Therapeutic efficacy of in-vivo IL-12 plasmid delivery using microbubble-assisted ultrasound in a B16F10 mouse melanoma model: A proof of concept

International audienceIn-vivo targeted delivery of immunostimulatory molecules for melanoma treatment is a promising strategy to overcome complexity, toxicity, and cost associated with current immunotherapies. Among these molecules, interleukine-12 (IL-12) is a potent immunostimulatory cytokine that plays a major role in antitumoral immune response. However, systemic administration of IL-12 induces severe side effects, highlighting the need for efficient and safe in-vivo delivery modalities. Microbubble-assisted ultrasound (MB-assisted US) is an emerging non-invasive and targeted method for therapeutic molecule delivery. This study aimed to evaluate its efficacy for intratumoral (i.t.) delivery of a plasmid encoding IL-12 (pIL-12) in a mouse melanoma model. In-vitro, delivery of 5 or 10 g of pIL-12 into melanoma cell suspensions using MB-assisted US increased IL-12 concentration to 1429 ± 125 and 2352 ± 125 pg/mL, respectively, whereas pIL-12 treatment alone did not elicit IL-12 secretion. Similarly, acoustically mediated delivery of 10 or 50 g of pIL-12 into melanoma spheroids significantly increased IL-12 concentration - 131 ± 7 and 250 ± 60 pg/mL respectively - compared to pIL-12 alone (0 pg/mL for 10 g and 7.5 ± 7.5 pg/mL for 50 g). In-vivo, acoustically mediated pIL-12 delivery increased serum mIL-12 concentration by 5-fold compared with i.t. pIL-12 injection alone, promoting NK cell recruitment and activation within the tumor microenvironment. By day 15, this strategy reduced tumor volume by 2.5-fold relative to i.t. pIL-12 alone and improved mouse health status. These findings confirm that MB-assisted US is a relevant modality for in-vivo delivery of immunostimulatory molecules in melanoma therapy

Deep evolutionary conservation of a sex-determining locus without sequence homology

International audienceSex determination is fundamental to eukaryotic life, yet its molecular basis varies widely across the tree of life. In most animal clades, sex-determining mechanisms are highly diverse and evolve rapidly. Here, we identify an exception in aculeate Hymenoptera, an ancient and diverse clade of haplodiploid insects that includes ants, bees, and stinging wasps. By integrating comparative genomics across Hymenoptera with genetic mapping in bumblebees and hornets, we reveal that the ANTSR locus, a multiallelic noncoding locus, has been maintained for over 150 My as the primary instructive signal for female development. This locus is located in a conserved synteny block that originated at the base of Aculeata and functions as a highly polymorphic, zygosity-based sex determiner, with only heterozygous individuals developing as females across lineages. Despite its deep evolutionary conservation, this sex locus shows no detectable sequence homology among lineages. These findings demonstrate that an essential noncoding locus can retain its function over deep evolutionary time without sequence conservation. More broadly, our results highlight haplodiploid insects as a powerful model for studying the evolution of sex determination mechanisms beyond those linked to sex chromosomes

Evaluation du développement cognitif et émotionnel d’adultes autistes ayant un handicap intellectuel sévère à l’aide de la Batterie d’Evaluation Cognitive et Socio-émotionnelle pour Adultes (BECS-A)

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Effectiveness of Non-Pharmacological Interventions in Addressing Behavioral and Psychological Symptoms of Dementia and Reducing Caregiver Burden: A Narrative Review

AbstractBackground: Behavioral and Psychological Symptoms of Dementia(BPSD), are highly prevalent and significantly impact patient well-being and caregiver burden. Non-pharmacological interventions (NPIs) are increasingly recommended as first-line strategies due to the risks associated with pharmacological treatments.Objective: This narrative review aims to identify and classify traditional, recent, and modern NPIs for BPSD, summarize their outcomes and limitations, and discuss their effectiveness in reducing caregiver burden.Methods: Evidence from randomized controlled trials, systematic reviews, and meta-analyses was synthesized. Interventions were categorized as traditional (cognitive stimulation, reminiscence, music therapy), recent (aromatherapy, physical exercise, animal-assisted therapy, caregiver psychoeducation), and modern (virtual reality, robotic companions, COMPAs app). Key findings, populations, benefits, and limitations were summarized in a comparative table.Results: Traditional NPIs are accessible and effective for improving cognition, mood, and social interaction. Recent interventions, including animal-assisted therapy and psychoeducation, target relational and emotional dimensions, reducing agitation, depression, and caregiver stress. Modern technological approaches show promise for enhancing communication, engagement, and emotional well-being, though usability, accessibility, and long-term evidence remain limited. NPIs collectively improve caregiver self-efficacy, reduce burnout, and enhance patient outcomes.Conclusion: A blended, patient-centered approach combining traditional, recent, and modern NPIs appears most effective in managing BPSD and supporting caregivers. Future research should focus on large-scale trials, standardization, cost-effectiveness, and implementation strategies to integrate NPIs into routine Alzheimer’s care

