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Article ; Online: MET-Activating Ubiquitin Multimers.

Kawakami, Naoya / Sato, Hiroki / Terasaka, Naohiro / Matsumoto, Kunio / Suga, Hiroaki

Angewandte Chemie (International ed. in English)

2023 Volume 62, Issue 36, Page(s) e202307157

Abstract: Receptor tyrosine kinases (RTKs) are generally activated through their dimerization and/or oligomerization induced by their cognate ligands, and one such RTK hepatocyte growth factor (HGF) receptor, known as MET, plays an important role in tissue ... ...

Abstract	Receptor tyrosine kinases (RTKs) are generally activated through their dimerization and/or oligomerization induced by their cognate ligands, and one such RTK hepatocyte growth factor (HGF) receptor, known as MET, plays an important role in tissue regeneration. Here we show the development of ubiquitin (Ub)-based protein ligand multimers, referred to as U-bodies, which act as surrogate agonists for MET and are derived from MET-binding macrocyclic peptides. Monomeric Ub constructs (U-body) were first generated by genetic implantation of a macrocyclic peptide pharmacophore into a structural loop of Ub (lasso-grafting) and subsequent optimization of its flanking spacer sequences via mRNA display. Such U-body constructs exhibit potent binding affinity to MET, thermal stability, and proteolytic stability. The U-body constructs also partially/fully inhibited or enhanced HGF-induced MET-phosphorylation. Their multimerization to dimeric, tetrameric, and octameric U-bodies linked by an appropriate peptide linker yielded potent MET activation activity and downstream cell proliferation-promoting activity. This work suggests that lasso-grafting of macrocycles to Ub is an effective approach to devising protein-based artificial RTK agonists and it can be useful in the development of a new class of biologics for various therapeutic applications.
MeSH term(s)	Hepatocyte Growth Factor/metabolism ; Ubiquitin/metabolism ; Protein Binding ; Proto-Oncogene Proteins c-met/metabolism ; Phosphorylation ; Peptides/pharmacology ; Peptides/metabolism
Chemical Substances	Hepatocyte Growth Factor (67256-21-7) ; Ubiquitin ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Peptides
Language	English
Publishing date	2023-07-31
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202307157
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Article: [A Case of Sigmoid Colon Cancer with Intussusception Prolapsing through the Anus].

Arimoto, Akira / Sakamoto, Hiroki / Asakura, Yu / Yokoyama, Kunio / Matsumoto, Taku / Ueno, Nozomi / Yoshikawa, Takuro

Gan to kagaku ryoho. Cancer & chemotherapy

2023 Volume 49, Issue 13, Page(s) 1717–1719

Abstract: A 76-year-old woman presented to the hospital with the colon prolapsing through the anus. The enhanced abdominal computed tomography(CT)showed intussusception of the sigmoid colon due to sigmoid colon cancer. It was difficult to reduce the ... ...

Abstract	A 76-year-old woman presented to the hospital with the colon prolapsing through the anus. The enhanced abdominal computed tomography(CT)showed intussusception of the sigmoid colon due to sigmoid colon cancer. It was difficult to reduce the intussusception, and we did not recognize the ileus and ischemic change of the colon. Therefore, we performed an elective surgery. Hartmann's procedure and lymph node dissection were performed 8 days after the hospitalization. The postoperative course was uneventful. We report a case of sigmoid colon cancer with intussusception prolapsing through the anus.
MeSH term(s)	Female ; Humans ; Aged ; Sigmoid Neoplasms/complications ; Sigmoid Neoplasms/surgery ; Sigmoid Neoplasms/pathology ; Intussusception/etiology ; Intussusception/surgery ; Anal Canal/pathology ; Colon, Sigmoid/pathology ; Intestinal Obstruction
Language	Japanese
Publishing date	2023-01-24
Publishing country	Japan
Document type	Case Reports ; English Abstract ; Journal Article
ZDB-ID	604842-0
ISSN	0385-0684
ISSN	0385-0684
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Zs.B 2573: Show issues

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Article ; Online: Met receptor is essential for MAVS-mediated antiviral innate immunity in epithelial cells independent of its kinase activity.

