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Article ; Online: The C-terminal Amphipathic Helix of Carboxypeptidase E Mediates Export from the ER and Secretion via Lysosomes.

Armoza-Eilat, Shir / Malis, Yehonathan / Caspi, Michal / Tarabe, Raneen / Shomron, Olga / Hirschberg, Koret / Rosin-Arbesfeld, Rina

Journal of molecular biology

2023 Volume 435, Issue 15, Page(s) 168171

Abstract: Carboxypeptidase E (CPE), an essential enzyme in the biosynthetic production line of most ...

Abstract	Carboxypeptidase E (CPE), an essential enzyme in the biosynthetic production line of most peptide hormones and neuropeptides, is predominantly expressed in endocrine tissues and in the nervous system. CPE is active in acidic environments where it cleaves the C'-terminal basic residues of peptide precursors to generate their bioactive form. Consequently, this highly conserved enzyme regulates numerous fundamental biological processes. Here, we combined live-cell microscopy and molecular analysis to examine the intracellular distribution and secretion dynamics of fluorescently tagged CPE. We show that, in non-endocrine cells, tagged-CPE is a soluble luminal protein that is efficiently exported from the ER via the Golgi apparatus to lysosomes. The C'-terminal conserved amphipathic helix serves as a lysosomal and secretory granule targeting and a secretion motif. Following secretion, CPE may be reinternalized into the lysosomes of neighboring cells.
MeSH term(s)	Carboxypeptidase H/genetics ; Carboxypeptidase H/metabolism ; Golgi Apparatus/enzymology ; Lysosomes/enzymology ; Neuropeptides/metabolism
Chemical Substances	Carboxypeptidase H (EC 3.4.17.10) ; Neuropeptides
Language	English
Publishing date	2023-06-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2023.168171
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Article ; Online: The C-terminal Amphipathic Helix of Carboxypeptidase E Mediates Export from the ER and Secretion via Lysosomes

Armoza-Eilat, Shir / Malis, Yehonathan / Caspi, Michal / Tarabe, Raneen / Shomron, Olga / Hirschberg, Koret / Rosin-Arbesfeld, Rina

Journal of Molecular Biology. 2023 Aug., v. 435, no. 15 p.168171-

2023

Abstract: Carboxypeptidase E (CPE), an essential enzyme in the biosynthetic production line of most ...

Abstract	Carboxypeptidase E (CPE), an essential enzyme in the biosynthetic production line of most peptide hormones and neuropeptides, is predominantly expressed in endocrine tissues and in the nervous system. CPE is active in acidic environments where it cleaves the C’-terminal basic residues of peptide precursors to generate their bioactive form. Consequently, this highly conserved enzyme regulates numerous fundamental biological processes. Here, we combined live-cell microscopy and molecular analysis to examine the intracellular distribution and secretion dynamics of fluorescently tagged CPE. We show that, in non-endocrine cells, tagged-CPE is a soluble luminal protein that is efficiently exported from the ER via the Golgi apparatus to lysosomes. The C’-terminal conserved amphipathic helix serves as a lysosomal and secretory granule targeting and a secretion motif. Following secretion, CPE may be reinternalized into the lysosomes of neighboring cells.
Keywords	Golgi apparatus ; biosynthesis ; carboxypeptidase E ; exports ; lysosomes ; microscopy ; molecular biology ; nervous system ; neuropeptides ; secretion ; secretory granules ; surfactants ; Live-cell microscopy ; Secretory pathway ; Lysosomal targeting signal
Language	English
Dates of publication	2023-08
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2023.168171
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Article ; Online: Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a.

Skalka, N / Caspi, M / Lahav-Ariel, L / Loh, Y P / Hirschberg, K / Rosin-Arbesfeld, R

Oncogene

2016 Volume 35, Issue 50, Page(s) 6416–6428

Abstract: ... that carboxypeptidase E (CPE) is a novel regulator of the canonical Wnt signaling pathway. Here, we show that CPE and ...

