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Abstract Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer’s disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women’s increased susceptibility to dementia, there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features and pursuing sex-specific analysis. We bring together 14 different genomic and neuropathology datasets (6960 individuals) and we integrate our GWAS findings with transcriptomic and phenotypic data aiming to also identify biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1 and OPCML. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Post-GWAS analyses illuminate the functional and biological mechanisms underlying AD and reveal sex-specific differences. Finally, through PheWAS and Mendelian Randomization analysis, we identify causal links with AD neuropathology pointing to disrupted lipid metabolism, as well as impaired peripheral immune response and liver dysfunction as part of a vicious cycle that fuels neurodegeneration.

Abstract Circuit-based biomarkers distinguishing the gradual progression of Lewy pathology across synucleinopathies remain unknown. Here, we show that seeding of α-synuclein preformed fibrils in mouse dorsal striatum and motor cortex leads to distinct prodromal-phase cortical dysfunction across months. Our findings reveal that while both seeding sites had increased cortical pathology and hyperexcitability, distinct differences in electrophysiological and cellular ensemble patterns were crucial in distinguishing pathology spread between the two seeding sites. Notably, while beta-band spike-field-coherence reflected a significant increase beginning in Layer-5 and then spreading to Layer-2/3, the rate of entrainment and the propensity of stochastic beta-burst dynamics was markedly seeding location-specific. This beta dysfunction was accompanied by gradual superficial excitatory ensemble instability following cortical, but not striatal, preformed fibrils injection. We reveal a link between Layer-5 dendritic vulnerabilities and translaminar beta event dysfunction, which could be used to differentiate symptomatically similar synucleinopathies.

Ultra-high-speed synchrotron-based hard X-ray (i.e. above 10 keV) imaging is gaining a growing interest in a number of scientific domains for tracking non-repeatable dynamic phenomena at spatio-temporal microscales. This work describes an optimized indirect X-ray imaging microscope designed to achieve high performance at micrometre pixel size and megahertz acquisition speed. The entire detector optical arrangement has an improved sensitivity within the near-ultraviolet (NUV) part of the emitted spectrum (i.e. 310–430 nm wavelength). When combined with a single-crystal fast-decay scintillator, such as LYSO:Ce (Lu2−xYxSiO5:Ce), it exploits the potential of the NUV light-emitting scintillators. The indirect arrangement of the detector makes it suitable for high-dose applications that require high-energy illumination. This allows for synchrotron single-bunch hard X-ray imaging to be performed with improved true spatial resolution, as herein exemplified through pulsed wire explosion and superheated near-nozzle gasoline injection experiments at a pixel size of 3.2 µm, acquisition rates up to 1.4 MHz and effective exposure time down to 60 ps.

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell, and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.

Purpose To compare outcomes, between stemmed and stemless reverse shoulder arthroplasty (RSA) at a minimum follow-up of 5 years. Methods The authors retrospectively assessed a consecutive series of 45 patients that underwent RSA between September 2014 and October 2018 (23 stemless and 22 stemmed). All patients underwent plain anteroposterior and scapular Y-view radiographs for assessment immediately post-operatively and at final follow-up. At a minimum follow-up of 5 years, an independent observer assessed the clinical scores, including Constant score, QuickDASH score, and American Shoulder and Elbow Surgeons score. Results Of the 45 patients that underwent RSA, 5 patients died (11%), 2 were revised due to infection (4%), and 4 patients were lost to follow-up (9%). This left a final cohort of 34 patients (18 stemless and 16 stemmed). Significant differences between groups were found immediately post-operatively for lateralisation shoulder angle (LSA) (p = 0.021), but at 5 years post-operative for distalisation shoulder angle (DSA) (p = 0.017) and QuickDASH scores (p = 0.041) (Table 4), while the outcomes were comparable for absolute Constant scores, ASES score, and range of motion. Finally, stemless RSA had a 17% complication rate, while stemmed RSA had a 31% complication rate. Conclusion Stemless RSA had significantly more lateralisation, and significantly less distalisation, compared to stemmed RSA. Furthermore, at a 5-year follow-up, stemless RSA granted significantly greater QuickDASH scores. Finally, stemless RSA had comparable complication rates as stemmed RSA. The clinical relevance of this study is that stemless RSA is a safe alternative to stemmed RSA, while granting comparable or greater scores. Level of Evidence: III, Comparative Study

PFOA is a legacy Per- and Polyfluorinated Substances (PFAS), a group of chemicals widely used in various industrial applications and consumer products. Although there has been a voluntary phase out of PFOA since 2005, it is still widely detected in various water supplies. A growing body of evidence suggests an association between PFOA exposure, particularly during developmental stages, with increased risks of neurodegenerative diseases (NDs). The neurotoxic mechanism of developmental PFOA exposure, however, remains poorly understood. Utilizing human induced-pluripotent stem cell (hiPSC)-derived cortical neurons, we investigated the effect of PFOA exposure prior to differentiation and assessed changes in neuronal characteristics, transcriptome, and neurodegeneration markers mimicking a Developmental Origin of Health and Disease (DoHAD) paradigm. Exposure to PFOA before neuron differentiation resulted in persistent alterations in nuclear morphology, neuronal network, and calcium activity. RNA sequencing analysis further revealed transcriptomic changes aligning with Alzheimer’s Disease (AD) after PFOA exposure. These observations were further corroborated by alterations in tau phosphorylation markers, the presence of fibrillar tau, an increase in liquid droplets, and a decrease in RNA translational efficiency characterized using a battery of biochemical assays. Taken together, our results revealed persistent deficits of key neuronal characteristics induced by pre-differentiation PFOA exposure, suggesting impairments in several AD-related pathways that can together contribute to the elevation of AD risk after pre-differentiation PFOA exposure.

