Scientific Publications

@article{nokeyv,

title = {Analyses of the Cellular Interactions between the Ossification of Collagen-Based Barrier Membranes and the Underlying Bone Defects},

author = {Said Alkildani and Yanru Ren and Luo Liu and Denis Rimashevskiy and Reinhard Schnettler and Milena Radenković and Stevo Najman and Sanja Stojanović and Ole Jung and Mike Barbeck },

url = { https://doi.org/10.3390/ijms24076833},

doi = {10.3390/ijms24076833},

year  = {2023},

date = {2023-04-06},

urldate = {2023-04-06},

journal = {International Journal of Molecular Sciences},

volume = {24},

number = {7},

abstract = {Barrier membranes are an essential tool in guided bone Regeneration (GBR), which have been widely presumed to have a bioactive effect that is beyond their occluding and space maintenance functionalities. A standardized calvaria implantation model was applied for 2, 8, and 16 weeks on Wistar rats to test the interactions between the barrier membrane and the underlying bone defects which were filled with bovine bone substitute materials (BSM). In an effort to understand the barrier membrane’s bioactivity, deeper histochemical analyses, as well as the immunohistochemical detection of macrophage subtypes (M1/M2) and vascular endothelial cells, were conducted and combined with histomorphometric and statistical approaches. The native collagen-based membrane was found to have ossified due to its potentially osteoconductive and osteogenic properties, forming a “bony shield” overlying the bone defects. Histomorphometrical evaluation revealed the resorption of the membranes and their substitution with bone matrix. The numbers of both M1- and M2-macrophages were significantly higher within the membrane compartments compared to the underlying bone defects. Thereby, M2-macrophages significantly dominated the tissue reaction within the membrane compartments. Statistically, a correlation between M2-macropahges and bone regeneration was only found at 2 weeks post implantationem, while the pro-inflammatory limb of the immune response correlated with the two processes at 8 weeks. Altogether, this study elaborates on the increasingly described correlations between barrier membranes and the underlying bone regeneration, which sheds a light on the understanding of the immunomodulatory features of biomaterials.},

keywords = {M8},

pubstate = {published},

tppubtype = {article}

}

@bachelorthesis{nokeyw,

title = {Chronic stress promotes colorectal cancer progression by enhancing glycolysis through β2-AR/CREB1 signal pathway},

author = {Yunfeng Guan and Wang Yao and Hao Yu and Ying Feng and Yiyang Zhao and Xiangyang Zhan and Yan Wang},

url = {https://www.ijbs.com/v19p2006.htm},

doi = {10.7150/ijbs.79583},

year  = {2023},

date = {2023-04-02},

urldate = {2023-04-02},

journal = {International Journal of Biological Sciences},

volume = {19},

issue = {7},

abstract = {Colorectal cancer (CRC) is a common malignancy worldwide, and chronic stress has been considered as

a significant risk factor for CRC. However, the role of chronic stress in CRC progression is unclear. The

present study showed that pre-exposure to chronic stress facilitated CRC tumor growth in mice, and

epinephrine promoted CRC cell proliferation in vitro. Metabolomics analysis revealed that chronic stress

reshaped metabolic pathways to enhance glycolysis. Additional studies have shown that stress enhanced

the expression levels of glycolytic-associated enzymes, including GLUT1, HK2 and PFKP. Mechanistically,

chronic stress activated the β2-AR/PKA/CREB1 pathway, as a result, phosphorylated CREB1

transcriptional induced glycolytic enzymes expression. Furthermore, stress-induced cell proliferation and

tumor growth could be reversed by administration of glycolysis inhibitor 2-deoxyglucose (2-DG) and