Imamura, Ryu / Sato, Hiroki / Chih-Cheng Voon, Dominic / Shirasaki, Takayoshi / Honda, Masao / Kurachi, Makoto / Sakai, Katsuya / Matsumoto, Kunio

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 40, Page(s) e2307318120

Abstract: Epithelial tissue is at the forefront of innate immunity, playing a crucial role in the recognition and elimination of pathogens. Met is a receptor tyrosine kinase that is necessary for epithelial cell survival, proliferation, and regeneration. Here, we ... ...

Abstract	Epithelial tissue is at the forefront of innate immunity, playing a crucial role in the recognition and elimination of pathogens. Met is a receptor tyrosine kinase that is necessary for epithelial cell survival, proliferation, and regeneration. Here, we showed that Met is essential for the induction of cytokine production by cytosolic nonself double-stranded RNA through retinoic acid-inducible gene-I-like receptors (RLRs) in epithelial cells. Surprisingly, the tyrosine kinase activity of Met was dispensable for promoting cytokine production. Rather, the intracellular carboxy terminus of Met interacted with mitochondrial antiviral-signaling protein (MAVS) in RLR-mediated signaling to directly promote MAVS signalosome formation. These studies revealed a kinase activity-independent function of Met in the promotion of antiviral innate immune responses, defining dual roles of Met in both regeneration and immune responses in the epithelium.
MeSH term(s)	Epithelial Cells ; Receptor Protein-Tyrosine Kinases ; Immunity, Innate ; Antiviral Agents ; Cytokines
Chemical Substances	Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Antiviral Agents ; Cytokines
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2307318120
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Zs.A 1148: Show issues

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Article ; Online: Rho family small GTPase Rif regulates Wnt5a-Ror1-Dvl2 signaling and promotes lung adenocarcinoma progression.

Nishita, Michiru / Kamizaki, Koki / Hoshi, Kyoka / Aruga, Kana / Nishikaku, Ikumi / Shibuya, Hiroshi / Matsumoto, Kunio / Minami, Yasuhiro

The Journal of biological chemistry

2023 Volume 299, Issue 10, Page(s) 105248

Abstract: Rho in filopodia (Rif), a member of the Rho family of small GTPases, induces filopodia formation primarily on the dorsal surface of cells; however, its function remains largely unclear. Here, we show that Rif interacts with Ror1, a receptor for Wnt5a ... ...

Abstract	Rho in filopodia (Rif), a member of the Rho family of small GTPases, induces filopodia formation primarily on the dorsal surface of cells; however, its function remains largely unclear. Here, we show that Rif interacts with Ror1, a receptor for Wnt5a that can also induce dorsal filopodia. Our immunohistochemical analysis revealed a high frequency of coexpression of Ror1 and Rif in lung adenocarcinoma. Lung adenocarcinoma cells cultured on Matrigel established front-rear polarity with massive filopodia on their front surfaces, where Ror1 and Rif were accumulated. Suppression of Ror1 or Rif expression inhibited cell proliferation, survival, and invasion, accompanied by the loss of filopodia and cell polarity in vitro, and prevented tumor growth in vivo. Furthermore, we found that Rif was required to activate Wnt5a-Ror1 signaling at the cell surface leading to phosphorylation of the Wnt signaling pathway hub protein Dvl2, which was further promoted by culturing the cells on Matrigel. Our findings reveal a novel function of Rif in mediating Wnt5a-Ror1-Dvl2 signaling, which is associated with the formation of polarized filopodia on 3D matrices in lung adenocarcinoma cells.
Language	English
Publishing date	2023-09-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.105248
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Article ; Online: Two-Chain Mature Hepatocyte Growth Factor-Specific Positron Emission Tomography Imaging in Tumors Using

