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Mdm2 targeting via PROteolysis TArgeting Chimeras (PROTAC) is efficient in p53 wildtype, p53-mutated, and abemaciclib-resistant estrogen receptor-positive cell lines and superior to mdm2 inhibition
No full textPurpose
The human double minute 2 homolog hdm2, alias mdm2, is the main negative-regulator of the tumor suppressor p53. In that capacity, mdm2 is a promising but not yet utilized molecular target for the treatment of breast cancer, however, its inhibition by small molecules is rather inappropriate. Instead, mdm2 degradation by PROteolysis TArgeting Chimeras (PROTAC) is expected to be highly specific, to exhibit pronounced efficiency and minimal side effects. Moreover, there is profound evidence that mdm2-specific PROTAC degraders are efficient even in tumor cells harboring p53 loss-of-function mutations.
Methods
We comparatively treated p53 wildtype / abemaciclib-sensitive and -resistant MCF-7, as well as p53-mutated T-47D estrogen receptor-positive breast cancer cells in-vitro with the mdm2 inhibitor AMG-232 and an mdm2 PROTAC degrader. The molecular signaling as a function of mdm2 inhibition and degradation was assessed and cell viability and cell cycle kinetics were monitored. In addition, potential PROTAC effects on the expression of immune-related markers MHC-I, MHC-II, PD-L1, PD-L2, and CD276 were determined.
Results
PROTAC treatment considerably attenuated cell proliferations and was superior to mdm2 inhibition in p53 wildtype and even in p53-mutated cells. Proliferation-associated pathways were significantly but differentially affected, including p73, retinoblastoma protein, and the transcription factor E2F1. MHC-I and CD276 were significantly downregulated.
Conclusion
The data reveal deeper insight into PROTAC-induced molecular mechanisms in luminal breast cancer cells with and without p53 mutations. The study provides the basis to evaluate the therapeutic applicability of anti-mdm2 PROTAC degraders in an appropriate preclinical in-vivo setting, for example in humanized tumor mice
Testing the Tomographic Fermi Liquid Hypothesis with High-Order Cyclotron Resonance
No full textThe tomographic Fermi liquid (TFL) hypothesis posits starkly different relaxation times for odd and even angular harmonics of electron distribution function in two-dimensional systems, but its experimental
verification remains elusive. Traditional electrical transport struggles to discern these lifetimes, as resistivity is largely unaffected by electron scattering. Here, we demonstrate that high-order cyclotron resonance (CR) offers a direct probe: The linewidth of the mth CR peak directly reflects the relaxation rate γm ¼ 1=τm of the corresponding angular harmonic. Combining theory and terahertz photoconductivity measurements in graphene, we show that the third-order CR exhibits a narrower linewidth than the secondorder CR, yielding τ3 > τ2. This hierarchy defies conventional impurity or phonon scattering models,
instead aligning with TFL predictions where odd harmonics evade relaxation via head-on collisions. Our results provide definitive evidence for the TFL regime and establish high-order CR as a powerful tool to unravel hydrodynamic transport in quantum materials
Data archive of "Radiation-induced dynamical formation of Floquet-Bloch bands in Dirac Hamiltonians"
No full textDataset containing numerical results used for the visualization in the publication "Radiation-induced dynamical formation of Floquet-Bloch bands in Dirac Hamiltonians
Iron Chelators in the Management of Autoimmune-Induced Alopecia: A Focus on Hypoxia-Inducible Factor 1 Modulation and Hair Restoration
No full textAutoimmune-induced alopecia, such as alopecia areata, involves immune-mediated damage to hair follicles, leading to significant hair loss. Emerging therapies that stabilize hypoxia-inducible factor 1-alpha (HIF-1α) show promise in counteracting follicular degradation and supporting hair regrowth. This communication highlights the potential of iron chelators, specifically deferoxamine (DFO) and deferiprone (DFP), to stabilize HIF-1α by reducing iron availability, thereby promoting vascularization, cellular proliferation, and a regenerative environment in the hair follicle niche. Clinical trials with iron chelators demonstrated improvements in hair density, thickness, and elasticity, as well as a reduction in hair loss by up to 66.8% over six months. These findings underscore the therapeutic potential of iron chelators in autoimmune alopecia management. Future research should explore the synergistic use of iron chelators with immune-modulating therapies, positioning them as viable options in the evolving field of alopecia treatment
