HARNESSING iNKT CELLS WITH RECOMBINANT CD1d FUSION PROTEINS TO REDIRECT INNATE AND ADAPTIVE IMMUNITY TO THE TUMOR

Les thérapies du cancer, comme la radiothérapie et la chimiothérapie, sont couramment utilisées mais ont de nombreux effets secondaires. Ces thérapies invasives pour le patient nécessitent d'être améliorées et de nombreuses avancées ont été faites afin d'adapter et de personnaliser le traitement du cancer. L'immunothérapie a pour but de renforcer le système immunitaire du patient et de le rediriger de manière spécifique contre la tumeur. Dans notre projet, nous activons les lymphocytes Invariant Natural Killer T (iNKT) afin de mettre en place une immunothérapie innovatrice contre le cancer. Les cellules iNKT sont une unique sous-population de lymphocytes T qui ont la particularité de réunir les propriétés de l'immunité innée ainsi qu'adaptative. En effet, les cellules iNKT expriment à leur surface des molécules présentes aussi sur les cellules tueuses NK, caractéristique de l'immunité innée, ainsi qu'un récepteur de cellules T (TCR) qui représente l'immunité adaptative. Les cellules iNKT reconnaissent avec leur TCR des antigènes présentés par la molécule CD1d. Les antigènes sont des protéines, des polysaccharides ou des lipides reconnus par les cellules du système immunitaire ou les anticorps pour engendrer une réponse immunitaire. Dans le cas des cellules iNKT, l'alpha-galactosylceramide (αGC) est un antigène lipidique fréquemment utilisé dans les études cliniques comme puissant activateur. Après l'activation des cellules iNKT avec l'αGC, celles-ci produisent abondamment et rapidement des cytokines. Ces cytokines sont des molécules agissant comme des signaux activateurs d'autres cellules du système immunitaire telles que les cellules NK et les lymphocytes T. Cependant, les cellules iNKT deviennent anergiques après un seul traitement avec l'αGC c'est à dire qu'elles ne peuvent plus être réactivées, ce qui limite leur utilisation dans l'immunothérapie du cancer. Dans notre groupe, Stirnemann et al ont publié une molécule recombinante innovante, composée de la molécule CD1d soluble et chargée avec le ligand αGC (αGC/sCD1d). Cette protéine est capable d'activer les cellules iNKT tout en évitant l'anergie. Dans le système immunitaire, les anticorps sont indispensables pour combattre une infection bactérienne ou virale. En effet, les anticorps ont la capacité de reconnaître et lier spécifiquement un antigène et permettent l'élimination de la cellule qui exprime cet antigène. Dans le domaine de l'immunothérapie, les anticorps sont utilisés afin de cibler des antigènes présentés seulement par la tumeur. Ce procédé permet de réduire efficacement les effets secondaires lors du traitement du cancer. Nous avons donc fusionné la protéine recombinante αGC/CD1d à un fragment d'anticorps qui reconnaît un antigène spécifique des cellules tumorales. Dans une étude préclinique, nous avons démontré que la protéine αGC/sCD1d avec un fragment d'anticorps dirigé contre la tumeur engendre une meilleure activation des cellules iNKT et entraîne un effet anti-tumeur prolongé. Cet effet anti-tumeur est augmenté comparé à une protéine αGC/CD1d qui ne cible pas la tumeur. Nous avons aussi montré que l'activation des cellules iNKT avec la protéine αGC/sCD1d-anti-tumeur améliore l'effet anti- tumoral d'un vaccin pour le cancer. Lors d'expériences in vitro, la protéine αGC/sCD1d-anti- tumeur permet aussi d'activer les cellules humaines iNKT et ainsi tuer spécifiquement les cellules tumorales humaines. La protéine αGC/sCD1d-anti-tumeur représente une alternative thérapeutique prometteuse dans l'immunothérapie du cancer. - Les cellules Invariant Natural Killer T (iNKT), dont les effets anti-tumoraux ont été démontrés, sont de puissants activateurs des cellules Natural Killer (NK), des cellules dendritiques (DC) et des lymphocytes T. Cependant, une seule injection du ligand de haute affinité alpha-galactosylceramide (αGC) n'induit une forte activation des cellules iNKT que durant une courte période. Celle-ci est alors suivie d'une longue phase d'anergie, limitant ainsi leur utilisation pour la thérapie. Comme alternative prometteuse, nous avons montré que des injections répétées d'αGC chargé sur une protéine recombinante de CD1d soluble (αGC/sCD1d) chez la souris entraînent une activation prolongée des cellules iNKT, associée à une production continue de cytokine. De plus, le maintien de la réactivité des cellules iNKT permet de prolonger l'activité anti-tumorale lorsque la protéine αGC/sCD1d est fusionnée à un fragment d'anticorps (scFv) dirigé contre la tumeur. L'inhibition de la croissance tumorale n'est optimale que lorsque les souris sont traitées avec la protéine αGC/sCD1d-scFv ciblant la tumeur, la protéine αGC/sCD1d-scFv non-appropriée étant moins efficace. Dans le système humain, les protéines recombinantes αGC/sCD1d-anti-HER2 et anti-CEA sont capables d'activer et de faire proliférer des cellules iNKT à partir de PBMCs issues de donneurs sains. De