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Eye disorders spanning a range of ocular tissue are common in patients with movement disorders. Highlighting these ocular manifestations will benefit patients and may even aid in diagnosis. In this educational review we outline the anatomy and function of the ocular tissues with a focus on the tissues most affected in movement disorders. We review the movement disorders associated with ocular pathology and where possible explore the underlying cellular basis thought to be driving the pathology and provide a brief overview of ophthalmic investigations available to the neurologist. This review does not cover intracranial primary visual pathways, higher visual function, or the ocular motor system.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, largely associated to morbidity and mortality. Over the past decades, research in appearance and progression of this arrhythmia have turned into significant advances in its management. However, the incidence of AF continues to increase with the aging of the population and many important fundamental and translational underlaying mechanisms remain elusive. Here, we review recent advances in molecular and cellular basis for AF initiation, maintenance and progression. We first provide an overview of the basic molecular and electrophysiological mechanisms that lead and characterize AF. Next, we discuss the upstream regulatory factors conducting the underlying mechanisms which drive electrical and structural AF-associated remodeling, including genetic factors (risk variants associated to AF as transcriptional regulators and genetic changes associated to AF), neurohormonal regulation (i.e., cAMP) and oxidative stress imbalance (cGMP and mitochondrial dysfunction). Finally, we discuss the potential therapeutic implications of those findings, the knowledge gaps and consider future approaches to improve clinical management.

Magnetic resonance imaging (MRI) of the brain combined with voxel-based morphometry (VBM) revealed changes in gray matter volume (GMV) in various disorders. However, the cellular basis of GMV changes has remained largely unclear. We correlated changes in GMV with cellular metrics by imaging mice with MRI and two-photon in vivo microscopy at three time points within 12 weeks, taking advantage of age-dependent changes in brain structure. Imaging fluorescent cell nuclei allowed inferences on (i) physical tissue volume as determined from reference spaces outlined by nuclei, (ii) cell density, (iii) the extent of cell clustering, and (iv) the volume of cell nuclei. Our data indicate that physical tissue volume alterations only account for 13.0% of the variance in GMV change. However, when including comprehensive measurements of nucleus volume and cell density, 35.6% of the GMV variance could be explained, highlighting the influence of distinct cellular mechanisms on VBM results.

Purpose of review To discuss recent advances of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in pharmacology, cell biology, and intracellular signaling in cancer. Recent findings Recent studies provide new insights into the pharmacology, cell biology of the VIP/PACAP system and show they play important roles in a number of human cancers, as well as in tumor growth/differentiation and are providing an increased understanding of their signaling cascade that is suggesting new treatment targets/approaches. Summary Recent insights from studies of VIP/PACAP and their receptors in both central nervous system disorders and inflammatory disorders suggest possible new treatment approaches. Elucidation of the exact roles of VIP/PACAP in these disorders and development of new therapeutic approaches involving these peptides have been limited by lack of specific pharmacological tools, and exact signaling mechanisms involved, mediating their effects. Reviewed here are recent insights from the elucidation of structural basis for VIP/PACAP receptor activation as well as the signaling cascades mediating their cellular effects (using results primarily from the study of their effects in cancer) that will likely lead to novel targets and treatment approaches in these diseases.

Fluid intake is an essential innate behaviour that is mainly caused by two distinct types of thirst1-3. Increased blood osmolality induces osmotic thirst that drives animals to consume pure water. Conversely, the loss of body fluid induces hypovolaemic thirst, in which animals seek both water and minerals (salts) to recover blood volume. Circumventricular organs in the lamina terminalis are critical sites for sensing both types of thirst-inducing stimulus4-6. However, how different thirst modalities are encoded in the brain remains unknown. Here we employed stimulus-to-cell-type mapping using single-cell RNA sequencing to identify the cellular substrates that underlie distinct types of thirst. These studies revealed diverse types ofexcitatory and inhibitory neuron in each circumventricular organ structure. We show that unique combinations of theseneuron types are activated under osmotic and hypovolaemic stresses. These results elucidate the cellular logic that underlies distinct thirst modalities. Furthermore, optogenetic gain of function in thirst-modality-specific cell types recapitulated water-specific and non-specific fluid appetite caused by the two distinct dipsogenic stimuli. Together, these results show that thirst is a multimodal physiological state, and that different thirst states are mediated by specific neuron types in the mammalian brain.

