Université de Toulouse

Fostamatinib is available in France since October 2021 for the treatment of adult chronic immune thrombocytopenia (ITP). French health authorities requested a 3-year, prospective, multicenter registry to provide real-world evidence about the effectiveness and safety of fostamatinib. Patients' characteristics, treatment response (ongoing exposure to fostamatinib and a platelet count ≥ 30 × 109/L with no rescue in the previous 4 weeks) after 3, 6, 12, and 24 months (M); bleeding; fostamatinib discontinuation; adverse drug reactions (ADRs) and other events of interest have been analyzed. In total, 164 patients were included (median age: 59 years; 55.5% women; 84.1% had previous bleeding; 30 had secondary ITP; 89.0% had chronic ITP). The median ITP duration was 7.2 years and the median number of previous ITP treatments was 6. The response rate was 44.0% (70/159) at M3, 41.9% (62/148) at M6, 32.4% (44/136) at M12 and 20.0% (21/105) at M24. Concomitant treatment (mostlyTPO-RA) was used in > 60.0% of responders at each endpoint. The cumulative discontinuation rate at each endpointwas, respectively, 27.0%, 44.6%, 55.9%, and 76.2%. Seventy-one (43.3%) patients experienced at least one bleeding duringfostamatinib exposure; none was fatal. One hundred adverse drug reactions (8 serious) were observed in 61 (36.7%)patients, including diarrhea in 28 (17.1%) patients, arterial hypertension in 17 (10.4%). Seven thrombosis (4.3%) and40 infections (12 serious) were reported in 25 patients (15.2%), mostly in patients with known risk factors. In conclusion,fostamatinib in combination with TPO-RA should be considered in difficult-to-treat ITP patients. No new safety signal was observed.

Colorectal and lung cancers are among the most common and deadly worldwide, often carrying significant stigma-especially when linked to preventable behaviors like drinking and smoking. Alcohol increases colorectal cancer risk, while smoking is the primary cause of lung cancer, leading to perceptions of self-infliction that can worsen distress, delay diagnosis, and hinder treatment. This study is the first to compare the acceptability of smoking versus drinking in cancer contexts. Using a factorial design, 132 community members and 126 healthcare professionals evaluated 72 scenarios varying by cancer type, behavior levels, diagnosis stage, post-diagnosis behavior, and activity level. Overall, drinking was viewed as more acceptable than smoking, especially among those physically active or who quit post-diagnosis. Healthcare professionals were slightly more accepting than the general public. Notably, stigma around smoking lessened at advanced cancer stages. Findings suggest the need for stigma-reducing interventions and more compassionate, nonjudgmental care in oncology settings.

Understanding the interplay of environmental and anthropogenic drivers is essential to interpret past changes and anticipate future dynamics of marine fish stocks. Using Norwegian spring-spawning herring (NSSH) as a case study, we applied an iterative structured causal modelling framework combining causal knowledge analysis and inference—using structural equation models—to quantify the respective effects of climate and fisheries on stock biomass and catches. Initial simple models, grounded in prior ecological understanding, yielded implausible estimates when confronted with observational data, underscoring the necessity to treat data structure and content as integral to model design. We gradually incorporated multiple causal pathways, feedback loops, and confounders. Final models explained over 90% of observed variation in both biomass and catch and showed strong support for the roles of recruitment, prior biomass, and total allowable catch (TAC) advice. We found no causal effect of ocean climate variables (Relative Heat Content and Arctic Water Content) on year-to-year changes in NSSH biomass, nor of Spawning Stock Biomass on catches. Instead, catch levels were primarily governed by TAC advice and the degree of agreement between fishing nations. We conclude that reliable causal inference in ecological systems requires iterative model refinement, causal knowledge analysis, and explicit accounting for data structure. Adopting and transparently reporting this approach would benefit ecological studies used to support fisheries management.

