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Ota T, Ishikawa T, Sakakida T, Endo Y, Matsumura S, Yoshida J, Hirai Y, Mizushima K, Oka K, Doi T, Okayama T, Inoue K, Kamada K, Uchiyama K, Takagi T, Konishi H, Naito Y, Itoh Y. Treatment with broad-spectrum antibiotics upregulates Sglt1 and induces small intestinal villous hyperplasia in mice. J Clin Biochem Nutr 2022; 70:21-27. [PMID: 35068677 PMCID: PMC8764108 DOI: 10.3164/jcbn.21-42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/02/2021] [Indexed: 11/22/2022] Open
Abstract
Although extensive evidence indicates that the gut microbiota plays a crucial role in regulating glucose homeostasis, the exact regulatory mechanism remains unclear. This study aimed to investigate the effect of broad-spectrum antibiotics on the expression of glucose transporters, histomorphology of the small intestine, and glucose metabolism in mice. C57BL/6 mice were administered drinking water with or without a broad-spectrum antibiotic combination for 4 weeks. Thereafter, an oral glucose tolerance test was performed. Body weight, small intestine histopathology, mRNA levels of glucose transporters (SGLT1 and GLUT2) and intestinal transcription factors (CDX1 and CDX2) were evaluated. SGLT1 and CDX1 were upregulated in the small intestine upon antibiotic administration compared with that in the control group. The height and surface area of the jejunal villi were significantly higher upon antibiotic administration than in the control group. Fasting glucose levels were significantly higher upon antibiotic administration than in the control group. The present results indicate that treatment with broad-spectrum antibiotics upregulates SGLT1 and CDX1 and induces hyperplasia in the small intestine, thus increasing fasting blood glucose levels. Our results further the current understanding of the effects of broad-spectrum antibiotics on the gut microbiota and glucose homeostasis that may have future clinical implications.
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Affiliation(s)
- Takayuki Ota
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Tomoki Sakakida
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Yuki Endo
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Shinya Matsumura
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Juichirou Yoshida
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Yasuko Hirai
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Katsura Mizushima
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Kaname Oka
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Toshifumi Doi
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Tetsuya Okayama
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Ken Inoue
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Kazuhiro Kamada
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Hideyuki Konishi
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Yuji Naito
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine
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Areco VA, Kohan R, Talamoni G, Tolosa de Talamoni NG, Peralta López ME. Intestinal Ca 2+ absorption revisited: A molecular and clinical approach. World J Gastroenterol 2020; 26:3344-3364. [PMID: 32655262 PMCID: PMC7327788 DOI: 10.3748/wjg.v26.i24.3344] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/11/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Ca2+ has an important role in the maintenance of the skeleton and is involved in the main physiological processes. Its homeostasis is controlled by the intestine, kidney, bone and parathyroid glands. The intestinal Ca2+ absorption occurs mainly via the paracellular and the transcellular pathways. The proteins involved in both ways are regulated by calcitriol and other hormones as well as dietary factors. Fibroblast growth factor 23 (FGF-23) is a strong antagonist of vitamin D action. Part of the intestinal Ca2+ movement seems to be vitamin D independent. Intestinal Ca2+ absorption changes according to different physiological conditions. It is promoted under high Ca2+ demands such as growth, pregnancy, lactation, dietary Ca2+ deficiency and high physical activity. In contrast, the intestinal Ca2+ transport decreases with aging. Oxidative stress inhibits the intestinal Ca2+ absorption whereas the antioxidants counteract the effects of prooxidants leading to the normalization of this physiological process. Several pathologies such as celiac disease, inflammatory bowel diseases, Turner syndrome and others occur with inhibition of intestinal Ca2+ absorption, some hypercalciurias show Ca2+ hyperabsorption, most of these alterations are related to the vitamin D endocrine system. Further research work should be accomplished in order not only to know more molecular details but also to detect possible therapeutic targets to ameliorate or avoid the consequences of altered intestinal Ca2+ absorption.