Previous studies have highlighted marked inter‐individual variations in factor VIII (FVIII) clearance between patients with haemophilia (PWH). The half‐life of infused FVIII has been reported to vary from as little as 5.3 hours in some adult PWH, up to as long as 28.8 hours in other individuals. These differences in clearance kinetics have been consistently observed using a number of different plasma‐derived and recombinant FVIII products. Furthermore, recent studies have demonstrated that half‐life for extended half‐life (EHL‐) FVIII products also demonstrates significant inter‐patient variation. Since time spent with FVIII trough levels

PET hypoxia imaging can assess tissue viability in acute ischemic stroke (AIS). [18F]FMISO is an established tracer but requires substantial accumulation time, limiting its use in hyperacute AIS. [64Cu]CuATSM requires less accumulation time and has shown promise as a hypoxia tracer. We compared these tracers in a M2-occlusion model (M2CAO) with preserved collateral blood flow. Rats underwent M2CAO and [18F]FMISO ( n = 12) or [64Cu]CuATSM ( n = 6) examinations. [64Cu]CuATSM animals were also examined with MRI. Pimonidazole was used as a surrogate for [18F]FMISO in an immunofluorescence analysis employed to profile levels of hypoxia in neurons (NeuN) and astrocytes (GFAP). There was increased [18F]FMISO uptake in the M2CAO cortex. No increase in [64Cu]CuATSM activity was found. The pimonidazole intensity of neurons and astrocytes was increased in hypoxic regions. The pimonidazole intensity ratio was higher in neurons than in astrocytes. In the majority of animals, immunofluorescence revealed a loss of astrocytes within the core of regions with increased pimonidazole uptake. We conclude that [18F]FMISO is superior to [64Cu]CuATSM in detecting hypoxia in AIS, consistent with an earlier study. [18F]FMISO may provide efficient diagnostic imaging beyond the hyperacute phase. Results do not provide encouragement for the use of [64Cu]CuATSM in experimental AIS.

The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development. This Perspective outlines the Human Developmental Cell Atlas initiative, which uses state-of-the-art technologies to map and model human development across gestation, and discusses the early milestones that have been achieved.

Human brain development is a complex process where multiple cellular and developmental events are coordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS) is an X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1, which encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a ‘disease-in-a-dish’ model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development. This article has an associated First Person interview with the first author of the paper.

The trachea delivers inhaled air into the lungs for gas exchange. Anomalies in tracheal development can result in life-threatening malformations, such as tracheoesophageal fistula and tracheomalacia. Given the limitations of current therapeutic approaches, development of technologies for the reconstitution of a three-dimensional trachea from stem cells is urgently required. Recently, single-cell sequencing technologies and quantitative analyses from cell to tissue scale have been employed to decipher the cellular basis of tracheal morphogenesis. In this Review, recent advances in mammalian tracheal development and the generation of tracheal tissues from pluripotent stem cells are summarized., Summary: This Review summarizes the current knowledge of mammalian tracheal development, which is distinct from lung in large part, and discusses the generation of tracheal tissues from human pluripotent stem cells.

