Scutoids unveil the three-dimensional packing in curved epithelia

As animals develop, the initial simple planar epithelia of the early embryos must acquire complex three-dimensional architectures to form the final functional tissues of the organism. Epithelial bending is, therefore, a general principle of all developing systems. Scholarly publications depict epithelial cells as prisms where their basal and apical faces resemble polygons with the same number of sides. The accepted view is that, when a tissue bend, the cells of the epithelia modify their shape from columnar to what has been traditionally called “bottle shape”. However, the morphology and packing of curved epithelia remain largely unknown. Here, through mathematical and computational modelling, we show that cells in bent epithelia necessarily undergo intercalations along the apico-basal axis. This event forces cells to exchange their neighbours between their basal and apical surfaces. Therefore, the traditional view of epithelial cells as simple prisms is incompatible with this phenomenon. Consequently, epithelial cells are compelled to adopt a novel geometrical shape that we have named “scutoid”. The in-depth analysis of diverse epithelial tissues and organs confirm the generation of apico-basal transitions among cell during morphogenesis. Using biophysics arguments, we determine that scutoids support the energetic minimization on the tissue and conclude that the transitions along the apico-basal axis stabilize the threedimensional packing of the tissue. Altogether, we argue that scutoids are nature’s solution to bend efficiently epithelia, and the missing piece for developing a unifying and realistic model of epithelial architecture

Evolutionary 3D Image Segmentation of Curve Epithelial Tissues of Drosophila melanogaster

Analysing biological images coming from the microscope is challenging; not only is it complex to acquire the images, but also the three-dimensional shapes found on them. Thus, using automatic approaches that could learn and embrace that variance would be highly interesting for the field. Here, we use an evolutionary algorithm to obtain the 3D cell shape of curve epithelial tissues. Our approach is based on the application of a 3D segmentation algorithm called LimeSeg, which is a segmentation software that uses a particle-based active contour method. This program needs the fine tuning of some hyperparameters that could present a long number of combinations, with the selection of the best parametrisation being highly time-consuming. Our evolutionary algorithm automatically selects the best possible parametrisation with which it can perform an accurate and non-supervised segmentation of 3D curved epithelial tissues. This way, we combine the segmentation potential of LimeSeg and optimise the parameters selection by adding automatisation. This methodology has been applied to three datasets of confocal images from Drosophila melanogaster, where a good convergence has been observed in the evaluation of the solutions. Our experimental results confirm the proper performing of the algorithm, whose segmented images have been compared to those manually obtained for the same tissues.Ministerio de Ciencia, Innovación y Universidades TIN2017-88209-C2Junta de Andalucía US-1263341Junta de Andalucía P18-RT-2778Ministerio de Economía, Industria y Competitividad BFU2016-74975-PMinisterio de Ciencia e Innovación PID2019-103900GB-10

Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy

Duchenne muscle dystrophy (DMD) is a genetic disorder characterized by progressive skeletal muscle weakness. Dystrophin deficiency induces instability of the sarcolemma during muscle contraction that leads to muscle necrosis and replacement of muscle by fibro-adipose tissue. Several therapies have been developed to counteract the fibrotic process. We report the effects of nintedanib, a tyrosine kinase inhibitor, in the mdx murine model of DMD. Nintedanib reduced proliferation and migration of human fibroblasts in vitro and decreased the expression of fibrotic genes such as COL1A1, COL3A1, FN1, TGFB1, and PDGFA. We treated seven mdx mice with 60 mg/kg/day nintedanib for 1 month. Electrophysiological studies showed an increase in the amplitude of the motor action potentials and an improvement of the morphology of motor unit potentials in the animals treated. Histological studies demonstrated a significant reduction of the fibrotic areas present in the skeletal muscles. Analysis of mRNA expression from muscles of treated mice showed a reduction in Col1a1, Col3a1, Tgfb1, and Pdgfa. Western blot showed a reduction in the expression of collagen I in skeletal muscles. In conclusion, nintedanib reduced the fibrotic process in a murine model of dystrophinopathy after 1 month of treatment, suggesting its potential use as a therapeutic drug in DMD patients.España, Ministerio de Economía y Competitividad BFU2016-74975-PEspaña, Instituto Ramón y Cajal PI13/0134

