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The sea urchin Paracentrotus lividus has been used as a model system in biology for more than a century. Over the past decades, it has been at the center of a number of studies in cell, developmental, ecological, toxicological, evolutionary, and aquaculture research. Due to this previous work, a significant amount of information is already available on the development of this species. However, this information is fragmented and rather incomplete. Here, we propose a comprehensive developmental atlas for this sea urchin species , describing its ontogeny from fertilization to juvenile stages. Our staging scheme includes three periods divided into 33 stages, plus 15 independent stages focused on the development of the coeloms and the adult rudiment. For each stage, we provide a thorough description based on observations made on live specimens using light microscopy, and when needed on fixed specimens using confocal microscopy. Our descriptions include, for each stage, the main anatomical characteristics related, for instance, to cell division, tissue morphogenesis, and/or organogenesis. Altogether, this work is the first of its kind providing, in a single study, a comprehensive description of the development of P. lividus embryos, larvae, and juveniles, including details on skeletogenesis, ciliogenesis, myogenesis, coelomogenesis, and formation of the adult rudiment as well as on the process of metamorphosis in live specimens. Given the renewed interest for the use of sea urchins in ecotoxicological, developmental, and evolutionary studies as well as in using marine invertebrates as alternative model systems for biomedical investigations, this study will greatly benefit the scientific community and will serve as a reference for specialists and non-specialists interested in studying sea urchins.

Biomineralization is ubiquitous in both unicellular and multicellular living systems and has remained elusive due to a limited understanding of physicochemical and biomolecular processes. Echinoderms, identified with diverse architectures of calcite-based structures in the dermis, present an enigma of how cellular processes control shape and form of individual structures. Specifically, in holothurians (sea cucumbers), multi-cellular clusters construct discrete single-crystal calcite `ossicles' (≈100 micrometer length scale), with diverse morphologies both across species and even within an individual animal. The local rules that might encode these unique morphologies in calcite ossicles in holothurians remain largely unknown. Here we show how transport processes in a cellular syncytium impart a top-down control on ossicle geometry via symmetry breaking, branching, and fusion in finite cellular clusters. As a unique example of cellular masonary, we show how coordination within a small cluster of cells builds calcite structures about an order of magnitude larger than any individual participating cell. We establish live imaging of ossicle growth in Apostichopus parvimensis juveniles revealing how individual crystalline seeds (≈1-2 micrometer) grow inside a multi-cellular syncytial complex with the biomineral completely wrapped within a membrane-bound cytoplasmic sheath. Constructing a topological description of ossicle geometries from 3D micro-CT (computational tomography) data reveals the hidden growth history and conserved patterns across ossicle types. We further demonstrate vesicle transport on the surface of the ossicle, rather than cell motility, regulates material transport to the ossicle tips via a unique cytoskeletal architecture. Finally, using reduced order models of conserved transport on self-closing active branching networks, we highlight the hidden universality in the growth process of distinct ossicles. The system presented here serves as a unique playground merging top-down cellular physiology and classical branching morphogenesis with bottom-up non-equilibrium mineralization processes at the interface of living and non-living matter.Competing Interest StatementThe authors have declared no competing interest.

Although the adult pentaradial body plan of echinoderms evolved from a bilateral ancestor, identifying axial homologies between the morphologically divergent echinoderms and their bilaterian relatives has been an enduring problem in zoology. The expression of conserved bilaterian patterning genes in echinoderms provides a molecular framework for resolving this puzzle. Recent studies in juvenile asteroids suggest that the bilaterian antero-posterior axis maps onto the medio-lateral axis that is perpendicular to each of the five rays of the pentaradial body plan. Here we test this hypothesis in another echinoderm class, the ophiuroids, using the cosmopolitan brittle star Amphipholis squamata. Our results show that the general principles of axial patterning are similar to those described in asteroids, and comparisons with existing molecular data from other echinoderm taxa support the idea that medio-lateral deployment of the AP patterning program across the rays predates the evolution of the asterozoan and likely the echinoderm crown-groups. Our data also reveal expression differences between A. squamata and asteroids, which we attribute to secondary modifications specific to ophiuroids. Together, this work provides important comparative data to reconstruct the evolution of axial properties in echinoderm body plans.Competing Interest StatementThe authors have declared no competing interest.

