Innate immune signaling pathways initiate host defenses against viral pathogens. Receptors specific for viral nucleic acids activate these pathways culminating in cell-to-cell communication and/or cell death. In mammals, this cell- to-cell communication is achieved through the production of interferons and pro- inflammatory cytokines, which activate antiviral defenses in uninfected neighboring cells and instruct adaptive immune responses. The production of these signaling molecules is essential for the defense against viral infection, but must also be tightly regulated to prevent unnecessary inflammation. As an antiviral defense, cell death is also an effective mechanism to limit viral replication and spread but comes with the cost of tissue damage and inflammation. Therefore, regulating these antiviral responses is critical for controlling the spread of infection as well as preventing unnecessary pathologies related to excessive signaling. Hundreds of genes are involved in controlling these immune responses and a wide variety of mechanisms are utilized to regulate them. One mechanism to regulate gene function is the generation of protein variants through alternative translation. While polycistronic transcripts are a common feature of bacterial and viral gene expression, the process of alternative translation as a means to regulate gene function is not a feature generally attributed to mammalian mRNA. This dissertation describes a novel regulator of antiviral signaling that is generated through alternative translation. Expression of the transcript encoding the antiviral adaptor protein, MAVS, results in the production of two proteins: the full-length MAVS adaptor and a truncated variant, miniMAVS. Production of these proteins is in part regulated by cis-acting elements that control translation initiation. Production of miniMAVS regulates antiviral signaling by limiting interferon production induced by full-length MAVS, whereas both MAVS variants positively regulate cell death. To identify other examples of alternative translation in mammalian cells a genome-wide ribosomal profiling technique was used to generate a candidate list of antiviral truncation variants. This dissertation therefore demonstrates that protein variants generated through alternative translation of polycistronic mRNAs can be an effective mechanism for immune regulation and may be more common than previously understood.

