The effects of mild hypoxia on hypoglossal motoneurones in neonates

The patency of the upper airway is dependent on the activity of the genioglossus muscle, the main protrusor muscle of the tongue. The force generated by this muscle opposes the negative intraluminal pressure produced by the contraction of the diaphragm during inspiration. Recent studies suggest that there is an immaturity in genioglossus muscle control in neonates and obstructive apnoea may occur when the activity of this muscle is reduced or absent without a corresponding decrease in the activity of the diaphragm. However, little is known of the processes mediating and influencing the activity of the hypoglossal nerve, the motor nerve of the genioglossus muscle, at this stage in development. In newborn babies, central apnoea (when there is no inspiratory effort) is usually followed by obstructive apnoea (when although there is inspiratory effort there is no inspiratory flow). It is therefore possible that hypoxia which develops during central apnoea, inhibits the activity of the genioglossus muscle and as a consequence the airway becomes obstructed. The aim of this study was therefore to determine whether hypoglossal motoneurones are inhibited during hypoxia in neonates. This study has investigated the effect of mild levels of hypoxaemia (PaO2 47.2 ± 3.8mmHg) on the activity of hypoglossal motoneurones in anaesthetized neonatal kittens (27 days old). The results showed that the majority of hypoglossal motoneurones increased in discharge frequency during hypoxia but for a substantial proportion the increase was only transient. Furthermore, some motoneurones showed a decrease in discharge frequency. Intracellular recordings showed that during similar levels of hypoxia, although a large proportion of the motoneurones were depolarized, at least some of these repolarized despite the continuing hypoxia. In addition, some hypoglossal motoneurones were hyperpolarized. This is the clearest evidence that inhibitory mechanisms, in addition to excitatory mechanisms, mediate the effects of hypoxia on hypoglossal output in neonates. Furthermore, the results suggest that hypoxia has an effect on the hypoglossal motoneurones independently of, or in addition to, its effect through respiratory rhythm. In some preliminary studies, the transmembrane input resistance increased during the hyperpolarization in response to hypoxia. One possibility is that the inhibition is mediated by the removal of an excitatory input. If the inhibition found in this study occurs in human babies it may be a compounding factor in apnoeas of the newborn

Dynamique laryngée au cours des apnées en période périnatale chez l'agneau

L'instabilité respiratoire chez le nouveau-né humain au cours des premiers mois après la naissance est caractérisée par des apnées et la respiration périodique (RP) particulièrement chez les prématurés. Des observations chez les nouveau-nés humains et chez les animaux attribuent une importance majeure à la dynamique laryngée dans l'adaptation respiratoire à la naissance. Cependant, quelques études suggèrent aussi l'implication du larynx dans la genèse des apnées prolongées potentiellement dangereuses pour le nouveau-né. La dynamique laryngée au cours des apnées périnatales est encore peu connue. Le but de ce travail était d'étudier l'activité électromyographique (EMG) des muscles laryngés et leur coordination avec d'autres muscles respiratoires au cours des apnées et au cours de la RP chez l'agneau nouveau-né et l'agneau f¶tal sans sédation. Nous avons étudié l'EMG des muscles laryngés et des muscles respiratoires thoraciques à partir d'électrodes chroniques au cours : (1) de 243 occlusions externes des voies aériennes supérieures (VAS) en relation des stades éveil/sommeil (12 agneaux), (2) de 59 épisodes de RP au retour à l'air ambiant après hypoxie (16 agneaux) et (3) de périodes d'apnée et de mouvements respiratoires chez 11 agneaux f¶taux à la fin de la gestation. 1. Nos résultats montrent que l'augmentation progressive des efforts coordonnés des muscles glottiques accompagnait l'augmentation des efforts respiratoires contre l'occlusion des VAS en éveil et en sommeil calme (NREM). Cependant, cette réponse de défense contre l'occlusion était faible et désorganisée ou absente en sommeil agité (REM). 2. Des phases de ventilation oscillaient avec des phases d'apnée ou d'hypopnée au cours des épisodes de RP (durée de 25 à 235 secondes). L'EMG du muscle thyroaryténoïdien (TA) - adducteur glottique, absent en ventilation de base et lors des efforts ventilatoires, était tonique et continu en phase apnéique et hypopnéique de la RP. Au contraire, l'activiste EMG phasique inspiratoire et tonique expiratoire du muscle cricothyroïdien - abducteur glottique, généralement absente au cours des apnées et hypopnées, était pressante au cours des efforts ventilatoires. L'EMG des muscles abdominaux était silencieux au cours de la RP. 3. Finalement, l'analyse de 92 périodes du sommeil REM et de 90 périodes du sommeil NREM chez l'agneau f¶tal montre que l'activité EMG tonique, continue du muscle TA était présent au cours des apnées f¶tales quel que soit le stade de sommeil. Cette activité était interrompue par chaque décharge EMG du diaphragme (Di). De plus une coordination précise entre le muscle TA et le Di a été observée chez tous les f¶tus à l'exception de deux ou des décharges occasionnelles du Di survenaient malgré la présence de l'EMG tonique du muscle TA. En conclusion, nos résultats chez l'agneau montrent que : (1) le sommeil REM peut avoir un effet néfaste sur la réponse de défense des muscles laryngés et thoraciques contre l'occlusion des VAS, (2) une contraction glottique en phase apnéique de la RP suggère une fermeture glottique préservant l'air alvéolaire pour la continuité des échanges gazeux au cours de l'apnée et (3) une coordination précise entre le muscle TA et le Di est généralement établie avant la naissance. Cependant, cette coordination peut occasionnellement être prise en défaut chez l'agneau f¶tal