The origin of the pentaradial body plan of echinoderms from a bilateral ancestor is one of the most enduring zoological puzzles. Since echinoderms are defined by morphological novelty, even the most basic axial comparisons with their bilaterian relatives are problematic. Here, we used conserved antero-posterior (AP) axial molecular markers to determine whether the highly derived adult body plan of echinoderms masks underlying patterning similarities with other deuterostomes. To revisit this classical question, we used RNA tomography and in situ hybridizations in the sea star Patiria miniata to investigate the expression of a suite of conserved transcription factors with well-established roles in the establishment of AP polarity in bilaterians. We find that the relative spatial expression of these markers in P. miniata ambulacral ectoderm shows similarity with other deuterostomes, with the midline of each ray representing the most anterior territory and the most lateral parts exhibiting a more posterior identity. Interestingly, there is no ectodermal territory in the sea star that expresses the characteristic bilaterian trunk genetic patterning program. This suggests that from the perspective of ectoderm patterning, echinoderms are mostly head-like animals, and prompts a reinterpretation of the evolutionary trends that made echinoderms the most derived animal group.Competing Interest StatementP.P. and D.R.R. are employees and shareholders of Pacific Biosciences.

Background Concern for cardiovascular disease (particularly atrial fibrillation-AF) among women with breast cancer is becoming a major issue. We aimed at determining the incidence of cardiovascular disease events (AF, arterial and cardiac events, venous-thromboembolism-VTE) in patients diagnosed with breast cancer, and assessing potential risk factors. Methods We reviewed medical records of all patients diagnosed with breast cancer from 2010 to 2011 in our cancer center. Baseline characteristics of patients and tumors were collected. The main outcome was the occurrence of cardiovascular disease events (AF, VTE, arterial and cardiac events) during the 5-years follow-up. Results Among the 682 breast cancer patients, 22 (3.2%) patients had a history of atrial fibrillation. Thirty-four patients (5%) presented at least one cardiovascular disease event, leading to a cumulative incidence of 5.8% events at 5-years ([3.8–7.7] CI 95%), with most of them occurring in the first 2 years. AF cumulative incidence was 1.1% ([0.1–2.1] CI 95%). Factors associated with the occurrence of cardiovascular disease events (including AF) were an overexpression of HER-2 (HR 2.6 [1.21–5.56] p  < 0.011), UICC-stage III tumors or more (HR 5.47 [2.78–10.76] p  < 0.001) and pre-existing cardiovascular risk factors (HR 2.91 [1.36–6.23] p  < 0.004). Conclusion The incidence of cardiovascular disease events was 5.8% ([3.8–7.7] CI 95%), with HER-2 over-expression, UICC-stage III tumors or more and pre-existing cardiovascular diseases being associated with them. These findings call for the development of preventive strategies in patients diagnosed with breast cancer.

To maintain homeostasis, hypothalamic neurons in the arcuate nucleus must dynamically sense and integrate a multitude of peripheral signals. Blood-borne molecules must therefore be able to circumvent the tightly sealed vasculature of the blood–brain barrier to rapidly access their target neurons. However, how information encoded by circulating appetite-modifying hormones is conveyed to central hypothalamic neurons remains largely unexplored. Using in vivo multiphoton microscopy together with fluorescently labeled ligands, we demonstrate that circulating ghrelin, a versatile regulator of energy expenditure and feeding behavior, rapidly binds neurons in the vicinity of fenestrated capillaries, and that the number of labeled cell bodies varies with feeding status. Thus, by virtue of its vascular connections, the hypothalamus is able to directly sense peripheral signals, modifying energy status accordingly.

Netrin-1 is upregulated in cancers as a protumoural mechanism 1 . Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care 2 , we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments. We describe netrin-1 upregulation in a majority of human endometrial carcinomas and demonstrate that netrin-1 blockade, using the anti-netrin-1 antibody NP137, is effective both in a mouse model and in patients with endometrial carcinomas.

Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50–70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20–100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.

Prebiotics, a subset of biostimulants, have garnered attention for their potential to enhance soil conditions and promote plant growth, offering a promising alternative to conventional agricultural inputs. This study explores how two commercial prebiotics, K1® and NUTRIGEO L® (SPK and SPN), impact soil functions compared to a control (SP). The experiment involved agricultural soil amended with organic wheat straws and cultivated with Zea mays L. Previous research demonstrated substantial effects of these prebiotics on plant biomass, soil parameters, and microbial community ten weeks after application. The present study delves deeper, focusing on soil microbial abundance, enzyme activities, and metabolic diversity. Analysis revealed that SPN notably increased the fungi-to-bacteria ratio, and both prebiotics elevated the activity of several key enzymes. SPN enhanced α-glucosidase and β-galactosidase activities, while SPK increased arylsulfatase, phosphatase, alkaline phosphatase, and urease activities. Enzymatic indexes confirmed the positive impact on soil functional diversity and fertility. Additionally, prebiotic treatments showed distinct metabolic profiles, with SPK degrading eleven carbon sources more rapidly across five groups and SPN accelerating the decomposition rate of four carbon sources from three groups. These findings highlight the ability of prebiotics to shape microbial communities and enhance soil fertility by modulating their functional activity and diversity.