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Yeast cell death can occur during wine alcoholic fermentation. It is generally considered toresult from ethanol stress that impacts membrane integrity. This cell death mainly occurswhen grape musts processing reduces lipid availability, resulting in weaker membrane resistanceto ethanol. However the mechanisms underlying cell death in these conditions remainunclear. We examined cell death occurrence considering yeast cells ability to elicit an appropriateresponse to a given nutrient limitation and thus survive starvation. We show here thata set of micronutrients (oleic acid, ergosterol, pantothenic acid and nicotinic acid) in low,growth-restricting concentrations trigger cell death in alcoholic fermentation when nitrogenlevel is high. We provide evidence that nitrogen signaling is involved in cell death and thateither SCH9 deletion or Tor inhibition prevent cell death in several types of micronutrient limitation.Under such limitations, yeast cells fail to acquire any stress resistance and areunable to store glycogen. Unexpectedly, transcriptome analyses did not reveal any majorchanges in stress genes expression, suggesting that post-transcriptional events critical forstress response were not triggered by micronutrient starvation. Our data point to the factthat yeast cell death results from yeast inability to trigger an appropriate stress responseunder some conditions of nutrient limitations most likely not encountered by yeast in thewild. Our conclusions provide a novel frame for considering both cell death and the managementof nutrients during alcoholic fermentation.

In alcoholic fermentation, under oenological conditions, the environmental parameters impacting fermentation kinetics and aroma production have been widely studied. The nitrogen content of grape must was found to be one of the most important parameters for both of these aspects of fermentation. Many studies have been performed on the effect of mineral nitrogen addition. However, it has increasingly been observed that the nature of the nitrogen added leads to different results. Our work focused on the effects of peptide addition on both fermentation kinetics and aroma production. Peptides are one of the less well understood sources of assimilable nitrogen, as their incorporation by yeast remains unclear. In this study, we compared the effect of the addition of a “classic” assimilable nitrogen source (ammonium + amino acids) with that of peptide addition in both white and red must fermentation by screening 18 Saccharomyces cerevisiae strains in total. Our data show that peptide addition enhances fermentation kinetics and leads to specific changes in the production of fermentative aromas. The impact of peptides on thiol synthesis is rather limited.

Yeast cell death can occur during wine alcoholic fermentation and lead to sluggish or stuck fermentations. The mechanisms underlying cell death during yeast starvation in alcoholic fermentations remain unclear. In this work we addressed yeast cell death using conceptual framework from ageing studies showing that yeast resistance to starvation can be influenced by the nature of the nutrient limiting cell growth. We examined cell death occurrence considering yeast cells ability to elicit an appropriate response to a set of nutrient limitations. We show that several micronutrients limitations (oleic acid, ergosterol, pantothenic acid and nicotinic acid) trigger cell death in a nitrogen-dependent manner. We provide evidence that the nitrogen Tor/Sch9 signaling pathway is involved in triggering cell death. In such conditions, yeast cells fail to acquire stress resistance given a restriction at a post-transcriptional level. We have examined the ability of different nitrogen sources to trigger cell death and show that they impact differentially on cell death and that NH+ 4 had a strong death inducing capacity. Finally, the QTLs approaches allowed the mapping of a set of loci controlling cell death under oleic acid and pantothenic acid starvation consistent with a multigenic control.

Yeast cell death can occur during wine alcoholic fermentation and lead to sluggish or stuck fermentations. The mechanisms underlying cell death during yeast starvation in alcoholic fermentations remain unclear. In this work we addressed yeast cell death using conceptual framework from ageing studies showing that yeast resistance to starvation can be influenced by the nature of the nutrient limiting cell growth. We examined cell death occurrence considering yeast cells ability to elicit an appropriate response to a set of nutrient limitations. We show that several micronutrients limitations (oleic acid, ergosterol, pantothenic acid and nicotinic acid) trigger cell death in a nitrogen-dependent manner. We provide evidence that the nitrogen Tor/Sch9 signaling pathway is involved in triggering cell death. In such conditions, yeast cells fail to acquire stress resistance given a restriction at a post-transcriptional level. We have examined the ability of different nitrogen sources to trigger cell death and show that they impact differentially on cell death and that NH 4  + had a strong death inducing capacity. Finally, the QTLs approaches allowed the mapping of a set of loci controlling cell death under oleic acid and pantothenic acid starvation consistent with a multigenic control.

Lake Chad, in the Sahelian zone of west-central Africa, provides food and water to ~50 million people and supports unique ecosystems and biodiversity. In the past decades, it became a symbol of current climate change, held up by its dramatic shrinkage in the 1980s. Despites a partial recovery in response to increased Sahelian precipitation in the 1990s, Lake Chad is still facing major threats and its contemporary variability under climate change remains highly uncertain. Here, using a new multi-satellite approach, we show that Lake Chad extent has remained stable during the last two decades, despite a slight decrease of its northern pool. Moreover, since the 2000s, groundwater, which contributes to ~70% of Lake Chad’s annual water storage change, is increasing due to water supply provided by its two main tributaries. Our results indicate that in tandem with groundwater and tropical origin of water supply, over the last two decades, Lake Chad is not shrinking and recovers seasonally its surface water extent and volume. This study provides a robust regional understanding of current hydrology and changes in the Lake Chad region, giving a basis for developing future climate adaptation strategies.