Structure-Function Relationship of the Ligand-Binding Domain of the Fibroblast Growth Factor Receptor

The interactions between FGF and fibroblast growth factor receptors are responsible for the regulation of key cellular processes. FGF is important in both germ cell and embryonic developments. FGF continues to play important roles during adulthood by regulating embryogenesis, cell differentiation, and wound healing (1-7). The regulations of these cellular events are initiated through FGF binding to the fibroblast growth factor receptors. The complex formed by FGF and the receptor involves a key interaction with heparin. Through interactions with heparin, the FGF, FGFR and Heparin form a 2:2:2 complex (8). This complex formation results in autophosphorylation in the tyrosine kinase domain in the cytoplasm. The autophosphorylation events lead to downstream signaling that result in the regulation of previously mentioned cellular processes (9, 10). Mutations within the FGF or FGFR may interfere with signaling or protein stability. Changes in the signaling efficiency by FGF or the FGFR are shown to lead to disease states There exist many point mutations in the FGF receptor that result in craniofacial, hypogonadotropic hypogonadism, anosmia, and tumor development. Using site-directed mutagenesis we have shown non-covalent interactions formed by Kallmann syndrome linked mutations result in a loss-of-binding between FGF and the FGF receptor. This evidence has shown that the non-covalent ligand binding interactions lost are due to changes in the D2 structure or binding site. Additionally, the R203C mutation, linked to breast cancer, was tested and determined to break a D2 stabilizing cation-ð bond. The cation-ð stabilized the binding interaction with heparin and provides stability to the D2 domain. Although the decreased stability of the D2 domain supports a loss-of-function, we are currently investigating intermolecular disulfide bond formation between adjacent receptor. This is a known mechanism among FGF receptors that may lead to signaling in the absence of a ligand

Classification of Lymphomas and Hematological Neoplasia in the Era of Genomic Research

This Special Issue contains review articles focusing on several lymphoma entities included in the current WHO classification. The aim of the book is to guide the readers in understanding the evolution of lymphoma classification. The clinicopathological entities described in this issue have been analyzed through the molecular mechanisms involved in their pathogenesis

Obesity and functional genomics-identified genes : a focus on the high-fat diet-induced gene trefoil factor 2 (Tff2) and the exercise-induced gene secreted protein acidic and rich in cysteine (Sparc) within the context of energy metabolism