Articular cartilage does not regenerate in adults. A lot of time and resources have been dedicated to cartilage regeneration research. The current understanding suggests that multi-disciplinary approach including biologic, genetic, and mechanical stimulations may be needed for cell-based cartilage regeneration. This review summarizes contents of a workshop sponsored by International Combined Orthopaedic Societies during the 2019 annual meeting of the Orthopaedic Research Society held in Austin, Texas. Three approaches for cell-based cartilage regeneration were introduced, including cellular basis of chondrogenesis, gene-enhanced cartilage regeneration, and physical modulation to divert stem cells to chondrogenic cell fate. While the complicated nature of cartilage regeneration has not allowed us to achieve successful regeneration of hyaline articular cartilage so far, the utilization of multi-disciplinary approaches in various fields of biomedical engineering will provide means to achieve this goal faster. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:463-472, 2020.

Background Hypophosphatasia (HPP) is an inherited disorder characterized by defective mineralization of the bone and teeth that is also associated with a deficiency of serum alkaline phosphatase (ALP). Patients with HPP exhibit a broad range of symptoms including stillbirth with an unmineralized skeleton, premature exfoliation and dental caries in childhood, and pseudo-fractures in adulthood. The broad clinical spectrum of HPP is attributed to various mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Nevertheless, the molecular mechanisms underlying the genotypic and phenotypic relationship of HPP remain unclear. Highlight The expression of HPP-related TNSALP mutants in mammalian cells allows us to determine for the effects of mutations on the properties of TNSALP, which could contribute to a better understanding of the relationship between structure and function of TNSALP. Conclusion Molecular characterization of TNSALP mutants helps establish the etiology and onset of HPP.

Bone is composed of a complex mixture of many dynamic cell types. Flow cytometry and in vivo lineage tracing have offered early progress toward deconvoluting this heterogeneous mixture of cells into functionally well-defined populations suitable for further studies. Single-cell sequencing is poised as a key complementary technique to better understand the cellular basis of bone metabolism and development. However, single-cell sequencing approaches still have important limitations, including transcriptional effects of cell isolation and sparse sampling of the transcriptome, that must be considered during experimental design and analysis to harness the power of this approach. Accounting for these limitations requires a deep knowledge of the tissue under study. Therefore, with the emergence of accessible tools for conducting and analyzing single-cell RNA sequencing (scRNA-seq) experiments, bone biologists will be ideal leaders in the application of scRNA-seq to the skeleton. Here we provide an overview of the steps involved with a single-cell sequencing analysis of bone, focusing on practical considerations needed for a successful study. © 2019 American Society for Bone and Mineral Research.

Although the process by which the cortical tissues of the brain fold has been the subject of considerable study and debate over the past few decades, a single mechanistic description of the phenomenon has yet to be fully accepted. Rather, two competing explanations of cortical folding have arisen in recent years; known as the axonal tension and the differential tangential expansion models. In the present review, these two models are introduced by analyzing the computational, theoretical, materials-based, and cell studies which have yielded them. Then Four-dimensional bioprinting is presented as a powerful technology which can not only be used to test both models of cortical folding de novo, but can also be used to explore the reciprocal effects that folding associated mechanical stresses may have on neural development. Therein, the fabrication of “smart” tissue models which can accurately simulate the in vivo folding process and recapitulate physiologically relevant stresses are introduced. We also provide a general description of both cortical neurobiology as well as the cellular basis of cortical folding. Our discussion also entails an overview of both 3D and 4D bioprinting technologies, as well as a brief commentary on recent advancements in printed central nervous system tissue engineering.

Tendon injuries are common and can dramatically impair patient mobility and productivity, resulting in a significant socioeconomic burden and reduced quality of life. Because the tendon healing process results in the formation of a fibrotic scar, injured tendons never regain the mechanical strength of the uninjured tendon, leading to frequent re-injury. Many tendons are also prone to the development of peritendinous adhesions and excess scar formation, which further reduce tendon function and lead to chronic complications. Despite this, there are currently no treatments that adequately improve the tendon healing process due in part to a lack of information regarding the contributions of various cell types to tendon healing and how their activity may be modulated for therapeutic value. In this review, we summarize recent efforts to identify and characterize the distinct cell populations involved at each stage of tendon healing. In addition, we examine the mechanisms through which different cell populations contribute to the fibrotic response to tendon injury, and how these responses can be affected by systemic factors and co-morbidities. We then discuss gaps in our current understanding of tendon fibrosis and highlight how new technologies and research areas are shedding light on this clinically important and intractable challenge. A better understanding of the complex cellular environment during tendon healing is crucial to the development of new therapies to prevent fibrosis and promote tissue regeneration.