β2-AR antagonist ICI118,551, respectively. Altogether, these findings define novel insights into the

stress-induced epinephrine-mediated CRC progression from the point of view of tumor energy

metabolism reprogramming and provide a perspective on targeting glycolysis as a potential approach in

stress-associated CRC treatment.},

keywords = {M8},

pubstate = {published},

tppubtype = {bachelorthesis}

}

@phdthesis{nokey,

title = {Nutritional programming of white adipose tissue growth and metabolism in adulthood},

author = {Kristina Then},

url = {https://mediatum.ub.tum.de/doc/1703263/document.pdf},

year  = {2023},

date = {2023-03-27},

abstract = {Diet-induced obesity is a rapidly increasing health concern in modern society and has been associated with the development of numerous health issues, including cardiovascular disease and type 2 diabetes. Despite multiple interventions designed to promote body mass loss, affected patients often experience limited success in maintaining long-term outcomes. One underlying mechanism that contributes to this phenomenon is commonly known as the ‘yo-yo effect’ and remains poorly understood. To investigate the underlying role of adipogenic potential, we conducted a study on male C57BL/6N mice, examining cell fate decisions, terminal differentiation, and proliferation of adipocyte progenitor cells. Mice were initially fed a high-fat diet until they reached a body mass of at least 40 g, followed by a one-week control diet or caloric-restricted, pair-fed high-fat diet. In addition, we assessed mitochondrial function in white

adipocytes during body mass loss and subsequent regain by feeding the male C57BL/6N mice a high-fat diet for 24 weeks, followed by an eight-week control diet-induced obesity remission and a high-fat diet refeeding for 12 weeks. Short-term high-fat diet recovery had a significant impact on the fate of stromal-vascular fraction cells, as determined by cell culture and flow cytometry experiments. Specifically, we focused on three distinct white adipose tissue 

 ubpopulations, characterized by the expression of CD55, VAP1, or CD142, which contribute to diet- and fat depot-specific changes in adipogenic potential. Flow cytometry and immunofluorescence imaging revealed a proliferation stop in epididymal white adipose tissue in its plateau phase at 40 g body mass. Following full controldiet-induced obesity remission, mitochondrial capacity and content remained reduced in epididymal adipocytes, as determined by high-resolution  respirometry and citrate synthase activity. In contrast, inguinal adipocyte mitochondria retained their function. Protein expression analysis revealed only minor effects in the expression levels of proteins that belong mainly to adipocyte differentiation, lipid metabolism, and inflammation. High-fat diet refeeding doubled

body mass and fat mass gain within the first weeks of the diet change in comparison to mice receiving a high-fat diet for the first time. Our results emphasize the importance of fat depot specificity for metabolic obesity consequences and associated treatments. We identified CD142+ adipogenesis-regulatory cells as a reversible silencer of differentiation capacity of adipocyte progenitor cells. Additionally, we found that epididymal adipocyte mitochondria exhibit a persisting restriction due to high-fat diet feeding, while inguinal adipocyte mitochondria are more resilient. These alterations are concomitant and likely implicated in the etiology of a ‘yo-yo effect’, characterized by enhanced body mass gain upon re-exposure to a high-fat diet.},

keywords = {M8, ViewPoint},

pubstate = {published},

tppubtype = {phdthesis}

}

@article{nokey,

title = {WWC2 expression in the testis: Implications for spermatogenesis and male fertility},

author = {Höffken and V. and Di Persio and S. and Laurentino and S. and Wyrwoll and M. J. and Terwort and N. and Hermann and A. and Röpke and A. and Oud and M. S. and Wistuba and J. and Kliesch and S. and Pavenstädt and H. J. and Tüttelmann and F. and Neuhaus and N. and & Kremerskothen and J.},

url = {https://faseb.onlinelibrary.wiley.com/doi/pdfdirect/10.1096/fj.202200960R},

doi = {10.1096/fj.202200960R},

year  = {2023},

date = {2023-03-27},

journal = {FASEB Journal},

volume = {37},

issue = {5},

abstract = {The family of WWC proteins is known to regulate cell proliferation and organ growth control via the Hippo signaling pathway. As WWC proteins share a similar domain structure and a common set of interacting proteins, they are supposed to fulfill compensatory functions in cells and tissues. While all three WWC family

