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Visual-verbal paired-associate learning (PAL) is thought to be related to reading acquisition and, more specifically, to word reading skills. To date, the uniqueness and strength of this relationship has remained unclear because most studies have been conducted in opaque orthographies such as English, and few studies have controlled for all of the strongest cognitive and linguistic predictors of reading acquisition. Critically, PAL is a complex task involving different components, and there is still no consensus on which is more involved, crossmodal associative learning or verbal learning, although the latter has received much support in the literature. The first aim of this study was to test the unique contribution of PAL in French, which has an intermediate level of orthographic transparency compared to other languages. The second aim of this study was to disentangle the mechanisms that account for this relationship. A battery of reading and reading-related tests as well as a visual-verbal PAL task were administered to 227 French children in first and second grade. The results showed that PAL makes a unique contribution to word reading in French, but not to nonword reading scores, over and above the strongest language predictors of reading: phonological awareness, rapid automatic naming, short-term phonological memory, vocabulary, and age. Our data do not support the putative involvement of the crossmodal associative learning mechanism. We therefore suggest that verbal learning explains the entire contribution of PAL.

Gene activity is tightly controlled by reversible chemical modifications called epigenetic marks, which are of various types and modulate gene accessibility without affecting the DNA sequence. Despite an increasing body of evidence demonstrating the role of oxidative-type modifications of histones in gene expression regulation, there remains a complete absence of structural data at the atomistic level to understand the molecular mechanisms behind their regulatory action. Owing to μs time-scale MD simulations and protein communication networks analysis, we describe the impact of histone H3 hyperoxidation (i.e., S-sulfonylation) on the nucleosome core particle dynamics. Our results reveal the atomic-scale details of the intrinsic structural networks within the canonical histone core and their perturbation by hyperoxidation of the histone H3 C110. We show that this modification involves local rearrangements of the communication networks and destabilizes the dyad, and that one modification is enough to induce a maximal structural signature. Our results suggest that cysteine hyperoxidation in the nucleosome core particle might favor its disassembly.

Abstract NR2F2 encodes COUP-TFII, an orphan nuclear receptor required for the development of the steroidogenic lineages of the murine fetal testes and ovaries. Pathogenic variants in human NR2F2 are associated with testis formation in 46,XX individuals, however, the function of COUP-TFII in the human testis is unknown. We report a de novo heterozygous variant in NR2F2 (c.737G > A, p.Arg246His) in a 46,XY under-masculinized boy with primary hypogonadism. The variant, located within the ligand-binding domain, is predicted to be highly damaging. In vitro studies indicated that the mutation does not impact the stability or subcellular localization of the protein. NR5A1, a related nuclear receptor that is a key factor in gonad formation and function, is known to physically interact with COUP-TFII to regulate gene expression. The mutant protein did not affect the physical interaction with NR5A1. However, in-vitro assays demonstrated that the mutant protein significantly loses the inhibitory effect on NR5A1-mediated activation of both the LHB and INSL3 promoters. The data support a role for COUP-TFII in human testis formation. Although mutually antagonistic sets of genes are known to regulate testis and ovarian pathways, we extend the list of genes, that together with NR5A1 and WT1, are associated with both 46,XX and 46,XY DSD.

Abstract The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of SRY is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer is required for appropriate SRY expression to initiate testis-determination in humans. Comparative sequence analysis of SRY 5’ regions in mammals identified an evolutionary conserved SF-1/NR5A1-binding motif within a 250 bp region of open chromatin located 5 kilobases upstream of the SRY transcription start site. Genomic analysis of 46,XY individuals with disrupted testis-determination, including a large multigenerational family, identified unique single-base substitutions of highly conserved residues within the SF-1/NR5A1-binding element. In silico modelling and in vitro assays demonstrate the enhancer properties of the NR5A1 motif. Deletion of this hemizygous element by genome-editing, in a novel in vitro cellular model recapitulating human Sertoli cell formation, resulted in a significant reduction in expression of SRY. Therefore, human NR5A1 acts as a regulatory switch between testis and ovary development by upregulating SRY expression, a role that may predate the eutherian radiation. We show that disruption of an enhancer can phenocopy variants in the coding regions of SRY that cause human testis dysgenesis. Since disease causing variants in enhancers are currently rare, the regulation of gene expression in testis-determination offers a paradigm to define enhancer activity in a key developmental process.

