Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC

Spectrally stable nitrogen-vacancy centers in diamond formed by carbon implantation into thin microstructures

The nitrogen-vacancy center (NV) in diamond, with its exceptional spin coherence and convenience in optical spin initialization and readout, is increasingly used both as a quantum sensor and as a building block for quantum networks. Employing photonic structures for maximizing the photon collection efficiency in these applications typically leads to broadened optical linewidths for the emitters, which are commonly created via nitrogen ion implantation. With studies showing that only native nitrogen atoms contribute to optically coherent NVs, a natural conclusion is to either avoid implantation completely, or substitute nitrogen implantation by an alternative approach to vacancy creation. Here, we demonstrate that implantation of carbon ions yields a similar yield of NVs as implantation of nitrogen ions, and that it results in NV populations with narrow optical linewidths and low charge-noise levels even in thin diamond microstructures. We measure a median NV linewidth of 150 MHz for structures thinner than 5 $\mu$m, with no trend of increasing linewidths down to the thinnest measured structure of 1.9 $\mu$m. We propose a modified NV creation procedure in which the implantation is carried out after instead of before the diamond fabrication processes, and confirm our results in multiple samples implanted with different ion energies and fluences

Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma

Neuroblastoma is the most common paediatric solid tumour and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be sensitive to indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models, indisulam induces rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlight a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrates metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour regression without relapse was observed in both xenograft and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss, RNA splicing and metabolic changes confirmed in vivo. Our data show that dual-targeting of metabolism and RNA splicing with anticancer indisulam is a promising therapeutic approach for high-risk neuroblastoma

Lipid remodelling in the reef-building honeycomb worm, Sabellaria alveolata, reflects acclimation and local adaptation to temperature

Acclimation and adaptation, which are key to species survival in a changing climate, can be observed in terms of membrane lipid composition. Remodelling membrane lipids, via homeoviscous adaptation (HVA), counteracts membrane dysfunction due to temperature in poikilotherms. In order to assess the potential for acclimation and adaptation in the honeycomb worm, Sabellaria alveolata, a reefbuilding polychaete that supports high biodiversity, we carried out common-garden experiments using individuals from along its latitudinal range. Individuals were exposed to a stepwise temperature increase from 15 °C to 25 °C and membrane lipid composition assessed. Our results suggest that S. alveolata was able to acclimate to higher temperatures, as observed by a decrease in unsaturation index and 20:5n-3. However, over the long-term at 25 °C, lipid composition patterns are not consistent with HVA expectations and suggest a stress response. Furthermore, unsaturation index of individuals from the two coldest sites were higher than those from the two warmest sites, with individuals from the thermally intermediate site being in-between, likely reflecting local adaptation to temperature. Therefore, lipid remodelling appears limited at the highest temperatures in S. alveolata, suggesting that individuals inhabiting warm environments may be close to their upper thermal tolerance limits and at risk in a changing climate

Les remaniements historiques du régime des eaux d'un marais littoral : le Marais breton-vendéen

ABSTRACT The marsh lying on the Brittany-Vendée border is an Atlantic coastal wetland which underwent considerable change during the last centuries. The development of human activities such as salt production, agriculture and oyster industry obliged man to fight against storm surges and seasonal freshwater floods. In this paper are shown the historical changes in water control with new dikes, waterways and sluices. A general account is given of the evolution in brackish water flow related to various types of management.RÉSUMÉ Le marais breton-vendéen est un marais littoral atlantique qui a encore notablement évolué au cours de la période historique récente. Au colmatage naturel se sont ajoutées diverses actions anthropiques comportant une multiplicité d'aménagements : digues, polders, canaux, vannages, etc.. De tout temps, l'homme a lutté à la fois contre l'intrusion marine et l'inondation liée aux afflux saisonniers d'eau douce. Nous présentons les étapes successives de l'aménagement des réseaux hydrographiques et les conséquences concernant la gestion hydraulique et le régime de salinité des eaux.Baudet J., Gruet Yves, Maillard Y. Les remaniements historiques du régime des eaux d'un marais littoral : le Marais breton-vendéen . In: Norois, n°133-135, Janvier-Septembre 1987. Espaces côtiers et sociétés littorales. Colloque international des 28, 29 et 30 novembre 1986 à Nantes. pp. 11-22