Handling imperfection: A taxonomy for machine learning on data with data quality defects
No full textIn recent years, machine learning (ML) has become ubiquitous in sectors including transportation, security, health, and finance to analyze large amounts of data and support decision-making. However, real-world datasets used in ML often exhibit various data quality (DQ) defects that can significantly impair the performance and validity of ML models and thus also the decisions derived from them. Therefore, a plethora of methods across various research strands have been proposed to address DQ defects and mitigate their negative impact on ML-based data analysis and decision support. This has resulted in a fragmented research landscape, where comparisons and classifications of methods dealing with ML on data with DQ defects are very challenging for both researchers and practitioners. Thus, based on a structured design process, we develop and present a taxonomy for this research field. The taxonomy serves as a systematic framework to classify and organize existing research and methods according to relevant dimensions and facilitates future work in this area. Its reliability, understandability, completeness, and usefulness are supported by an evaluation with external researchers and practitioners. Finally, we identify current trends and research gaps and derive challenges and directions for future research
Elevated long-to-very-long-chain ceramide ratio correlates with disease severity in inflammatory bowel disease and primary sclerosing cholangitis
No full textThere is strong evidence that ceramides play a significant role in the pathology of inflammatory bowel disease (IBD) and chronic liver injury. Long-chain (LC) and very long-chain (VLC) ceramides have opposing functions, yet the associations of circulating levels of ceramide species in patients with IBD and primary sclerosing cholangitis (PSC)—as inflammatory biliary-hepatic disease closely linked to IBD— with disease severity remain poorly studied. This study investigates whether serum levels of ceramide (Cer) and hexosylceramide, a glycated ceramide derivative, are associated with disease severity in these conditions. Serum levels of eight ceramide and five hexosylceramide species were measured in 16 healthy controls, 57 patients with IBD, 7 patients with PSC, and 13 patients with PSC-IBD. Lipid levels were determined using direct flow injection analysis with a triple quadrupole mass spectrometer. Patients with IBD exhibited higher levels of Cer 18:1;O2/16:0 and Cer 18:1;O2/18:0 compared to controls. Their LC/VLC ceramide ratio was elevated and positively correlated with C-reactive protein and fecal calprotectin. However, ceramide and hexosylceramide levels were not associated with stool consistency, disease localization, or extra-intestinal manifestations. Patients with PSC and PSC-IBD also had increased LC/VLC ceramide ratios, primarily due to a decline in VLC ceramide species. In PSC-IBD, this ratio correlated positively with cholestasis markers. Additionally, serum hexosylceramide 18:1;O2/16:0 and 24:1 levels were specifically elevated in PSC. This study demonstrates that an altered LC/VLC ceramide balance is associated with disease severity in IBD, PSC-IBD, and PSC, highlighting its potential as a biomarker for IBD, PSC-IBD, and PSC. As our PSC cohorts were small, a confirmatory study is required
What is needed to act as a professional change agent for sustainability? A scoping review
Get PDFProfessionals across diverse work environments play a crucial role in facilitating and accelerating essential transformations towards sustainability. Recognising the urgent need to avert severe, irreversible harm to vital Earth systems, professional actors have been increasingly identified as a key target group for sustainability-related training programmes. While Education for Sustainable Development (ESD) scholarship has significantly contributed to identifying key competences of higher education programmes, there is a noticeable gap in research dedicated to competences needed from a professional perspective. This gap makes it challenging to design training programmes to foster such competences. To address this research gap, the authors of this article conducted a scoping review on SCOPUS, Web of Science and ERIC to identify professional sustainability competences outlined in the literature. Furthermore, they examined training activities designed to cultivate these competences and corresponding evaluation practices. By evaluating the abstracts of 475 identified articles, a sample of 37 papers was generated, which were then coded based on a qualitative content analysis. The results show that, consistent with higher education learning outcomes, systems thinking competence, interpersonal competence and strategic competence are particularly relevant. Anticipatory competence, however, assumes a secondary role, while intrapersonal competence and implementation competence – contrary to the higher education context – are considered as not emerging but pivotal. In addition, leadership competence emerges as particularly relevant in the professional field. Finally, this review indicates that intentional competence development in professional training is often not thoroughly evaluated
