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Book ; Online ; Thesis: The impact of adipose tissue on COVID-19 severity

Zickler, Martin [Verfasser] / Gabriel, Guelsah [Akademischer Betreuer]

2023

Author's details	Martin Zickler ; Betreuer: Guelsah Gabriel
Keywords	Naturwissenschaften ; Science
Subject code	sg500
Language	English
Publisher	Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky
Publishing place	Hamburg
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article: T-705-Derived Prodrugs Show High Antiviral Efficacies against a Broad Range of Influenza A Viruses with Synergistic Effects When Combined with Oseltamivir.

Ganter, Benedikt / Zickler, Martin / Huchting, Johanna / Winkler, Matthias / Lüttjohann, Anna / Meier, Chris / Gabriel, Gülsah / Beck, Sebastian

Pharmaceutics

2023 Volume 15, Issue 6

Abstract: Emerging influenza A viruses (IAV) bear the potential to cause pandemics with unpredictable consequences for global human health. In particular, the WHO has declared avian H5 and H7 subtypes as high-risk candidates, and continuous surveillance of these ... ...

Abstract	Emerging influenza A viruses (IAV) bear the potential to cause pandemics with unpredictable consequences for global human health. In particular, the WHO has declared avian H5 and H7 subtypes as high-risk candidates, and continuous surveillance of these viruses as well as the development of novel, broadly acting antivirals, are key for pandemic preparedness. In this study, we sought to design T-705 (Favipiravir) related inhibitors that target the RNA-dependent RNA polymerase and evaluate their antiviral efficacies against a broad range of IAVs. Therefore, we synthesized a library of derivatives of T-705 ribonucleoside analogues (called T-1106 pronucleotides) and tested their ability to inhibit both seasonal and highly pathogenic avian influenza viruses in vitro. We further showed that diphosphate (DP) prodrugs of T-1106 are potent inhibitors of H1N1, H3N2, H5N1, and H7N9 IAV replication. Importantly, in comparison to T-705, these DP derivatives achieved 5- to 10-fold higher antiviral activity and were non-cytotoxic at the therapeutically active concentrations. Moreover, our lead DP prodrug candidate showed drug synergy with the neuraminidase inhibitor oseltamivir, thus opening up another avenue for combinational antiviral therapy against IAV infections. Our findings may serve as a basis for further pre-clinical development of T-1106 prodrugs as an effective countermeasure against emerging IAVs with pandemic potential.
Language	English
Publishing date	2023-06-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15061732
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Cellular Importin-α3 Expression Dynamics in the Lung Regulate Antiviral Response Pathways against Influenza A Virus Infection.

Cell reports

2024 Volume 43, Issue 4, Page(s) 114023

Language	English
Publishing date	2024-03-22
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2024.114023
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Article ; Online: Evolution of crossover interference enables stable autopolyploidy by ensuring pairwise partner connections in Arabidopsis arenosa.

Morgan, Chris / White, Martin A / Franklin, F Chris H / Zickler, Denise / Kleckner, Nancy / Bomblies, Kirsten

Current biology : CB

2021 Volume 31, Issue 21, Page(s) 4713–4726.e4

Abstract: Polyploidy is a major driver of evolutionary change. Autopolyploids, which arise by within-species whole-genome duplication, carry multiple nearly identical copies of each chromosome. This presents an existential challenge to sexual reproduction. Meiotic ...