plus, la protéine αGC/sCD1d-scFv a la capacité d'activer directement des clones iNKT humains en l'absence de cellules présentatrices d'antigènes (CPA), contrairement au ligand αGC libre. Mais surtout, la lyse des cellules tumorales par les iNKT humaines n'est obtenue que lorsqu'elles sont incubées avec la protéine αGC/sCD1d-scFv anti- tumeur. En outre, la redirection de la cytotoxicité des cellules iNKT vers la tumeur est supérieure à celle obtenue avec une stimulation par des CPA chargées avec l'αGC. Afin d'augmenter les effets anti-tumoraux, nous avons exploité la capacité des cellules iNKT à activer l'immunité adaptive. Pour ce faire, nous avons combiné l'immunothérapie NKT/CD1d avec un vaccin anti-tumoral composé d'un peptide OVA. Des effets synergiques ont été obtenus lorsque les traitements avec la protéine αGC/sCD1d-anti-HER2 étaient associés avec le CpG ODN comme adjuvant pour la vaccination avec le peptide OVA. Ces effets ont été observés à travers l'activation de nombreux lymphocytes T CD8+ spécifique de la tumeur, ainsi que par la forte expansion des cellules NK. Les réponses, innée et adaptive, élevées après le traitement avec la protéine αGC/sCD1d-anti-HER2 combinée au vaccin OVA/CpG ODN étaient associées à un fort ralentissement de la croissance des tumeurs B16- OVA-HER2. Cet effet anti-tumoral corrèle avec l'enrichissement des lymphocytes T CD8+ spécifiques observé à la tumeur. Afin d'étendre l'application des protéines αGC/sCD1d et d'améliorer leur efficacité, nous avons développé des fusions CD1d alternatives. Premièrement, une protéine αGC/sCD1d dimérique, qui permet d'augmenter l'avidité de la molécule CD1d pour les cellules iNKT. Dans un deuxième temps, nous avons fusionné la protéine αGC/sCD1d avec un scFv dirigé contre le récepteur 3 du facteur de croissance pour l'endothélium vasculaire (VEGFR-3), afin de cibler l'environnement de la tumeur. Dans l'ensemble, ces résultats démontrent que la thérapie médiée par la protéine recombinante αGC/sCD1d-scFv est une approche prometteuse pour rediriger l'immunité innée et adaptive vers le site tumoral. - Invariant Natural Killer T cells (iNKT) are potent activators of Natural Killer (NK), dendritic cells (DC) and T lymphocytes, and their anti-tumor activities have been well demonstrated. However, a single injection of the high affinity CD1d ligand alpha-galactosylceramide (αGC) leads to a strong but short-lived iNKT cell activation followed by a phase of long-term anergy, limiting the therapeutic use of this ligand. As a promising alternative, we have demonstrated that when αGC is loaded on recombinant soluble CD1d molecules (αGC/sCD1d), repeated injections in mice led to the sustained iNKT cell activation associated with continued cytokine secretion. Importantly, the retained reactivity of iNKT cell led to prolonged antitumor activity when the αGC/sCD1d was fused to an anti-tumor scFv fragments. Optimal inhibition of tumor growth was obtained only when mice were treated with the tumor-targeted αGC/CD1d-scFv fusion, whereas the irrelevant αGC/CD1d-scFv fusion was less efficient. When tested in a human system, the recombinant αGC/sCD1d-anti-HER2 and -anti-CEA fusion proteins were able to expand iNKT cells from PBMCs of healthy donors. Furthermore, the αGC/sCD1d-scFv fusion had the capacity to directly activate human iNKT cells clones without the presence of antigen-presenting cells (APCs), in contrast to the free αGC ligand. Most importantly, tumor cell killing by human iNKT cells was obtained only when co- incubated with the tumor targeted sCD1d-antitumor scFv, and their direct tumor cytotoxicity was superior to the bystander killing obtained with αGC-loaded APCs stimulation. To further enhance the anti-tumor effects, we exploited the ability of iNKT cells to transactivate the adaptive immunity, by combining the NKT/CD1d immunotherapy with a peptide cancer vaccine. Interestingly, synergistic effects were obtained when the αGC/sCD1d- anti-HER2 fusion treatment was combined with CpG ODN as adjuvant for the OVA peptide vaccine, as seen by higher numbers of activated antigen-specific CD8 T cells and NK cells, as compared to each regimen alone. The increased innate and adaptive immune responses upon combined tumor targeted sCD1d-scFv treatment and OVA/CpG vaccine were associated with a strong delay in B16-OVA-HER2 melanoma tumor growth, which correlated with an enrichment of antigen-specific CD8 cells at the tumor site. In order to extend the application of the CD1d fusion, we designed alternative CD1d fusion proteins. First, a dimeric αGC/sCD1d-Fc fusion, which permits to augment the avidity of the CD1d for iNKT cells and second, an αGC/sCD1d fused to an anti vascular endothelial growth factor receptor-3 (VEGFR-3) scFv, in order to target tumor stroma environment. Altogether, these results demonstrate that the iNKT-mediated immunotherapy via recombinant αGC/sCD1d-scFv fusion is a promising approach to redirect the innate and adaptive antitumor immune response to the tumor site.

