@article{IUedaWoersdoerferetal.2020,
  author    = {I, Takashi and Ueda, Yuichiro and W{\"o}rsd{\"o}rfer, Philipp and Sumita, Yoshinori and Asahina, Izumi and Erg{\"u}n, S{\"u}leyman},
  title     = {Resident CD34-positive cells contribute to peri-endothelial cells and vascular morphogenesis in salivary gland after irradiation},
  series = {Journal of Neural Transmission},
  volume    = {127},
  journal   = {Journal of Neural Transmission},
  issn      = {0300-9564},
  doi       = {10.1007/s00702-020-02256-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235613},
  pages     = {1467-1479},
  year      = {2020},
  abstract  = {Salivary gland (SG) hypofunction is a common post-radiotherapy complication. Besides the parenchymal damage after irradiation (IR), there are also effects on mesenchymal stem cells (MSCs) which were shown to contribute to regeneration and repair of damaged tissues by differentiating into stromal cell types or releasing vesicles and soluble factors supporting the healing processes. However, there are no adequate reports about their roles during SG damage and regeneration so far. Using an irradiated SG mouse model, we performed certain immunostainings on tissue sections of submandibular glands at different time points after IR. Immunostaining for CD31 revealed that already one day after IR, vascular impairment was induced at the level of capillaries. In addition, the expression of CD44—a marker of acinar cells—diminished gradually after IR and, by 20 weeks, almost disappeared. In contrast, the number of CD34-positive cells significantly increased 4 weeks after IR and some of the CD34-positive cells were found to reside within the adventitia of arteries and veins. Laser confocal microscopic analyses revealed an accumulation of CD34-positive cells within the area of damaged capillaries where they were in close contact to the CD31-positive endothelial cells. At 4 weeks after IR, a fraction of the CD34-positive cells underwent differentiation into α-SMA-positive cells, which suggests that they may contribute to regeneration of smooth muscle cells and/or pericytes covering the small vessels from the outside. In conclusion, SG-resident CD34-positive cells represent a population of progenitors that could contribute to new vessel formation and/or remodeling of the pre-existing vessels after IR and thus, might be an important player during SG tissue healing.},
  language  = {en}
}
@article{WoersdoerferIAsahinaetal.2020,
  author    = {W{\"o}rsd{\"o}rfer, Philipp and I, Takashi and Asahina, Izumi and Sumita, Yoshinori and Erg{\"u}n, S{\"u}leyman},
  title     = {Do not keep it simple: recent advances in the generation of complex organoids},
  series = {Journal of Neural Transmission},
  volume    = {127},
  journal   = {Journal of Neural Transmission},
  issn      = {0300-9564},
  doi       = {10.1007/s00702-020-02198-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235628},
  pages     = {1569-1577},
  year      = {2020},
  abstract  = {3D cell culture models which closely resemble real human tissues are of high interest for disease modelling, drug screening as well as a deeper understanding of human developmental biology. Such structures are termed organoids. Within the last years, several human organoid models were described. These are usually stem cell derived, arise by self-organization, mimic mechanisms of normal tissue development, show typical organ morphogenesis and recapitulate at least some organ specific functions. Many tissues have been reproduced in vitro such as gut, liver, lung, kidney and brain. The resulting entities can be either derived from an adult stem cell population, or generated from pluripotent stem cells using a specific differentiation protocol. However, many organoid models only recapitulate the organs parenchyma but are devoid of stromal components such as blood vessels, connective tissue and inflammatory cells. Recent studies show that the incorporation of endothelial and mesenchymal cells into organoids improved their maturation and might be required to create fully functional micro-tissues, which will allow deeper insights into human embryogenesis as well as disease development and progression. In this review article, we will summarize and discuss recent works trying to incorporate stromal components into organoids, with a special focus on neural organoid models.},
  language  = {en}
}
@article{WoersdoerferErguen2023,
  author    = {W{\"o}rsd{\"o}rfer, Philipp and Erg{\"u}n, S{\"u}leyman},
  title     = {"Organoids": insights from the first issues},
  series = {Organoids},
  volume    = {2},
  journal   = {Organoids},
  number    = {2},
  issn      = {2674-1172},
  doi       = {10.3390/organoids2020006},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313694},
  pages     = {79 -- 81},
  year      = {2023},
  abstract  = {No abstract available},
  language  = {en}
}
@article{GruschwitzHartungKleefeldtetal.2023,