Micro Air Vehicles (MAVs) are defined as a class of vehicles with their larger dimension not exceeding 15 cm and weighing 100 gm. The three main approaches for providing lift for such vehicles are through fixed, rotating and flapping wings. The flapping wing MAVs are more efficient in the low Reynolds-number regime than conventional wings and rotors. Natural flapping flyers, such as birds and insects, serve as a natural source of inspiration for the development of MAV. Flapping wing design is one of the major challenges to develop an MAV because it is not only responsible for the lift, but also propulsion and maneuvers. Two important issues are addressed in this thesis: (1) an equivalent beam-type modeling of actual insect wing is proposed based on the experimental data and (2) development of the numerical framework for design and analysis of insect scale smart flapping wing. The experimental data is used for structural modeling of the blowfly Calliphora wing as a stepped cantilever beam with nine spanwise sections of varying mass per unit lengths, flexural rigidity (EI) and torsional rigidity (GJ) values. Natural frequencies, both in bending and torsion, are obtained by solving the homogeneous part of the respective governing differential equations using the finite element method. It is found that natural frequency in bending and torsion are 3.17 and 1.57 times higher than flapping frequency of Calliphora wing, respectively. The results provide guidelines for the biomimetic structural design of insect-scale flapping wings. In addition to the structural modeling of the insect wing, development of the biomimetic mechanisms played a very important role to achieve a deeper insight of the flapping flight. Current biomimetic flapping wing mechanisms are either dynamically scaled or rely on pneumatic and motor-driven flapping actuators. Unfortunately, these mechanisms become bulky and flap at very low frequency. Moreover, mechanisms designed with conventional actuators lead to high weight and system-complexity which makes it difficult to mimic the complex wingbeat kinematics of the natural flyers. The usage of the actuator made of smart materials such as ionic polymer metal composites (IPMCs) and piezoceramics to design flapping wings is a potential alternative. IPMCs are a relatively new type of smart material that belongs to the family of Electroactive Polymers (EAP) which is also known as “artificial muscles”. In this work, structural modeling and aerodynamic analysis of a dragonfly inspired IPMC flapping wing are performed using numerical simulations. An optimization study is performed to obtain improved flapping actuation of the IPMC wing. Later, a comparative study of the performances of three IPMC flapping wings having the same size as the actual wings of three different dragonfly species Aeshna Multicolor, Anax Parthenope Julius and Sympetrum Frequens is conducted. It is found that the IPMC wing generates sufficient lift to support its own weight and carry a small payload. In addition to the IPMC, piezoelectric materials are also considered to design a dragonfly inspired flapping wing because they have several attractive features such as high bandwidth, high output force, compact size and high power density. The wings of birds and insects move through a large angle which may be obtained using piezofan through large deflection. Piezofan which is one of the simple motion amplifying mechanisms couples a piezoelectric unimorph to an attached flexible wing and is competent to produce large deflection especially at resonance. Non-linear dynamic model for the piezoelectrically actuated flapping wing is done using energy method. It is shown that flapping angle variations of the smart flapping wing are similar to the actual dragonfly wing for a specific feasible voltage. Subsequently, a comparative study of the performances of three piezoelectrically actuated flapping wings is performed. Numerical results show that the flapping wing based on geometry of dragonfly Sympetrum Frequens wing is suitable for low speed flight and it represents a potential candidate for use in insect scale micro air vehicles. In this study, single crystal piezoceramic is also considered for the flapping wing design because they are the potential new generation materials and have attracted considerable attention due to superior electromechanical properties. It is found that the use of single crystal piezoceramic can lead to considerable amount of wing weight reduction and increase of aerodynamic forces compared to conventional piezoelectric materials such as PZT-5H. It can also be noted that natural fliers flap their wings in a vertical plane with a change in the pitch of the wings during a flapping cycle. In order to capture this particular feature of the wingbeat kinematics, coupled flapping-twisting non-linear dynamic modeling of piezoelectrically actuated flapping wing is done using energy method. Excitation by the piezoelectric harmonic force generates only the flap bending motion, which in turn, induces the elastic twist motion due to interaction between flexural and torsional vibrations modes. It is found that the value of average lift reaches to its maximum when the smart flapping wing is excited at a frequency closer to the natural frequency in torsion. Moreover, consideration of the elastic twisting of flapping wing leads to an increase in the lift force.

No description available.

In most man-made flight, vehicle control is achieved by deflecting flaps. However, in nature, morphing surfaces are found on both flying and swimming creatures. Morphing is used in nature because it is a more efficient form of control. This thesis investigates using morphing flaps to control a class of UAVs known as ducted fan vehicles. Specifically, this thesis discusses both the challenges and benefits of using morphing control surfaces. To achieve morphing, a piezoelectric device known as Macro Fiber Composites is used. These devices are embedded in the skin of the vehicles control surface, and when actuated, they cause the control surface to increase or decrease camber. This thesis describes experiments that were performed to investigate the performance of this type of actuator. Specifically, the actuation bandwidth of these devices is presented and compared to a servo. Results show that the morphing control surfaces can actuate at frequencies twice as high as a servo. / Master of Science

The work presented herein focuses on the design of distributed autonomous controllers for collective behaviour of Micro-unmanned Aerial Vehicles (MAVs). Two alternative approaches to this topic are introduced: one based upon the Evolutionary Robotics (ER) paradigm, the other one upon flocking principles. Three computer simulators have been developed in order to carry out the required experiments, all of them having their focus on the modelling of fixed-wing aircraft flight dynamics. The employment of fixed-wing aircraft rather than the omni-directional robots typically employed in collective robotics significantly increases the complexity of the challenges that an autonomous controller has to face. This is mostly due to the strict motion constraints associated with fixed-wing platforms, that require a high degree of accuracy by the controller. Concerning the ER approach, the experimental setups elaborated have resulted in controllers that have been evolved in simulation with the following capabilities: (1) navigation across unknown environments, (2) obstacle avoidance, (3) tracking of a moving target, and (4) execution of cooperative and coordinated behaviours based on implicit communication strategies. The design methodology based upon flocking principles has involved tests on computer simulations and subsequent experimentation on real-world robotic platforms. A customised implementation of Reynolds’ flocking algorithm has been developed and successfully validated through flight tests performed with the swinglet MAV. It has been notably demonstrated how the Evolutionary Robotics approach could be successfully extended to the domain of fixed-wing aerial robotics, which has never received a great deal of attention in the past. The investigations performed have also shown that complex and real physics-based computer simulators are not a compulsory requirement when approaching the domain of aerial robotics, as long as proper autopilot systems (taking care of the ”reality gap” issue) are used on the real robots.