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Affiliation(s)
- Vanessa A Areco
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - Romina Kohan
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - Germán Talamoni
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - Nori G Tolosa de Talamoni
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - María E Peralta López
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
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Lang F, Guelinckx I, Lemetais G, Melander O. Two Liters a Day Keep the Doctor Away? Considerations on the Pathophysiology of Suboptimal Fluid Intake in the Common Population. Kidney Blood Press Res 2017; 42:483-494. [PMID: 28787716 DOI: 10.1159/000479640] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 04/19/2017] [Indexed: 11/19/2022] Open
Abstract
Suboptimal fluid intake may require enhanced release of antidiuretic hormone (ADH) or vasopressin for the maintenance of adequate hydration. Enhanced copeptin levels (reflecting enhanced vasopressin levels) in 25% of the common population are associated with enhanced risk of metabolic syndrome with abdominal obesity, type 2 diabetes, hypertension, coronary artery disease, heart failure, vascular dementia, cognitive impairment, microalbuminuria, chronic kidney disease, inflammatory bowel disease, cancer, and premature mortality. Vasopressin stimulates the release of glucocorticoids which in turn up-regulate the serum- and glucocorticoid-inducible kinase 1 (SGK1). Moreover, dehydration upregulates the transcription factor NFAT5, which in turn stimulates SGK1 expression. SGK1 is activated by insulin, growth factors and oxidative stress via phosphatidylinositide-3-kinase, 3-phosphoinositide-dependent kinase PDK1 and mTOR. SGK1 is a powerful stimulator of Na+/K+-ATPase, carriers (e.g. the Na+,K+,2Cl- cotransporter NKCC, the NaCl cotransporter NCC, the Na+/H+ exchanger NHE3, and the Na+ coupled glucose transporter SGLT1), and ion channels (e.g. the epithelial Na+ channel ENaC, the Ca2+ release activated Ca2+ channel Orai1 with its stimulator STIM1, and diverse K+ channels). SGK1 further participates in the regulation of the transcription factors nuclear factor kappa-B NFκB, p53, cAMP responsive element binding protein (CREB), activator protein-1, and forkhead transcription factor FKHR-L1 (FOXO3a). Enhanced SGK1 activity fosters the development of hypertension, obesity, diabetes, thrombosis, stroke, inflammation including inflammatory bowel disease and autoimmune disease, cardiac fibrosis, proteinuria, renal failure as well as tumor growth. The present brief review makes the case that suboptimal fluid intake in the common population may enhance vasopressin and glucocorticoid levels thus up-regulating SGK1 expression and favouring the development of SGK1 related pathologies.
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Affiliation(s)
- Florian Lang
- Department of Physiology I, University of Tuebingen, Tuebingen, Germany
| | | | | | - Olle Melander
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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Khachab M, Kanaan A, Awad D, Deeba E, Osman S, Nassar CF. Colectomy induces an aldosterone-mediated increase in jejunal glucose uptake in rats. Life Sci 2017; 174:43-49. [PMID: 28254387 DOI: 10.1016/j.lfs.2017.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/15/2017] [Accepted: 02/24/2017] [Indexed: 11/25/2022]
Abstract
AIMS The main function of the colon is water and electrolyte absorption. Total colectomy eliminates this colonic function and may alter the absorptive capacity of the small intestine for nutrients. This study examines the effect of total colectomy on jejunal glucose absorption and investigates the potential role of aldosterone in mediating the alterations in glucose uptake post-colectomy using the aldosterone antagonist spironolactone. MAIN METHODS Total colectomy with ileo-rectal anastomosis was performed on anesthetized rats. Sham rats were identically handled without colon resection. Two days post-surgery, groups of colectomized rats were injected with either a daily subcutaneous dose of spironolactone or sesame oil for 12days. Body weight changes and food and water intake were measured in all experimental groups. Glucose absorption was measured by in-vivo single pass perfusion in the rat jejunum of control, sham, colectomized, colectomized with spironolactone, and colectomized with sesame oil treatment. Na/K ATPase, SGK1, SGLT1 and GLUT2 expressions were determined in jejunal mucosa in control, colectomized and colectomized/spironolactone injected rats by Western blot analysis. Histological assessment was performed on jejunal sections in control and colectomized groups. KEY FINDINGS Glucose absorption significantly increased in colectomized rats with an observed increase in Na/K ATPase and SGK1 expression. No significant expression change in SGLT1 and GLUT2 was detected in the jejunum in colectomized rats. Spironolactone, however, significantly decreased the glucose uptake post-colectomy and normalized Na/K ATPase and SGK1 expression. SIGNIFICANCE Our results suggest that jejunal glucose uptake increases post-colectomy as a possible consequence of an aldosterone-mediated function.