Une liste des Cerophytidae, Elateridae, Eucnemidae et Throscidae du bassin genevois est présentée avec quelques commentaires et annotations. Le présent travail est basé sur des prospections de terrain ciblées, sur une analyse critique de la littérature et des recherches dans les collections muséales et privées. Une espèce de Cerophytidae, 102 espèces d’Elateridae, 14 espèces d’Eucnemidae et 9 espèces de Throscidae sont recensées dans le bassin genevois. 13 espèces insuffisamment documentées (Elateridae) sont à considérer comme douteuses et sont donc répertoriées séparément. Enfin, 9 espèces (8 Elateridae et 1 Throscidae) potentiellement présentes dans le bassin genevois mais pour l’heure non recensées, sont également mentionnées et discutées. Les résultats montrent que du point de vue patrimonial, 44 espèces saproxyliques sont de grande valeur, car rares et/ou exigeantes envers leur habitat.

Abstract Toll-like receptor 3 (TLR3) is a pattern recognition receptor mainly known for its role in innate immune response to infection. Indeed, binding of double-stranded RNA (dsRNA) to TLR3 triggers a pro-inflammatory cascade leading to cytokine release and immune cell activation. Its anti-tumoral potential has emerged progressively, associated with a direct impact on tumor cell death induction and with an indirect action on immune system reactivation. Accordingly, TLR3 agonists are currently being tested in clinical trials for several adult cancers. Meanwhile, TLR3 variants have been linked to auto-immune disorders, and as risk factors of viral infection and cancers. However, aside from neuroblastoma, TLR3 role in childhood cancers has not been evaluated. Here, by integrating public transcriptomic data of pediatric tumors, we unveil that high TLR3 expression is largely associated with a better prognosis in childhood sarcomas. Using osteosarcomas and rhabdomyosarcomas as models, we show that TLR3 efficiently drives tumor cell death in vitro and induces tumor regression in vivo. Interestingly, this anti-tumoral effect was lost in cells expressing the homozygous TLR3 L412F polymorphism, which is enriched in a rhabdomyosarcomas cohort. Thus, our results demonstrate the therapeutic potential associated with the targeting of TLR3 in pediatric sarcomas, but also the need to stratify patients eligible for this clinical approach with respect to the TLR3 variants expressed.

Down syndrome cell adhesion molecule (Dscam) gene encodes a cell adhesion molecule required for neuronal wiring. A remarkable feature of arthropod Dscam is massive alternative splicing generating thousands of different isoforms from three variable clusters of alternative exons. Dscam expression and diversity arising from alternative splicing have been studied during development, but whether they exert functions in adult brains has not been determined. Here, using honey bees, we find that Dscam expression is critically linked to memory retention as reducing expression by RNAi enhances memory after reward learning in adult worker honey bees. Moreover, alternative splicing of Dscam is altered in all three variable clusters after learning. Since identical Dscam isoforms engage in homophilic interactions, these results suggest a mechanism to alter inclusion of variable exons during memory consolidation to modify neuronal connections for memory retention.

The future of work and the ever-changing skills demand in the labour market has been a constant debate and pressing challenge for higher education institutions (HEI’s), governments and industry. In the current context, HEI’s must increase the transformational effect of education on people’s employability, on organizations’ competitiveness and on society’s progress. This paper presents the design and development of a mock-up career guidance tool to empower lifelong learners through digital reskilling and upskilling. We discuss the methods used for designing a skills alignment tool and a smart catalogue for identifying stackable training pathways in two specific disciplinary domains. The skills alignment methodology features a skill gap analysis (SGA) in the occupational domains of Data Science and Chemistry, linked to the evolution and demand of the European labour market through an ESCO compatible tool. The smart program catalog presents the necessary program information to facilitate the creation of stackable training pathways. Considerations are made for the importance of virtual career guidance tools for lifelong learners as we face the ever-changing demand of the labor market and as we continue to embrace online education, micro-credentialing and the digital transformation of higher education.