In this paper, we study the representation theory of the Fuss–Catalan algebras, FC n ( a , b ) . We prove that this algebra is cellular with a cellular basis and forms a tower of recollement, as defined by Cox, Martin, Parker, and Xi [7] , and hence, it is quasi-hereditary algebra if a , b are non-zero complex numbers.

Congenital malformations, or structural birth defects, are now the leading cause of infant mortality in the United States and Europe (Dolk et al., 2010; Heron et al., 2009). Of the congenital malformations, congenital heart disease (CHD) is the most common (Dolk et al., 2010; Heron et al., 2009). Thus, a molecular understanding of heart development is an essential goal for improving clinical approaches to CHD. However, CHDs are commonly a result of genetic defects that manifest themselves in a spatial and temporal manner during the early stages of embryogenesis, leaving them mostly intractable to mass spectrometry-based analysis. Here, we describe the technologies and advancements in the field of mass spectrometry over the past few years that have begun to provide insights into the molecular and cellular basis of CHD and prospects for these types of approaches in the future.

The growth of individual cells underlies the development of biological forms. In plants, cells are interconnected by rigid walls, fixing their position with respect to one another and generating mechanical feedbacks between cells. Current research is shedding new light on how plant growth is controlled by physical inputs at the level of individual cells and growing tissues. In this review, we discuss recent progress in our understanding of the cellular basis of growth from a biomechanical perspective. We describe the role of the cell wall and turgor pressure in growth and highlight the often-overlooked role of cell geometry in this process. It is becoming apparent that a combination of experimental and theoretical approaches is required to answer new emerging questions in the biomechanics of plant morphogenesis. We summarise how this multidisciplinary approach brings us closer to a unified understanding of the generation of biological forms in plants.

Synaptic transmission is a fundamental neurobiological process enabling exchange of signals between neurons as well as neurons and their non-neuronal effectors. The complex molecular machinery of the synaptic vesicle cycle and transmitter release has emerged and developed in the course of the evolutionary race, to ensure adaptive gain and survival of the fittest. In parallel, a generous arsenal of biomolecules and neuroactive peptides have co-evolved, which selectively target the transmitter release machinery, with the aim of subduing natural rivals or neutralizing prey. With advances in neuropharmacology and quantitative biology, neurotoxins targeting presynaptic mechanisms have attracted major interest, revealing considerable potential as carriers of molecular cargo and probes for meddling synaptic transmission mechanisms for research and medical benefit. In this review, we investigate and discuss key facets employed by the most prominent bacterial and animal toxins targeting the presynaptic secretory machinery. We explore the cellular basis and molecular grounds for their tremendous potency and selectivity, with effects on a wide range of neural functions. Finally, we consider the emerging preclinical and clinical data advocating the use of active ingredients of neurotoxins for the advancement of molecular medicine and development of restorative therapies.

International audience; While virtually all animals show certain abilities for regeneration after an injury, these abilities vary greatly among metazoans. Porifera (Sponges) is basal metazoans characterized by a wide variety of different regenerative processes, including whole-body regeneration (WBR). Considering phylogenetic position and unique body organization, sponges are highly promising models, as they can shed light on the origin and early evolution of regeneration in general and WBR in particular. The present review summarizes available data on the morphogenetic and cellular mechanisms accompanying different types of WBR in sponges. Sponges show a high diversity of WBR, which principally could be divided into (1) WBR from a body fragment and (2) WBR by aggregation of dissociated cells. Sponges belonging to different phylogenetic clades and even to different species and/or differing in the anatomical structure undergo different morphogeneses after similar operations. A common characteristic feature of WBR in sponges is the instability of the main body axis: a change of the organism polarity is described during all types of WBR. The cellular mechanisms of WBR are different across sponge classes, while cell dedifferentiations and transdifferentiations are involved in regeneration processes in all sponges. Data considering molecular regulation of WBR in sponges are extremely scarce. However, the possibility to achieve various types of WBR ensured by common morphogenetic and cellular basis in a single species makes sponges highly accessible for future comprehensive physiological, biochemical, and molecular studies of regeneration processes.