L'obesité est un problème de santé en soi et c'est aussi un facteur de risque pour de nombreux autres problèmes de santé. Outre le contrôle de l'alimentation et l'activité physique, les options pharmacologiques contre l'obésité restent limitées et de nouvelles options thérapeutiques sont nécessaires. Dans ce contexte, la génomique fonctionnelle peut identifier de nouvelles options pour gérer et étudier l'obésité. Notre groupe de recherche a identifié deux gènes liés aux deux principaux facteurs ayant un impact sur le développement de l'obésité : La diète, principalement riche en gras (HFD) et l'exercice. Ces deux gènes clés sont le trefoil factor family member 2 (Tff2) et la secreted protein acidic and rich in cysteine (SPARC). Alors que Tff2 a été identifié comme un gène induit par la HFD, SPARC a été caractérisé comme un gène induit par l'exercice. Notre groupe de recherche a également constaté que les souris Tff2 knock-out (KO) sont protégées contre l'obésité induite par la HFD. Par conséquent, ma thèse explore Tff2 et Sparc dans le contexte de l'obésité et le métabolisme énergétique. Tff2 est principalement exprimé dans le système digestif où elle a une propriété de protection des muqueuses, tandis que Sparc est plus largement distribué et s'exprime principalement lors de remodelage tissulaire dans des situations telles que les blessures et la croissance. Les parties théoriques de cette thèse décrivent diverses propriétés de Tff2 et Sparc décrites dans la littérature telles que le métabolisme et les rôles cellulaires ainsi que les implications et les applications potentielles des données que j'ai générées. Pour mes données de recherche rapportées dans cette thèse, elles sont divisées en trois publications. La première, explore des souris Tff2 KO pour expliquer leur protection contre l'obésité induite par la HFD. Les souris Tff2 KO avaient des taux plus faibles de glucose, de triglycérides et de glycérol. Leurs niveaux d'expression génique et protéique indiquent moins de stockage de graisse et une dépense énergétique accrue en améliorant l'utilisation des lipides et du glucose via la phosphorylation oxydative. Nos données mettent en évidence les voies liées à Tff2 comme potentielles cibles pour les thérapies contre l'obésité. Via une expérimentation animale, la deuxième étude vise à identifier des implications de SPARC principalement dans le muscle dans les contextes de l'exercice. Les souris ont été divisées en huit groupes en fonction de trois variables (âge, génotype et exercice). Les effets du Sparc KO sur la composition corporelle, l'adiposité et le métabolisme sont vers une réduction du tissu adipeux blanc et du poids corporel, mais avec un phénotype métabolique et fonctionnel musculaire négatif. Alors que ces effets négatifs s'aggravent avec le vieillissement, ils sont relativement améliorés par l'exercice. Nos données suggèrent aussi que les changements induits par l'exercice dans le phénotype du muscle squelettique (métabolisme, force et développement), y compris les changements induits par le lactate, dépendent de SPARC. Le troisième article à deux parties. Tout d'abord, j'explore les conséquences du Sparc KO et les compare aux effets du vieillissement. J'observe également les effets de l'exercice. Dans la deuxième partie, j'étudie les effets de la surexpression de Sparc et les compare aux avantages de l'exercice. Les mesures étaient principalement liées au poids des tissus, à l'adiposité, au métabolisme et à la force musculaire. Collectivement, ces résultats, et les données de la deuxième étude, montrent que les souris Sparc KO développe un phénotype semblable au vieillissement, tandis que la surexpression de SPARC et l'exercice génèrent des avantages similaires. Ces avantages visent à contrer à la fois le phénotype du vieillissement induit par le déficit en SPARC et à améliorer les changements liés à l'âge. Les applications potentielles de ces résultats sont de construire/optimiser des modèles d'animaux basés sur Sparc KO et, d'autre part, de développer des thérapies contre l'obésité, les troubles métaboliques ou liés à l'âge basées sur l'introduction de SPARC ou le ciblage des voies liées à SPARC pour imiter l'exercice. L'exploration de telles voies moléculaires permettrait à la fois d'élucider certains mécanismes et de développer une nouvelle génération d'options thérapeutiques pour l'obésité et les troubles métaboliques, y compris les troubles liés à l'âge. De telles approches seraient basées sur le ciblage de TFF2, SPARC ou de leurs voies connexes.Obesity represents a challenge for health professionals. It is a health problem itself and it is also a risk factor for numerous health problems. Beside diet control and physical activity, the pharmacological options against obesity remain limited and novel therapeutic options are required. Within this context, functional genomics represents an emerging approach to identify novel options to manage and study obesity. Our research group has previously conducted functional genomics explorations to identify genes related to the two main factors impacting obesity development: Diet (mainly high fat) and exercise. Indeed, both diet, especially high-fat diet (HFD), and exercise are at the center of obesity management. Those functional genomics studies identified two key genes: Trefoil factor family member 2 (Tff2) and secreted protein acidic and rich in cysteine (SPARC). Whereas Tff2 was identified as a HFD-induced gene, SPARC was characterized as an exercise-induced gene. Following that, our research group has also found that Tff2 knock-out (KO) in mice protects them from the HFD-induced obesity. Therefore, my thesis explores Tff2 and Sparc within the context of obesity and energy metabolism. Tff2 is mainly expressed in the digestive system where it has mucus protection property, whereas Sparc is more widely distributed and is expressed mainly during tissues remodeling in situations such as injuries and growth. The theoretical parts of this thesis describe various properties of both Tff2 and Sparc reported in the literatures such as metabolism and cellular roles as well as implications and potential applications of the data I generated. For the research parts reported in this thesis, they are divided into three publications. The first one, explores Tff2 KO-related pathways of mice at the genomic, proteinic and biochemical levels to elucidate the processes behind their protection from the HFD-induced obesity. Tff2 KO mice had lower levels of serum glucose, triglycerides and glycerol. Western blotting and Q_RT-PCR revealed that the expression levels of selected genes and proteins are toward less fat storage and increased energy expenditure by enhancing lipid and glucose utilization via oxidative phosphorylation. The data highlight Tff2-related pathways as potential targets for obesity therapies. Via an animal experiment, the second study aims to identify selected implications of SPARC mainly within the muscle in the contexts of exercise. Mice were divided into eight groups based on three variables (age, genotype and exercise): Old or young × Sparc KO or wild type × sedentary or exercise. The exercised groups were trained before all mice were sacrificed. Sparc KO effects on body composition, adiposity and metabolic patterns are toward a reduced white adipose tissue and body weight, but with a negative metabolic and functional phenotype of the skeletal muscle. Whereas such negative effects on skeletal muscle are worsened with ageing, they are relatively improved by exercise. Importantly, our data suggest that the exercise-induced changes in the skeletal muscle phenotype, in terms of increased performance (metabolic, strength and development) including lactate-induced changes, are SPARC-dependent. The third paper studies and compares both Sparc KO and Sparc overexpression in male and female mice. First, I explore the consequences of Sparc KO and compare them to the ageing phenotype. I also observe the effects of exercise. In the second part, I study the consequences of SPARC overexpression and compare them to the exercise benefits. The measurements were mainly related to tissue weights, adiposity, metabolism, and muscle strength. Collectively, these findings and data show that Sparc KO mice manifest an ageing-like phenotype, whereas SPARC overexpression and exercise generate similar benefits. These benefits are towards counteracting both SPARC deficiency-induced ageing-like phenotype as well as reversing the age-related changes. The potential applications of these findings are to build/optimize Sparc KO-based animal models of various health conditions and, on the other hand, to develop therapies based on introducing SPARC or targeting SPARC-related pathways to mimic exercise against obesity, age-related and metabolic disorders. Exploring such molecular patterns would allow both mapping some underlying mechanisms and developing a new generation of therapeutic options for obesity and metabolic disorders, including age-related disorders. Such approaches would be based on targeting TFF2, SPARC or their related pathways