Abstract	The Wnt pathway has essential roles in cell proliferation, cell fate determination and tumorigenesis by regulating the expression of a wide range of target genes. As a core signaling cascade, the canonical Wnt pathway is regulated at different levels by numerous proteins. We have previously shown that carboxypeptidase E (CPE) is a novel regulator of the canonical Wnt signaling pathway. Here, we show that CPE and the Wnt3a ligand are co-secreted from cells. We show that although the C'-terminal Lys residue of Wnt3a is critical for its activity and is important for the effect of CPE on the Wnt pathway, CPE does not execute its effect by removing this Wnt3a residue. Interestingly, CPE through its N'-terminal sequence, forms aggregates with Wnt3a and possible endoplasmic reticulum (ER) stress leading to its loss of function. Together, our current results provide a mechanistic insight into the way CPE regulates the canonical Wnt signaling pathway.
MeSH term(s)	Animals ; COS Cells ; Carboxypeptidase H/physiology ; Cercopithecus aethiops ; Endoplasmic Reticulum Stress ; HEK293 Cells ; Humans ; Protein Aggregates ; Wnt Signaling Pathway ; Wnt3A Protein/metabolism
Chemical Substances	Protein Aggregates ; Wnt3A Protein ; Carboxypeptidase H (EC 3.4.17.10)
Language	English
Publishing date	2016-12-15
Publishing country	England
Document type	Journal Article
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/onc.2016.173
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Article: Female hyperandrogenism and elite sport.

Hirschberg, Angelica Lindén

Endocrine connections

2020 Volume 9, Issue 4, Page(s) R81–R92

Abstract: ... to allow female athletes with endogenous testosterone levels in the male range (i.e. 10-20 times higher ...

Abstract	Emerging evidence indicates that testosterone, which can increase muscle mass and strength, stimulates erythropoiesis, promotes competitive behaviour, and enhances the physical performance of women. Indeed, the levels of testosterone within the normal female range are related to muscle mass and athletic performance in female athletes. Furthermore, among these athletes, the prevalence of hyperandrogenic conditions, including both polycystic ovary syndrome and rare differences/disorders of sex development (DSD), which may greatly increase testosterone production, are elevated. Thus, if the androgen receptors of an individual with XY DSD are functional, her muscle mass will develop like that of a man. These findings have led to the proposal that essential hyperandrogenism is beneficial for athletic performance and plays a role in the choice by women to compete in athletic activities. Moreover, a recent randomized controlled trial demonstrated a significant increase in the lean mass and aerobic performance by young exercising women when their testosterone levels were enhanced moderately. Circulating testosterone is considered the strongest factor to explain the male advantage in sport performance, ranging between 10 and 20%. It appears to be unfair to allow female athletes with endogenous testosterone levels in the male range (i.e. 10-20 times higher than normal) to compete against those with normal female androgen levels. In 2012, this consideration led international organizations to establish eligibility regulations for the female classification in order to ensure fair and meaningful competition, but the regulations are controversial and have been challenged in court.
Language	English
Publishing date	2020-03-17
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2668428-7
ISSN	2049-3614
ISSN	2049-3614
DOI	10.1530/EC-19-0537
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Article: Production of high-value compounds: carotenoids and vitamin E.

Hirschberg, J

Current opinion in biotechnology

1999 Volume 10, Issue 2, Page(s) 186–191

Abstract: ... of successful manipulation of carotenoid composition and vitamin E activity in plants using gene-transfer ...

Abstract	The unraveling in recent years of the pathways and genes that are responsible for biosynthesis of vitamins and carotenoids in plants has provided new molecular tools that can be utilized to genetically modify the content and composition of these compounds in vivo. There have been recent examples of successful manipulation of carotenoid composition and vitamin E activity in plants using gene-transfer technology.
MeSH term(s)	Carotenoids/biosynthesis ; Cloning, Molecular ; Gene Transfer Techniques ; Plants/genetics ; Plants/metabolism ; Vitamin E/biosynthesis
Chemical Substances	Vitamin E (1406-18-4) ; Carotenoids (36-88-4)
Language	English
Publishing date	1999-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1052045-4
ISSN	1879-0429 ; 0958-1669
ISSN (online)	1879-0429
ISSN	0958-1669
DOI	10.1016/s0958-1669(99)80033-0
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Article: Diskussionsbemerkung zum Beitrag von E. Förster: Psyche und Person.