  author    = {Gruschwitz, Philipp and Hartung, Viktor and Kleefeldt, Florian and Erg{\"u}n, S{\"u}leyman and Lichthardt, Sven and Huflage, Henner and Hendel, Robin and Kunz, Andreas Steven and Pannenbecker, Pauline and Kuhl, Philipp Josef and Augustin, Anne Marie and Bley, Thorsten Alexander and Petritsch, Bernhard and Grunz, Jan-Peter},
  title     = {Standardized assessment of vascular reconstruction kernels in photon-counting CT angiographies of the leg using a continuous extracorporeal perfusion model},
  series = {Scientific Reports},
  volume    = {13},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-023-39063-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357912},
  year      = {2023},
  abstract  = {This study evaluated the influence of different vascular reconstruction kernels on the image quality of CT angiographies of the lower extremity runoff using a 1st-generation photon-counting-detector CT (PCD-CT) compared with dose-matched examinations on a 3rd-generation energy-integrating-detector CT (EID-CT). Inducing continuous extracorporeal perfusion in a human cadaveric model, we performed CT angiographies of eight upper leg arterial runoffs with radiation dose-equivalent 120 kVp acquisition protocols (CTDIvol 5 mGy). Reconstructions were executed with different vascular kernels, matching the individual modulation transfer functions between scanners. Signal-to-noise-ratios (SNR) and contrast-to-noise-ratios (CNR) were computed to assess objective image quality. Six radiologists evaluated image quality subjectively using a forced-choice pairwise comparison tool. Interrater agreement was determined by calculating Kendall's concordance coefficient (W). The intraluminal attenuation of PCD-CT images was significantly higher than of EID-CT (414.7 ± 27.3 HU vs. 329.3 ± 24.5 HU; p < 0.001). Using comparable kernels, image noise with PCD-CT was significantly lower than with EID-CT (p ≤ 0.044). Correspondingly, SNR and CNR were approximately twofold higher for PCD-CT (p < 0.001). Increasing the spatial frequency for PCD-CT reconstructions by one level resulted in similar metrics compared to EID-CT (CNRfat; EID-CT Bv49: 21.7 ± 3.7 versus PCD-CT Bv60: 21.4 ± 3.5). Overall image quality of PCD-CTA achieved ratings superior to EID-CTA irrespective of the used reconstruction kernels (best: PCD-CT Bv60; worst: EID-CT Bv40; p < 0.001). Interrater agreement was good (W = 0.78). Concluding, PCD-CT offers superior intraluminal attenuation, SNR, and CNR compared to EID-CT in angiographies of the upper leg arterial runoff. Combined with improved subjective image quality, PCD-CT facilitates the use of sharper convolution kernels and ultimately bears the potential of improved vascular structure assessability.},
  language  = {en}
}
@article{PatzerKunzHuflageetal.2023,
  author    = {Patzer, Theresa Sophie and Kunz, Andreas Steven and Huflage, Henner and Conrads, Nora and Luetkens, Karsten Sebastian and Pannenbecker, Pauline and Paul, Mila Marie and Erg{\"u}n, S{\"u}leyman and Bley, Thorsten Alexander and Grunz, Jan-Peter},
  title     = {Ultrahigh-resolution photon-counting CT in cadaveric fracture models: spatial frequency is not everything},
  series = {Diagnostics},
  volume    = {13},
  journal   = {Diagnostics},
  number    = {10},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics13101677},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319281},
  year      = {2023},
  abstract  = {In this study, the impact of reconstruction sharpness on the visualization of the appendicular skeleton in ultrahigh-resolution (UHR) photon-counting detector (PCD) CT was investigated. Sixteen cadaveric extremities (eight fractured) were examined with a standardized 120 kVp scan protocol (CTDI\(_{vol}\) 10 mGy). Images were reconstructed with the sharpest non-UHR kernel (Br76) and all available UHR kernels (Br80 to Br96). Seven radiologists evaluated image quality and fracture assessability. Interrater agreement was assessed with the intraclass correlation coefficient. For quantitative comparisons, signal-to-noise-ratios (SNRs) were calculated. Subjective image quality was best for Br84 (median 1, interquartile range 1-3; p ≤ 0.003). Regarding fracture assessability, no significant difference was ascertained between Br76, Br80 and Br84 (p > 0.999), with inferior ratings for all sharper kernels (p < 0.001). Interrater agreement for image quality (0.795, 0.732-0.848; p < 0.001) and fracture assessability (0.880; 0.842-0.911; p < 0.001) was good. SNR was highest for Br76 (3.4, 3.0-3.9) with no significant difference to Br80 and Br84 (p > 0.999). Br76 and Br80 produced higher SNRs than all kernels sharper than Br84 (p ≤ 0.026). In conclusion, PCD-CT reconstructions with a moderate UHR kernel offer superior image quality for visualizing the appendicular skeleton. Fracture assessability benefits from sharp non-UHR and moderate UHR kernels, while ultra-sharp reconstructions incur augmented image noise.},
  language  = {en}
}
@article{HuflageGrunzPatzeretal.2023,