Warashina, Shota / Sato, Hiroki / Zouda, Maki / Takahashi, Maiko / Wada, Yasuhiro / Passioura, Toby / Suga, Hiroaki / Watanabe, Yasuyoshi / Matsumoto, Kunio / Mukai, Hidefumi

Molecular pharmaceutics

2023 Volume 20, Issue 4, Page(s) 2029–2038

Abstract: Two-chain hepatocyte growth factor (tcHGF), the mature form of HGF, is associated with malignancy and anticancer drug resistance; therefore, its quantification is an important indicator for cancer diagnosis. In tumors, activated tcHGF hardly discharges ... ...

Abstract	Two-chain hepatocyte growth factor (tcHGF), the mature form of HGF, is associated with malignancy and anticancer drug resistance; therefore, its quantification is an important indicator for cancer diagnosis. In tumors, activated tcHGF hardly discharges into the systemic circulation, indicating that tcHGF is an excellent target for molecular imaging using positron emission tomography (PET). We recently discovered HGF-inhibitory peptide-8 (HiP-8) that binds specifically to human tcHGF with nanomolar affinity. The purpose of this study was to investigate the usefulness of HiP-8-based PET probes in human
MeSH term(s)	Mice ; Humans ; Animals ; Hepatocyte Growth Factor/metabolism ; Peptides/chemistry ; Neoplasms/diagnostic imaging ; Positron-Emission Tomography/methods ; Chelating Agents/chemistry ; Copper Radioisotopes/chemistry ; Cell Line, Tumor
Chemical Substances	Hepatocyte Growth Factor (67256-21-7) ; Peptides ; Chelating Agents ; Copper Radioisotopes
Language	English
Publishing date	2023-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.2c01020
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Zs.A 6250: Show issues

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Article ; Online: Early hematopoietic cell transplantation for familial hemophagocytic lymphohistiocytosis in a regional treatment network in Japan.

Ishimura, Masataka / Eguchi, Katsuhide / Sonoda, Motoshi / Tanaka, Tamami / Shiraishi, Akira / Sakai, Yasunari / Yasumi, Takahiro / Miyamoto, Takayuki / Voskoboinik, Ilia / Hashimoto, Kunio / Matsumoto, Shirou / Ozono, Shuichi / Moritake, Hiroshi / Takada, Hidetoshi / Ohga, Shouichi

International journal of hematology

2024

Abstract: Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous ... ...

Abstract	Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50-81] vs. 122 [89-209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications.
Language	English
Publishing date	2024-03-20
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1076875-0
ISSN	1865-3774 ; 0917-1258 ; 0925-5710
ISSN (online)	1865-3774
ISSN	0917-1258 ; 0925-5710
DOI	10.1007/s12185-024-03721-3
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Zs.A 269: Show issues

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Article ; Online: Walking aids and complicated orthopedic diseases are risk factors for falls in hemodialysis patients: an observational study.

Ishii, Takeo / Matsumoto, Wataru / Hoshino, Yui / Kagawa, Yasuhiro / Iwasaki, Emi / Takada, Hiromi / Honma, Takashi / Oyama, Kunio

BMC geriatrics

2023 Volume 23, Issue 1, Page(s) 319

Abstract: Background: Aging and an increased fall risk have been demonstrated in hemodialysis patients at home and in a facility. However, studies investigating the cause of falls to prevent fractures in dialysis rooms are scarce. This study aimed to explore the ... ...