Abstract Modern morphometric-based approaches provide valuable metrics to quantify and understand macroevolutionary and macroecological patterns and processes. Here we describe TriloMorph, an openly accessible database for morpho-geometric information of trilobites, together with a landmark acquisition protocol. In addition to morphological traits, the database contains contextual data on chronostratigraphic age, geographic location, taxonomic information and lithology of landmarked specimens. In this first version, the dataset has broad taxonomic and temporal coverage and comprises more than 55% of all trilobite genera and 85% of families recorded in the Paleobiology Database through the Devonian. We provide a release of geometric morphometric data of 277 specimens linked to published references. Additionally, we established a Github repository for constant input of morphometric data by multiple contributors and present R functions that help with data retrieval and analysis. This is the first attempt of an online, dynamic and collaborative morphometric repository. By bringing this information into a single open database we enhance the possibility of performing global palaeobiological research, providing a major complement to current occurrence-based databases.

The first line of defense against invading pathogens usually relies on innate immune systems. In this context, the recognition of exogenous RNA structures is primordial to fight, notably, against RNA viruses. One of the most efficient immune response pathways is based on the sensing of RNA double helical motifs by the oligoadenylate synthase (OAS) proteins, which in turn triggers the activity of RNase L and, thus, cleaves cellular and viral RNA. In this contribution, by using long-range molecular dynamics simulations, complemented with enhanced sampling techniques, we elucidate the structural features leading to the activation of OAS by interaction with a model double-strand RNA oligomer mimicking a viral RNA. We characterize the allosteric regulation induced by the nucleic acid leading to the population of the active form of the protein. Furthermore, we also identify the free energy profile connected to the active vs. inactive conformational transitions in the presence and absence of RNA. Finally, the role of two RNA mutations, identified as able to downregulate OAS activation, in shaping the protein/nucleic acid interface and the conformational landscape of OAS is also analyzed.

Domestication of horses fundamentally transformed long-range mobility and warfare1. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling2-4 at Botai, Central Asia around 3500 BC3. Other longstanding candidate regions for horse domestication, such as Iberia5 and Anatolia6, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 BC, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association7 between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 BC8,9 driving the spread of Indo-European languages10. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium BC Sintashta culture11,12.

Abstract Background PTEN hamartoma syndrome (PHTS) is an autosomal dominant disorder characterized by pathogenic variants in the tumor suppressor gene phosphatase and tensin homolog (PTEN). It is associated with an increased risk of muco-cutaneous features, hamartomatous tumors, and cancers. Mosaicism has been found in a few cases of patients with de novo PHTS, identified from blood samples. We report a PHTS patient with no variant identified from blood sample. Constitutional PTEN mosaicism was detected through sequencing of DNA from different tumoral and non-tumoral samples. Case presentation Our patient presented clinical Cowden syndrome at 56 years of age, with three major criteria (macrocephaly, Lhermitte Duclos disease, oral papillomatosis), and two minor criteria (structural thyroid lesions, esophageal glycogenic acanthosis). Deep sequencing of PTEN of blood leukocytes did not reveal any pathogenic variants. Exploration of tumoral (colonic ganglioneuroma, esophageal papilloma, diapneusia fibroids) and non-tumoral stomach tissues found the same PTEN pathogenic variant (NM_000314.4 c.389G > A; p.(Arg130Gln)), with an allelic frequency of 12 to 59%, confirming genomic mosaicism for Cowden syndrome. Conclusions This case report, and review of the literature, suggests that systematic tumor analysis is essential for patients presenting PTEN hamartoma syndrome in the absence of any causal variant identified in blood leukocytes, despite deep sequencing. In 65 to 70% of cases of clinical Cowden syndrome, no pathogenic variant in the PTEN is observed in blood samples: mosaicism may explain a significant number of these patients. Tumor analysis would improve our knowledge of the frequency of de novo variations in this syndrome. Finally, patients with mosaicism for PTEN may not have a mild phenotype; medical care identical to that of heterozygous carriers should be offered.