Rules of tissue packing involving different cell types: human muscle organization

Natural packed tissues are assembled as tessellations of polygonal cells. These include skeletal muscles and epithelial sheets. Skeletal muscles appear as a mosaic composed of two different types of cells: the “slow” and “fast” fibres. Their relative distribution is important for the muscle function but little is known about how the fibre arrangement is established and maintained. In this work we capture the organizational pattern in two different healthy muscles: biceps brachii and quadriceps. Here we show that the biceps brachii muscle presents a particular arrangement, based on the different sizes of slow and fast fibres. By contrast, in the quadriceps muscle an unbiased distribution exists. Our results indicate that the relative size of each cellular type imposes an intrinsic organization into natural tessellations. These findings establish a new framework for the analysis of any packed tissue where two or more cell types exist.España, Gobierno BFU2011-2573

Recubrimientos recomendables por razones de durabilidad, a disponer en estructuras de hormigón sometidas a la clase específica de exposición Qb (ataque químico de intensidad media)

Es una realidad cada vez más aceptada que la durabilidad del hormigón es una propiedad igual de importante que la resistencia mecánica o la estabilidad de volumen. No es el objeto del presente trabajo ahondar en las causas de esta evidencia sino en contribuir a hacer del diseño de la durabilidad una materia incorporada al quehacer diario de los técnicos y especialistas. Solo si la durabilidad de una estructura se puede proyectar y verificar, será posible conseguir vidas útiles con una cierta garantía o seguridad en que se alcanzarán los periodos de servicio que se especifiquen. En el diseño de la durabilidad se ha dedicado mucho tiempo en el pasado a aclarar los mecanismos de ataque (por ejemplo: por sulfatos o por reacción árido-álcali) o como realizar ensayos acelerados en estos casos y también en el caso concreto de la corrosión de la armadura. En el caso de la corrosión, la envergadura de los costes de reparaciones ha estimulado la publicación de modelos y ensayos que, si bien necesitan todavía calibración, al menos suponen una cierta ayuda para el proyectista

Scutoids are a geometrical solution to three-dimensional packing of epithelia

As animals develop, tissue bending contributes to shape the organs into complex three-dimensional structures. However, the architecture and packing of curved epithelia remains largely unknown. Here we show by means of mathematical modelling that cells in bent epithelia can undergo intercalations along the apico-basal axis. This phenomenon forces cells to have different neighbours in their basal and apical surfaces. As a consequence, epithelial cells adopt a novel shape that we term “scutoid”. The detailed analysis of diverse tissues confirms that generation of apico-basal intercalations between cells is a common feature during morphogenesis. Using biophysical arguments, we propose that scutoids make possible the minimization of the tissue energy and stabilize three-dimensional packing. Hence, we conclude that scutoids are one of nature's solutions to achieve epithelial bending. Our findings pave the way to understand the three-dimensional organization of epithelial organs.España Ministerio de Ciencia y Tecnología BFU2013-48988-C2-1-P and BFU2016-8079

Functional recovery in patients with schizophrenia: recommendations from a panel of experts

