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Anti-coronaviral activities of natural products and their derivatives
Get PDFThe COVID-19 pandemic, caused by SARS-CoV-2, has had a profound impact on global
health and economies, highlighting the urgent need for novel, effective antiviral agents.
Following its first report in Wuhan, China in 2019, it quickly spread around the world with
more than 7 million fatalities and over 777 million reported cases as of February 2025. While
vaccines have played a crucial role in decreasing disease severity, the continuous emergence
of new mutant strains, particularly the Omicron subvariants, poses a significant challenge.
These variants have demonstrated an increased ability to evade immune detection, reducing the
efficacy of existing vaccines and antibody therapies. Moreover, the period between disease
outbreaks has become shorter, and there is a possibility that more viral epidemics will occur
soon. Thus, the identification of pan-coronaviral inhibitors, capable of targeting viral structures
essential for replication and host entry, is crucial for pandemic preparedness and long-term
antiviral strategies. The present PhD thesis demonstrates that natural product derivatives can
serve as pan-coronaviral inhibitors.
The main protease (Mpro or 3CLpro) in coronaviruses represents a promising specific drug target
as it is essential for the cleavage of the virus polypeptide and has a unique cleavage site that
does not exist in human host proteases. Here we explored potential natural pan-coronavirus
drugs using in vitro and in silico approaches and three coronavirus main proteases as treatment
targets. Hypericin, rosmarinic acid, isorhamnetin, and luteolin inhibited Mpro of SARS-CoV-2,
while hypericin and isorhamnetin inhibited Mpro of SARS-CoV-1; hypericin showed inhibitory
effects toward Mpro of MERS-CoV. Microscale thermophoresis confirmed the binding of these
compounds to Mpro with high affinity. Cytotoxity results showed that rosmarinic acid and
luteolin were not cytotoxic toward MRC-5 cells, whereas hypericin and isorhamnetin showed
slightl toxicity. These findings highlight hypericin’s potential as a lead compound for further
development in antiviral drug discovery as a pan-anti-coronaviral agent by binding to and
inhibiting Mpro of several human-pathogenic coronaviruses.
The receptor-binding domain (RBD) within the S1 subunit plays a pivotal role in binding to
the angiotensin-converting enzyme 2 (ACE2) receptor on host cells, facilitating viral entry,
represents a promising target for therapeutic intervention. We demonstrated that a
diketopiperazine/piperidine alkaloid and natural isoquinoline derivatives inhibited SARS-CoV-
2 pseudovirus and live virus entry in host cells while showing low toxicity. Microscale
thermophoresis revealed these compounds strongly bound to the RBDs of SARS-CoV-2,III
SARS-CoV-2 XBB, SARS-CoV-1, MERS-CoV, and HCoV-HKU1, with their Kd values
increasing as RBD sequence similarity decreased. These findings showed that these
compounds, should be considered for further development as potential pan-coronavirus entry
inhibitors.Getrennte Zählungen ; Illustrationen, Diagramm
A dilatant visco-elasto-viscoplasticity model with globally continuous tensile cap : stable two-field mixed formulation
Get PDFRocks break if shear stresses exceed their strength. It is therefore important for typical geoscientific applications to take shear failure mechanism and the subsequent development of mode-II shear bands or faults into account. Many existing codes incorporate non-associated Drucker-Prager or Mohr-Coulomb plasticity models to simulate this behavior. Yet, when effective mean stress becomes extensional, for example when fluid pressure becomes large, the dominant failure mode changes to a mode-I (opening) mode, which initiates plastic volumetric deformation. It is rather difficult to represent both failure modes in numerical models in a self-consistent manner, while also accounting for the nonlinear visco-elastic host rock rheology, which varies from being nearly incompressible in the mantle to being compressible in surface-near regions. Here, we present a simple plasticity model that is designed to overcome these difficulties. We employ a combination of a linearized Drucker-Prager shear failure envelope with a circular tensile cap function in way that ensures continuity and smoothness of both yield surface and flow potential in the entire stress space. A Perzyna-type viscoplastic regularization ensures that the resulting localization zones are mesh-insensitive. To deal with the near incompressibility condition, a mixed two-field finite element formulation is employed. The local nonlinear iterations at the integration-point level are used to determine the stress increments. The global Newton-Raphson iterations are applied to solve the discretized momentum and continuity residual equations. The presented plasticity model is implemented in an open-source 2D unstructured finite element code GeoTech2D. The results of several typical test cases that range from crustal scale deformation to the propagation of fluid-induced tensile failure zones demonstrate rapid convergence. The robustness of the solution scheme is enhanced by the adaptive time stepping algorithm
Methodische Bildanalyse von mpMRT-Bildern der Prostata im Rahmen des onkologischen Follow-up von Patienten mit fokaler Therapie des Prostatakarzinoms mittels HIFU Focal One ®
Get PDF108 Seiten ; Illustrationen, Diagramm
Improving organ dose sparing in left-sided breast cancer with yaw-limited volumetric modulated arc therapy : a dosimetric comparison to conventional and intensity modulated radiation therapy approaches
Get PDFBackground:
To assess the dose-sparing capabilities of a yaw-limited volumetric modulated arc therapy (YL_VMAT) beam setup for adjacent organs at risk (OAR) in comparison with 3D-conventional radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT) and conventional VMAT for radiation therapy in left-sided breast cancer patients.