Abstract	Polyploidy is a major driver of evolutionary change. Autopolyploids, which arise by within-species whole-genome duplication, carry multiple nearly identical copies of each chromosome. This presents an existential challenge to sexual reproduction. Meiotic chromosome segregation requires formation of DNA crossovers (COs) between two homologous chromosomes. How can this outcome be achieved when more than two essentially equivalent partners are available? We addressed this question by comparing diploid, neo-autotetraploid, and established autotetraploid Arabidopsis arenosa using new approaches for analysis of meiotic CO patterns in polyploids. We discover that crossover interference, the classical process responsible for patterning of COs in diploid meiosis, is defective in the neo-autotetraploid but robust in the established autotetraploid. The presented findings suggest that, initially, diploid-like interference fails to act effectively on multivalent pairing and accompanying pre-CO recombination interactions and that stable autopolyploid meiosis can emerge by evolution of a "supercharged" interference process, which can now act effectively on such configurations. Thus, the basic interference mechanism responsible for simplifying CO patterns along chromosomes in diploid meiosis has evolved the capability to also simplify CO patterns among chromosomes in autopolyploids, thereby promoting bivalent formation. We further show that evolution of stable autotetraploidy preadapts meiosis to higher ploidy, which in turn has interesting mechanistic and evolutionary implications.
MeSH term(s)	Arabidopsis/genetics ; Chromosome Segregation/genetics ; Diploidy ; Meiosis/genetics ; Polyploidy
Language	English
Publishing date	2021-09-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2021.08.028
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Article ; Online: Hamster model for post-COVID-19 alveolar regeneration offers an opportunity to understand post-acute sequelae of SARS-CoV-2.

Heydemann, Laura / Ciurkiewicz, Małgorzata / Beythien, Georg / Becker, Kathrin / Schughart, Klaus / Stanelle-Bertram, Stephanie / Schaumburg, Berfin / Mounogou-Kouassi, Nancy / Beck, Sebastian / Zickler, Martin / Kühnel, Mark / Gabriel, Gülsah / Beineke, Andreas / Baumgärtner, Wolfgang / Armando, Federico

Nature communications

2023 Volume 14, Issue 1, Page(s) 3267

Abstract: COVID-19 survivors often suffer from post-acute sequelae of SARS-CoV-2 infection (PASC). Current evidence suggests dysregulated alveolar regeneration as a possible explanation for respiratory PASC, which deserves further investigation in a suitable ... ...

Abstract	COVID-19 survivors often suffer from post-acute sequelae of SARS-CoV-2 infection (PASC). Current evidence suggests dysregulated alveolar regeneration as a possible explanation for respiratory PASC, which deserves further investigation in a suitable animal model. This study investigates morphological, phenotypical and transcriptomic features of alveolar regeneration in SARS-CoV-2 infected Syrian golden hamsters. We demonstrate that CK8
MeSH term(s)	Animals ; Cricetinae ; Humans ; SARS-CoV-2 ; COVID-19 ; Post-Acute COVID-19 Syndrome ; Cell Differentiation ; Alveolar Epithelial Cells ; Disease Progression ; Mesocricetus
Language	English
Publishing date	2023-06-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39049-5
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Article ; Online: Mobilisation practices during the SARS-CoV-2 pandemic: A retrospective analysis (MobiCOVID).

Schellenberg, Clara M / Lindholz, Maximilian / Grunow, Julius J / Boie, Sebastian / Bald, Annika / Warner, Linus O / Ulm, Bernhard / Milnik, Annette / Zickler, Daniel / Angermair, Stefan / Reißhauer, Anett / Witzenrath, Martin / Menk, Mario / Balzer, Felix / Ocker, Thomas / Weber-Carstens, Steffen / Schaller, Stefan J

Anaesthesia, critical care & pain medicine

2023 Volume 42, Issue 5, Page(s) 101255

Abstract: Background: Corona Virus Disease 2019 (COVID-19) patients display risk factors for intensive care unit acquired weakness (ICUAW). The pandemic increased existing barriers to mobilisation. This study aimed to compare mobilisation practices in COVID-19 ... ...