Le développement d'une réponse antivirale contre les virus, incluant le virus de l'immunodéficience humaine (VIH), le virus de la grippe, le virus respiratoire syncytial (VRS) ou le SARS-CoV-2, repose sur l'activation d'adaptateurs intracellulaires qui conduisent à la production d'interférons et de cytokines proinflammatoires. Une activation correctement équilibrée de ces voies permet à la cellule de monter un état antiviral, essentiel pour restreindre la réplication et la propagation du virus. Les acides nucléiques viraux à base d'ADN, présents à l’intérieur de la cellule, peuvent être reconnus par la GMP-AMP Synthase cyclique (cGAS), qui transduit ensuite le signal via l'adaptateur Stimulateur des gènes d'interféron (STING). D'autre part, les acides nucléiques viraux à ARN sont reconnus par les récepteurs de type RIG-I (RLR), qui interagissent ensuite avec l'adaptateur de signalisation antivirale mitochondrial (MAVS). STING et MAVS sont des protéines pivots de signalisation localisées dans des compartiments membranaires, régulées par plusieurs modifications post-traductionnelles (PTM) et, lors de l'activation, elles subissent des événements de polymérisation allant jusqu'à la formation d'agrégats fonctionnels. Des données soutiennent un rôle des espèces réactives de l'oxygène (ROS) dans la régulation des voies dépendantes de STING et MAVS, mais les mécanismes restent mal définis. Les ROS sont connus pour modifier la structure et l'activité des protéines de signalisation via des PTMs oxydatives réversibles sur des cystéines (Cys ox-PTM). Les Cys ox-PTM réversibles consistent en une variété de modifications, les plus étudiées étant la S-sulfénylation (Cys-SOH), la S-glutathionylation (Cys-SSG) et le disulfure (S-S). Afin d’identifier les Cys ox-PTM qui affectent les protéines de signalisation impliquées dans la réponse antivirale, nous avons effectué une identification à l'échelle du protéome des Cys ox-PTM induites par les ROS en utilisant un marquage bioswitch à base de maléimide couplé à la spectrométrie de masse. Nous avons identifié 2720 sites Cys ox-PTM uniques englobant 1473 protéines avec une abondance, localisation et fonctions distinctes. Parmi ceux-ci, nous avons découvert l'oxydation de STING sur la Cys148 et Cys206. Cette dernière étant inductible par le stress oxydatif ou par le ligand naturel 2'3'-cGAMP et joue un rôle inhibiteur pour empêcher l'hyperactivation de STING par la formation de polymères inactifs contenant des liaisons intermoléculaires S-S. En outre, nous avons observé que MAVS était également capable de former des polymères intermoléculaires contenant des S-S en réponse à une infection par des virus à ARN, et que l'ancrage de la protéine à la membrane était essentiel pour la formation de ces polymères. Le couplage du marquage par bioswitch à base de maléimide à l'analyse par immunoblot a confirmé que MAVS était oxydé pendant une infection avec un virus à ARN. Nous avons également constaté que des Cys situées dans des positions clés pour la formation de polymères de MAVS actifs étaient essentielles pour transduire la signalisation en aval et finalement activer le promoteur IFNβ en réponse à l'infection virale. Nos études établissent un mécanisme direct par lequel les ROS contrôlent la réponse immunitaire innée cGAS/STING et RLRs/MAVS-dépendante. Ils offrent un nouveau terrain pour la conception de thérapies ciblant des adaptateurs pertinents pour les infections virales, telles que la vaccination, mais aussi pour les troubles auto-immuns et inflammatoires. / The development of an antiviral response against viruses, including Human Immunodeficiency Virus (HIV), influenza, Respiratory Syncytial Virus (RSV) or SARS-CoV-2, relies on the activation of intracellular adaptors that ultimately lead to the production of interferons and proinflammatory cytokines. Properly balanced activation of these pathways allows the cell to mount an antiviral state, essential to restrict virus replication and spreading. Intracellular DNA viral nucleic acids can be recognized by the cyclic GMP-AMP Synthase (cGAS), which then transduces the signal through the Stimulator of Interferon Genes (STING) adaptor. On the other hand, RNA viral nucleic acids are recognized by the RIG-I-like Receptors (RLRs), which then interact with the Mitochondrial Antiviral Signaling (MAVS) adaptor. STING and MAVS are signaling hub proteins localized in membranous compartments, regulated by several posttranslational modifications (PTMs) and, upon activation, they undergo polymerization events going as far as the formation of functional aggregates. Compelling evidence supports a role of reactive oxygen species (ROS) in the regulation of STING and MAVS-dependent pathways, but the mechanisms remain ill-defined. ROS are known to modify signaling protein structure and activity through reversible oxidative PTM of Cysteines (Cys ox-PTM). Reversible Cys ox-PTMs consist of a variety of modifications, the most widely studied being S-sulfenylation (Cys-SOH), S-glutathionylation (Cys-SSG) and disulfide (S-S). To unveil the Cys ox-PTMs that affect signaling proteins involved in the antiviral response, we performed a proteome wide identification of the Cys ox-PTMs induced by ROS using maleimide-based bioswitch labeling coupled to mass spectrometry. We identified 2720 unique Cys ox-PTM sites encompassing 1473 proteins with distinct abundance, location, and functions. Among these, we uncovered the oxidation of STING at Cys148 and Cys206. The latter was inducible by oxidative stress or by the natural ligand 2’3’-cGAMP and plays an inhibitory role to prevent STING hyperactivation through the formation of inactive polymers containing intermolecular S-S bonds. Further, we observed that MAVS was also able to form intermolecular S-S containing polymers in response to RNA virus infection, and that the anchoring of the protein to the membrane was essential for these polymers to form. Maleimide-based bioswitch labeling couple to immunoblot analysis confirmed that MAVS was oxidized during RNA virus infection. We also found that Cys located in positions key for the formation of active polymers were essential for MAVS to transduce downstream signaling and ultimately activate IFNβ promoter in response to virus infection. Our studies establish a direct mechanism by which ROS control the cGAS/STING and the RLRs/MAVS-dependent innate immune response. They provide new ground for the design of therapies targeting adaptors relevant to viral infections, such as vaccination, but also to autoimmune and inflammatory disorders.

