Université Bourgogne Europe

Age-related diseases are often associated with a disruption of RedOx balance that can lead to lipid peroxidation with the formation of oxysterols, especially those oxidized on carbon-7: 7-ketocholesterol (also known as 7-oxo-cholesterol) and 7β-hydroxycholesterol. Like cholesterol, these oxysterols have 27 carbons, they are composed of a sterane nucleus and have a hydroxyl function in position 3. The oxysterols 7-ketocholesterol and 7β-hydroxycholesterol are mainly formed by cholesterol autoxidation and are biomarkers of oxidative stress. These two oxysterols are frequently found at increased levels in the biological fluids (plasma, cerebrospinal fluid), tissues and/or organs (arterial wall, retina, brain) of patients with age-related diseases, especially cardiovascular diseases, neurodegenerative diseases (mainly Alzheimer's disease), ocular diseases (cataract, age-related macular degeneration), and sarcopenia. Depending on the cell type considered, 7-ketocholesterol and 7β-hydroxycholesterol induce either caspase- dependent or -independent types of cell death associated with mitochondrial and peroxisomal dysfunctions, autophagy and oxidative stress. The caspase dependent type of cell death associated with oxidative stress and autophagy is defined as oxiapoptophagy. These two oxysterols are also inducers of inflammation. These biological features associated with the toxicity of 7-ketocholesterol, and 7β-hydroxycholesterol are often observed in patients with age-related diseases, suggesting an involvement of these oxysterols in the pathophysiology of these disorders. The cytotoxic effects of 7-ketocholesterol and 7β-hydroxycholesterol are counteracted on different cell models by representative nutrients of the Mediterranean diet: ω3 and ω9 fatty acids, polyphenols, and tocopherols. There are also evidences, mainly in cardiovascular diseases, of the benefits of α-tocopherol and phenolic compounds. These in vitro and in vivo observations on 7-ketocholesterol and 7β-hydroxycholesterol, which are frequently increased in age-related diseases, reinforce the interest of nutritherapeutic treatments to prevent and/or cure age-related diseases currently without effective therapies.

Oxysterols can be derived from the diet, physiologically produced via specific enzymes, or are generated by autoxidation. These molecules have physiological properties and can also adversely affect vital organs. Indeed, some of them have pro-oxidant and pro-inflammatory activities and can lead to major pathologies. The present review focuses on oxysterols (7-ketocholesterol, 7β-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, 5,6α-epoxycholesterol, 5,6β-epoxycholesterol, and cholestane-3β, 5α, 6β-triol) involved either in cholesterol metabolism, age-related diseases (such as cardiovascular, neurodegenerative, and eye diseases, e.g., sarcopenia), and inflammatory diseases (especially Behcet’s disease and bowel and lung diseases (e.g., sarcoidosis, COVID-19)). Metabolic pathways associated with oxysterol-induced inflammation are discussed considering the cytokinic TLR4 pathway, non-cytokinic pathways, and the contribution of Ca2+ and K+ channels. Therapeutic approaches targeting oxysterol-induced inflammation either by natural or synthetic molecules are also presented.

Tribological behavior at both tool/chip and tool/work material interfaces should be highly considered while simulating the machining process. In fact, it is no longer accurate to suppose one independent constant friction coefficient at the tool/chip interface, since in reality it depends on the applied contact conditions, including the sliding velocity and pressure. The contact conditions at both above mentioned interfaces may affect the thermal and mechanical phenomena and consequently the surface integrity predictions. In this article, the influence of contact conditions (sliding velocity) on the tribological behavior of uncoated tungsten carbide tool against OFHC copper work material was investigated. Series of tribology tests combined with numerical simulations of the contact process were performed under different sliding speeds and contact pressures, in order to identify the friction coefficient and the heat partition between OFHC copper and tungsten carbide. The friction coefficient in function of the sliding velocity was then integrated into a FE model of the orthogonal cutting of OFHC copper and applied to surface integrity prediction.