members WWC1, WWC2, and WWC3 are found co-expressed in most human organs including lung, brain, kidney, and liver, in the testis only WWC2 displays

a relatively high expression. In this study, we investigated the testicular WWC2 expression in spermatogenesis and male fertility. We show that the Wwc2 mRNA

expression level in mouse testes is increased during development in parallel with germ cell proliferation and differentiation. The cellular expression of each individual WWC family member was evaluated in published single-cell mRNA datasets of murine and human testes demonstrating a high WWC2 expression

predominantly in early spermatocytes. In line with this, immunohistochemistry revealed cytosolic WWC2 protein expression in primary spermatocytes from human testes displaying full spermatogenesis. In accordance with these findings, markedly lower WWC2 expression levels were detected in testicular tissues from

mice and men lacking germ cells. Finally, analysis of whole-exome sequencing data of male patients affected by infertility and unexplained severe spermatogenic failure revealed several heterozygous, rare WWC2 gene variants with a proposed damaging function and putative impact on WWC2 protein structure. Taken together, our findings provide novel insights into the testicular expression of WWC2 and show its cell-specific expression in spermatocytes. As rare WWC2

variants were identified in the background of disturbed spermatogenesis, WWC2 may be a novel candidate gene for male infertility},

keywords = {Fritz, M8},

pubstate = {published},

tppubtype = {article}

}

@article{nokeyu,

title = {Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies},

author = {Qingyu Xu and Alexander Streuer and Johann-Christoph Jann and Eva Altrock and Nanni Schmitt and Johanna Flach and Carla Sens-Albert and Felicitas Rapp and Julia Wolf and Verena Nowak and Nadine Weimer and Julia Obländer and Iris Palme and Mariia Kuzina and Ahmed Jawhar and Ali Darwich and Cleo-Aron Weis and Alexander Marx and Patrick Wuchter and Victor Costina and Evelyn Jäger and Elena Sperk and Michael Neumaier and Alice Fabarius and Daniel Nowak},

url = {https://doi.org/10.1038/s41467-023-37175-8},

doi = {10.1038/s41467-023-37175-8},

year  = {2023},

date = {2023-03-17},

urldate = {2023-03-17},

journal = {Nature Communications},

number = {1497},

abstract = {Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.},

keywords = {M8},

pubstate = {published},

tppubtype = {article}

}

@article{nokeyt,

title = {Impact of Angiopoietin-2 on Kidney Diseases},

author = {Mei Li and Zoran Popovic and Chang Chu and Christoph Reichetzeder and Wolfgang Pommer and Bernhard K. Krämer and Berthold Hocher},

url = {https://doi.org/10.1159/000529774},

doi = {10.1159/000529774},

year  = {2023},

date = {2023-03-14},

urldate = {2023-03-14},

journal = {Karger},

volume = {9},

issue = {3},

pages = {14},

abstract = {Background: Angiopoietins (Ang) are essential angiogenic factors involved in angiogenesis, vascular maturation, and inflammation. The most studied angiopoietins, angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), behave antagonistically to each other in vivo to sustain vascular endothelium homeostasis. While Ang-1 typically acts as the endothelium-protective mediator, its context-dependent antagonist Ang-2 can promote endothelium permeability and vascular destabilization, hence contributing to a poor outcome in vascular diseases via endothelial injury, vascular dysfunction, and microinflammation. The pathogenesis of kidney diseases is associated with endothelial dysfunction and chronic inflammation in renal diseases. Summary: Several preclinical studies report overexpression of Ang-2 in renal tissues of certain kidney disease models; additionally, clinical studies show increased levels of circulating Ang-2 in the course of chronic kidney disease, implying that Ang-2 may serve as a useful biomarker in these patients. However, the exact mechanisms of Ang-2 action in renal diseases remain unclear. Key Messages: We summarized the recent findings on Ang-2 in kidney diseases, including preclinical studies and clinical studies, aiming to provide a systematic understanding of the role of Ang-2 in these diseases.},