Eukaryotic ribosome synthesis is a highly complex, multistep process that is best characterized in the yeast Saccharomyces cerevisiae. It is orchestrated by >200 ribosome assembly factors and 75 small nucleolar ribonucleoproteins (snoRNPs), which guide site-specific chemical modifications of precursor rRNA (pre-rRNA). While canonical box C/D snoRNPs guide 2′-O-methylation, the atypical box C/D snoRNPs snR4 and snR45 guide acetylation of 18S rRNA residues C1280 and C1773, respectively, catalyzed by the acetyltransferase Kre33. Here, we identify and characterize Ynl050c/Sni445 as a novel ribosome assembly factor and previously unrecognized auxiliary component of the snR4 and snR45 box C/D snoRNPs. Sni445 associates with snR4 and snR45 in their free form and is required for their stable incorporation into 90S pre-ribosomes. Genetic interactions link Sni445 and the snR4 and snR45 snoRNAs to ribosomal proteins Rps20 (uS10) and Rps14 (uS11), which are positioned near the respective acetylation sites in the 40S subunit. Moreover, Sni445 physically interacts with Kre33 within the 90S pre-ribosome, and its absence abolishes acetylation of C1280 and C1773. Our findings suggest that Sni445 facilitates the recruitment of snR4 and snR45 snoRNPs to 90S particles and might promote their interaction with Kre33, thereby enabling the site-specific acetylation of 18S rRNA by Kre33.

Abstract. Accurate urban climate modeling is crucial for addressing the growing impacts of urban heat islands (UHI) and climate change. Physics-based tools such as the Urban Weather Generator (UWG) are widely used but often limited by high parameterization needs and a lack of specialized data. In this study, we develop a hybrid framework combining UWG simulations with deep learning, introducing two models: NUWG-Sim (Neural Urban Weather Generator on Simulations), trained solely on simulated data, and NUWG-city, which is fine-tuned with ground weather station data. To systematically evaluate model performance across heterogeneous urban contexts, we structure our experiments around Local Climate Zones (LCZs) in Toulouse, France. Our methodology involves generating over 3400 UWG initialization files, simulating urban air temperatures time series for diverse surface parameters, and training a neural model on these series. We then fine-tune the model with observed data from selected weather stations, analyzing how the number and diversity of stations environments impact performance on unseen stations from different LCZs. Results show that even limited fine-tuning significantly improves performance, particularly when training includes stations from LCZs similar to the test set. The approach highlights the potential of physics-informed neural models for city-specific urban climate monitoring.

Abstract The ongoing panzootic of H5N1 clade 2.3.4.4b high pathogenicity avian influenza virus (HPAIV) has increasingly affected non-traditional hosts like seabirds and mammals, including recent outbreaks in fur farms, in which transmission from infected gulls were suspected. To assess bird-to-mammal spillover and mammal-to-bird spillback dynamics, we performed experimental infections in yellow-legged gulls (Larus michahellis) and American minks (Neogale vison) using HPAIV strains isolated from gulls (H5N1/gull) and a farm mink outbreak (H5N1/mink). Minks challenged with H5N1/gull developed subclinical infection with limited shedding, but viral neurotropism in two out of four animals led to spontaneous emergence of key mammalian adaptation mutations in the brain, which demonstrates that H5N1 clade 2.3.4.4b spillover events from gulls to minks can lead to fast mammalian adaptation. In contrast, mammal-to-bird spillback, modelled by challenging gulls with the H5N1/mink strain, yielded no evidence of infection, suggesting a lower risk of sustained bird-mammal-bird transmission chains of 2.3.4.4b H5N1 HPAIV.

MRPS genes, which encode components of the small mitoribosomal subunit, have not been previously linked to adult-onset neurological diseases. These genes play a critical role in mitochondrial translation and the biogenesis of the oxidative phosphorylation system. Whole Genome Sequencing was performed on adult patients presenting with an unexplained neurological picture. In parallel, functional studies were carried out in patient-derived fibroblasts to assess mitochondrial translation and the status of oxidative phosphorylation pathways. Bi-allelic pathogenic variants in MRPS22, MRPS23, and MRPS34 were identified in four patients from unrelated families. All patients presented a similar complex neurological phenotype, including cerebellar ataxia, distal motor neuropathy, pyramidal syndrome, and a distinctive leukoencephalopathy on brain MRI. Additional findings included elevated cerebrospinal fluid (CSF) protein levels and profound cerebral folate deficiency. Functional analyses revealed impaired mitochondrial translation and multiple defects in oxidative phosphorylation. Treatment with oral folinic acid resulted in clinical stabilization, radiological improvement, and normalization of CSF 5-methyltetrahydrofolate levels. Our findings expand the spectrum of mitochondrial diseases caused by defects in mitoribosomal proteins, highlighting their role in adult-onset neurological disorders with distinctive brain imaging features, high CSF protein levels, and cerebral folate deficiency.