Acid taste, evoked mainly by protons (H+), is a core taste modality for many organisms. The hedonic valence of acid taste is bidirectional: animals prefer slightly but avoid highly acidic foods. However, how animals discriminate low from high acidity remains poorly understood. To explore the taste perception of acid, we use the fruit fly as a model organism. We find that flies employ two competing taste sensory pathways to detect low and high acidity, and the relative degree of activation of each determines either attractive or aversive responses. Moreover, we establish one member of the fly Otopetrin family, Otopetrin-like a (OtopLa), as a proton channel dedicated to the gustatory detection of acid. OtopLa defines a unique subset of gustatory receptor neurons and is selectively required for attractive rather than aversive taste responses. Loss of otopla causes flies to reject normally attractive low-acid foods. Therefore, the identification of OtopLa as a low-acid sensor firmly supports our competition model of acid taste sensation. Altogether, we have discovered a binary acid-sensing mechanism that may be evolutionarily conserved between insects and mammals., Many animals, including mammals and insects, like slightly acidic yet dislike highly acidic foods, but how animals discriminate low from high acidity is unclear. Here the authors demonstrate that the fruit fly uses an evolutionarily conserved taste receptor to distinguish low from high concentrations of acid.

Cells emerged at the very beginning of life on Earth and, in fact, are coterminous with life. They are enclosed within an excitable plasma membrane, which defines the outside and inside domains via their specific biophysical properties. Unicellular organisms, such as diverse protists and algae, still live a cellular life. However, fungi, plants, and animals evolved a multicellular existence. Recently, we have developed the cellular basis of consciousness (CBC) model, which proposes that all biological awareness, sentience and consciousness are grounded in general cell biology. Here we discuss the biomolecular structures and processes that allow for and maintain this cellular consciousness from an evolutionary perspective.

The defense organization of our organism is found in the immune system, which has two important components, the innate and the adaptive immunity, where different molecules, cells, and organs are involved and coordinated to protect us from external and internal damage [...]

Organotin(IV) compounds have wide applications in industrial and agricultural fields owing to their ability to act as poly(vinyl chloride) stabilizers and catalytic agents as well as their medicinal properties. Moreover, organotin(IV) compounds may have applications as antitumor, anti-inflammatory, antifungal, or antimicrobial agents based on the observation of synergistic effects following the binding of their respective ligands, resulting in the enhancement of their biological activities. In this review, we describe the antiproliferative activities of organotin(IV) compounds in various human cancer cell lines based on different types of ligands. We also discuss the molecular mechanisms through which organotin(IV) compounds induce cell death via apoptosis through the mitochondrial intrinsic pathway. Finally, we present the mechanisms of cell cycle arrest induced by organotin(IV) compounds. Our report provides a basis for studies of the antitumor activities of organotin(IV) compounds and highlights the potential applications of these compounds as anticancer metallodrugs with low toxicity and few side effects.

Heart malformation is the leading cause of human birth defects, and many of the congenital heart diseases (CHDs) originate from genetic defects that impact cardiac development and maturation. During development, the vertebrate heart undergoes a series of complex morphogenetic processes that increase its ability to pump blood. One of these processes leads to the formation of the finger-like muscular projections called trabeculae. Trabeculae increase cardiac output and permit nutrition and oxygen uptake in the embryonic myocardium prior to coronary vascularization without increasing heart size. Cardiac trabeculation is also crucial for the development of the intraventricular fast conduction system. Alterations in cardiac trabecular development can manifest as a variety of congenital defects such as left ventricular noncompaction. In this review, we discuss the latest advances in understanding the molecular and cellular mechanisms underlying cardiac trabecular development.