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Affiliation(s)
- Maha Khachab
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, El-Kurah, Lebanon.
| | - Amjad Kanaan
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, El-Kurah, Lebanon
| | - Dania Awad
- Faculty of Health Sciences, Lebanese University, Tripoli, Lebanon
| | - Elie Deeba
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, El-Kurah, Lebanon
| | - Samira Osman
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, El-Kurah, Lebanon
| | - Camille F Nassar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, El-Kurah, Lebanon
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Li Z, Sun F, Zhang Y, Chen H, He N, Chen H, Song P, Wang Y, Yan S, Zheng S. Tacrolimus Induces Insulin Resistance and Increases the Glucose Absorption in the Jejunum: A Potential Mechanism of the Diabetogenic Effects. PLoS One 2015; 10:e0143405. [PMID: 26599323 PMCID: PMC4657894 DOI: 10.1371/journal.pone.0143405] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 10/07/2015] [Indexed: 12/16/2022] Open
Abstract
Background The use of the immunosuppressive drug tacrolimus (TAC) is related to new onset diabetes after transplantation. Herein, we examined the effect of intraperitoneal administered TAC on intestinal glucose absorption in mice. Methods Animals received low, medium, or high dose TAC (0.5, 1, or 5 mg/kg/d, respectively), or 0.9% saline solution (control) for 14 days. Oral glucose tolerance test (OGTT), insulin concentration test, and serum TAC concentration measurements was performed after 14 days of TAC exposure. Plasma insulin was assessed and electrogenic glucose absorption were measured by the sodium-dependent increase of the short-circuit current. Expression levels of the glucose transporters sodium glucose co-transporter (SGLT) 1, glucose transporter (GLUT) 2, and GLUT5 were also determined. Results Oral glucose absorption assessed by OGTT was significantly enhanced in the low, medium, and high groups. Serum insulin was elevated in the medium and high group compared with the control. Moreover, glucose-induced Isc was significantly higher in TAC administrated groups, which indicates that SGLT1 activity increased. Transcription levels and protein abundance of SGLT1 in the experimental groups also increased compared with the control. Conclusions TAC induced insulin resistance and strengthened intestinal glucose absorption by increasing the activity and expression of the glucose transporter, SGLT1.
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Affiliation(s)
- Zhiwei Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fei Sun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yaohui Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hao Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ningning He
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hui Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Penghong Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yan Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Yan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- * E-mail:
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Abstract
For humans and rodents, duodenum is a very important site of calcium absorption since it is exposed to ionized calcium released from dietary complexes by gastric acid. Calcium traverses the duodenal epithelium via both transcellular and paracellular pathways in a vitamin D-dependent manner. After binding to the nuclear vitamin D receptor, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] upregulates the expression of several calcium transporter genes, e.g., TRPV5/6, calbindin-D9k, plasma membrane Ca(2+)-ATPase1b, and NCX1, thereby enhancing the transcellular calcium transport. This action has been reported to be under the regulation of parathyroid-kidney-intestinal and bone-kidney-intestinal axes, in which the plasma calcium and fibroblast growth factor-23 act as negative feedback regulators, respectively. 1,25(OH)2D3 also modulates the expression of tight junction-related genes and convective water flow, presumably to increase the paracellular calcium permeability and solvent drag-induced calcium transport. However, vitamin D-independent calcium absorption does exist and plays an important role in calcium homeostasis under certain conditions, particularly in neonatal period, pregnancy, and lactation as well as in naturally vitamin D-impoverished subterranean mammals.