Decoding Cerebrospinal Fluid: Integrative Metabolomics Across Multiple Platforms

International audienceCerebrospinal fluid (CSF) is a key biological matrix that reflects the physiological and pathological states of the central nervous system (CNS). It supports brain function by regulating ionic balance, facilitating molecular transport, and clearing metabolic waste. In this article, we present a standardized protocol for CSF collection along with an integrative multiplatform metabolomic workflow that combines proton nuclear magnetic resonance spectroscopy (1 H-NMRS) and high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Integrating these complementary analytical modalities enhances metabolite coverage and improves analytical robustness, enabling a more comprehensive and reliable characterization of the CSF metabolome. This workflow supports the discovery of potential biomarkers and advances our understanding of neurochemical alterations within the CNS

Enigma portal case: exceptional urinary crystals

International audienceQuiz focusing on the cytological analysis of urine in a case of urinary tract infection caused by E. coli, and its management with ceftriaxone treatment

Portrait de l'artiste en Ottoman. Deux regards sur Pierre Loti

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Brain size reduction in dogs was already established at least by the Late Neolithic of western Europe, 5,000 years ago

The timing and causes of brain size reduction in domestic dogs remain uncertain. Using endocast's volume as a proxy for brain size, this study provides a first insight into long-term brain size evolution in the wolf-dog lineage. We compared endocranial volumes of 185 modern and 22 prehistoric wolves and dogs ranging from Western Europe to Australia, and spanning the Pleniglacial (35 Ky BP) to the Late Neolithic (5 Ky BP). Our results reveal that Pleistocene so called "protodogs" show no brain size reduction compared to coeval Pleistocene wolves. Instead, we observed a slightly larger relative endocranial volume in the 35,000-year-old 'protodog' from Goyet, which could suggest increased behavioural flexibility in the presence of humans. This hypothesis needs to be tested further. In contrast, Late Neolithic dogs show a drastic 46% brain size reduction with an endocranial volumes comparable to modern small terrier and toy breeds. The anxious and wary temperaments of these Late Neolithic dogs, induced by the brain tissue reorganization associated with such a size reduction, could have served an alerting purpose, among the many other potential roles dogs could have played within this Late Neolithic socio-ecosystems

Formulaic Lanthanide Pairing Using Combinations of Covalent Macrocycles and Metallamacrocycles

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Process evaluation of a school-based vaccination intervention to improve HPV vaccine coverage: A mixed-method study embedded in the French PrevHPV cluster randomized controlled trial

International audienceBackgroundHuman papillomavirus vaccine coverage (HPV VC) remains suboptimal in many countries. French authorities launched the PrevHPV research program, which included a cluster randomized controlled trial (cRCT) to evaluate the effectiveness of an ‘at-school vaccination’ intervention. Within this trial, we conducted a process evaluation of this intervention, specifically analyzing (i) its implementation, (ii) its mechanisms of impact, and (iii) the contextual factors influencing implementation (facilitators/barriers).MethodWe conducted a mixed-method study embedded in the PrevHPV cRCT (April 2021–April 2022). ‘At-school vaccination’ consisted of vaccination day(s) on school premises where mobile vaccination teams (MVTs) initiated HPV vaccination free of charge for eligible adolescents (i.e., non-vaccinated adolescents aged 11+). Quantitative data were collected through activity reports and self-administered questionnaires of adolescents and school staff. Qualitative data collected through six focus groups with school staff and MVTs were analyzed using thematic analysis.ResultsOf the 31 schools (14,772 adolescents) randomized to implement ‘at-school vaccination’, 12 (39 %) dropped out. Among the participating schools, analysis of implementation showed that 17 % of adolescents returned valid consent forms, of whom 89 % initiated vaccination. MVTs played a central role in implementing vaccination day(s), supported by several school staff (e.g., school nurses, education assistants). Regarding mechanisms of impacts, satisfaction with the vaccination days was high among adolescents and school staff. The intervention generated both positive and negative group effects among adolescents. Contextual factors that facilitated implementation included the preparation of a list of adolescents to be vaccinated and the availability and motivation of school staff. The main barriers related to the management of consent forms and missing health records.ConclusionWe formulated recommendations for implementing at-school vaccination, which may be particularly helpful for the French school HPV vaccination campaigns that were scaled up nationally in 2023. We also discussed potential macro-level improvement strategies, involving modifications to the legislative framework