Activity-dependent long-term changes in synaptic transmission known as synaptic plasticity are fundamental processes in brain function and are recognized as the cellular basis of learning and memory. While the neuronal mechanisms underlying synaptic plasticity have been largely identified, the involvement of astrocytes in these processes has been less recognized. However, astrocytes are emerging as important cells that regulate synaptic function by interacting with neurons at tripartite synapses. In this review, we discuss recent evidence suggesting that astrocytes are necessary elements in long-term synaptic depression (LTD). We highlight the mechanistic heterogeneity of astrocyte contribution to this form of synaptic plasticity and propose that astrocytes are integral participants in LTD., The authors would like to thank María José Acuyo Ruiz for assistance with the figures. This work was supported by grants from the Spanish Ministry of Science and Innovation (Ramón y Cajal RYC-2016-20414 and RTI2018-094887-B-I00) and Fondo Europeo de Desarrollo Regional (FEDER) to M.N.; and National Institutes of Health-MH (R01MH119355), National Institutes of Health-NINDS (R01NS097312), and National Institutes of Health-NIDA (R01DA048822) to A.A.

Tissue repair and regeneration are ubiquitous phenomena and are required for the long-term survival of animals in the natural environment. However, the ability of tissue repair and regeneration in different animals varies widely. Some lower invertebrates (such as polyps and worms) can regenerate a new individual. Lower vertebrate animals such as newt can regenerate limbs, retina, lens, spinal cord and tail. Zebrafish can regenerate heart and fins [1, 2]. Higher vertebrates, such as mammals, cannot completely regenerate tissues and organs, and can only undergo simple healing and fibrotic repair [1, 2].

Daniloski, Jordan et al. report a genome-wide CRISPR–Cas9-mediated loss-of-function screen to identify host factors required for SARS-CoV-2 viral infection.

Allergic inflammatory diseases are a global public health concern affecting millions of people. Although there are several potential hypotheses, details regarding their molecular mechanisms are still ambiguous. Recently, a group of β-galactoside-binding proteins, galectins, have been revealed as important factors in altering allergic chronic inflammatory diseases. In this review, we describe the molecular and cellular basis of how galectins modulate inflammatory reactions. We also provide an overview of clinical features related to galectins. Finally, we discuss the potential issues that might lead to misrepresentation of the exact biological functions of galectins.

Pancreatic islets play an essential role in regulating blood glucose level. Although the molecular pathways underlying islet cell differentiation are beginning to be resolved, the cellular basis of islet morphogenesis and fate allocation remain unclear. By combining unbiased and targeted lineage tracing, we address the events leading to islet formation in the mouse. From the statistical analysis of clones induced at multiple embryonic timepoints, here we show that, during the secondary transition, islet formation involves the aggregation of multiple equipotent endocrine progenitors that transition from a phase of stochastic amplification by cell division into a phase of sublineage restriction and limited islet fission. Together, these results explain quantitatively the heterogeneous size distribution and degree of polyclonality of maturing islets, as well as dispersion of progenitors within and between islets. Further, our results show that, during the secondary transition, α- and β-cells are generated in a contemporary manner. Together, these findings provide insight into the cellular basis of islet development., The cellular basis of islet morphogenesis and fate allocation remain unclear. Here, the authors use a R26-CreER-R26R-Confetti mouse line to follow quantitatively the clonal dynamics of islet formation showing how, during the secondary transition, islet progenitors amplify through rounds of stochastic cell division before becoming restricted to α and β cell sublineages.