The exceptional flying characteristics of airborne insects motivates the design of biomimetic wing structures that can exhibit a similar structural dynamic behavior. For this purpose, this investigation describes a method for both manufacturing a biomimetic insect-sized wing using the photolithography technique and analyzing its structural dynamic response. The geometry of a crane fly forewing (family Tipulidae) is acquired using a micro-computed tomography scanner. A computer-aided design model is generated from the measurements of the reconstructed scanned model of the insect wing to design the photomasks of the membrane and the venation network required for the photolithography procedure. A composite material wing is manufactured by patterning the venation network using photoresist SU-8 on a Kapton film for the assembling of the wing. A single material artificial wing is fabricated using the photoresist SU-8 for both the membrane and the network of veins. Experiments are conducted using a modal shaker and a digital image correlation (DIC) system to determine the natural frequencies and the mode shapes of the artificial wing from the fast Fourier transform of the displacement response of the wing. The experimental results are compared with those from a finite element (FE) model of the wing. A numerical simulation of the fluid-structure interaction is conducted by coupling the FE model of the artificial wing with a computational fluid dynamics model of the surrounding airflow. From these simulations, the deformation response and the coefficients of drag and lift of the artificial wing are predicted for different freestream velocities and angles of attack. Wind-tunnel experiments are conducted using the DIC system to determine the structural deformation response of the artificial wing under different freestream velocities and angles of attack. The vibration modes are dominated by a bending and torsional deformation response. The deformation along the span of the wing increases nonlinearly from the root of the wing to the tip of the wing with Reynolds number. The aerodynamic performance, defined as the ratio of the coefficient of lift to the coefficient of drag, of the artificial wing increases with Reynolds number and angle of attack up to the critical angle of attack.