Automatic front-crawl temporal phase detection using adaptive filtering of inertial signals

This study introduces a novel approach for automatic temporal phase detection and inter-arm coordination estimation in front-crawl swimming using inertial measurement units (IMUs). We examined the validity of our method by comparison against a video-based system. Three waterproofed IMUs (composed of 3D accelerometer, 3D gyroscope) were placed on both forearms and the sacrum of the swimmer. We used two underwater video cameras in side and frontal views as our reference system. Two independent operators performed the video analysis. To test our methodology, seven well-trained swimmers performed three 300 m trials in a 50 m indoor pool. Each trial was in a different coordination mode quantified by the index of coordination. We detected different phases of the arm stroke by employing orientation estimation techniques and a new adaptive change detection algorithm on inertial signals. The difference of 0.2 +/- 3.9% between our estimation and video-based system in assessment of the index of coordination was comparable to experienced operators' difference (1.1 +/- 3.6%). The 95% limits of agreement of the difference between the two systems in estimation of the temporal phases were always less than 7.9% of the cycle duration. The inertial system offers an automatic easy-to-use system with timely feedback for the study of swimming.

Bayesian Networks for Probabilistic Inference and Decision Analysis in Forensic Science

Continuing developments in science and technology mean that the amounts of information forensic scientists are able to provide for criminal investigations is ever increasing. The commensurate increase in complexity creates difficulties for scientists and lawyers with regard to evaluation and interpretation, notably with respect to issues of inference and decision. Probability theory, implemented through graphical methods, and specifically Bayesian networks, provides powerful methods to deal with this complexity. Extensions of these methods to elements of decision theory provide further support and assistance to the judicial system. Bayesian Networks for Probabilistic Inference and Decision Analysis in Forensic Science provides a unique and comprehensive introduction to the use of Bayesian decision networks for the evaluation and interpretation of scientific findings in forensic science, and for the support of decision-makers in their scientific and legal tasks. Includes self-contained introductions to probability and decision theory. Develops the characteristics of Bayesian networks, object-oriented Bayesian networks and their extension to decision models. Features implementation of the methodology with reference to commercial and academically available software. Presents standard networks and their extensions that can be easily implemented and that can assist in the reader's own analysis of real cases. Provides a technique for structuring problems and organizing data based on methods and principles of scientific reasoning. Contains a method for the construction of coherent and defensible arguments for the analysis and evaluation of scientific findings and for decisions based on them. Is written in a lucid style, suitable for forensic scientists and lawyers with minimal mathematical background. Includes a foreword by Ian Evett. The clear and accessible style of this second edition makes this book ideal for all forensic scientists, applied statisticians and graduate students wishing to evaluate forensic findings from the perspective of probability and decision analysis. It will also appeal to lawyers and other scientists and professionals interested in the evaluation and interpretation of forensic findings, including decision making based on scientific information.

Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.

In the damaged heart, cardiac adaptation relies primarily on cardiomyocyte hypertrophy. The recent discovery of cardiac stem cells in the postnatal heart, however, suggests that these cells could participate in the response to stress via their capacity to regenerate cardiac tissues. Using models of cardiac hypertrophy and failure, we demonstrate that components of the Notch pathway are up-regulated in the hypertrophic heart. The Notch pathway is an evolutionarily conserved cell-to-cell communication system, which is crucial in many developmental processes. Notch also plays key roles in the regenerative capacity of self-renewing organs. In the heart, Notch1 signaling takes place in cardiomyocytes and in mesenchymal cardiac precursors and is activated secondary to stimulated Jagged1 expression on the surface of cardiomyocytes. Using mice lacking Notch1 expression specifically in the heart, we show that the Notch1 pathway controls pathophysiological cardiac remodeling. In the absence of Notch1, cardiac hypertrophy is exacerbated, fibrosis develops, function is altered, and the mortality rate increases. Therefore, in cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response, and may thereby contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and may facilitate the expansion of a transient amplifying cell compartment.

Immune system's role in viral encephalitis.

Viral infections can be a major thread for the central nervous system (CNS), therefore, the immune system must be able to mount a highly proportionate immune response, not too weak, which would allow the virus to proliferate, but not too strong either, to avoid collateral damages. Here, we aim at reviewing the immunological mechanisms involved in the host defense in viral CNS infections. First, we review the specificities of the innate as well as the adaptive immune responses in the CNS, using several examples of various viral encephalitis. Then, we focus on three different modes of interactions between viruses and immune responses, namely human Herpes virus-1 encephalitis with the defect in innate immune response which favors this disease; JC virus-caused progressive multifocal leukoencephalopathy and the crucial role of adaptive immune response in this example; and finally, HIV infection with the accompanying low grade chronic inflammation in the CNS in some patients, which may be an explanation for the presence of cognitive disorders, even in some well-treated HIV-infected patients. We also emphasize that, although the immune response is generally associated with viral replication control and limited cellular death, an exaggerated inflammatory reaction can lead to tissue damage and can be detrimental for the host, a feature of the immune reconstitution inflammatory syndrome (IRIS). We will briefly address the indication of steroids in this situation.

Innate receptors for adaptive immunity.

Pattern recognition receptors (PRRs) are commonly known as sensor proteins crucial for the early detection of microbial or host-derived stress signals by innate immune cells. Interestingly, some PRRs are also expressed and functional in cells of the adaptive immune system. These receptors provide lymphocytes with innate sensing abilities; for example, B cells express Toll-like receptors, which are important for the humoral response. Strikingly, certain other NOD-like receptors are not only highly expressed in adaptive immune cells, but also exert functions related specifically to adaptive immune system pathways, such as regulating antigen presentation. In this review, we will focus particularly on the current understanding of PRR functions intrinsic to B and T lymphocytes; a developing aspect of PRR biology.

Local-global splitting for spatiotemporal-adaptive multiscale methods

We present a novel spatiotemporal-adaptive Multiscale Finite Volume (MsFV) method, which is based on the natural idea that the global coarse-scale problem has longer characteristic time than the local fine-scale problems. As a consequence, the global problem can be solved with larger time steps than the local problems. In contrast to the pressure-transport splitting usually employed in the standard MsFV approach, we propose to start directly with a local-global splitting that allows to locally retain the original degree of coupling. This is crucial for highly non-linear systems or in the presence of physical instabilities. To obtain an accurate and efficient algorithm, we devise new adaptive criteria for global update that are based on changes of coarse-scale quantities rather than on fine-scale quantities, as it is routinely done before in the adaptive MsFV method. By means of a complexity analysis we show that the adaptive approach gives a noticeable speed-up with respect to the standard MsFV algorithm. In particular, it is efficient in case of large upscaling factors, which is important for multiphysics problems. Based on the observation that local time stepping acts as a smoother, we devise a self-correcting algorithm which incorporates the information from previous times to improve the quality of the multiscale approximation. We present results of multiphase flow simulations both for Darcy-scale and multiphysics (hybrid) problems, in which a local pore-scale description is combined with a global Darcy-like description. The novel spatiotemporal-adaptive multiscale method based on the local-global splitting is not limited to porous media flow problems, but it can be extended to any system described by a set of conservation equations.