The Tumor Microenvironment of High Grade Serous Ovarian Cancer

The Special Issue on high grade serous ovarian cancer (HGSOC) and the contribution of the tumor microenviroment (TME) consists of reviews contributed by leaders in the OC field. As HGSOC metastases have a highly complex TME, there is an urgent need to better understand the TME in general, its distinct components in particular, and the role of the TME in the context of disease recurrence and development of chemoresistance. The Special Issue incorporates the current understanding of the different parts of thd TME components, including the cancer cells themselves, the cells surrounding the cancer cells or stromal cells, and the cells of the immune system, which are attracted to the site of metastases. In addition to these cells of the TME, the role of various cellular factors made by the cells of the TME are also the subject of the reviews. In addition, reviews in this Special Issue cover the complex relationships between the molecular mechanisms of HGSOC progression, including genomic, epigenomic and transcriptomic changes and changes in the immune cell landscape, as these may provide attractive new molecular targets for HGSOC therapy

Diagnosis, Treatment and Prevention of Age-Related Macular Degeneration

In this reprint, we hope to review the basics and highlight the latest developments in AMD. This demonstrates the benefits of the international scientific community working on this disease, to limit its negative impacts, the most vital of which is the loss of visual function, leading to a loss of autonomy and a decrease in patients’ quality of life

Electrical and Electro-Optical Biosensors

Electrical and electro-optical biosensing technologies are critical to the development of innovative POCT devices, which can be used by both professional and untrained personnel for the provision of necessary health information within a short time for medical decisions to be determined, being especially important in an era of global pandemics. This Special Issue includes a few pioneering works concerning biosensors utilizing electrochemical impedance, localized surface plasmon resonance, and the bioelectricity of sensing materials in which the amount of analyte is pertinent to the signal response. The presented results demonstrate the potential of these label-free biosensing approaches in the detection of disease-related small-molecule metabolites, proteins, and whole-cell entities

Animal Modeling in Cancer

Dear Readers, Understanding the pathological mechanisms involved in human diseases and their possible treatment has been historically based on comparative analysis of diverse animal species that share a similar genetic, physiological and behavioural composition. The ancient Greeks were the first to use animals as models for anatomy and physiology, and this was consequently adopted by other cultures and led to important discoveries. In recent years, there have been many efforts to understand and fight cancer through new revolutionary personalized treatments and wider screenings that help diagnose and treat cancer. A fundamental part of this effort is to develop suitable cancer animal models that simulate the different disease variants and their progression. Ranging from tumor-derived xenografts to genetically engineered models, a wide variety of systems are applied for this purpose, and many technological breakthroughs are changing the way cancer is studied and analyzed. In this Special Issue, we collected a set of research articles and reviews that focus on the generation of cancer animal models that are used for understanding the disease and contribute to designing and testing new drugs for cancer prevention or treatment. Vladimir Korinek Collection Edito