Résumé : Le développement local se fonde en priorité sur les capacités endogènes, les ressources endogènes de production, les potentialités et les richesses d’un territoire. L’objectif majeur de la recherche est d’analyser la contribution du bien culturel « Zangbéto kpakliyaou» » au développement local dans la ville de Porto-Novo. Pour atteindre cet objectif, plusieurs méthodes de collectes de données ont été utilisés notamment, la recherche documentaire, les enquêtes par questionnaires et les entretiens semi-directifs sur un effectif total de 152 sujets identifiés selon les techniques du choix raisonné et du choix accidentel. En se basant sur la théorie de l’identité culturelle de Bajoit (1997, p.82), selon laquelle, tout développement local doit nécessairement prendre en compte les réalités culturelles des territoires, les potentialités culturelles, les ressources territoriales ainsi que de toutes les caractéristiques relatives aux communautés, les résultats de recherche présentent le « Zangbéto kpakliyaou» » comme un bien culturel relativement bien connu dans la commune (98%). C’est une ressource clé, un élément essentiel et important dans le développement local de cette ville. Il reste cependant peu valorisé (60%) et il urge (88%) de trouver des mécanismes de valorisation, de promotion et de transmission en vue d’une contribution significative au rayonnement culturel de la ville de Porto-Novo. En effet, le bien culturel selon la théorie de l’identité culturelle n’a pas seulement une contribution économique à apporter, sa valorisation ou promotion peut offrir plusieurs autres opportunités s’agissant d’autres modèles de développement et ce, à travers l’ouverture aux tierces et à d’autres cultures. Le métissage ou la croisade avec d’autres peuples peut favoriser non pas uniquement l’économie locale mais aussi le social ainsi qu’un nouveau modèle de développement profitable pour le développement local. Mots-clés : Bien culturel, développement local, « zangbéto kpakliyahou », Porto-novo, Bénin.

Sirtuin 6 (SIRT6) is an NAD+-dependent histone H3 deacetylase that is prominently found associated with chromatin, attenuates transcriptionally active promoters and regulates DNA repair, metabolic homeostasis and lifespan. Unlike other sirtuins, it has low affinity to free histone tails but demonstrates strong binding to nucleosomes. It is poorly understood how SIRT6 docking on nucleosomes stimulates its histone deacetylation activity. Here, we present the structure of human SIRT6 bound to a nucleosome determined by cryogenic electron microscopy. The zinc finger domain of SIRT6 associates tightly with the acidic patch of the nucleosome through multiple arginine anchors. The Rossmann fold domain binds to the terminus of the looser DNA half of the nucleosome, detaching two turns of the DNA from the histone octamer and placing the NAD+ binding pocket close to the DNA exit site. This domain shows flexibility with respect to the fixed zinc finger and moves with, but also relative to, the unwrapped DNA terminus. We apply molecular dynamics simulations of the histone tails in the nucleosome to show that in this mode of interaction, the active site of SIRT6 is perfectly poised to catalyze deacetylation of the H3 histone tail and that the partial unwrapping of the DNA allows even lysines close to the H3 core to reach the enzyme.

Abstract The eradication of rats (Rattus norvegicus, R. exulans and R. rattus) on islands is essential for the preservation of island ecosystems, including seabird populations, which are particularly vulnerable to rat predation. However, the long‐term positive effects of rat eradication on seabird colonies and populations are often understudied. Brown rats (R. norvegicus) were eradicated from Tromelin Island in 2005. No other significative active restoration actions (such as artificial social attraction, translocation or habitat manipulations) have been implemented, which provides a unique opportunity to investigate natural seabird recolonization and recovery processes after rat eradication. We used seabird annual nest counts conducted from 2005 to 2022 and georeferenced data of occupied nests, to precisely describe the rebuilding of the seabird community of Tromelin Island. Despite the lack of any active restoration actions after the eradication of rats, and the remoteness of the island, 17 years after rat eradication, the seabird community increased from two to seven breeding species, and from 353 to 4758 breeding pairs (total for all species). The recovery of masked and red‐footed booby populations was mostly due to the improved breeding success and in fine to auto‐recruitment. Inter‐ and intra‐specific social attraction accelerated the arrival of new species and boosted their population growth. On a finer spatial scale, recolonizing species showed different patterns of colony settlement linked to intra‐specific attraction. The dynamics of the community of Tromelin Island after rat eradication can be regarded as a natural experiment that informs the processes of colony settlement, population dynamics and connectivity in tropical seabirds. Our results demonstrate the huge benefits of eradicating rats from seabird islands, even when no additional active restoration actions are feasible.