Hirschberg, W

Zeitschrift fur Kinder- und Jugendpsychiatrie

1992 Volume 20, Issue 1, Page(s) 62–63

Title translation	Comment on the contribution by E. Förster: Psyche and person.
MeSH term(s)	Brain/physiopathology ; Humans ; Mental Disorders/physiopathology ; Mental Processes/physiology
Language	German
Publishing date	1992-03
Publishing country	Switzerland
Document type	Comment ; Letter
ZDB-ID	184566-4
ISSN	0301-6811
ISSN	0301-6811
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Article: Compaction Properties of Particulate Proteins in Binary Powder Mixtures with Common Excipients.

Holmfred, Else / Hirschberg, Cosima / Rantanen, Jukka

Pharmaceutics

2023 Volume 16, Issue 1

Abstract: The increasing interest in protein- and peptide-based oral pharmaceuticals has culminated in the first protein-based products for oral delivery becoming commercially available. This study investigates the compaction properties of proteins in binary ... ...

Abstract	The increasing interest in protein- and peptide-based oral pharmaceuticals has culminated in the first protein-based products for oral delivery becoming commercially available. This study investigates the compaction properties of proteins in binary mixtures with common excipients up to 30% (
Language	English
Publishing date	2023-12-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics16010019
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Article: Different sleep pattern in over-weight/obese women with polycystic ovary syndrome.

Oberg, Emma / Blomberg, Liselotte / Åkerstedt, Torbjörn / Hirschberg, Angelica Lindén

Frontiers in endocrinology

2023 Volume 14, Page(s) 1068045

Abstract: Context: Sleep duration and sleep quality have important health implications although our knowledge of objectively measured sleep variables in women with Polycystic Ovary Syndrome (PCOS) is limited.: Objective: To compare sleep variables assessed by ... ...

Abstract	Context: Sleep duration and sleep quality have important health implications although our knowledge of objectively measured sleep variables in women with Polycystic Ovary Syndrome (PCOS) is limited. Objective: To compare sleep variables assessed by actigraphy in over-weight/obese women with PCOS and controls, and to assess sleep variables after behavioral modification intervention in comparison with minimal intervention in a randomized trial. Design: Randomized controlled trial, and a control group. Setting: Outpatient gynecological clinic at a university hospital in Sweden. Participants: 39 women fulfilling all Rotterdam PCOS criteria, randomized to behavioral modification intervention or minimal intervention and 21 controls with no other metabolic disease, all aged 18-40 years with a BMI ≥ 27 kg/m Intervention: A four-month behavioral modification intervention including weekly group meetings focusing on behavioral and healthy lifestyle aspects. Minimal intervention reflecting standard care. Main outcome measure: Sleep durations and sleep efficiency assessed by actigraphy. Results: Compared to the control group, women with PCOS had significantly shorter time in bed (501 vs 548 min, p= 0.049), sleep time over 24 hours (448 vs 567 min, p=0.005) and sleep time at night (434 vs 511 min, p=0.002), poorer sleep efficiency (87 vs 93%, p<0.001), and longer wakefulness after sleep onset (64 vs 38 min, p<0.001). However, total sleep time at night for women with PCOS (7.2hrs) was within the normal range. Following behavioral modification intervention, the reduction from baseline in sleep over 24 hours and in the daytime sleep were significant compared to the minimal intervention group (78 min, p=0.009 and 43 min, p=0.003 respectively). Conclusions: We found over-weight/obese women with PCOS to have normal sleep duration, but worse sleep efficiency than controls. Behavioral modification intervention seems to reduce the amount of daytime sleep, suggesting improved sleep behavior. Clinical trials registration: https://doi.org/10.1186/ISRCTN48947168, identifier ISRCTN48947168.
MeSH term(s)	Female ; Humans ; Polycystic Ovary Syndrome/complications ; Polycystic Ovary Syndrome/therapy ; Polycystic Ovary Syndrome/metabolism ; Obesity/complications ; Obesity/therapy ; Overweight ; Behavior Therapy ; Sleep
Language	English
Publishing date	2023-02-10
Publishing country	Switzerland
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1068045
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Article ; Online: Maternal serum levels of prokineticin-1 related to pregnancy complications and metformin use in women with polycystic ovary syndrome: a post hoc analysis of two prospective, randomised, placebo-controlled trials.