Palatability of insecticides and protein in sugar solutions to Argentine ants
No full textInvasive ant species like Linepithema humile cause significant ecological and economic harm, making effective control strategies essential. Insecticide baits are currently the most effective approach for controlling ants. Therefore, quantifying how palatable or unpalatable baits, bait additives, or toxicants are, is critical for developing effective control methods. Recent research shows that when animals can compare a test food containing a bitterant with another option, they are much better at detecting the bitterant and thus rejecting the test food. Here, we deploy a newly developed comparative evaluation methodology to examine the palatability to L. humile workers of three toxicants commonly used in invasive ant control: fipronil, spinosad, and imidacloprid. Additionally, we tested egg-white protein in sucrose solutions to assess its impact on bait acceptance. Ants showed no significant preference between pure sucrose and sucrose-toxicant solutions, indicating that they either cannot detect the toxicants or do not find them distasteful. Survival tests confirmed that the toxicant concentrations used, fipronil at 0.0001% and 0.001%, spinosad at 0.015% and 0.15%, and imidacloprid at 0.005%, were lethal, with a survival rate of 50% or below after 72 h. However, ants found egg protein additive unpalatable, significantly preferring pure sucrose to a sucrose egg-white protein mix. These findings confirm that three major toxicants are suitable for use in baits, and that reported abandonment or avoidance of toxic baits is not due to the unpalatability of these toxicants. However, the addition of egg protein alone to sucrose baits, even at ratios which optimise colony growth, is likely counterproductive. Future research should investigate the relative preference of invasive ants for various bait matrixes over naturally available food, ensuring more effective pest management strategies
A Novel Impedance Platform Based on Printed Polymer Electrodes for Automated Virus Neutralization Assays
No full textCell-based neutralization assays are of central importance for the development of new vaccine candidates as well as quality assurance of already approved vaccines. Suppression of viral infection by neutralizing antibodies present in serum of vaccinated individuals serves as an indicator for efficacy of a vaccine. Established readouts used to date are hardly automated, provide no time resolution and require expensive reagents. These shortcomings are limiting factors in vaccine development. In contrast, when virus-compatible host cells are grown on multi-electrode arrays, the cellular infection state and the associated cell response are assessable by impedance measurements. Unlike endpoint assays, the host cell response is followed continuously in real time, label-free and noninvasively. Here, a sensor platform comprising hardware, software and disposable electrode arrays is described suitable for fully automated cell-based neutralization assays tailored for high throughput screening campaigns. To develop cost-effective, disposable electrode arrays for impedance measurements, we screen printed film electrodes made from conducting polymers on the bottom of multi-well plates. The polymer electrodes were characterized for their host cell compatibility and readout performance in comparison to established gold-film electrodes. Hard- and software were tailored for robust and routine use in virological assays. Virus titration, virus neutralization as well as antiviral drug (Efavirenz) intervention studies were conducted using vesicular stomatitis virus (VSV) pseudotypes or the Env HIV-1 infectious molecular clones Ce1176 and X1632 as viral model systems. The assays showed very similar analytical performance in terms of titration curves and dose–response relationships for polymer electrodes compared to commercial gold-film electrode arrays and reporter-based endpoint assays. Considering their technical advantages over established assays, impedance readings based on low-cost polymer electrode arrays may become an attractive alternative to conventional assays using luminescent or colorimetric readouts