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Cellular senescence is a form of cell cycle arrest that limits the proliferative potential of cells, including tumour cells. However, inability of immune cells to subsequently eliminate senescent cells from the organism may lead to tissue damage, inflammation, enhanced carcinogenesis and development of age-related diseases. We found that the anticancer agent mitochondria-targeted tamoxifen (MitoTam), unlike conventional anticancer agents, kills cancer cells without inducing senescence in vitro and in vivo. Surprisingly, it also selectively eliminates both malignant and non-cancerous senescent cells. In naturally aged mice treated with MitoTam for 4 weeks, we observed a significant decrease of senescence markers in all tested organs compared to non-treated animals. Mechanistically, we found that the susceptibility of senescent cells to MitoTam is linked to a very low expression level of adenine nucleotide translocase-2 (ANT2), inherent to the senescent phenotype. Restoration of ANT2 in senescent cells resulted in resistance to MitoTam, while its downregulation in non-senescent cells promoted their MitoTam-triggered elimination. Our study documents a novel, translationally intriguing role for an anticancer agent targeting mitochondria, that may result in a new strategy for the treatment of age-related diseases and senescence-associated pathologies.

Summary Metformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

Die historische Narratolgie hat in den letzten Jahren zunehmend an Relevanz gewonnen. Die Studie entwirft anhand der Auseinandersetzung mit Zeit in Erzähltexten der Frühen Neuzeit eine historische Narratologie, die erzählerische Faktoren, die Struktur der erzählten Welt und semantische Elemente in ihren Ansatz einbindet und somit den Bogen schlägt zwischen formgeschichtlichen und kontextualisierenden Ansätzen. Mit Hilfe dieses Ansatzes werden in kurzen Beispiellektüren, umfassenderen Romanlektüren und durch literarhistorische Seitenblicke die vielfältigen, parallel bestehenden, teils widersprüchlichen Konzepte von Zeit in literarischen Erzähltexten der Frühen Neuzeit rekonstruiert. Die Lektüren führen vor der Folie des frühneuzeitlichen Modernisierungsprozesses vor, dass es in literarischen Texten nicht die eine Zeit gibt, sondern eine Vielzahl von erzählten Zeiten. Die Befunde der Studie lassen sich in methodischer Hinsicht und mit Blick auf kulturgeschichtliche Fragen weiterdenken, interessant sind sie also gleichermaßen für erzähltheoretische wie literarhistorische Forschungsfragen.

Type 2 diabetes mellitus represents a major health problem with increasing prevalence worldwide. Limited efficacy of current therapies has prompted a search for novel therapeutic options. Here we show that treatment of pre-diabetic mice with mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, improves glucose tolerance and reduces body weight with most pronounced reduction of visceral adipose tissue due to reduced food intake, suppressed adipogenesis and elimination of senescent cells. Glucose-lowering effect of mitochondrially targeted tamoxifen is linked to improvement of type 2 diabetes mellitus-related hormones profile and is accompanied by reduced lipid accumulation in liver. Lower senescent cell burden in various tissues, as well as its inhibitory effect on pre-adipocyte differentiation, results in lower level of circulating inflammatory mediators that typically enhance metabolic dysfunction. Targeting senescence with mitochodrially targeted tamoxifen thus represents an approach to the treatment of type 2 diabetes mellitus and its related comorbidities, promising a complex impact on senescence-related pathologies in aging population of patients with type 2 diabetes mellitus with potential translation into the clinic. Senescent cells play a role in pathogenesis of diabetes, and senolytic agents can improve obesity- and diabetes-related pathologies. Here the authors report that mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, alleviates symptoms of obesity and prediabetes in mice, potentially via reduction of food intake and elimination of senescent cells.

Multiple studies indicate that iron chelators enhance their anti-cancer properties by inducing NDRG1, a known tumor and metastasis suppressor. However, the exact role of NDRG1 remains controversial, as newer studies have shown that NDRG1 can also act as an oncogene. Our group recently introduced mitochondrially targeted iron chelators deferoxamine (mitoDFO) and deferasirox (mitoDFX) as effective anti-cancer agents. In this study, we evaluated the ability of these modified chelators to induce NDRG1 and the role of NDRG1 in breast cancer. We demonstrated that both compounds specifically increase NDRG1 without inducing other NDRG family members. We have documented that the effect of mitochondrially targeted chelators is at least partially mediated by GSK3α/β, leading to phosphorylation of NDRG1 at Thr 346 and to a lesser extent on Ser 330 . Loss of NDRG1 increases cell death induced by mitoDFX. Notably, MDA-MB-231 cells lacking NDRG1 exhibit reduced extracellular acidification rate and grow slower than parental cells, while the opposite is true for ER+ MCF7 cells. Moreover, overexpression of full-length NDRG1 and the N-terminally truncated isoform (59112) significantly reduced sensitivity towards mitoDFX in ER+ cells. Furthermore, cells overexpressing full-length NDRG1 exhibited a significantly accelerated tumor formation, while its N-terminally truncated isoforms showed significantly impaired capacity to form tumors. Thus, overexpression of full-length NDRG1 promotes tumor growth in highly aggressive triple-negative breast cancer.