Abstract	Background: Aging and an increased fall risk have been demonstrated in hemodialysis patients at home and in a facility. However, studies investigating the cause of falls to prevent fractures in dialysis rooms are scarce. This study aimed to explore the related factors for accidental falls statistically in dialysis facilities for future fall prevention. Methods: This study included 629 hemodialysis patients with end-stage renal disease. The patients were divided into two groups: the fall and non-fall groups. The main outcome was the presence or absence of falls in the dialysis room. Univariate and multivariate logistic analyses were performed; multivariate analysis was conducted using covariates significantly correlated in the univariate analysis. Results: A total of 133 patients experienced falling accidents during the study period. The multivariate analysis indicated that the use of walking aid (p < 0.001), orthopedic diseases (p < 0.05), cerebrovascular disease, and age were significantly correlated with falls. Conclusions: In the dialysis clinic, patients who use walking aids and have complicated orthopedic or cerebrovascular conditions are at a high risk of falling in the dialysis room. Therefore, establishing a safe environment may help prevent falls, not only for these patients but also among other patients with similar conditions.
MeSH term(s)	Humans ; Risk Factors ; Renal Dialysis/adverse effects ; Kidney Failure, Chronic/epidemiology ; Kidney Failure, Chronic/therapy ; Walking ; Ambulatory Care Facilities
Language	English
Publishing date	2023-05-22
Publishing country	England
Document type	Observational Study ; Journal Article
ZDB-ID	2059865-8
ISSN	1471-2318 ; 1471-2318
ISSN (online)	1471-2318
ISSN	1471-2318
DOI	10.1186/s12877-023-04015-9
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Article ; Online: Dynamic changes in patient admission and their disabilities in multiple sclerosis and neuromyelitis optica: A Japanese nationwide administrative data study.

Matsumoto, Yuki / Tarasawa, Kunio / Misu, Tatsuro / Namatame, Chihiro / Takai, Yoshiki / Kuroda, Hiroshi / Fujihara, Kazuo / Fushimi, Kiyohide / Fujimori, Kenji / Aoki, Masashi

Multiple sclerosis and related disorders

2023 Volume 81, Page(s) 105349

Abstract: Background: The real-world data evidences how establishment of neuromyelitis optica (NMO) disease concept and development disease modifying therapy affect the patients with multiple sclerosis (MS) and NMO are lacking. The aim of this study is to clarify ...

Abstract	Background: The real-world data evidences how establishment of neuromyelitis optica (NMO) disease concept and development disease modifying therapy affect the patients with multiple sclerosis (MS) and NMO are lacking. The aim of this study is to clarify the diachronic trend of the severity and admissions of patients with MS and NMO. Methods: We retrospectively investigated the trends in admissions, treatments, and disabilities in the patients with MS and NMO using the Japanese administrative data between 2012 and 2017. Results: We analyzed acute stage 9545 and 2035 admissions in each 6100 MS and 1555 NMO patients. The annual number of admission in MS significantly decreased in 6 years; however, those in NMO consistently increased. The patient proportion with lower disability was significantly increased in MS and NMO. These trends were especially observed in patients admitted to centralized hospitals with more active treatments, such as second-line disease modifying therapy for MS and plasmapheresis for NMO. Patients with NMO using DMT for MS diminished in 6 years. Conclusion: A gradual improvement of disability in patients with MS and NMO was observed, probably due to advanced treatments, increased NMO awareness, and decreased misdiagnosis, which seems to be the key for better prognosis in MS and NMO.
MeSH term(s)	Humans ; Multiple Sclerosis/epidemiology ; Multiple Sclerosis/therapy ; Neuromyelitis Optica/epidemiology ; Neuromyelitis Optica/therapy ; Retrospective Studies ; Patient Admission ; Japan/epidemiology
Language	English
Publishing date	2023-11-25
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2645330-7
ISSN	2211-0356 ; 2211-0348
ISSN (online)	2211-0356
ISSN	2211-0348
DOI	10.1016/j.msard.2023.105349
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Article ; Online: Dimer Interface in Natural Variant NK1 Is Dispensable for HGF-Dependent Met Receptor Activation.

Tahira, Yumiko / Sakai, Katsuya / Sato, Hiroki / Imamura, Ryu / Matsumoto, Kunio

International journal of molecular sciences

2021 Volume 22, Issue 17

Abstract: NK1, a splicing variant of hepatocyte growth factor (HGF), binds to and activates Met receptor by forming an NK1 dimer and 2:2 complex with Met. Although the structural mechanism underlying Met activation by HGF remains incompletely resolved, it has been ...