Le Contrôle Non-Destructif (CND) en vue de l’inspection de composants composites est un élément critique dans la chaine de valeur en aérospatial. Les méthodes se basant sur une inspection par ultrason (UT) sont, depuis des décennies, les méthodes les plus couramment déployées dans l’industrie aéronautique. Elles ont, chez la plupart des constructeurs, longtemps été perçues comme étant presque les seules capables de détecter des défauts de 6mm avec la probabilité de détection (PoD) requise. A côté de ses capacités de détection, la méthode UT possède quelques inconvénients tels que le besoin d’un contact entre la sonde et la surface de la pièce ou encore le besoin d’un fluide couplant qui rend l’inspection plus ardue (le faisceau doit rentrer perpendiculairement avec un angle précis) et plus couteuse, économiquement et environnementalement. Il existe cependant d’autres méthodes bien connues au sein de la communauté du CND offrant d’autres perspectives : soit avec des capacités de détection similaires aux UT, voire meilleures pour des applications ciblées, soit avec une réduction des coûts d’inspection (plus rapide, pas de besoin de couplant) et plus adaptées aux géométries complexes des pièces aéronautiques comme les doubles courbures. Parmi ces méthodes, peuvent être citées les méthodes digitales que sont la thermographie (IRT), la shearographie (ST), les rayons X (RX) ainsi que les ultrasons laser (LUT). En dépit des excellentes avancées technologiques récentes dans ces domaines, ces méthodes restent encore sous-estimées et souvent non considérées comme candidats pour accélérer considérablement, compléter ou précéder une inspection par ultrason. Cet article présente l’application de concert de deux de ces méthodes intégrées à un démonstrateur robotique visant à l’automatisation de l’inspection de pièces de grandes tailles. La réalisation du démonstrateur est le délivrable du projet de R&D LDCOMP groupant 9 organismes et sociétés wallonnes et québécoise visant à développer les méthodes digitales de CND et accroitre le niveau de maturité vers des solutions efficaces, robustes, rapides et offrant un niveau de détection élevé. La démonstration de la faisabilité d’inspection d’un panneau composite de grande taille (~2m) ainsi qu’une structure à géométrie cylindrique et double courbure sera décrite à l’aide d’une solution robotisée comprenant de la thermographie (IRT) et de la shearographie (ST).

La shearographie est une méthode de contrôle non destructif (CND) exploitant l’interférométrie dans le domaine des ondes visibles. Cette méthode utilisée dans l’aéronautique, le spatial ou le naval permet de détecter les décollements, les délaminages ou vérifier la porosité des matériaux composites. Pour les pièces de grandes dimensions, plusieurs acquisitions sont nécessaires pour contrôler l’intégralité de la pièce. Le capteur de shearographie peut être déplacé sur ces positions d’acquisitions par un opérateur ou bien être intégré dans une cellule robotisée. Cette robotisation permet d’automatiser l’inspection et de réduire les facteurs humains. Cet article présente dans sa seconde partie – après un bref rappel des principes physiques exploités par cette méthode de CND – les grandes étapes de l’inspection par shearographie automatisée. Les opportunités et freins de cette robotisation sont détaillés. Dans une troisième partie, cet article détaille l’utilité d’avoir le jumeau numérique de la machine d’inspection. Ce jumeau simule le comportement du capteur pour visualiser les zones couvertes par une position d’inspection. Il devient aisé de définir manuellement le scénario d’inspection pour une pièce donnée. La validation du scénario peut alors être réalisée d’un point de vue robotique (absence de collision, respect des vitesses) et procédé d’inspection. Le jumeau numérique est confronté, dans un but d’être validé, aux résultats obtenus dans le monde physique (robot et capteur). En dernière section, cet article présente des résultats d’autoapprentissage de scénarios d’inspection. Ces algorithmes experts calculent de manière automatique les scénarios en utilisant le jumeau numérique de la machine. Les résultats sont optimisés tant en terme de nombre de vues utiles à couvrir la pièce, que dans les trajectoires robotiques. Les discussions seront ouvertes sur comment évaluer les résultats.

Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer's disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women's increased susceptibility to dementia, there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features and pursuing sex-specific analysis. We bring together 14 different genomic and neuropathology datasets (6960 individuals) and we integrate our GWAS findings with transcriptomic and phenotypic data aiming to also identify biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1 and OPCML. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Post-GWAS analyses illuminate the functional and biological mechanisms underlying AD and reveal sex-specific differences. Finally, through PheWAS and Mendelian Randomization analysis, we identify causal links with AD neuropathology pointing to disrupted lipid metabolism, as well as impaired peripheral immune response and liver dysfunction as part of a vicious cycle that fuels neurodegeneration. [ABSTRACT FROM AUTHOR]

The surface chemical states of Pd(100) during CO oxidation were investigated using ambient pressure x-ray photoelectron spectroscopy and mass spectroscopy. Under the reactant ratio of CO/O 2 = 0.1, i.e. an oxygen-rich reaction condition, the formation of surface oxides was observed with the onset of CO oxidation reaction at T = 525 K. As the reactant ratio (CO/O 2 ) increased from 0.1 to 1.0, ∼ 90 % surface oxides remains on surface during the reaction. Upon the formation of surface oxides, the core level shift of oxygen gas phase peak was observed, indicating that change of surface work function. As CO oxidation takes places, i.e. making a transition from CO covered surface to the oxidic surface, the work functions of surface oxide on Pd(100) and Pt(110) display opposite behavior.

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson's disease.