ABSTRACT: Patients with follicular lymphoma who experience disease progression within 24 months of diagnosis (POD24) have a lower survival. Positron emission tomography (PET) response and circulating tumor DNA (ctDNA) minimal residual disease (MRD) assessment at end of induction (EOI) may allow their early identification. A representative cohort of 141 patients from the RELEVANCE phase 3 trial with both available serum samples for ctDNA testing and PET images at randomization and at EOI (week 24) was investigated. Twelve percent were POD24. ctDNA was analyzed using a customized 130-kilobase capture panel, with phased variant (PV) enriched regions representing 39% of the panel. ctDNA was detected in 140 patients (99.3%) at baseline. To optimize specificity, only PVs, found in 124 patients (88%), were considered for ctDNA MRD assessment at EOI. Median progression-free survival (PFS) from EOI was not reached (NR) for the 112 patients with undetected ctDNA at EOI vs 17.7 months (95% confidence interval [CI], 1.4 to NR) for patients with positive ctDNA (MRD+) (P = .0038). Similarly, median PFS was NR for the 104 patients with undetected disease on PET at EOI vs 28.3 months (95% CI, 2.9 to NR; P = .0002) for patients with PET positivity. Both tests had a negative predictive value (NPV) of >90% for POD24. The positive predictive value was 58.3% for ctDNA MRD and 45% for PET but increased to 85.7% when both parameters were combined, without alteration of NPV. These data show that the combination of PET response and ctDNA MRD at EOI allows an early prediction of POD24, which may lead to a preemptive treatment decision. This trial was registered at www.clinicaltrials.gov as #NCT01650701.

This paper explores Text-to-Knowledge Graph (T2KG) construction, assessing Zero-Shot Prompting, Few-Shot Prompting, and Fine-Tuning methods with Large Language Models. Through comprehensive experimentation with Llama2, Mistral, and Starling, we highlight the strengths of FT, emphasize dataset size's role, and introduce nuanced evaluation metrics. Promising perspectives include synonym-aware metric refinement, and data augmentation with Large Language Models. The study contributes valuable insights to KG construction methodologies, setting the stage for further advancements.

We report on numerical predictions and experimental observations of a novel type of temporal localized dissipative structures that manifest themselves in the self-defocusing regime of driven nonlinear optical resonators with two polarization modes. These chiral dissipative solitons, which we term "polarization faticons," break both temporal and polarization symmetry and consist of two bright lobes of opposite polarization handedness, interlocked by a domain wall. Our study reveals that faticons are connected to a vectorial modulational instability, from which they can be excited through a collapsing dynamic. Faticons could offer a novel pathway for frequency comb generation in normal dispersion resonators. More generally, they offer new fundamental insights into vectorial localized dissipative structures and could be relevant to other multicomponent dissipative systems.

Simultaneously increasing the spectral bandwidth and average output power of mid-infrared supercontinuum sources remains a major challenge for their practical application. We particularly address this issue for the long mid-infrared spectral region through experimental developments of short tapered rods made from selenide glass by means of supercontinuum generation in the femtosecond regime. Our simple post-processing of glass rods unlocks potentially higher-power and coherent fiber-based supercontinuum sources beyond the 10-μm waveband. By using a 5-cm-long tapered Ge-Se-Te rod pumped at 6 μm, a supercontinuum spanning from 2 to 15 μm (3–14 μm) with an average output power of 93 mW (170 mW) is obtained for 500-kHz (1-MHz) repetition rate. Additional experiments on other glass families (silica and tellurite) covering distinct spectral regions are also reported to develop and support our analyses. We demonstrate that ultra-broadband spectral broadenings over entire glass transmission windows can be achieved in few-cm-long segments of tapered rods by a fine adjustment of input modal excitation. Numerical simulations are used to confirm the main contribution of the fundamental mode in the ultrafast nonlinear dynamics, as well as the possible preservation of coherence features. Our study opens a new route, to our knowledge, towards the power scaling of high-repetition-rate fiber supercontinuum sources over the full molecular fingerprint region.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by an excessive collagen deposition ultimately leading to tissue stiffening and functional decline.Beyond IPF, other progressive pulmonary fibrosis are often associated with connective tissue diseases and may develop in 18-32% of patients.Therapeutic options are limited to nintedanib and pirfenidone which are only able to reduce fibrosis progression without curing it.The current lack of biomarker to accurately assess and predict disease progression and therapy efficacy for IPF remains a major clinical concern.Methods: In our study, collagen deposition was monitored in bleomycin-induced lung fibrosis in mice by in vivo molecular imaging using a collagen-targeted radiopharmaceutical, [ 68 Ga]Ga-NODAGA-collagelin. Fibrosis progression was also monitored using computed tomography, the gold standard technique to detect lung fibrosis in patients. Results:We demonstrated that the bleomycin-induced increase in collagen lung content can be accurately quantified by [ 68 Ga]Ga-NODAGA-collagelin PET imaging in correlation with disease stage and severity.The lung uptake of [ 68 Ga]Ga-NODAGA-collagelin was mainly found in fibrotic areas of lungs in bleomycin-receiving mice.Most interestingly, [ 68 Ga]Ga-NODAGA-collagelin PET imaging allowed the in vivo non-invasive monitoring of nintedanib efficacy as well as the anti-fibrotic effect of the JAK inhibitor, tofacitinib.Conclusion: Thus, collagen-targeted PET imaging appears as a promising non-invasive tool for staging, monitoring and prediction of disease progression and therapy efficacy towards personalized medicine in IPF.