During the construction of Strasbourg Cathedral, men aspired to see it radiate eternally. However, like any monument, it experiences structural weakening due to the effects of time, but also to the many external aggressions that damage the materials. Regular interventions therefore make it possible to preserve this building over time. It is in this context of conservation that the cathedral lives to the rhythm of a major restoration campaign since 2014. The objective of this project was to carry out a modeling and a BIM model of the stair turret in the south-east corner of the main tower built entirely of sandstone. This work was part of the preparatory phase of the restoration work on the south-east stair turret of the high tower scheduled for 2024–2025. The objective was to carry out a diagnosis of the turret (35 m high, 168 steps) with the help of a 3D and BIM model. This study could be understood as the beginning of a more global work of 3D representation extendable to the entire monument. In addition, in the spirit of gathering information and building knowledge base, it could be interesting to develop a complete BIM model of the entire building later.

Abstract For centuries, reindeer herding has been an integral part of the subsistence, lifeways, economy and cosmology of the Sámi of northern Fennoscandia. Despite its importance, the timing and details of early reindeer domestication are still highly debated. Identifying domesticated individuals in the archaeological record remains complicated due to the presence of two interbreeding subspecies in Fennoscandia and a mixed socio-economic organisation by Sámi populations, which was mainly a combination of wild reindeer hunting and small-scale reindeer herding. This study proposes methodological improvement for identifying domestic individuals using 2D landmark and sliding semi-landmark based geometric morphometrics on the isolated lower molars of 389 modern specimens, and 90 teeth from four archaeological sites in Finnish Lapland. Our results indicate that despite the significant impact of wear on overall tooth morphology, our protocol is very useful for identifying subspecies (classification accuracy of the two species is between 78 and 91% depending on the wear class) and understanding the morphological changes induced by the domestication process. We suggest that the morphological variation observable among modern populations has been impacted by recent changes in herding strategies in northern Fennoscandia, and that the archaeological domesticated reindeer populations were relatively different, probably due to selection by the Sámi. This study also highlights the importance of using other direct evidence or contextual archaeological data to better trace the early evidence of a domesticated reindeer economy in northern Fennoscandia, and aid in reconstructing the socio-economic changes in Sámi populations over time.

The Magdalenian camp site of Pincevent was discovered in 1964, near Montereau-Fault-Yonne (Seine-et-Marne). Assuring the preservation and transmission of this exceptional archaeological heritage has become one of the main goals of scientific research since the beginning of archaeological excavations. Accordingly, the excavation field crew was particularly interested in developing innovative methods for the recording of the features of habitation surfaces. Photography played a major role in this process. This article describes how the evolution of these methods was directed towards the identification of occupation floors and the demonstration of the coherence of their structure. This approach was constructed in connection with the adoption of new research tools (photogrammetry and spatial analysis). The article thus addresses the role played by written and oral archives in this process, both through the processing and analysis of two series of photographs taken on the site and the production of semi-directive interviews with the actors who worked on the development of these methods.

Abstract Background Forty-six ,XY Differences/Disorders of Sex Development (DSD) are characterized by a broad phenotypic spectrum ranging from typical female to male with undervirilized external genitalia, or more rarely testicular regression with a typical male phenotype. Despite progress in the genetic diagnosis of DSD, most 46,XY DSD cases remain idiopathic. Methods To determine the genetic causes of 46,XY DSD, we studied 165 patients of Tunisian ancestry, who presented a wide range of DSD phenotypes. Karyotyping, candidate gene sequencing, and whole-exome sequencing (WES) were performed. Results Cytogenetic abnormalities, including a high frequency of sex chromosomal anomalies (85.4%), explained the phenotype in 30.9% (51/165) of the cohort. Sanger sequencing of candidate genes identified a novel pathogenic variant in the SRY gene in a patient with 46,XY gonadal dysgenesis. An exome screen of a sub-group of 44 patients with 46,XY DSD revealed pathogenic or likely pathogenic variants in 38.6% (17/44) of patients. Conclusion Rare or novel pathogenic variants were identified in the AR, SRD5A2, ZNRF3, SOX8, SOX9 and HHAT genes. Overall our data indicate a genetic diagnosis rate of 41.2% (68/165) in the group of 46,XY DSD.