Intérêt d'une Consultation spécialisée multidisciplinaire en neuro-urologie et urologie fonctionnelle [Benefit of a specialized multidisciplinary clinic in neuro-urology and functional urology].

Functional disorders encounter for a large amount of the medical activity, including in urology. The decreased quality of life due to lower urinary tract symptoms requires a prompt management, with primary assessment undergone in community. Referral to a specialist is required when simple management has failed, and whenever any of these coexists: hematuria, recurrent urinary infection, and neurological condition. The specialized clinic in neurourology and functional urology aim at further investigating the underlying disorder responsible for the urinary symptoms and preventing urinary tract complications. A multidisciplinary team is the key to accurately assess patients with regards to their bother and handicap, therefore offering the most appropriate conservative, medical or surgical management.

PERSONAL(ONTO) : Personalizing the Learning Process in Virtual Environments by means of Adaptive Formative Itineraries based on Reusable Learning Objects and Ontologies TIN2006-15107-C02

Personalization in e-learning allows the adaptation of contents, learning strategiesand educational resources to the competencies, previous knowledge or preferences of the student. This project takes a multidisciplinary perspective for devising standards-based personalization capabilities into virtual e-learning environments, focusing on the conceptof adaptive learning itinerary, using reusable learning objects as the basis of the system and using ontologies and semantic web technologies.

The effects of nitric oxide on the immune system during Trypanosoma cruzi infection

Trypanosoma cruzi infection triggers substantial production of nitric oxide (NO), which has been shown to have protective and toxic effects on the host's immune system. Sensing of trypomastigotes by phagocytes activates the inducible NO-synthase (NOS2) pathway, which produces NO and is largely responsible for macrophage-mediated killing of T. cruzi. NO is also responsible for modulating virtually all steps of innate and adaptive immunity. However, NO can also cause oxidative stress, which is especially damaging to the host due to increased tissue damage. The cytokines IFN-³ and TNF-±, as well as chemokines, are strong inducers of NOS2 and are produced in large amounts during T. cruzi acute infection. Conversely, TGF-² and IL-10 negatively regulate NO production. Here we discuss the recent evidence describing the mechanisms by which NO is able to exert its antimicrobial and immune regulatory effects, the mechanisms involved in the oxidative stress response during infection and the implications of NO for the development of therapeutic strategies against T. cruzi.

Adaptive intelligent agent approach to guide the web navigation on the PLAN-G distance learning platform

Hypermedia systems based on the Web for open distance education are becoming increasinglypopular as tools for user-driven access learning information. Adaptive hypermedia is a new direction in research within the area of user-adaptive systems, to increase its functionality by making it personalized [Eklu 961. This paper sketches a general agents architecture to include navigationaladaptability and user-friendly processes which would guide and accompany the student during hislher learning on the PLAN-G hypermedia system (New Generation Telematics Platform to Support Open and Distance Learning), with the aid of computer networks and specifically WWW technology [Marz 98-1] [Marz 98-2]. The PLAN-G actual prototype is successfully used with some informatics courses (the current version has no agents yet). The propased multi-agent system, contains two different types of adaptive autonomous software agents: Personal Digital Agents {Interface), to interacl directly with the student when necessary; and Information Agents (Intermediaries), to filtrate and discover information to learn and to adapt navigation space to a specific student

Schistosoma mansoni triggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses.