Ujvari, Dorina / Trouva, Anastasia / Hirschberg, Angelica Lindén / Vanky, Eszter

BMJ open

2023 Volume 13, Issue 11, Page(s) e073619

Abstract: Objective: Serum prokineticin-1 (s-PROK1) in the second and third trimester of pregnancy is positively correlated to preeclampsia, intrauterine growth restriction (IUGR) and preterm delivery. Women with polycystic ovary syndrome (PCOS) are prone to ... ...

Abstract	Objective: Serum prokineticin-1 (s-PROK1) in the second and third trimester of pregnancy is positively correlated to preeclampsia, intrauterine growth restriction (IUGR) and preterm delivery. Women with polycystic ovary syndrome (PCOS) are prone to these adverse pregnancy outcomes. However, the contribution of PROK1 to the development of pregnancy complications and the effect of metformin and hyperandrogenism on s-PROK1 in PCOS have not been studied previously. Design: This work is a post hoc analysis of two prospective, randomised, placebo-controlled trials. Setting: Pregnant women with PCOS were included from 11 study centres in Norway. Participants: From 313 women, 264 participated in the present study after exclusions due to dropouts or insufficient serum samples. Intervention: Women with PCOS were randomly administered with metformin or placebo, from first trimester to delivery. Primary and secondary outcome measures: s-PROK1 was analysed using ELISA at gestational week 19 and related to pregnancy complications, fasting insulin levels, homoeostatic model assessment for insulin resistance (HOMA-IR), testosterone, or androstenedione levels, metformin use, PCOS phenotype and hyperandrogenism. Results: Maternal s-PROK1 in the second trimester did not predict pregnancy-induced hypertension, pre-eclampsia or late miscarriage/preterm delivery in women with PCOS. However, s-PROK1 was lower in women who used metformin before inclusion, both in those randomised to metformin and to placebo, compared with those who did not. s-PROK1 was also lower in those who used metformin both at conception and during pregnancy compared with those who used metformin from inclusion or did not use metformin at all. s-PROK1 was lower in hyperandrogenic compared with normo-androgenic women with PCOS. Conclusions: Maternal s-PROK1 in the second trimester did not predict pregnancy complications in PCOS. Those who used metformin at conception and/or during pregnancy had lower s-PROK1. PCOS women with hyperandrogenism exhibited lower s-PROK1 compared with normo-adrogenic phenotypes. Trial registration number: NCT03259919 and NCT00159536.
MeSH term(s)	Infant, Newborn ; Female ; Pregnancy ; Humans ; Metformin/therapeutic use ; Polycystic Ovary Syndrome/complications ; Polycystic Ovary Syndrome/drug therapy ; Hypoglycemic Agents/therapeutic use ; Hyperandrogenism/chemically induced ; Hyperandrogenism/complications ; Hyperandrogenism/drug therapy ; Premature Birth ; Prospective Studies ; Pregnancy Complications/drug therapy ; Pregnancy Complications/chemically induced ; Pre-Eclampsia/drug therapy ; Gastrointestinal Hormones/therapeutic use ; Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
Chemical Substances	Metformin (9100L32L2N) ; Hypoglycemic Agents ; PROK1 protein, human ; Gastrointestinal Hormones ; Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
Language	English
Publishing date	2023-11-21
Publishing country	England
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2023-073619
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Article: The pathogenesis of nasal polyposis by immunoglobulin E and interleukin-5 is completed by transforming growth factor-beta1.