Geophysical and geological data from the North Mozambique Channel acquired during the 2020–2021 SISMAORE oceanographic cruise reveal a corridor of recent volcanic and tectonic features 200 km wide and 600 km long within and north of Comoros Archipelago. Here we identify and describe two major submarine tectono-volcanic fields: the N’Droundé province oriented N160°E north of Grande-Comore Island, and the Mwezi province oriented N130°E north of Anjouan and Mayotte Islands. The presence of popping basaltic rocks sampled in the Mwezi province suggests post-Pleistocene volcanic activity. The geometry and distribution of recent structures observed on the seafloor are consistent with a current regional dextral transtensional context. Their orientations change progressively from west to east (${\sim }$N160°E, ${\sim }$N130°E, ${\sim }$EW). The volcanism in the western part appears to be influenced by the pre-existing structural fabric of the Mesozoic crust. The 200 km-wide and 600 km-long tectono-volcanic corridor underlines the incipient Somalia–Lwandle dextral lithospheric plate boundary between the East-African Rift System and Madagascar.

In the present work, the synthesis of new ethacrynic acid (EA) derivatives containing nitrogen heterocyclic, urea, or thiourea moieties via efficient and practical synthetic procedures was reported. The synthesised compounds were screened for their anti-proliferative activity against two different cancer cell lines, namely, HL60 (promyelocytic leukaemia) and HCT116 (human colon carcinoma). The results of the in vitro tests reveal that compounds 1–3, 10, 16(a–c), and 17 exhibit potent anti-proliferative activity against the HL60 cell line, with values of the percentage of cell viability ranging from 20 to 35% at 1 μM of the drug and IC50 values between 2.37 μM and 0.86 μM. Compounds 2 and 10 showed a very interesting anti-proliferative activity of 28 and 48% at 1 μM, respectively, against HCT116. Two PyTAP-based fluorescent EA analogues were also synthesised and tested, showing good anti-proliferative activity. A test on the drug-likeness properties in silico of all the synthetised compounds was performed in order to understand the mechanism of action of the most active compounds. A molecular docking study was conducted on two human proteins, namely, glutathione S-transferase P1-1 (pdb:2GSS) and caspase-3 (pdb:4AU8) as target enzymes. The docking results show that compounds 2 and 3 exhibit significant binding modes with these enzymes. This finding provides a potential strategy towards developing anticancer agents, and most of the synthesised and newly designed compounds show good drug-like properties.

The chemical composition of the essential oils of two plants (Tagetes minuta L. and Lavandula coronopifolia L.) harvested from the Day region (in the north of Djibouti) is the subject of this study. The extraction of essential oils was carried out by hydrodistillation, and the average yield was obtained at a rate of approximately 0.25% for Tagetes minuta L. and 0.42% for Lavandula coronopifolia L. The analyses of these essential oils by gas chromatography coupled with mass spectrometry identified 13 compounds in the essential oil of Tagetes minuta L., including dihydrotagetone (20.8%), artemisia (17.9%), (Z)-tagetenone (12.4%), (-)-spathulenol (11.0%) and estragole (9.5%), were obtained as majority compounds, with a percentage of 71.6%. The essential oil of Lavandula coronopifolia L. is characterized by the presence of 42 compounds, including cis-caryophyllene (18.9%), dehydronerolidol (12.8%), isolongifolanone (11.2%), caryophyllene oxide (8.2%), 10-epi-β-eudesmol (7.7%) and humulene (5.1%), were obtained as the majority chemical constituents, with a percentage of 63.9%. The antimicrobial activities of the essential oils at concentrations of 5% were measured against 12 bacterial strains (Gram positive: Staphylococcus aureus (ATCC 29213), Enterococcus faecalis (ATCC 29212), Streptococcus agalactiae (ATCC 27956), Staphylococcus epidermidis and Corynebacterium sp.; Gram Negative: Pseudomonas aeruginosa (ATCC 27853), Escherichia coli (ATCC 25922), Klebsiella pneumoniae (ATCC 700603), Acinetobacter baumannii (ATCC 19606), Shigella sonnei (ATCC 9290), Salmonella enterica sv. Typhimurium (ATCC 13311) and Enterobacter cloacae), and the results of in vitro experiments showed inhibitory effects against most strains tested except Staphylococcus aureus, Enterococcus faecalis and Streptococcus agalactiae. Additionally, both oils were tested for their ability to selectively kill 13 human cancer cells (K562, A549, HCT116, PC3, U87-MG, MIA-Paca2, HEK293, NCI-N87, RT4, U2OS, A2780, MRC-5 and JIMT-T1), and the results obtained, according to the values of IC50, show the significant activity of two essential oils, particularly on the HCT116 and A2780 lines, which present values between 0.25 µg/mL and 0.45 µg/mL, respectively.