Wound healing is a complex, dynamic process supported by a myriad of cellular events that must be tightly coordinated to efficiently repair damaged tissue. Derangement in wound-linked cellular behaviours, as occurs with diabetes and ageing, can lead to healing impairment and the formation of chronic, non-healing wounds. These wounds are a significant socioeconomic burden due to their high prevalence and recurrence. Thus, there is an urgent requirement for the improved biological and clinical understanding of the mechanisms that underpin wound repair. Here, we review the cellular basis of tissue repair and discuss how current and emerging understanding of wound pathology could inform future development of efficacious wound therapies.

International audience; Bioprinting is an emergent technology that has already demonstrated the capacity to create complex and/or vascularized multicellular structures with defined and organized architectures, in a reproducible and high throughput way. Here, we present the implementation of a complex liver model by the development of a three-dimensional extrusion bioprinting process, including parameters for matrix polymerization of methacrylated gelatin, using two hepatic cell lines, Huh7 and HepaRG. The printed structures exhibited long-term viability (28 days), proliferative ability, a relevant hepatocyte phenotype and functions equivalent to or better than those of their 2D counterparts using standard DMSO treatment. This work served as a basis for the bioprinting of complex multicellular models associating the hepatic parenchymal cells, HepaRG, with stellate cells (LX-2) and endothelial cells (HUVECs), able of colonizing the surface of the structure and thus recreating a pseudo endothelial barrier. When bioprinted in 3D monocultures, LX-2 expression was modulated by TGFβ-1 toward the induction of myofibroblastic genes such as ACTA2 and COL1A1. In 3D multicellular bioprinted structures comprising HepaRG, LX-2 and endothelial cells, we evidenced fibrillar collagen deposition, which is never observed in monocultures of either HepaRG or LX-2 alone. These observations indicate that a precise control of cellular communication is required to recapitulate key steps of fibrogenesis. Bioprinted 3D co-cultures therefore open up new perspectives in studying the molecular and cellular basis of fibrosis development and provide better access to potential inducers and inhibitors of collagen expression and deposition.

The first human electrocardiogram (ECG) ever recorded is accredited to the British physiologist Augustus D. Waller who, in 1887, published a paper depicting several beats of a one-lead ECG using a refined Lipmann capillary electrometer. The recordings were obtained with one electrode placed in the back and the other over the precordium. Subsequently, in 1895, Willem Einthoven, a Dutch physician and physiologist, further improved the capillary electrometer and mathematically corrected human ECG tracings to allow for inertia and friction in the capillary. For the corrected curves, and based on the mathematical tradition initiated by Descartes more than two centuries earlier, he labeled the successive deflections PQRST, labels that we still use today. Furthermore, Einthoven later improved the sensitivity of the capillary electrometer, developed the string galvanometer, and, in 1903, published recordings of human ECGs as we know them these days. For these extraordinary and related achievements, including the demonstration of its clinical application, he received the Nobel Prize in Medicine in 1924.

During embryonic development, the central nervous system forms as the neural plate and then rolls into a tube in a complex morphogenetic process known as neurulation. Neural tube defects (NTDs) occur when neurulation fails and are among the most common structural birth defects in humans. The frequency of NTDs varies greatly anywhere from 0.5 to 10 in 1000 live births, depending on the genetic background of the population, as well as a variety of environmental factors. The prognosis varies depending on the size and placement of the lesion and ranges from death to severe or moderate disability, and some NTDs are asymptomatic. This chapter reviews how mouse models have contributed to the elucidation of the genetic, molecular, and cellular basis of neural tube closure, as well as to our understanding of the causes and prevention of this devastating birth defect.

The adult mammalian heart was long thought to be a nonregenerating organ; however, recent evidence suggests otherwise. After many studies, a consensus has emerged that low levels of cardiomyocyte turnover occurs in the adult mammalian heart, originating primarily from preexisting cardiomyocytes with negligible contributions from any type of stem cell population. In this chapter, we highlight the critical studies that helped arrive at this conclusion We also discuss innovative approaches and potential therapeutic strategies that can generate new functional cardiac muscle tissue in the postnatal mammalian heart.