Methods:
In total, 80 treatment plans for 20 patients, of which 10 patients underwent CT-scans in deep inspiration breath-hold (DIBH) and 10 patients in free-breathing (FB) technique. Besides generally tangential-weighted static and IMRT beams, VMAT treatment plans with approximately 270° arc length have been compared and analyzed to a multi-field, yaw-adapted, unconventional partial VMAT technique retrospectively. The prescription dose was set to 40.05 Gy in 15 fractions.
Results:
We achieved a more pronounced steeper dose falloff directed from the thoracic wall to the adjacent lung tissue resulting in a significantly better ipsilateral lung and considerably cardiac dose sparing using the YL_VMAT method in general. Compared with standard techniques (IMRT, VMAT, 3D-CRT), YL-VMAT in combination with DIBH can achieve lower mean doses for the heart (1.05 Gy vs. 1.73 Gy, 2.16 Gy and 1.44 Gy), the left anterior descending (LAD) artery (3.68 Gy vs. 6.53 Gy, 5.13 Gy and 8.64 Gy) and the left lung (3.59 Gy vs. 5.39 Gy, 4.79 Gy and 5.87 Gy), respectively. Also with FB, the corresponding mean doses for the left lung and cardiac structures were lower with the YL-VMAT method than with IMRT (heart: 1.70 Gy vs. 2.44 Gy; LAD: 6.50 Gy vs. 11.97 Gy; left lung: 3.10 Gy vs. 4.72 Gy), VMAT (heart: 1.70 Gy vs. 2.52 Gy; LAD: 6.50 Gy vs. 9.06 Gy; left lung: 3.10 Gy vs. 4.46 Gy) and 3D-CRT (heart: 1.70 Gy vs. 2.78 Gy; LAD: 6.50 Gy vs. 15.09 Gy; left lung: 3.10 Gy vs. 5.77 Gy). In addition, we found out superiority of YL_VMAT for the V5, V10, and V20 Gy to the left lung. For DIBH and FB, all differences for the left lung were significant, with p < 0.05.
Conclusions:
With the YL_VMAT technique, dose exposures to radiosensitive OARs like the lung, heart and LAD artery can be reduced considerably to very low values in comparison to already established planning methods. The benefits must be weighed against the potential risks induced by an increased dose exposure to the contralateral breast
Interdisziplinäre Fragilitäts-Bewertungsinstrumente und deren prädiktiver Voraussagewert auf das perioperative Outcome betagterer Patientinnen mit Endometriumkarzinom - Eine explorative hypothesengenerierende retrospektive Kohortenstudie
Get PDF65 Seiten ; Illustratione
Histologische Subklassifikation, Manifestationsmuster und Therapieergebnisse von Patienten mit Marginalzonenlymphom an der Universitätsmedizin Mainz im Zeitraum von 2003 bis 2019
Get PDFVI, 79 Seiten ; Diagramm
Ethische Dilemmata in der Anästhesie : die Frage der Bluttransfusionen bei Zeugen Jehovas trotz religiöser Ablehnung – kann eine bindende Festlegung getroffen werden?