  author    = {Huflage, Henner and Grunz, Jan-Peter and Patzer, Theresa Sophie and Pannenbecker, Pauline and Feldle, Philipp and Sauer, Stephanie Tina and Petritsch, Bernhard and Erg{\"u}n, S{\"u}leyman and Bley, Thorsten Alexander and Kunz, Andreas Steven},
  title     = {Potential of unenhanced ultra-low-dose abdominal photon-counting CT with tin filtration: a cadaveric study},
  series = {Diagnostics},
  volume    = {13},
  journal   = {Diagnostics},
  number    = {4},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics13040603},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304122},
  year      = {2023},
  abstract  = {Objectives: This study investigated the feasibility and image quality of ultra-low-dose unenhanced abdominal CT using photon-counting detector technology and tin prefiltration. Materials and Methods: Employing a first-generation photon-counting CT scanner, eight cadaveric specimens were examined both with tin prefiltration (Sn 100 kVp) and polychromatic (120 kVp) scan protocols matched for radiation dose at three different levels: standard-dose (3 mGy), low-dose (1 mGy) and ultra-low-dose (0.5 mGy). Image quality was evaluated quantitatively by means of contrast-to-noise-ratios (CNR) with regions of interest placed in the renal cortex and subcutaneous fat. Additionally, three independent radiologists performed subjective evaluation of image quality. The intraclass correlation coefficient was calculated as a measure of interrater reliability. Results: Irrespective of scan mode, CNR in the renal cortex decreased with lower radiation dose. Despite similar mean energy of the applied x-ray spectrum, CNR was superior for Sn 100 kVp over 120 kVp at standard-dose (17.75 ± 3.51 vs. 14.13 ± 4.02), low-dose (13.99 ± 2.6 vs. 10.68 ± 2.17) and ultra-low-dose levels (8.88 ± 2.01 vs. 11.06 ± 1.74) (all p ≤ 0.05). Subjective image quality was highest for both standard-dose protocols (score 5; interquartile range 5-5). While no difference was ascertained between Sn 100 kVp and 120 kVp examinations at standard and low-dose levels, the subjective image quality of tin-filtered scans was superior to 120 kVp with ultra-low radiation dose (p < 0.05). An intraclass correlation coefficient of 0.844 (95\% confidence interval 0.763-0.906; p < 0.001) indicated good interrater reliability. Conclusions: Photon-counting detector CT permits excellent image quality in unenhanced abdominal CT with very low radiation dose. Employment of tin prefiltration at 100 kVp instead of polychromatic imaging at 120 kVp increases the image quality even further in the ultra-low-dose range of 0.5 mGy.},
  language  = {en}
}
@article{PatzerKunzHuflageetal.2023,
  author    = {Patzer, Theresa Sophie and Kunz, Andreas Steven and Huflage, Henner and Luetkens, Karsten Sebastian and Conrads, Nora and Gruschwitz, Philipp and Pannenbecker, Pauline and Erg{\"u}n, S{\"u}leyman and Bley, Thorsten Alexander and Grunz, Jan-Peter},
  title     = {Quantitative and qualitative image quality assessment in shoulder examinations with a first-generation photon-counting detector CT},
  series = {Scientific Reports},
  volume    = {13},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-023-35367-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357925},
  year      = {2023},
  abstract  = {Photon-counting detector (PCD) CT allows for ultra-high-resolution (UHR) examinations of the shoulder without requiring an additional post-patient comb filter to narrow the detector aperture. This study was designed to compare the PCD performance with a high-end energy-integrating detector (EID) CT. Sixteen cadaveric shoulders were examined with both scanners using dose-matched 120 kVp acquisition protocols (low-dose/full-dose: CTDI\(_{vol}\) = 5.0/10.0 mGy). Specimens were scanned in UHR mode with the PCD-CT, whereas EID-CT examinations were conducted in accordance with the clinical standard as "non-UHR". Reconstruction of EID data employed the sharpest kernel available for standard-resolution scans (ρ\(_{50}\) = 12.3 lp/cm), while PCD data were reconstructed with both a comparable kernel (11.8 lp/cm) and a sharper dedicated bone kernel (16.5 lp/cm). Six radiologists with 2-9 years of experience in musculoskeletal imaging rated image quality subjectively. Interrater agreement was analyzed by calculation of the intraclass correlation coefficient in a two-way random effects model. Quantitative analyses comprised noise recording and calculating signal-to-noise ratios based on attenuation measurements in bone and soft tissue. Subjective image quality was higher in UHR-PCD-CT than in EID-CT and non-UHR-PCD-CT datasets (all p < 0.001). While low-dose UHR-PCD-CT was considered superior to full-dose non-UHR studies on either scanner (all p < 0.001), ratings of low-dose non-UHR-PCD-CT and full-dose EID-CT examinations did not differ (p > 0.99). Interrater reliability was moderate, indicated by a single measures intraclass correlation coefficient of 0.66 (95\% confidence interval: 0.58-0.73; p < 0.001). Image noise was lowest and signal-to-noise ratios were highest in non-UHR-PCD-CT reconstructions at either dose level (p < 0.001). This investigation demonstrates that superior depiction of trabecular microstructure and considerable denoising can be realized without additional radiation dose by employing a PCD for shoulder CT imaging. Allowing for UHR scans without dose penalty, PCD-CT appears as a promising alternative to EID-CT for shoulder trauma assessment in clinical routine.},