keywords = {Fritz, M8, ViewPoint},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Loss of αβ but not γδ T cells in chickens causes a severe phenotype},

author = {von Heyl and T. and Klinger and R. and Aumann and D. and Zenner and C. and Alhussien and M. and Schlickenrieder and A. and Lengyel and K. and Vikkula and H.-K. and Mittermair and T. and Sid and H. and & Schusser and B.},

url = {https://www.biorxiv.org/content/10.1101/2023.03.10.531286v1.abstract},

doi = {10.1101/2023.03.10.531286},

year  = {2023},

date = {2023-03-12},

journal = {European Journal of Immunology},

volume = {53},

issue = {12},

abstract = {The availability of genetically modified mice has facilitated the study of mammalian T cells. No model has yet been developed to study these cells in chicken, an important livestock species with a high availability of γδ T cells. To investigate the role of γδ and αβ T cell populations in birds, we generated chickens lacking these T cell populations. This was achieved by genomic deletion of the constant region of the T cell receptor γ or αβ chain, leading to a complete loss of either γδ or αβ T cells. Our results show that a deletion of αβ T cells but not γδ T cells resulted in a severe phenotype in knockout chickens. The αβ T cell knockout chickens exhibited granulomas associated with inflammation of the spleen and the proventriculus. Immunophenotyping of αβ T cell knockout chickens revealed a significant increase in monocytes and the absence of CD4+ T cells and FoxP3+ regulatory T cells compared to wild type chickens. In addition, we observed a significant decrease in immunoglobulins, B lymphocytes, and changes in the bursa morphology. Our data reveal the consequences of T cell knockouts in chickens and provide new insights into their function in vertebrates.



Significance statement The lack of genetically modified chickens has severely limited research in avian immunology compared to other animal models. Here, we report the generation of two T cell knockout chicken lines that will contribute significantly to the understanding of T cell biology as a very important research model as well as an important livestock species. The generated animals reveal the function of different T cell populations in chickens and will help to better understand the role of these cells during the interaction with various pathogens in birds.



Competing Interest Statement

The authors have declared no competing interest.},

keywords = {M8},

pubstate = {published},

tppubtype = {article}

}

@article{nokeys,

title = {MiR-199a-5p-Regulated SMARCA4 Promotes Oral Squamous Cell Carcinoma Tumorigenesis},

author = {Mingyan Xu and Junling Zhang and Xuemei Lu and Fan Liu and Songlin Shi and Xiaoling Deng},

url = {https://doi.org/10.3390/ijms24054756},

doi = {10.3390/ijms24054756},

year  = {2023},

date = {2023-03-01},

urldate = {2023-03-01},

journal = {International Journal of Molecular Sciences},

volume = {24},

issue = {5},

abstract = {SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1), an ATPase subunit of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, plays an important regulatory role in many cytogenetic and cytological processes during cancer development. However, the biological function and mechanism of SMARCA4 in oral squamous cell carcinoma (OSCC) remain unclear. The present study aimed to investigate the role of SMARCA4 in OSCC and its potential mechanism. Using a tissue microarray, SMARCA4 expression was found to be highly upregulated in OSCC tissues. In addition, SMARCA4 upregulate expression led to increased migration and invasion of OSCC cells in vitro, as well as tumor growth and invasion in vivo. These events were associated with the promotion of epithelial–mesenchymal transition (EMT). Bioinformatic analysis and luciferase reporter assay confirmed that SMARCA4 is a target gene of microRNA miR-199a-5p. Further mechanistic studies showed that the miR-199a-5p regulated SMARCA4 can promote the invasion and metastasis of tumor cells through EMT. These findings indicate that the miR-199a-5p- SMARCA4 axis plays a role in tumorigenesis by promoting OSCC cell invasion and metastasis through EMT regulation. Our findings provide insights into the role of SMARCA4 in OSCC and the mechanism involved, which may have important implications for therapeutic purposes.},