Abstract	Background: Corona Virus Disease 2019 (COVID-19) patients display risk factors for intensive care unit acquired weakness (ICUAW). The pandemic increased existing barriers to mobilisation. This study aimed to compare mobilisation practices in COVID-19 and non-COVID-19 patients. Methods: This retrospective cohort study was conducted at Charité-Universitätsmedizin Berlin, Germany, including adult patients admitted to one of 16 ICUs between March 2018, and November 2021. The effect of COVID-19 on mobilisation level and frequency, early mobilisation (EM) and time to active sitting position (ASP) was analysed. Subgroup analysis on COVID-19 patients and the ICU type influencing mobilisation practices was performed. Mobilisation entries were converted into the ICU mobility scale (IMS) using supervised machine learning. The groups were matched using 1:1 propensity score matching. Results: A total of 12,462 patients were included, receiving 59,415 mobilisations. After matching 611 COVID-19 and non-COVID-19 patients were analysed. They displayed no significant difference in mobilisation frequency (0.4 vs. 0.3, p = 0.7), maximum IMS (3 vs. 3; p = 0.17), EM (43.2% vs. 37.8%; p = 0.06) or time to ASP (HR 0.95; 95% CI: 0.82, 1.09; p = 0.44). Subgroup analysis showed that patients in surge ICUs, i.e., temporarily created ICUs for COVID-19 patients during the pandemic, more commonly received EM (53.9% vs. 39.8%; p = 0.03) and reached higher maximum IMS (4 vs. 3; p = 0.03) without difference in mobilisation frequency (0.5 vs. 0.3; p = 0.32) or time to ASP (HR 1.15; 95% CI: 0.85, 1.56; p = 0.36). Conclusion: COVID-19 did not hinder mobilisation. Those treated in surge ICUs were more likely to receive EM and reached higher mobilisation levels.
MeSH term(s)	Adult ; Humans ; SARS-CoV-2 ; COVID-19 ; Retrospective Studies ; Pandemics ; Intensive Care Units
Language	English
Publishing date	2023-05-29
Publishing country	France
Document type	Journal Article
ISSN	2352-5568
ISSN (online)	2352-5568
DOI	10.1016/j.accpm.2023.101255
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Article ; Online: SARS-CoV-2 Infection Dysregulates Cilia and Basal Cell Homeostasis in the Respiratory Epithelium of Hamsters.

Schreiner, Tom / Allnoch, Lisa / Beythien, Georg / Marek, Katarzyna / Becker, Kathrin / Schaudien, Dirk / Stanelle-Bertram, Stephanie / Schaumburg, Berfin / Mounogou Kouassi, Nancy / Beck, Sebastian / Zickler, Martin / Gabriel, Gülsah / Baumgärtner, Wolfgang / Armando, Federico / Ciurkiewicz, Malgorzata

International journal of molecular sciences

2022 Volume 23, Issue 9

Abstract: Similar to many other respiratory viruses, SARS-CoV-2 targets the ciliated cells of the respiratory epithelium and compromises mucociliary clearance, thereby facilitating spread to the lungs and paving the way for secondary infections. A detailed ... ...

Abstract	Similar to many other respiratory viruses, SARS-CoV-2 targets the ciliated cells of the respiratory epithelium and compromises mucociliary clearance, thereby facilitating spread to the lungs and paving the way for secondary infections. A detailed understanding of mechanism involved in ciliary loss and subsequent regeneration is crucial to assess the possible long-term consequences of COVID-19. The aim of this study was to characterize the sequence of histological and ultrastructural changes observed in the ciliated epithelium during and after SARS-CoV-2 infection in the golden Syrian hamster model. We show that acute infection induces a severe, transient loss of cilia, which is, at least in part, caused by cilia internalization. Internalized cilia colocalize with membrane invaginations, facilitating virus entry into the cell. Infection also results in a progressive decline in cells expressing the regulator of ciliogenesis FOXJ1, which persists beyond virus clearance and the termination of inflammatory changes. Ciliary loss triggers the mobilization of p73
MeSH term(s)	Animals ; COVID-19 ; Cilia/metabolism ; Cricetinae ; Epithelium ; Homeostasis ; Mesocricetus ; Respiratory Mucosa/metabolism ; SARS-CoV-2
Language	English
Publishing date	2022-05-04
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/ijms23095124
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Article ; Online: Delayed Endovascular Repair With Procedural Anticoagulation: A Safe Strategy for Blunt Aortic Injury.

Zambetti, Benjamin R / Zickler, William P / Lewis, Richard H / Pettigrew, Benjamin D / Valaulikar, Ganpat S / Afzal, M Omer / Fischer, Peter E / Croce, Martin A / Magnotti, Louis J

Annals of vascular surgery

2022 Volume 84, Page(s) 195–200

Abstract: Background: Blunt aortic injury (BAI) and traumatic brain injury (TBI) are the leading causes of death after blunt trauma. The purposes of this study were to identify predictors of mortality for BAI and to examine the impact of procedural heparinization ...

