The Contribution of Mitochondrial Ion Channels to Cancer Development and Progression

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Exploring the capabilities of ChatGPT in women’s health: obstetrics and gynaecology

Artificial Intelligence (AI) is transforming healthcare, with Large Language Models (LLMs) like ChatGPT offering novel capabilities. This study evaluates ChatGPT’s performance in interpreting and responding to the UK Royal College of Obstetricians and Gynaecologists MRCOG Part One and Two examinations – international benchmarks for assessing knowledge and clinical reasoning in Obstetrics and Gynaecology. We analysed ChatGPT’s domain-specific accuracy, the impact of linguistic complexity, and its self-assessment confidence. A dataset of 1824 MRCOG questions was curated, ensuring minimal prior exposure to ChatGPT. ChatGPT’s responses were compared to known correct answers, and linguistic complexity was assessed using token counts and Type-Token ratios. Confidence scores were assigned by ChatGPT and analysed for self-assessment accuracy. ChatGPT achieved 72.2% accuracy on Part One and 50.4% on Part Two, performing better on Single Best Answer (SBA) than Extended Matching (EMQ) Questions. The findings highlight the potential and significant limitations of ChatGPT in clinical decision-making in women’s health

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo

Ion channels are non-conventional, druggable oncological targets. The intermediate-conductance calcium-dependent potassium channel (K(Ca)3.1) is highly expressed in the plasma membrane and in the inner mitochondrial membrane (mitoK(Ca)3.1) of various cancer cell lines. The role mitoK(Ca)3.1 plays in cancer cells is still undefined. Here we report the synthesis and characterization of two mitochondria-targeted novel derivatives of a high-affinity K(Ca)3.1 antagonist, TRAM-34, which retain the ability to block channel activity. The effects of these drugs were tested in melanoma, pancreatic ductal adenocarcinoma and breast cancer lines, as well as in vivo in two orthotopic models. We show that the mitochondria-targeted TRAM-34 derivatives induce release of mitochondrial reactive oxygen species, rapid depolarization of the mitochondrial membrane, fragmentation of the mitochondrial network. They trigger cancer cell death with an EC50 in the mu M range, depending on channel expression. In contrast, inhibition of the plasma membrane K(Ca)3.1 by membrane-impermeant Maurotoxin is without effect, indicating a specific role of mitoK(Ca)3.1 in determining cell fate. At sub-lethal concentrations, pharmacological targeting of mitoK(Ca)3.1 significantly reduced cancer cell migration by enhancing production of mitochondrial reactive oxygen species and nuclear factor-kappa B (NF-kappa B) activation, and by downregulating expression of Bcl-2 Nineteen kD-Interacting Protein (BNIP-3) and of Rho GTPase CDC-42. This signaling cascade finally leads to cytoskeletal reorganization and impaired migration. Overexpression of BNIP-3 or pharmacological modulation of NF-kappa B and CDC-42 prevented the migration-reducing effect of mitoTRAM-34. In orthotopic models of melanoma and pancreatic ductal adenocarcinoma, the tumors at sacrifice were 60% smaller in treated versus untreated animals. Metastasis of melanoma cells to lymph nodes was also drastically reduced. No signs of toxicity were observed. In summary, our results identify mitochondrial K(Ca)3.1 as an unexpected player in cancer cell migration and show that its pharmacological targeting is efficient against both tumor growth and metastatic spread in vivo

Spindly is required for rapid migration of human cells

Dynein is the sole processive minus-end-directed microtubule motor found in animals. It has roles in cell division, membrane trafficking, and cell migration. Together with dynactin, dynein regulates centrosomal orientation to establish and maintain cell polarity, controls focal adhesion turnover and anchors microtubules at the leading edge. In higher eukaryotes, dynein/dynactin requires additional components such as Bicaudal D to form an active motor complex and for regulating its cellular localization. Spindly is a protein that targets dynein/dynactin to kinetochores in mitosis and can activate its motility in vitro However, no role for Spindly in interphase dynein/dynactin function has been found. We show that Spindly binds to the cell cortex and microtubule tips and colocalizes with dynein/dynactin at the leading edge of migrating U2OS cells and primary fibroblasts. U2OS cells that lack Spindly migrated slower in 2D than control cells, although centrosome polarization appeared to happen properly in the absence of Spindly. Re-expression of Spindly rescues migration, but the expression of a mutant, which is defective for dynactin binding, failed to rescue this defect. Taken together, these data demonstrate that Spindly plays an important role in mediating a subset of dynein/dynactin's function in cell migration

Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction.

Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondrial energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/β-catenin signaling in vitro in colon cancer cells and in vivo in zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient and a generated zebrafish model lead to reduced Wnt signaling. We identify a mitochondria-Wnt signaling axis whereby a decrease in mitochondrial ATP reduces calcium uptake into the endoplasmic reticulum (ER), leading to endoplasmic reticulum stress and to impaired Wnt signaling. In turn, the recovery of the ATP level or the inhibition of endoplasmic reticulum stress restores Wnt activity. These findings reveal a mechanism that links mitochondrial energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologies

KSHV Reactivation from Latency Requires Pim-1 and Pim-3 Kinases to Inactivate the Latency-Associated Nuclear Antigen LANA

Host signal-transduction pathways are intimately involved in the switch between latency and productive infection of herpes viruses. As with other herpes viruses, infection by Kaposi's sarcoma herpesvirus (KSHV) displays these two phases. During latency only few viral genes are expressed, while in the productive infection the virus is reactivated with initiation of extensive viral DNA replication and gene expression, resulting in production of new viral particles. Viral reactivation is crucial for KSHV pathogenesis and contributes to the progression of KS. We have recently identified Pim-1 as a kinase reactivating KSHV upon over-expression. Here we show that another Pim family kinase, Pim-3, also induces viral reactivation. We demonstrate that expression of both Pim-1 and Pim-3 is induced in response to physiological and chemical reactivation in naturally KSHV-infected cells, and we show that they are required for KSHV reactivation under these conditions. Furthermore, our data indicate that Pim-1 and Pim-3 contribute to viral reactivation by phosphorylating the KSHV latency-associated nuclear antigen (LANA) on serine residues 205 and 206. This counteracts the LANA–mediated repression of the KSHV lytic gene transcription. The identification of Pim family kinases as novel cellular regulators of the gammaherpesvirus life cycle facilitates a deeper understanding of virus–host interactions during reactivation and may represent potential novel targets for therapeutic intervention

Science? Literature? „Alles verschlingende Unform?“ The genre essay from a field theoretical point of view

Von einer normativen Klassifizierung des Genres ‚Essay’ Abstand nehmend, zielt der Artikel auf eine Einordnung aus feldtheoretischer Perspektive ab, wobei gattungstypische Besonderheiten der Produktion sowie der Rezeption berücksichtigt werden: Anvisiert wird ein deskriptiver Zugang, der (literar-) historische Bedingungen und jeweils mit dem Genre assoziierte Werturteile berücksichtigt. An Publikationsund Selbstinszenierungsstrategien des Biochemikers und Essayisten Erwin Chargaff werden die theoretischen Überlegungen veranschaulicht.In contrast to normative classifications of the essay genre, the present article proposes a new perspective based on a field-theoretical approach. Distinctive features of the production and reception of the genre are considered: a descriptive approach is suggested that takes into account (literary-) historical conditions as well as value judgments associated with the genre. The theoretical considerations are illustrated with an example, namely the publication strategy of the biochemist and essayist Erwin Chargaff

Protocol for validation and quality assessment of L2A-products - Validation activities for Sentinel-2 and Landsat-8

The presentation reports on the methods and protocols used for validation of L2A-products on basis of reference data (AERONET sites) and provides examples of the final statistics. Validation should provide simple plots and statistical measures to characterize the performance of atmospheric correction algorithms. Validation of valid and invalid pixels classification relies on visual interpretation supported by statistical methods to ensure representativeness. Validation based on AERONET sites must be supplemented by using surface reflectance measurements provided by ad-hoc-campaigns and permanently operating stations (like RADCALNET for L2A-targets)

Mitochondrial genomes of ancient bowhead whales (Balaena mysticetus) from Svalbard

The endangered Spitsbergen stock of bowhead whales (Balaena mysticetus) has once been large with up to estimated 100,000 individuals. Genetic diversity of the extant Spitsbergen stock is unknown. We present 10 complete mitochondrial genomes of heterochronous ancient bowhead whale samples from Svalbard (14C age estimate range: 215–8885years) obtained via NGS of total genomic DNA extracts. The ten mitogenomes differed by nucleotide substitutions and/or indels, and there was a total of 160 variable positions. The average nucleotide diversity was p 1⁄4 0.0029. There was no statistically significant correlation between genetic divergence and time