emission and encompasses multiple aspects of the patient's life, making it difficult to settle on a definition and to develop reliable assessment criteria. In this consensus process based on a panel of experts in schizophrenia, we aimed to provide useful insights on functional recovery and its involvement in clinical practice and clinical research. Methods: After a literature review of functional recovery in schizophrenia, a scientific committee of 8 members prepared a 75-item questionnaire, including 6 sections: (I) the concept of functional recovery (9 items), (II) assessment of functional recovery (23 items), (III) factors influencing functional recovery (16 items), (IV) psychosocial interventions and functional recovery (8 items), (V) pharmacological treatment and functional recovery (14 items), and (VI) the perspective of patients and their relatives on functional recovery (5 items). The questionnaire was sent to a panel of 53 experts, who rated each item on a 9-point Liken scale. Consensus was achieved in a 2-round Delphi dynamics, using the median (interquartile range) scores to consider consensus in either agreement (scores 7-9) or disagreement (scores 1-3). Items not achieving consensus in the first round were sent back to the experts for a second consideration. Results: After the two recursive rounds, consensus was achieved in 64 items (85.3%): 61 items (81.3%) in agreement and 3 (4.0%) in disagreement all of them from section II (assessment of functional recovery). Items not reaching consensus were related to the concepts of functional recovery (1 item, 13%), functional assessment (5 items, 6.7%), factors influencing functional recovery (3 items, 4.0%), and psychosocial interventions (2 items, 5.6%). Conclusions: Despite the lack of a well-defined concept of functional recovery, we identified a trend towards a common archetype of the definition and factors associated with functional recovery, as well as its applicability in clinical practice and clinical research.This project was funded by Janssen. The funding body participated in study design and data interpretation

EpiGraph: an open-source platform to quantify epithelial organization

Here we present EpiGraph, an image analysis tool that quantifies epithelial organization. Our method combines computational geometry and graph theory to measure the degree of order of any packed tissue. EpiGraph goes beyond the traditional polygon distribution analysis, capturing other organizational traits that improve the characterization of epithelia. EpiGraph can objectively compare the rearrangements of epithelial cells during development and homeostasis to quantify how the global ensemble is affected. Importantly, it has been implemented in the open-access platform Fiji. This makes EpiGraph very user friendly, with no programming skills required.España Ministerio de Economia, Industria y Competitividad BFU2016-74975-PEspaña, Programa Ramón y Cajal (PI13/ 01347

Do nutritional supplements have a role in age macular degeneration prevention?

Purpose. To review the proposed pathogenic mechanisms of age macular degeneration (AMD), as well as the role of antioxidants (AOX) and omega-3 fatty acids (omega-3) supplements in AMD prevention. Materials and Methods. Current knowledge on the cellular/molecular mechanisms of AMD and the epidemiologic/experimental studies on the effects of AOX and omega-3 were addressed all together with the scientific evidence and the personal opinion of professionals involved in the Retina Group of the OFTARED (Spain). Results. High dietary intakes of omega-3 and macular pigments lutein/zeaxanthin are associated with lower risk of prevalence and incidence in AMD. The Age-Related Eye Disease study (AREDS) showed a beneficial effect of high doses of vitamins C, E, beta-carotene, and zinc/copper in reducing the rate of progression to advanced AMD in patients with intermediate AMD or with one-sided late AMD. The AREDS-2 study has shown that lutein and zeaxanthin may substitute beta-carotene because of its potential relationship with increased lung cancer incidence. Conclusion. Research has proved that elder people with poor diets, especially with low AOX and omega-3 micronutrients intake and subsequently having low plasmatic levels, are more prone to developing AMD. Micronutrient supplementation enhances antioxidant defense and healthy eyes and might prevent/retard/modify AMD

CartoCell, a high-content pipeline for 3D image analysis, unveils cell morphology patterns in epithelia

Decades of research have not yet fully explained the mechanisms of epithelial self-organization and 3D packing. Single-cell analysis of large 3D epithelial libraries is crucial for understanding the assembly and function of whole tissues. Combining 3D epithelial imaging with advanced deep-learning segmentation methods is essential for enabling this high-content analysis. We introduce CartoCell, a deep-learning-based pipeline that uses small datasets to generate accurate labels for hundreds of whole 3D epithelial cysts. Our method detects the realistic morphology of epithelial cells and their contacts in the 3D structure of the tissue. CartoCell enables the quantification of geometric and packing features at the cellular level. Our single-cell cartography approach then maps the distribution of these features on 2D plots and 3D surface maps, revealing cell morphology patterns in epithelial cysts. Additionally, we show that CartoCell can be adapted to other types of epithelial tissues