Filter-based spectral systems are highly competitive due to their compactness, simplicity, and well-defined spectral characteristics. However, their primary drawback remains low detection efficiency. This work explores various strategies to enhance detection efficiency. While an additional row of beamsplitters can significantly improve illumination, alternative folded beam path designs—eliminating the need for beamsplitters—prove to be far more effective. Additionally, a novel approach utilizing a freeform mirror is introduced, enabling differential adjustment of detection efficiency across different spectral regions. For the first time, a comprehensive comparison of these strategies is presented.

This work provides a comprehensive analysis of the maximum chromatic axial split of two-element hyperchromats, with the distance between the two lenses being a key variable. Purely refractive and diffractive systems are considered, as well as hybrid layouts combining refractive and diffractive elements. In order to achieve extreme chromatic axial splitting and accordingly a minimum equivalent Abbe number for lens combinations, a three-step procedure was used. In the first paraxial step, purely optical quantities such as focal lengths of the lenses, inter-lens distances and dispersion properties of the lenses were investigated. In the second step, which also takes place in the paraxial domain, additional geometric boundary conditions such as the radii, diameters and thicknesses of the lenses are taken into account. The results of this step serve as an input for the final optimization using optical design software, which derives practical solutions for minimum equivalent Abbe numbers with diffraction-limited image quality. As a significant result, the comparison with directly cemented lens doublets shows that the introduction of a distance between the elements allows for a much stronger chromatic decomposition for refractive, diffractive and also hybrid combinations. Quantitatively, the minimum equivalent Abbe number for refractive systems is reduced from 2.5 (without spacing) to 1.79 (with spacing). For hybrid combinations, a corresponding reduction from 0.4 to 0.29 is achieved.

Hybrid polymers combine the benefits of inorganic and organic material properties, offering superior thermal, mechanical, and chemical stability, making them ideal for optical applications. This study focuses on the fabrication and characterization of antireflective (AR) structures within hybrid polymers using reactive ion etching (RIE). The etching process produces nanopillars with controlled heights, achieving excellent AR performance across a broad spectral range from 450 nm to 2 µm. Optical characterization, including angle-resolved transmission and reflection measurements, shows that the structured samples maintain high transmission efficiency and reduced reflectance at varying incidence angles. Thermal stability tests reveal that the AR structures preserve their optical properties after exposure to temperatures up to 250 °C. Higher temperatures cause significant material yellowing, which is attributed to changes in the bulk material rather than damage to the structured surface. Hydrophobicity measurements show significant water repellency in structured samples, with contact angles more than twice those of unstructured layers. These findings highlight the potential of hybrid polymers with moth-eye-inspired nanostructures for high-performance, durable optical components in demanding environments.

Objective While statins have demonstrated a variety of antineoplastic effects in preclinical studies, several retrospective clinical studies and observational studies have not shown a consistent chemopreventive benefit against prostate cancer (PCa). Therefore, in this population‐based cohort study, we examined the association of statin intake on prostate specific antigen (PSA) values and risk of development of PCa. Method N = 4,314 men from the Swiss section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were evaluated. N = 761 men were statin users [Stat+]. The median follow‐up was 9.6 years. A transrectal prostate biopsy was performed in men with a PSA‐level ≥ 3 ng/mL. Mortality and incidence data was obtained through registry linkages. PCa incidence, total serum PSA level, free‐to‐total PSA level, and overall survival were compared between [Stat+] and [Stat−] patients. Results Total PSA values were significantly lower in [Stat+] patients at baseline (1.5 vs. 1.8 ng/mL, p < 0.001) and at last follow‐up (1.8 vs. 2.1 ng/mL, p < 0.001). PCa detection during the follow‐up period was significantly associated with baseline PSA. The overall incidence of PCa showed no statistical difference among [Stat+] and [Stat−] groups (7.4% vs. 9.5%, p = 0.08), indicating that statin use had no effect on the risk of developing PCa during follow‐up. [Stat+] patients had a significantly higher overall mortality risk compared to [Stat−] patients (HR 2.04, p < 0.001). Discussion A significant risk reduction in the development of PCa in [Stat+] patients was not found. We did observe lower PSA values among [Stat+] patients, compared to [Stat−] patients, with an increasing difference during follow‐up. Lower prostate‐specific antigen (PSA) values were found among statin users, compared to statin non‐users. A significant prostate cancer (PCa) risk reduction in statin users was not observed. Statin users had a significantly higher overall mortality risk than statin non‐users.

The accumulation of solid electrolyte interphases (SEI) in graphite anodes related to elevated formation rates (0.1C, 1C and 2C), cycling rates (1C and 2C), and electrode-separator lamination is investigated. As shown previously, the lamination technique is beneficial for the capacity aging in graphite-LiNi1/3Mn1/3Co1/3O2 cells. Here, surface resistance growth phenomena are quantified using electrochemical impedance spectroscopy (EIS). The graphite anodes were extracted from the graphite NMC cells in their fully discharged state and irreversible accumulations of lithium in the SEI are revealed using neutron depth profiling (NDP). In this post-mortem study, NDP reveals uniform lithium accumulations as a function of depth with lithium situated at the surface of the graphite particles thus forming the SEI. The SEI was found to grow logarithmically with cycle number starting with the main formation in the initial cycles. Furthermore, the EIS measurements indicate that benefits from lamination arise from surface resistance growth phenomena aside from SEI growth in superior anode fractions.