Abstract	Background: Blunt aortic injury (BAI) and traumatic brain injury (TBI) are the leading causes of death after blunt trauma. The purposes of this study were to identify predictors of mortality for BAI and to examine the impact of procedural heparinization during thoracic endovascular aortic repair (TEVAR) on neurologic outcomes in patients with BAI/TBI. Methods: Patients with BAI were identified over an 8 year period. Age, gender, severity of injury and shock, time to TEVAR, morbidity, and mortality were recorded and compared. Multivariable logistic regression (MLR) was performed to determine independent predictors of mortality. Youden's index determined optimal time to TEVAR. Results: A total of 129 patients were identified. The majority (74%) were male with a median age and injury severity score (ISS) of 40 years and 29, respectively. Of these, 26 (20%) had a concomitant TBI. Patients with BAI/TBI had higher injury burden at presentation (ISS 37 vs. 29, P = 0.002; Glasgow Coma Scale [GCS] 6 vs. 15, P < 0.0001), underwent fewer TEVAR procedures (31 vs. 53%, P = 0.039), and suffered increased mortality (39 vs. 16%, P = 0.009). All TEVARs had procedural anticoagulation, including patients with TBI, without change in neurologic function. The optimal time to TEVAR was 14.8 hr. Mortality increased in TEVAR patients before 14.8 hr (8.7 vs. 0%, P = 0.210). MLR identified TEVAR as the only modifiable factor that reduced mortality (odds ratio 0.11; 95% confidence interval 0.03-0.45, P = 0.002). Conclusions: TEVAR use was identified as the only modifiable predictor of reduced mortality in patients with BAI. Delayed TEVAR with the use of procedural heparin provides a safe option regardless of TBI with improved survival and no difference in discharge neurologic function.
MeSH term(s)	Anticoagulants/adverse effects ; Aorta, Thoracic/diagnostic imaging ; Aorta, Thoracic/injuries ; Aorta, Thoracic/surgery ; Aortic Diseases/etiology ; Endovascular Procedures/adverse effects ; Female ; Humans ; Male ; Retrospective Studies ; Risk Factors ; Treatment Outcome ; Vascular System Injuries/complications ; Vascular System Injuries/diagnostic imaging ; Vascular System Injuries/surgery ; Wounds, Nonpenetrating/complications ; Wounds, Nonpenetrating/diagnostic imaging ; Wounds, Nonpenetrating/surgery
Chemical Substances	Anticoagulants
Language	English
Publishing date	2022-03-03
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1027366-9
ISSN	1615-5947 ; 0890-5096
ISSN (online)	1615-5947
ISSN	0890-5096
DOI	10.1016/j.avsg.2022.01.025
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Zs.A 2882: Show issues

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Article ; Online: Impact of Endovascular Stenting on Outcomes in Patients with Traumatic Subclavian Artery Injury.

Zambetti, Benjamin R / Stuber, Jacqueline D / Patel, Devanshi D / Lewis, Richard H / Huang, Dih-Dih / Zickler, William P / Fischer, Peter E / Magnotti, Arianna L / Croce, Martin A / Magnotti, Louis J

Journal of the American College of Surgeons

2022 Volume 234, Issue 4, Page(s) 444–449

Abstract: Background: Traumatic subclavian artery injury (SAI) remains uncommon but can lead to significant morbidity and mortality. Although open and endovascular repair offer excellent limb salvage rates, their role in blunt and penetrating injuries is not well ...