Hirschberg, Andor / Jókúti, Adrienn / Darvas, Zsuzsa / Almay, Krisztina / Répássy, Gábor / Falus, András

The Laryngoscope

2003 Volume 113, Issue 1, Page(s) 120–124

Abstract: ... pathological mechanisms comprise several factors including cytokines and immunoglobulin E (IgE). The study was ... nasal mucosa samples (n = 9) were taken during routine endonasal surgeries. Immunoglobulin E (n = 13), IL-5 (n ...

Abstract	Objectives/hypothesis: Nasal polyps are benign mucosal protrusions into the nasal cavity of multifactorial origin and are characterized by chronic mucosal inflammation. The suggested multifactorial pathological mechanisms comprise several factors including cytokines and immunoglobulin E (IgE). The study was designed to examine the suggested roles of IgE, interleukin-5 (IL-5), and transforming growth factor-beta1 (TGF-beta1) in the pathogenesis of nasal polyposis. Methods: Nasal polyps (n = 34) and healthy nasal mucosa samples (n = 9) were taken during routine endonasal surgeries. Immunoglobulin E (n = 13), IL-5 (n = 22), and TGF-beta1 (n = 27) concentrations were measured with enzyme-linked immunosorbent assay technique in homogenized polyp tissue and in control mucosa. Atopic and nonatopic groups were selected and compared. Histomorphological examination and immunohistochemical analysis to detect IL-5 and TGF-beta1 were performed in five specimens. Results: The level of tissue-bound IgE was significantly higher in polyps compared with control specimens and in atopic compared with nonatopic polyps, but between nonatopic polyps and control specimens the difference was not significant. However, significant correlation was found between tissue and serum IgE in the complete polyp (P =.001) and atopic polyps group (P =.05). Tissue IL-5 concentration was significantly higher in polyps compared with control specimens, in which it was below the limit (15 pg/mL), and there was no difference between atopic and nonatopic polyps. In atopic polyps there was significant correlation between tissue IgE and IL-5. Transforming growth factor-beta1 concentration proved to be significantly higher in control mucosa than in polyps, with no difference between atopic and nonatopic polyps. Immunohistochemical analysis revealed numerous IL-5-positive eosinophil cells and TGF-beta1 positivity in the lamina propria of polyp samples, but none in control specimens. Conclusions: High tissue TGF-beta1 quantity in healthy nasal mucosa without its active form on the cell surface and its low quantity in polyps may reflect its essential role in the inhibitory mechanisms of nasal polyposis. Interleukin-5 plays a key role in the eosinophil recruitment and activation, and both atopic and nonatopic pathways might activate this process. The main sources of IL-5 and TGF-beta1 are the eosinophils and macrophages. Immediate hypersensitivity, besides other mechanisms, might be related to atopic polyps, but the involvement of other, local allergic mechanisms in IgE production of nonatopic polyp tissue cannot be excluded.
MeSH term(s)	Adolescent ; Adult ; Biomarkers/analysis ; Biopsy, Needle ; Case-Control Studies ; Culture Techniques ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Immunoglobulin E/analysis ; Immunoglobulin E/metabolism ; Immunohistochemistry ; Interleukin-5/analysis ; Interleukin-5/metabolism ; Male ; Middle Aged ; Nasal Mucosa/metabolism ; Nasal Mucosa/pathology ; Nasal Polyps/immunology ; Nasal Polyps/pathology ; Nasal Polyps/surgery ; Probability ; Prognosis ; Sampling Studies ; Sensitivity and Specificity ; Statistics, Nonparametric ; Transforming Growth Factor beta/analysis ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta1
Chemical Substances	Biomarkers ; Interleukin-5 ; TGFB1 protein, human ; Transforming Growth Factor beta ; Transforming Growth Factor beta1 ; Immunoglobulin E (37341-29-0)
Language	English
Publishing date	2003-01
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	80180-x
ISSN	1531-4995 ; 0023-852X
ISSN (online)	1531-4995
ISSN	0023-852X
DOI	10.1097/00005537-200301000-00022
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