Le travail présenté dans cette thèse est consacré à la modélisation de la dynamique de locomotion des "soft robots", i.e. les systèmes multi-corps mobiles compliants. Ces compliances peuvent être localisées et considérées comme des liaisons passives du système,ou bien introduites par des flexibilités distribuées le long des corps. La dynamique de ces systèmes est modélisée en adoptant une approche Lagrangienne basée sur les outils mathématiques développés par l'école américaine de mécanique géométrique. Du point de vue algorithmique, le calcul de ces modèles dynamiques s'appuie sur un algorithme récursif et efficace de type Newton-Euler, ici étendu aux robots locomoteurs munis d'organes compliants. Poursuivant des objectifs de commande et de simulation rapide pour la robotique, l'algorithme proposé est capable de résoudre la dynamique externe directe ainsi que la dynamique inverse des couples internes. Afin de mettre en pratique l'ensemble de ces outils de modélisation, nous avons pris le vol battant des insectes comme exemple illustratif. Les équations non-linéaires qui régissent les déformations passives de l'aile sont établies en appliquant deux méthodes différentes. La première consiste à séparer le mouvement de l'aile en une composante rigide dite de "repère flottant" et une composante de déformation. Cette dernière est paramétrée dans le repère flottant par la méthode des modes supposés ici appliquée à l'aile vue comme une poutre d'Euler-Bernoulli soumise à la flexion et à la torsion. Quant à la seconde approche, les mouvements de l'aile n'y sont pas séparés mais directement paramétrés par les transformations finies rigides et absolues d'une poutre Cosserat. Cette approche est dite Galiléenne ou "géométriquement exacte" en raison du fait qu'elle ne requiert aucune approximation en dehors des inévitables discrétisations spatiale et temporelle imposées parla résolution numérique de la dynamique du vol. Dans les deux cas,les forces aérodynamiques sont prises en compte via un modèle analytique simplifié de type Dickinson. Les modèles et algorithmes résultants sont appliqués à la conception d'un simulateur du vol, ainsi qu'à la conception d'un prototype d'aile, dans le contexte du projet coopératif (ANR) EVA.

No description available.

Though still in relative infancy, the field of flapping flight has potential to have a far-reaching impact on human life. Nature presents a myriad of examples of successful uses of this locomotion. Human efforts in flapping flight have seen substantial improvement in recent times. Wing kinematics are a key aspect of this study. This study summarizes previous wing trajectory generators and presents a new trajectory generation method built upon previous methods. This includes a novel means of commanding unequal half-stroke durations subject to robotic trajectory continuity requirements. Additionally, previous optimization methods are improved upon. Experimental optimization is performed using the new trajectory generation method and a more traditional means. Methods for quantifying and compensating for sensor time-dependence are also discussed. Results show that the Polar Fourier Series trajectory generator advanced rapidly through the optimization process, especially during the initial phase of experimentation. The Modified Berman and Wang trajectory generator moved through the design space more slowly due to the increased number of kinematic parameters. When optimizing lift only, the trajectory generators produced similar results and kinematic forms. The findings suggest that the objective statement should be modified to reward efficiency while maintaining a certain amount of lift. It is expected that the difference between the capabilities of the two trajectory generators will become more apparent under such conditions.