Abstract	NK1, a splicing variant of hepatocyte growth factor (HGF), binds to and activates Met receptor by forming an NK1 dimer and 2:2 complex with Met. Although the structural mechanism underlying Met activation by HGF remains incompletely resolved, it has been proposed that the NK1 dimer structure participates in this activation. We investigated the NK1 dimer interface's role in Met activation by HGF. Because N127, V140, and K144 are closely involved in the head-to-tail NK1 dimer formation, mutant NK1 proteins with replacement of these residues by alanine were prepared. In Met tyrosine phosphorylation assays, N127-NK1, V140-NK1, and K144-NK1 showed 8.3%, 23.8%, and 52.2% activity, respectively, compared with wild-type NK1. Although wild-type NK1 promoted cell migration and scattering, N127-NK1, V140-NK1, and K144-NK1 hardly or marginally promoted them, indicating loss of activity of these mutant NK1 proteins to activate Met. In contrast, mutant HGFs (N127-HGF, V140-HGF, and K144-HGF) with the same amino acid replacements as in NK1 induced Met tyrosine phosphorylation and biological responses at levels comparable to those of wild-type HGF. These results indicate that the structural basis responsible for NK1-dependent Met dimer formation and activation differs from, or is at least distinguishable from, the structural basis responsible for HGF-dependent Met activation.
MeSH term(s)	Animals ; Binding Sites ; Cell Line, Tumor ; Dogs ; HEK293 Cells ; Hepatocyte Growth Factor/chemistry ; Hepatocyte Growth Factor/genetics ; Hepatocyte Growth Factor/metabolism ; Humans ; Madin Darby Canine Kidney Cells ; Mutation ; Protein Binding ; Protein Multimerization ; Proto-Oncogene Proteins c-met/chemistry ; Proto-Oncogene Proteins c-met/metabolism ; Signal Transduction
Chemical Substances	Hepatocyte Growth Factor (67256-21-7) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
Language	English
Publishing date	2021-08-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22179240
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Article ; Online: Dimer Interface in Natural Variant NK1 Is Dispensable for HGF-Dependent Met Receptor Activation

Yumiko Tahira / Katsuya Sakai / Hiroki Sato / Ryu Imamura / Kunio Matsumoto

International Journal of Molecular Sciences, Vol 22, Iss 9240, p

2021 Volume 9240

Abstract	NK1, a splicing variant of hepatocyte growth factor (HGF), binds to and activates Met receptor by forming an NK1 dimer and 2:2 complex with Met. Although the structural mechanism underlying Met activation by HGF remains incompletely resolved, it has been proposed that the NK1 dimer structure participates in this activation. We investigated the NK1 dimer interface’s role in Met activation by HGF. Because N127, V140, and K144 are closely involved in the head-to-tail NK1 dimer formation, mutant NK1 proteins with replacement of these residues by alanine were prepared. In Met tyrosine phosphorylation assays, N127-NK1, V140-NK1, and K144-NK1 showed 8.3%, 23.8%, and 52.2% activity, respectively, compared with wild-type NK1. Although wild-type NK1 promoted cell migration and scattering, N127-NK1, V140-NK1, and K144-NK1 hardly or marginally promoted them, indicating loss of activity of these mutant NK1 proteins to activate Met. In contrast, mutant HGFs (N127-HGF, V140-HGF, and K144-HGF) with the same amino acid replacements as in NK1 induced Met tyrosine phosphorylation and biological responses at levels comparable to those of wild-type HGF. These results indicate that the structural basis responsible for NK1-dependent Met dimer formation and activation differs from, or is at least distinguishable from, the structural basis responsible for HGF-dependent Met activation.
Keywords	growth factor ; HGF ; Met ; receptor tyrosine kinase ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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