Get PDFIV, 80 Seiten ; Diagramm
Tuning connectivity in a three-component assembly of metal–organic cage-cross-linked polymer networks
Get PDFNetwork connectivity strongly influences the dynamics and mechanical properties of materials such as natural tissues and hydrogels, which are known for their adaptability and self-healing. Metal–organic cages (MOCs), with modular structures and reversible coordination, provide a versatile platform to engineer connectivity in polymer networks. Here, we use an octahedral MOC to form transient poly(ethylene glycol) (PEG)-based hydrogels and investigate their viscoelastic behavior by varying the junction functionality and polymer architecture. A distinct low-frequency relaxation mode emerges after annealing, reflecting the interplay between cage formation and a mixture of homo- and heteroleptic metal complexes. Cage formation is undermined at both high and low polymer concentrations due to steric hindrance and chain overstretching, respectively. At an optimal polymer concentration, reducing cage content preserves the cage integrity and reveals a transition from phantom to affine network behavior. In contrast, replacing polymeric ligands with small-molecule equivalents results in misconnectivity and a lower modulus. Kinetics analysis at the microscale using Fluorescence Resonance Energy Transfer (FRET) shows that incorporation into polymer networks destabilizes the cage, likely due to chain dynamics. DFT calculations further reveal that only Pd2+, among several tested transition metal ions, provides the appropriate coordination environment and bond stability for robust cage formation. Despite this, the high junction functionality enables rapid and efficient self-healing. This work examines how tuning connectivity in transient networks can guide the design of materials with tailored properties such as recyclability, self-healing, and stimuli-responsiveness
Patient needs in the context of gynecologic oncology and breast cancer : a validation study
Get PDFMedical advancements and therapeutic innovations are progressing rapidly, necessitating corresponding adaptations in the delivery of patient-centered care. This study explores the needs of women diagnosed with gynecologic and breast cancers, using the frameworks of the National Academy of Medicine and the Picker Institute as reflective lenses. We conducted a qualitative, single-center study employing grounded theory methodology. Semi-structured interviews were carried out with 20 patients undergoing treatment for gynecologic malignancies and breast cancer at a university medical center. Interviews covered multiple phases of illness, including treatment initiation, adaptation, abstention, and future-oriented decisions. Data were analyzed inductively using constant comparative methods. Findings largely affirmed the relevance of the eight established domains of patient-centered care - personal values, clear information and education, emotional support, involvement of family and friends, physical comfort, coordinated care, continuity, and access to treatment. Three additional insights emerged: needs vary according to illness phase and tend to taper over time; they are grounded in ethical dimensions, including social identity, epistemic agency, and moral distress; and they are interdependent, requiring holistic rather than isolated responses. These results highlight that effective patient-centered care must account not only for the content of care but also for its timing, context and ethical significance, warranting integration into standard oncological practice
Interaction of the mitochondrial calcium/proton exchanger TMBIM5 with MICU1
Get PDFIon transport within mitochondria influences their structure, energy production, and cell death regulation. TMBIM5, a conserved calcium/proton exchanger in the inner mitochondrial membrane, contributes to mitochondrial structure, ATP synthesis, and apoptosis regulation. The relationship of TMBIM5 with the mitochondrial calcium uniporter complex formed by MCU, MICU1-3, and EMRE remains undefined. We generated Tmbim5-deficient Drosophila that exhibit disrupted cristae architecture, premature mitochondrial permeability transition pore opening, reduced calcium uptake, and mitochondrial swelling – resulting in impaired mobility and shortened lifespan. Crossing these with flies lacking mitochondrial calcium uniporter complex proteins was generally detrimental, but partial MICU1 depletion ameliorated the Tmbim5-deficiency phenotype. In human cells, MICU1 rescues morphological defects in TMBIM5-knockout mitochondria, while TMBIM5 overexpression exacerbates size reduction in MICU1-knockout mitochondria. Both proteins demonstrated opposing effects on submitochondrial localization and coexisted in the same macromolecular complex. Our findings establish a functional interplay between TMBIM5 and MICU1 in maintaining mitochondrial integrity, with implications for understanding calcium homeostasis mechanisms