AGuIX, a novel gadolinium-based nanoparticle, has been deployed in a pioneering double-blinded Phase II clinical trial aiming to assess its efficacy in enhancing radiotherapy for tumor treatment. This paper moves towards this goal by analyzing AGuIX uptake patterns in 23 patients. A phantom was designed to establish the relationship between AGuIX concentration and longitudinal ( T 1 ) relaxation. A 3T MRI and MP2RAGE sequence were used to generate patient T 1 maps. AGuIX uptake in tumors was determined based on longitudinal relaxivity. AGuIX (or placebo) was administered to 23 patients intravenously at 100 mg/kg 1–5 hours pre-imaging. Each of 129 brain metastases across 23 patients were captured in T 1 maps and examined for AGuIX uptake and distribution. Inferred AGuIX recipients had average tumor uptakes between 0.012 and 0.17 mg/ml, with a mean of 0.055 mg/ml. Suspected placebo recipients appeared to have no appreciable uptake. Tumors presented with varying spatial AGuIX uptake distributions, suspected to be related to differences in accumulation time and patient-specific bioaccumulation factors. This research demonstrates AGuIX's ability to accumulate in brain metastases, with quantifiable uptake via T 1 mapping. Future analyses will extend these methods to complete clinical trial data (~ 134 patients) to evaluate the potential relationship between nanoparticle uptake and possible tumor response following radiotherapy. Clinical Trial Registration Number: NCT04899908. Clinical Trial Registration Date: 25/05/2021.

Background and aimsSKN-1, a C. elegans transcription factor analogous to the mammalian NF-E2-related factor (Nrf2), has been known to promote oxidative stress resistance aiding nematodes’ longevity. Although SKN-1’s functions suggest its implication in lifespan modulation through cellular metabolism, the actual mechanism of how metabolic rearrangements contribute to SKN-1’s lifespan modulation has yet to be well characterized. Therefore, we performed the metabolomic profiling of the short-lived skn-1-knockdown C. elegans.MethodsWe analyzed the metabolic profile of the skn-1-knockdown worms with nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-tandem mass spectrometry (LC–MS/MS) and obtained distinctive metabolomic profiles compared to WT worms. We further extended our study with gene expression analysis to examine the expression level of genes encoding all metabolic enzymes.ResultsA significant increase in the phosphocholine and AMP/ATP ratio, potential biomarkers of aging, was observed, accompanied by a decrease in the transsulfuration metabolites, NADPH/NADP+ ratio, and total glutathione (GSHt), which are known to be involved in oxidative stress defense. skn-1-RNAi worms also exhibited an impairment in the phase II detoxification system, confirmed by the lower conversion rate of paracetamol to paracetamol-glutathione. By further examining the transcriptomic profile, we found a decrease in the expression of cbl-1, gpx, T25B9.9, ugt, and gst, which are involved in GSHt and NADPH synthesis as well as in the phase II detoxification system.ConclusionOur multi-omics results consistently revealed that the cytoprotective mechanisms, including cellular redox reactions and xenobiotic detoxification system, contribute to the roles of SKN-1/Nrf2 in the lifespan of worms.

IntroductionOccurrence of multiple brain metastases is a critical evolution of many cancers with significant neurological and overall survival consequences, despite new targeted therapy and standard whole brain radiotherapy (WBRT). A gadolinium-based nanoparticle, AGuIX, has recently demonstrated its effectiveness as theranostic and radiosensitiser agent in preclinical studies. The favourable toxicity profile in animals and its administration as a simple intravenous injection has motivated its use in patients with this first in human study.Methods and analysisThe NANO-RAD study is a phase I, first in human injection, monocentric, open-label, dose-escalation study to investigate the safety, the tolerability and the spectrum of side effects of AGuIX in combination with WBRT (30 Gy, 10 fractions of 3 Gy) for patients with multiple brain metastases. Five dose escalation cohorts are planned: 15, 30, 50, 75 and 100 mg/kg. A total of 15–18 patients will be recruited into this trial. The primary objective is to determine the maximum-tolerated dose of AGuIX nanoparticles combined with WBRT for the treatment of multiple brain metastases. Toxicity will be assessed using the National Cancer Institute Common Toxicity Criteria V.4.03. Secondary objectives are pharmacokinetic profile, distribution of AGuIX in metastases and surrounding healthy tissue visualised by MRI, intracranial progression-free survival and overall survival. Intracranial response will be determined according to Response Evaluation Criteria in Solid Tumour Criteria V.1.1 comparing MRI performed prior to treatment and at each follow-up visits.Ethics and disseminationApproval was obtained from the ethics committee Sud Est V, France (Reference number 15-CHUG-48). The study was approved by the French National Agency for the Safety of Medicines and Health Products (ANSM) (Reference number 151519A-12). The results will be published in peer-reviewed journals or disseminated through national and international conferences.Trial registration number NCT02820454; Pre-results.

This study reports the use of gadolinium-based AGuIX nanoparticles (NPs) as a theranostic tool for both image-guided radiation therapy and radiosensitization of brain tumors. Pharmacokinetics and regulatory toxicology investigations were performed on rodents. The AGuIX NPs' tumor accumulation was studied by MRI before 6-MV irradiation. AGuIX NPs exhibited a great safety profile. A single intravenous administration enabled the tumor delineation by MRI with a T tumor contrast enhancement up to 24 h, and the tumor volume reduction when combined with a clinical 6-MV radiotherapy. This study demonstrates the efficacy and the potential of AGuIX NPs for image-guided radiation therapy, promising properties that will be assessed in the upcoming Phase I clinical trial.