Hydrogen (H 2 ) has gained a lot of interest as an alternative energy vector, to reduce greenhouse gas emission issues caused by the fossil fuel industry. However, to make hydrogen a real energy carrier in a decarbonated economy, a secure and sustainable supply chain is needed. This approach requires notably safe storage and efficient strategies for recycling of raw materials. We discuss in this survey the state-of-the-art in the field of chemical hydrogen storage (CHS) materials, considering two possible vectors: ammonia borane and hydrosilanes. Regardless of the vector, to achieve real use, it is necessary to understand both the performance of the system and its life cycle, which relates to catalysts structure, and the activation of chemical bonds with efficient and complete catalytic cycles. We give herein an overview of hydrolysis and/or alcoholysis from metals, using coordination complexes, molecular supported catalysts or other materials, including nanocatalysts, with a focus on mechanistic information and understanding. Notably, the studies related to these two vectors can be considered somewhat complementary. Thus, the set of bibliographic report on ammonia borane is very documented in efficient catalytic systems, while its recycling remains at a very early stage. In comparison, hydrosilanes have been much less addressed specifically as a vector for hydrogen, while their reactivity at the molecular scale benefits from a relevant understanding from coordination chemistry studies. In addition, both hydrosilane polymerization and solvolysis reaction enables the release of H 2 , and produces by-products of which added value is already established. This opening the way to economical strategies where recycling can be optional. Nevertheless, the reversibility of hydrosilanes chemistry in H 2 uptake remains attractive and is another option to develop. • Ammonia borane synthesis and chemical properties. • Boranes regeneration after solvolysis – cumulative table for mechanochemistry approaches. • Catalytic hydrolysis and alcoholysis of hydrosilanes. • Catalytic dehydrogenative oligomerization of hydrosilanes. • Regeneration and reversibility of hydrosilane solvolysis products.

Abstract Variants in spliceosomal small nuclear RNA (snRNA) genes RNU4-2 (ReNU syndrome), RNU5B-1 , and RNU2-2 have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify de novo and biallelic variants in RNU2-2 associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive RNU2-2 NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a de novo variant in trans with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive RNU2-2 -NDDs share overlapping clinical features with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our findings support a gradient-of-impact model and a continuum between dominant and recessive inheritance, establishing RNU2-2 variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.

The functionalization of polycyclic aromatic hydrocarbons (PAHs) with N→B Lewis pairs, so-called borylative fusion, has recently emerged as a simple and powerful means to modulate their electronic and photophysical properties thanks to the extension of the π system. Herein, we considered a new class of PAHs appended with phosphine→borane Lewis pairs and investigated pyrene as well as anthracene derivatives. In these compounds, strong P→B interactions are enforced geometrically, but the π-system is not extended. Nevertheless, such P→B functionalization was found to significantly impact the optical and electrochemical properties. The P,B-functionalized PAHs display noticeably reduced HOMO-LUMO gaps and enhanced fluorescence. Both the number and position of P→B units turned out to play a significant role.

Abstract The digestive tract represents the most complex interface of an organism with its biotope. Food may be contaminated by pathogens and toxicants while an abundant and complex microbiota thrives in the gut lumen. The organism must defend itself against potentially noxious biotic or abiotic stresses while preserving its microbiota, provided it plays a beneficial role. The presence of intestinal viruses adds another layer of complexity. Starting from a differential sensitivity of two lines from the same Drosophila wild-type strain to ingested Pseudomonas aeruginosa , we report here that the presence of Nora virus in the gut epithelium promotes the sensitivity to this bacterial pathogen as well as to an ingested oxidizing xenobiotic. The genotype, age, nature of the ingested food and, to a limited extent, the microbiota are relevant parameters that influence the effects of Nora virus on host fitness. Mechanistically, we detect the initial presence of the virus essentially in progenitor cells. Upon stress such as infection, exposure to xenobiotics, aging or feeding on a rich-food diet, the virus is then detected in enterocytes, which correlates with a disruption of the intestinal barrier function in aged flies. Finally, we show that the virus proliferates only when ISCs are induced to divide. We propose that enterocytes essentially get infected through lineage from progenitor cells and are not directly infected. In conclusion, it is important to check that experimental strains are devoid of intestinal viruses when monitoring survival/life span of fly lines or when investigating the homeostasis of the intestinal epithelium as these viruses can constitute significant confounding factors.

