensatz beim Fehlen der p22phox - aktiv zu sein, allerdings geringer als bei Vorhandensein aller Untereinheiten. Zusammenfassend konnten die vorliegenden Daten verdeutlichen, dass die p22phox- und p47phox-tragende NADPH-Oxidase eine zentrale Rolle in der ROS-Produktion spielt. Die Sauerstoffradikalbildung wird dabei durch die Expression der einzelnen Untereinheiten als auch der Aktivität der Oxidase bestimmt. Weiterhin sprechen die Daten dafür, dass es sich bei der vaskulären NADPH-Oxidase nicht um ein konsekutiv-aktives Enzym, sondern eher um eine durch Agonisten–induzierte Aktivität der Oxidase handelt.
Die Bezüge Mahlers zu Schubert scheinen auch ohne genaue Prüfung sinnfällig zu sein: Eine Fülle von Beispielen könnte, dies die wohl zuverlässige Annahme, Nähen und auch direkte Bezugnahmen sowie Filiationen belegen. Auf der Suche nach Nachweisen stößt man bald auf den "Lindenbaum", der in der "Winterreise" Müllers und Schuberts einem der wohl vollendetsten Lieder seinen Namen gegeben hat und an eben diesen Lindenbaum, den Gustav Mahler in seinem 4. Gesellenlied "Die zwei blauen Augen" an exponierter Stelle beruft. Die forschungsgestützte Suche nach konkreten Belegen für die Bezugnahme Mahlers auf Schubert führt zu - so scheint es zumindest - reichen Ergebnissen: Das Scherzo der 1. Symphonie erinnert sicherlich an Schubert, aber auch an Bruckner: Darauf hat Jens Malte Fischer ebenso hingewiesen wie auf die generelle Nähe der Mahlerschen Gesellenlieder zu den beiden großen Liederzyklen Schuberts und Wilhelm Müllers, ja noch im letzten Kindertotenlied Mahlers nimmt Jens Malte Fischer die Vorbildhaftigkeit des abschließenden Liedes aus der "Schönen Müllerin" "Des Baches Wiegenlied" wahr.