keywords = {M8},

pubstate = {published},

tppubtype = {article}

}

@bachelorthesis{nokeypb,

title = {PtrVCS2 Regulates Drought Resistance by Changing Vessel Morphology and Stomatal Closure in Populus trichocarpa},

author = {Meng Li and Hao Dong and Jiyuan Li and Xiufang Dai and Jiaojiao Lin and Shuang Li and Chenguang Zhou and Vincent L. Chiang and Wei Li},

url = {https://www.mdpi.com/1422-0067/24/5/4458},

doi = {10.3390/ijms24054458},

year  = {2023},

date = {2023-02-24},

urldate = {2023-02-24},

journal = {Molecular Sciences},

volume = {24},

issue = {5},

abstract = {Drought has severe effects on plant growth, forest productivity, and survival throughout the world. Understanding the molecular regulation of drought resistance in forest trees can enable effective strategic engineering of novel drought-resistant genotypes of tree species. In this study, we identified a gene, PtrVCS2, encoding a zinc finger (ZF) protein of the ZF-homeodomain transcription factor in Populus trichocarpa (Black Cottonwood) Torr. & A. Gray. ex Hook. Overexpression of PtrVCS2 (OE-PtrVCS2) in P. trichocarpa resulted in reduced growth, a higher proportion of smaller stem vessels, and strong drought-resistance phenotypes. Stomatal movement experiments revealed that the OE-PtrVCS2 transgenics showed lower stomata apertures than wild-type plants under drought conditions. RNA-seq analysis of the OE-PtrVCS2 transgenics showed that PtrVCS2 regulates the expression of multiple genes involved in regulation of stomatal opening and closing, particularly the PtrSULTR3;1-1 gene, and several genes related to cell wall biosynthesis, such as PtrFLA11-12 and PtrPR3-3. Moreover, we found that the water use efficiency of the OE-PtrVCS2 transgenic plants was consistently higher than that of wild type plants when subjected to chronic drought stress. Taken together, our results suggest that PtrVCS2 plays a positive role in improving drought adaptability and resistance in P. trichocarpa.},

keywords = {M8},

pubstate = {published},

tppubtype = {bachelorthesis}

}

@article{nokeypc,

title = {Expression of pH-Sensitive GPCRs in Peritoneal Carcinomatosis of Colorectal Cancer—First Results},

author = {Philipp von Breitenbuch and Bernadett Kurz and Susanne Wallner and Florian Zeman and Christoph Brochhausen 4 and Hans-Jürgen Schlitt and Stephan Schreml},

url = {https://www.mdpi.com/2077-0383/12/5/1803},

doi = {10.3390/jcm12051803},

year  = {2023},

date = {2023-02-23},

urldate = {2023-02-23},

journal = {Journal of Clinical Medicine},

volume = {12},

issue = {5},

abstract = {Solid tumors have an altered metabolism with a so-called inside-out pH gradient (decreased pHe < increased pHi). This also signals back to tumor cells via proton-sensitive ion channels or G protein-coupled receptors (pH-GPCRs) to alter migration and proliferation. Nothing, however, is known about the expression of pH-GPCRs in the rare form of peritoneal carcinomatosis. Paraffin-embedded tissue samples of a series of 10 patients with peritoneal carcinomatosis of colorectal (including appendix) origin were used for immunohistochemistry to study the expression of GPR4, GPR65, GPR68, GPR132, and GPR151. GPR4 was just expressed weakly in 30% of samples and expression was significantly reduced as compared to GPR56, GPR132, and GPR151. Furthermore, GPR68 was only expressed in 60% of tumors and showed significantly reduced expression as compared to GPR65 and GPR151. This is the first study on pH-GPCRs in peritoneal carcinomatosis, which shows lower expression of GPR4 and GPR68 as compared to other pH-GPCRs in this type of cancer. It may give rise to future therapies targeting either the TME or these GPCRs directly.},

keywords = {M8, ViewPoint},

pubstate = {published},

tppubtype = {article}

}