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"Ernst, Martin"
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A new transgene mouse model using an extravesicular EGFP tag enables affinity isolation of cell-specific extracellular vesicles
The in vivo function of cell-derived extracellular vesicles (EVs) is challenging to establish since cell-specific EVs are difficult to isolate and differentiate. We, therefore, created an EV reporter using truncated CD9 to display enhanced green fluorescent protein (EGFP) on the EV surface. CD9truc-EGFP expression in cells did not affect EV size and concentration but enabled co-precipitation of EV markers TSG101 and ALIX from the cell-conditioned medium by anti-GFP immunoprecipitation. We then created a transgenic mouse where CD9truc-EGFP was inserted in the inverse orientation and double-floxed, ensuring irreversible Cre recombinase-dependent EV reporter expression. We crossed the EV reporter mice with mice expressing Cre ubiquitously (
CMV-Cre
), in cardiomyocytes (
αMHC-MerCreMer
) and renal tubular epithelial cells (
Pax8-Cre
), respectively. The CD9truc-EGFP positive mice showed Cre-dependent EGFP expression, and plasma CD9truc-EGFP EVs were immunoprecipitated only from CD9truc-EGFP positive
CD9truc-EGFPxCMV-Cre
and
CD9truc-EGFPxαMHC-Cre
mice, but not in
CD9truc-EGFPxPax8-
Cre and CD9truc-EGFP negative mice. In urine samples, CD9truc-EGFP EVs were detected by immunoprecipitation only in CD9truc-EGFP positive
CD9truc-EGFPxCMV-Cre
and
CD9truc-EGFPxPax8-Cre
mice, but not
CD9truc-EGFPxαMHC-Cre
and CD9truc-EGFP negative mice. In conclusion, our EV reporter mouse model enables Cre-dependent EV labeling, providing a new approach to studying cell-specific EVs in vivo and gaining a unique insight into their physiological and pathophysiological function.
Journal Article
تأملات نقدية : كيف يمكن للمجموعات التعلم من النجاح والفشل
يتناول هذا الكتاب الإرشادي عملية (التأملات النقدية) التي عادة ما يستخدمها القادة لمساعدة مجموعاتهم على تعلم دروس واستخلاص عبر من أحداث أساسية مرت بهم بصرف النظر عما إذا كانت هذه الأحداث إيجابية أم سلبية والعملية الأساسية موجزة وبسيطة تبدأ بحدث رئيس وتشمل ثلاث مراحل الاستكشاف والتأمل والتخطيط في مرحلة الاستكشاف ويكون الهدف هو السماح لأعضاء مجموعتك بأن تستعيد الحدث للمشاركة بالفهم ولتقدير الاختلافات وتحديد التطابقات الجزئية والتعامل مع التجربة بحيادية.
Book
Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease
Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures.
Plekhg5
gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.
Accumulating evidence suggests that disruption of autophagy is associated with neurodegeneration. Here the authors show that Plekhg5 acts as a GEF for Rab26, a small GTPase that promotes the autophagy of synaptic vesicles in neurons; mice lacking Plekgh5 develop late-onset motoneuron degeneration.
Journal Article
The role of FIBCD1 in response to Aspergillus fumigatus in lung epithelial cells
Chitin, a polysaccharide, is ubiquitously found in nature and has been known to be an active immunogen in mammals, and interacts with Toll-like, mannose and glucan receptors, to induce cytokine and chemokine secretions. FIBCD1 is a tetrameric type II transmembrane endocytic vertebrate receptor that binds chitin, is found in human lung epithelium and modulates lung epithelial inflammatory responses to
A
.
fumigatus
cell wall polysaccharides. We previously reported the detrimental role of FIBCD1 in a murine model of pulmonary invasive aspergillosis. However, the effect that chitin and chitin-containing
A
.
fumigatus
conidia exerts on lung epithelium following exposure through FIBCD1 is not yet fully explored. Using both
in vitro
and
in vivo
strategies, we examined how lung and lung epithelial gene expression are modified after exposure to fungal conidia or chitin fragments in the presence or absence of FIBCD1. FIBCD1 expression was associated with a decrease in inflammatory cytokines with increasing size of chitin (dimer-oligomer). Thus, our results demonstrate that FIBCD1 expression modulates cytokine and chemokine expression in response to
A
.
fumigatus
conidia that is modified by the presence of chitin particles.
Journal Article
Van Gogh and Britain
Van Gogh and Britain at Tate Britain will be the first major exhibition both to explore the impact of British culture on Vincent van Gogh and to trace the introduction of his art into Britain and its legacy in the works of British painters. Published to accompany the show, this lavishly illustrated publication illustrates fifty van Gogh paintings, and traces the story from the artist's obscure years in England in the 1870s through his growing influence and reputation to iconic status in the 1950s. These works are accompanied by paintings by British artists that affected him and which he in turn inspired.