Cyber-attack detection is crucial for securing Industrial Internet of Things (IIoT) systems. This study introduces advanced deep learning methodologies to identify potential cyber-attacks effectively in IIoT devices. Three novel stacked deep learning architectures, namely the StackMean, StackMax, and StackRF algorithms. These architectures aggregate and enhance the results of individual deep learning models. Specifically, StackMean computes average predicted class probabilities, StackMax selects maximum predicted class probabilities for more aggressive predictions, and StackRF leverages a random forest to aggregate base models. Theoretical analysis suggests that the proposed stacked deep learning model can boost detection accuracy compared to standalone single deep learning models. Moreover, these stacked models offer increased robustness against adversarial attacks by reducing reliance on specific neural network structures. Additionally, the synthetic minority oversampling technique (SMOTE) algorithm is integrated to address class imbalance challenges in the training dataset. Performance validation is conducted using three publicly available datasets. The detection performance is evaluated using five statistical scores. The results consistently indicate the superiority of the proposed stacked deep learning models over existing techniques. The effectiveness of the SMOTE algorithm is demonstrated through its ability to expand decision regions and minimize false negative signals during attack predictions. In addition, a statistical test is employed to compare the accuracy of individual models with the stacked models, demonstrating that the stacked models exhibit improved accuracy. By combining cutting-edge stacked deep learning architectures with strategic data augmentation techniques, this research significantly contributes to the robustness of cyber-attack detection within IIoT systems.

G-quadruplexes (G4s) are challenging targets for chemical biology interventions, notably because of their dynamic topological polymorphism. We found that the antibiotic small- molecule colistin (COL) interacts specifically with a single subtype of G4 structures, the so-called parallel G4s. This interaction triggers the aggregation of the G4/COL complexes in a structure-specific manner, which can thus be separated from the bulk solution by centrifugation. This unprecedented mode of affinity-precipitation was exploited here to design the COL-induced RNA G4 precipitation and sequencing (CoRP-seq) protocol, which allows for the assessment of the prevalence of RNA G4s in the transcriptome of human cells in a straightforward manner. CoRP-seq shines by its ultraspecificity, simplicity, and practical convenience, which thus advances G4 mapping further and addresses unmet needs in the field of G4omics.

The utilization of gelatin capsule waste (GCW) poses a challenge for the industry. This study investigates its potential as a functional food ingredient by evaluating the physico-chemical, rheological, and techno-functional properties of gelatin capsule waste powder (GCWP). To achieve this, the gelatin capsule waste (GCW) was mixed with maltodextrin at varying ratios (1:1, 1:2, 1:3, 1:4, and 1:5) and subjected to spray drying. The findings highlight maltodextrin’s crucial role in stabilizing the drying process, reducing stickiness, and enhancing handling and storage properties. All the obtained GCWP samples appeared light white and had a slightly sticky texture. The 1:5 (w/w) GCW-to-maltodextrin ratio produced the highest powder recovery with minimal stickiness, indicating enhanced drying efficiency. Increasing maltodextrin reduced gel strength, texture, and foaming properties while raising the glass transition temperature. The FTIR analysis indicated a decline in protein–protein interactions and increased polysaccharide interactions at higher maltodextrin levels. The rheological analysis demonstrated lower elastic and loss moduli with increased maltodextrin, affecting GCWP’s structural behavior. For overall properties, the GCW mixed with maltodextrin at a 1:1 ratio (GCW-1M) is recommended for future applications, particularly for its gelling characteristics. The GCW-1M, being rich in amino acids, demonstrates its potential as a functional food ingredient. However, certain properties, such as gel strength and powder stability (hygroscopicity and stickiness), require further optimization to enhance its industrial applicability as a functional food ingredient.

We study the time-optimal robust control of a two-level quantum system subjected to field inhomogeneities. We apply the Pontryagin maximum principle and we introduce a reduced space onto which the optimal dynamics is projected down. This reduction leads to a complete analytical derivation of the optimal solution in terms of elliptic functions and elliptic integrals. Necessary optimality conditions are then obtained for the original system. These conditions are verified numerically and lead to the optimal control protocol. Various examples, ranging from state-to-state transfer to the generation of a NOT gate, illustrate this study. The connection with other geometric optimization approaches that have been used to solve this problem is also discussed. Finally, we show how this method can be combined with numerical optimization algorithms to design robust control for higher-dimensional quantum systems, as illustrated by a Bose-Einstein condensate in an optical lattice.