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Affiliation(s)
- Kannikar Wongdee
- Office of Academic Management, Faculty of Allied Health Sciences, Burapha University, Chonburi, Thailand; Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Narattaphol Charoenphandhu
- Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
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Lang F, Stournaras C, Alesutan I. Regulation of transport across cell membranes by the serum- and glucocorticoid-inducible kinase SGK1. Mol Membr Biol 2014; 31:29-36. [PMID: 24417516 DOI: 10.3109/09687688.2013.874598] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The serum- and glucocorticoid-inducible kinase 1 (SGK1) is genomically upregulated by cell stress including energy depletion and hyperosmotic shock as well as a variety of hormones including glucocorticoids, mineralocorticoids and TGFβ. SGK1 is activated by insulin, growth factors and oxidative stress via phosphatidylinositide-3-kinase, 3-phosphoinositide-dependent kinase PDK1 and mTOR. SGK1 is a powerful stimulator of Na(+)/K(+)-ATPase, carriers (e.g., NCC, NKCC, NHE1, NHE3, SGLT1, several amino acid transporters) and ion channels (e.g., ENaC, SCN5A, TRPV4-6, ORAI1/STIM1, ROMK, KCNE1/KCNQ1, GluR6, CFTR). Mechanisms employed by SGK1 in transport regulation include direct phosphorylation of target transport proteins, phosphorylation and thus activation of other transport regulating kinases, stabilization of membrane proteins by phosphorylation and thus inactivation of the ubiquitin ligase NEDD4-2, as well as stimulation of transport protein expression by upregulation transcription factors (e.g., nuclear factor kappa-B [NFκB]) and by fostering of protein translation. SGK1 sensitivity of pump, carrier and channel activities participate in the regulation of epithelial transport, cardiac and neuronal excitability, degranulation, platelet function, migration, cell proliferation and apoptosis. SGK1-sensitive functions do not require the presence of SGK1 but are markedly upregulated by SGK1. Accordingly, the phenotype of SGK1 knockout mice is mild. The mice are, however, less sensitive to excessive activation of transport by glucocorticoids, mineralocorticoids, insulin and inflammation. Moreover, excessive SGK1 activity contributes to the pathophysiology of hypertension, obesity, diabetes, thrombosis, stroke, inflammation, autoimmune disease, fibrosis and tumor growth.
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Affiliation(s)
- Florian Lang
- Department of Physiology, University of Tübingen , Germany and
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Reduction of Intestinal Electrogenic Glucose Absorption After Duodenojejunal Bypass in a Mouse Model. Obes Surg 2013; 23:1361-9. [DOI: 10.1007/s11695-013-0954-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Lang F, Voelkl J. Therapeutic potential of serum and glucocorticoid inducible kinase inhibition. Expert Opin Investig Drugs 2013; 22:701-14. [PMID: 23506284 DOI: 10.1517/13543784.2013.778971] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Expression of serum-and-glucocorticoid-inducible kinase-1 (SGK1) is low in most cells, but dramatically increases under certain pathophysiological conditions, such as glucocorticoid or mineralocorticoid excess, inflammation with TGFβ release, hyperglycemia, cell shrinkage and ischemia. SGK1 is activated by insulin and growth factors via phosphatidylinositide-3-kinase, 3-phosphoinositide-dependent kinase and mammalian target of rapamycin. SGK1 sensitive functions include activation of ion channels (including epithelial Na(+) channel ENaC, voltage gated Na(+) channel SCN5A transient receptor potential channels TRPV4 - 6, Ca(2+) release activated Ca(2+) channel Orai1/STIM1, renal outer medullary K(+) channel ROMK, voltage gated K(+) channels KCNE1/KCNQ1, kainate receptor GluR6, cystic fibrosis transmembrane regulator CFTR), carriers (including Na(+),Cl(-) symport NCC, Na(+),K(+),2Cl(-) symport NKCC, Na(+)/H(+) exchangers NHE1 and NHE3, Na(+), glucose symport SGLT1, several amino acid transporters), and Na(+)/K(+)-ATPase. SGK1 regulates several enzymes (e.g., glycogen synthase kinase-3, ubiquitin-ligase Nedd4-2) and transcription factors (e.g., forkhead transcription factor 3a, β-catenin, nuclear factor kappa B). AREAS COVERED The phenotype of SGK1 knockout mice is mild and SGK1 is apparently dispensible for basic functions. Excessive SGK1 expression and activity, however, contributes to the pathophysiology of several disorders, including hypertension, obesity, diabetes, thrombosis, stroke, fibrosing disease, infertility and tumor growth. A SGK1 gene variant (prevalence ∼ 3 - 5% in Caucasians and ∼ 10% in Africans) is associated with hypertension, stroke, obesity and type 2 diabetes. SGK1 inhibitors have been developed and shown to reduce blood pressure of hyperinsulinemic mice and to counteract tumor cell survival. EXPERT OPINION Targeting SGK1 may be a therapeutic option in several clinical conditions, including metabolic syndrome and tumor growth.
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Affiliation(s)
- Florian Lang
- University of Tuebingen, Department of Physiology, Tuebingen, Germany.
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