Book
High folic acid diet enhances tumour growth in PyMT-induced breast cancer
Background:
The B-vitamin folate is among the most studied bioactive food compound, and a dietary intake meeting the daily requirements has been found to reduce the risk of cancer and cardiovascular diseases as well as preventing neural tube defects during fetal development. Several countries have therefore introduced dietary fortification with folic acid. However, clinical and animal studies suggest that folic acid has a dual role in cancer development.
Methods:
During the period of initial tumour progression, MMTV-PyMT (MMTV-
p
olyoma virus
m
iddle T) transgenic mice were fed with normal diet and high folic acid diet.
Results:
We found that PyMT-induced breast tumours highly express the cancer-specific folate receptor (FR), a feature they share with several human epithelial cancers in which expression of FR
α
correlates with tumour grade. Mice receiving a high folic acid diet displayed a significantly increased tumour volume compared with mice receiving normal diet. In the largest tumours, only found in mice on high folic acid diet, STAT3 was activated. In primary cells from PyMT tumours, STAT3 was activated upon treatment with folic acid in culture.
Conclusions:
Our results offer a novel molecular explanation for folic acid-induced growth of existing tumours.
Journal Article
The metalloproteinase PAPP-A is required for IGF-dependent chondrocyte differentiation and organization
Insulin-like growth factor (IGF) signaling is required for proper growth and skeletal development in vertebrates. Consequently, its dysregulation may lead to abnormalities of growth or skeletal structures. IGF is involved in the regulation of cell proliferation and differentiation of chondrocytes. However, the availability of bioactive IGF may be controlled by antagonizing IGF binding proteins (IGFBPs) in the circulation and tissues. As the metalloproteinase PAPP-A specifically cleaves members of the IGFBP family, we hypothesized that PAPP-A activity liberates bioactive IGF in cartilage. In PAPP-A knockout mice, the femur length was reduced and the mice showed a disorganized columnar organization of growth plate chondrocytes. Similarly, zebrafish lacking
pappaa
showed reduced length of Meckel’s cartilage and disorganized chondrocytes, reminiscent of the mouse knockout phenotype. Expression of chondrocyte differentiation markers (
sox9a
,
ihha
, and
col10a1
) was markedly affected in Meckel’s cartilage of
pappaa
knockout zebrafish, indicating that differentiation of chondrocytes was compromised. Additionally, the zebrafish
pappaa
knockout phenotype was mimicked by pharmacological inhibition of IGF signaling, and it could be rescued by treatment with exogenous recombinant IGF-I. In conclusion, our data suggests that IGF activity in the growing cartilage, and hence IGF signaling in chondrocytes, requires the presence of PAPP-A. The absence of PAPP-A causes aberrant chondrocyte organization and compromised growth in both mice and zebrafish.
Journal Article
Defective glycerol metabolism in aquaporin 9 (AQP9) knockout mice
Aquaporin-9 (AQP9) is an aquaglyceroporin membrane channel shown biophysically to conduct water, glycerol, and other small solutes. Because the physiological role/s of AQP9 remain undefined and the expression sites of AQP9 remain incomplete and conflicting, we generated AQP9 knockout mice. In the absence of physiological stress, knockout mice did not display any visible behavioral or severe physical abnormalities. Immunohistochemical analyses using multiple antibodies revealed AQP9 specific labeling in hepatocytes, epididymis, vas deferens, and in epidermis of wild type mice, but a complete absence of labeling in AQP9⁻/⁻ mice. In brain, no detectable labeling was observed. Compared with control mice, plasma levels of glycerol and triglycerides were markedly increased in AQP9⁻/⁻ mice, whereas glucose, urea, free fatty acids, alkaline phosphatase, and cholesterol were not significantly different. Oral administration of glycerol to fasted mice resulted in an acute rise in blood glucose levels in both AQP9⁻/⁻ and AQP9⁺/⁻ mice, revealing no defect in utilization of exogenous glycerol as a gluconeogenic substrate and indicating a high gluconeogenic capacity in nonhepatic organs. Obese Leprdb/Leprdb AQP9⁻/⁻ and obese Leprdb/Leprdb AQP9⁺/⁻ mice showed similar body weight, whereas the glycerol levels in obese Leprdb/Leprdb AQP9⁻/⁻ mice were dramatically increased. Consistent with a role of AQP9 in hepatic uptake of glycerol, blood glucose levels were significantly reduced in Leprdb/Leprdb AQP9⁻/⁻ mice compared with Leprdb/Leprdb AQP9⁺/⁻ in response to 3 h of fasting. Thus, AQP9 is important for hepatic glycerol metabolism and may play a role in glycerol and glucose metabolism in diabetes mellitus.
Journal Article