In preclinical mouse models of triple-negative breast cancer (TNBC), we show that a combination of chemotherapy with cisplatin (CDDP) and eribulin (Eri) was additive from an immunological point of view and was accompanied by the induction of an intratumoral immune and inflammatory response favored by the immunogenic cell death induced by CDDP, as well as by the vascular and tumor stromal remodeling induced by each chemotherapy. Unexpectedly, despite the favorable immune context created by this immunomodulatory chemotherapy combination, our models remained refractory to the addition of anti-PD-L1 immunotherapy. These surprising observations led us to discover that CDDP chemotherapy was simultaneously responsible for the production of TGF-β by several populations of cells present in tumors, which favored the emergence of different subpopulations of immune cells and cancer-associated fibroblasts characterized by immunosuppressive properties. Accordingly, co-treatment with anti-TGF-β restored the immunological synergy between this immunogenic doublet of chemotherapy and anti-PD-L1 in a CD8-dependent manner. Translational studies revealed the unfavorable prognostic effect of the TGF-β pathway on the immune response in human TNBC, as well as the ability of CDDP to induce this cytokine also in human TNBC cell lines, thus highlighting the clinical relevance of targeting TGF-β in the context of human TNBC treated with chemoimmunotherapy.

Gravity, the force that structures the cosmos, also shapes human physiology. It influences skeletal, muscular, cardiovascular, respiratory, and neurological systems, sustaining balance, blood circulation, and functional capacity. Unlike other senses, the brain lacks a dedicated gravity-sensing region and instead relies on a distributed vestibular network, graviception, to interpret gravitational cues. On Earth, gravity-driven blood pooling in the legs triggers compensatory responses that preserve cerebral perfusion. In microgravity, these mechanisms are altered, leading to fluid shifts toward the head, visual disturbances, cerebral changes, and increased thrombosis risk. Prolonged spaceflight induces muscle atrophy, bone demineralization, cardiovascular deconditioning, and orthostatic intolerance upon return to Earth. Whether these changes represent "adaptation" or "deconditioning" remains debated, but the outcomes resemble the physiological decline of frailty and aging. Earth-based analogs, including bed rest, dry immersion, and parabolic flights, reproduce many of these effects, linking gravitational unloading to postural instability, orthostatic hypotension, falls, and fractures. Such complications often fuel a vicious cycle of immobility and functional decline, central to both chronic illness and geriatric care. Viewing spaceflight as a model of accelerated aging offers new opportunities for clinical innovation. Research in altered gravity environments provides insights into countermeasures that preserve muscle mass, cardiovascular stability, and postural control. Strategies such as targeted exercise, optimized fluid management, and even hypergravity interventions may not only safeguard astronaut health but also translate into novel therapies for older adults. By bridging space medicine and aging research, these approaches can help mitigate frailty, reduce health care burdens, and enhance quality of life.

A new active composite film intended for bread packaging is described here. The active film has the aim of prolonging bread’s shelf life while avoiding the use of nanoparticles that, with very few exceptions, are a type of material not allowed by regulatory agencies like EFSA (European Food Safety Agency) and FDA (US Food and Drug Administration) in food contact materials. Moreover, the increasing consumer demand for natural and wholesome products, possibly “clean label”, and packaged in natural, non-petroleum-based materials has been taken into consideration. Accordingly, precursor materials from renewable sources were used to prepare the active film: pectin from citrus peel (PEC) and carboxymethyl cellulose (CMC) were used as the matrix, with oleic acid (OA) as plasticizer. Moreover, the bread preservative calcium propionate (CaP) was used as the crosslinker, and also zeolite microparticles loaded with silver ions (AgZ) were added to the films as an additional antimold agent. This strategy allows us to avoid the addition to bread of the now commonly used preservatives ethanol and calcium propionate, moving the latter to the packaging. Permeance measurements revealed excellent barrier properties against O2 and CO2, while the typical high water vapor permeance of polysaccharide films was mitigated by the non-hydrophilic OA plasticizer. Moreover, the quantities of Ag+ and CaP released in bread are low and below the limits imposed by regulatory agencies. The antimold activity of the films is excellent, with Aspergillus niger, Penicillium janthinellum, and wild-type Penicillim molds reduction on bread in the 99.20–99.95% range for the films containing only CaP and in the 99.97–99.998% range for the films containing both CaP and AgZ. Finally, the rheological properties of the film-forming solutions were investigated, demonstrating their potential application as coatings on natural packaging materials for bread, such as paper.

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