  language  = {en}
}
@article{SchreiberLohrBaltesetal.2023,
  author    = {Schreiber, Laura M. and Lohr, David and Baltes, Steffen and Vogel, Ulrich and Elabyad, Ibrahim A. and Bille, Maya and Reiter, Theresa and Kosmala, Aleksander and Gassenmaier, Tobias and Stefanescu, Maria R. and Kollmann, Alena and Aures, Julia and Schnitter, Florian and Pali, Mihaela and Ueda, Yuichiro and Williams, Tatiana and Christa, Martin and Hofmann, Ulrich and Bauer, Wolfgang and Gerull, Brenda and Zernecke, Alma and Erg{\"u}n, S{\"u}leyman and Terekhov, Maxim},
  title     = {Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research},
  series = {Frontiers in Cardiovascular Medicine},
  volume    = {10},
  journal   = {Frontiers in Cardiovascular Medicine},
  issn      = {2297-055X},
  doi       = {10.3389/fcvm.2023.1068390},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317398},
  year      = {2023},
  abstract  = {A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.},
  language  = {en}
}
@article{JanzWalzCirnuetal.2024,
  author    = {Janz, Anna and Walz, Katharina and Cirnu, Alexandra and Surjanto, Jessica and Urlaub, Daniela and Leskien, Miriam and Kohlhaas, Michael and Nickel, Alexander and Brand, Theresa and Nose, Naoko and W{\"o}rsd{\"o}rfer, Philipp and Wagner, Nicole and Higuchi, Takahiro and Maack, Christoph and Dudek, Jan and Lorenz, Kristina and Klopocki, Eva and Erg{\"u}n, S{\"u}leyman and Duff, Henry J. and Gerull, Brenda},
  title     = {Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes},
  series = {Molecular Metabolism},
  volume    = {79},
  journal   = {Molecular Metabolism},
  issn      = {2212-8778},
  doi       = {10.1016/j.molmet.2023.101859},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350393},
  year      = {2024},
  abstract  = {Highlights • Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs. • Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential. • Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy. Background Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. Methods We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)). Results Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation. Conclusions Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.},
  language  = {en}
}
@article{AktasUpcinHenkeetal.2019,
  author    = {Aktas, Bertal H. and Upcin, Berin and Henke, Erik and Padmasekar, Manju and Qin, Xuebin and Erg{\"u}n, S{\"u}leyman},
  title     = {The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells},
  series = {Stem Cells International},
  journal   = {Stem Cells International},
  doi       = {10.1155/2019/1608787},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227769},
  pages     = {1-20},
  year      = {2019},
  abstract  = {Pluripotent stem cells give rise to reproductively enabled offsprings by generating progressively lineage-restricted multipotent stem cells that would differentiate into lineage-committed stem and progenitor cells. These lineage-committed stem and progenitor cells give rise to all adult tissues and organs. Adult stem and progenitor cells are generated as part of the developmental program and play critical roles in tissue and organ maintenance and/or regeneration. The ability of pluripotent stem cells to self-renew, maintain pluripotency, and differentiate into a multicellular organism is highly dependent on sensing and integrating extracellular and extraorganismal cues. Proteins perform and integrate almost all cellular functions including signal transduction, regulation of gene expression, metabolism, and cell division and death. Therefore, maintenance of an appropriate mix of correctly folded proteins, a pristine proteome, is essential for proper stem cell function. The stem cells' proteome must be pristine because unfolded, misfolded, or otherwise damaged proteins would interfere with unlimited self-renewal, maintenance of pluripotency, differentiation into downstream lineages, and consequently with the development of properly functioning tissue and organs. Understanding how various stem cells generate and maintain a pristine proteome is therefore essential for exploiting their potential in regenerative medicine and possibly for the discovery of novel approaches for maintaining, propagating, and differentiating pluripotent, multipotent, and adult stem cells as well as induced pluripotent stem cells. In this review, we will summarize cellular networks used by various stem cells for generation and maintenance of a pristine proteome. We will also explore the coordination of these networks with one another and their integration with the gene regulatory and signaling networks.},
  language  = {en}
}