Abstract	Background: Traumatic subclavian artery injury (SAI) remains uncommon but can lead to significant morbidity and mortality. Although open and endovascular repair offer excellent limb salvage rates, their role in blunt and penetrating injuries is not well defined. The goal of this study was to examine the effect of mechanism of injury and type of repair on outcomes in patients with traumatic SAI. Study design: Patients undergoing procedures for traumatic SAI were identified from the Trauma Quality Improvement Program database between 2015 and 2018. Demographics, severity of injury and shock, type of subclavian repair (open vs endovascular), morbidity, and mortality were recorded. Patients with SAI were stratified by mechanism and type of repair and compared. Multivariable logistic regression (MLR) analysis was performed to determine independent predictors of mortality. Results: Seven hundred thirty-seven patients undergoing procedures for SAI were identified. Of these, 39% were penetrating. The majority were male (80%) with a median age and Injury Severity Score (ISS) of 37 and 21, respectively. 58% of patients were managed endovascularly. For patients with blunt injury, the type of repair affected neither morbidity (25% vs 19%, p = 0.116) nor mortality (11% vs 10%, p = 0.70). For patients with penetrating injuries, endovascular repair had significantly lower morbidity (12% vs 22%, p = 0.028) and mortality (6% vs 21%, p = 0.001). MLR identified endovascular repair as the only modifiable risk factor associated with reduced mortality (odds ratio, 0.35; 95% confidence interval, 0.14 to 0.87, p = 0.02). Conclusions: SAI results in significant morbidity and mortality regardless of mechanism. Although the type of repair did not affect mortality in patients with blunt injury, endovascular repair was identified as the only modifiable predictor of reduced mortality in patients with penetrating injuries.
MeSH term(s)	Endovascular Procedures/methods ; Female ; Humans ; Injury Severity Score ; Male ; Retrospective Studies ; Risk Factors ; Subclavian Artery/injuries ; Subclavian Artery/surgery ; Thoracic Injuries ; Time Factors ; Treatment Outcome ; Vascular System Injuries/surgery ; Wounds, Nonpenetrating/complications ; Wounds, Nonpenetrating/surgery ; Wounds, Penetrating/complications ; Wounds, Penetrating/surgery
Language	English
Publishing date	2022-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1181115-8
ISSN	1879-1190 ; 1072-7515
ISSN (online)	1879-1190
ISSN	1072-7515
DOI	10.1097/XCS.0000000000000077
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Article ; Online: Hamster model for post-COVID-19 alveolar regeneration offers an opportunity to understand post-acute sequelae of SARS-CoV-2

Laura Heydemann / Małgorzata Ciurkiewicz / Georg Beythien / Kathrin Becker / Klaus Schughart / Stephanie Stanelle-Bertram / Berfin Schaumburg / Nancy Mounogou-Kouassi / Sebastian Beck / Martin Zickler / Mark Kühnel / Gülsah Gabriel / Andreas Beineke / Wolfgang Baumgärtner / Federico Armando

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 19

Abstract: Abstract COVID-19 survivors often suffer from post-acute sequelae of SARS-CoV-2 infection (PASC). Current evidence suggests dysregulated alveolar regeneration as a possible explanation for respiratory PASC, which deserves further investigation in a ... ...

Abstract	Abstract COVID-19 survivors often suffer from post-acute sequelae of SARS-CoV-2 infection (PASC). Current evidence suggests dysregulated alveolar regeneration as a possible explanation for respiratory PASC, which deserves further investigation in a suitable animal model. This study investigates morphological, phenotypical and transcriptomic features of alveolar regeneration in SARS-CoV-2 infected Syrian golden hamsters. We demonstrate that CK8+ alveolar differentiation intermediate (ADI) cells occur following SARS-CoV-2-induced diffuse alveolar damage. A subset of ADI cells shows nuclear accumulation of TP53 at 6- and 14-days post infection (dpi), indicating a prolonged arrest in the ADI state. Transcriptome data show high module scores for pathways involved in cell senescence, epithelial-mesenchymal transition, and angiogenesis in cell clusters with high ADI gene expression. Moreover, we show that multipotent CK14+ airway basal cell progenitors migrate out of terminal bronchioles, aiding alveolar regeneration. At 14 dpi, ADI cells, peribronchiolar proliferates, M2-macrophages, and sub-pleural fibrosis are observed, indicating incomplete alveolar restoration. The results demonstrate that the hamster model reliably phenocopies indicators of a dysregulated alveolar regeneration of COVID-19 patients. The results provide important information on a translational COVID-19 model, which is crucial for its application in future research addressing pathomechanisms of PASC and in testing of prophylactic and therapeutic approaches for this syndrome.
Keywords	Science ; Q
Subject code	610
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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