The propensity of helminths, such as schistosomes, to immunomodulate the host's immune system is an essential aspect of their survival. Previous research has demonstrated how soluble schistosomal egg antigens (SEA) dampen TLR-signaling during innate immune responses. We show here that the suppressive effect by SEA on TLR signaling is simultaneously coupled to the activation of the Nlrp3 (NLR family, pyrin domain containing 3) inflammasome and thus IL-1β production. Therefore, the responsible protein component of SEA contains the second signal that is required to trigger proteolytic pro-IL-1β processing. Moreover, the SEA component binds to the Dectin-2/FcRγ (Fc receptor γ chain) complex and activates the Syk kinase signaling pathway to induce reactive oxygen species and potassium efflux. As IL-1β has been shown to be an essential orchestrator against several pathogens we studied the in vivo consequences of Schistosoma mansoni infection in mice deficient in the central inflammasome adapter ASC and Nlrp3 molecule. These mice failed to induce local IL-1β levels in the liver and showed decreased immunopathology. Interestingly, antigen-specific Th1, Th2, and Th17 responses were down-regulated. Overall, these data imply that component(s) within SEA induce IL-1β production and unravel a crucial role of Nlrp3 during S. mansoni infection.

Discovering similarities in the time use patterns of the Spanish Autonomous Communities by Fuzzy techniques

In 2000 the European Statistical Office published the guidelines for developing theHarmonized European Time Use Surveys system. Under such a unified framework,the first Time Use Survey of national scope was conducted in Spain during 2002–03. The aim of these surveys is to understand human behavior and the lifestyle ofpeople. Time allocation data are of compositional nature in origin, that is, they aresubject to non-negativity and constant-sum constraints. Thus, standard multivariatetechniques cannot be directly applied to analyze them. The goal of this work is toidentify homogeneous Spanish Autonomous Communities with regard to the typicalactivity pattern of their respective populations. To this end, fuzzy clustering approachis followed. Rather than the hard partitioning of classical clustering, where objects areallocated to only a single group, fuzzy method identify overlapping groups of objectsby allowing them to belong to more than one group. Concretely, the probabilistic fuzzyc-means algorithm is conveniently adapted to deal with the Spanish Time Use Surveymicrodata. As a result, a map distinguishing Autonomous Communities with similaractivity pattern is drawn.Key words: Time use data, Fuzzy clustering; FCM; simplex space; Aitchison distance

Implementation of zonal control algorithms in adaptive optical systems with sparse control matrices

Miralls deformables més i més grans, amb cada cop més actuadors estan sent utilitzats actualment en aplicacions d'òptica adaptativa. El control dels miralls amb centenars d'actuadors és un tema de gran interès, ja que les tècniques de control clàssiques basades en la seudoinversa de la matriu de control del sistema es tornen massa lentes quan es tracta de matrius de dimensions tan grans. En aquesta tesi doctoral es proposa un mètode per l'acceleració i la paral.lelitzacó dels algoritmes de control d'aquests miralls, a través de l'aplicació d'una tècnica de control basada en la reducció a zero del components més petits de la matriu de control (sparsification), seguida de l'optimització de l'ordenació dels accionadors de comandament atenent d'acord a la forma de la matriu, i finalment de la seva posterior divisió en petits blocs tridiagonals. Aquests blocs són molt més petits i més fàcils de fer servir en els càlculs, el que permet velocitats de càlcul molt superiors per l'eliminació dels components nuls en la matriu de control. A més, aquest enfocament permet la paral.lelització del càlcul, donant una com0onent de velocitat addicional al sistema. Fins i tot sense paral. lelització, s'ha obtingut un augment de gairebé un 40% de la velocitat de convergència dels miralls amb només 37 actuadors, mitjançant la tècnica proposada. Per validar això, s'ha implementat un muntatge experimental nou complet , que inclou un modulador de fase programable per a la generació de turbulència mitjançant pantalles de fase, i s'ha desenvolupat un model complert del bucle de control per investigar el rendiment de l'algorisme proposat. Els resultats, tant en la simulació com experimentalment, mostren l'equivalència total en els valors de desviació després de la compensació dels diferents tipus d'aberracions per als diferents algoritmes utilitzats, encara que el mètode proposat aquí permet una càrrega computacional molt menor. El procediment s'espera que sigui molt exitós quan s'aplica a miralls molt grans.

Between-year variation in population sex ratio increases with complexity of the breeding system in Hymenoptera.

While adaptive adjustment of sex ratio in the function of colony kin structure and food availability commonly occurs in social Hymenoptera, long-term studies have revealed substantial unexplained between-year variation in sex ratio at the population level. In order to identify factors that contribute to increased between-year variation in population sex ratio, we conducted a comparative analysis across 47 Hymenoptera species differing in their breeding system. We found that between-year variation in population sex ratio steadily increased as one moved from solitary species, to primitively eusocial species, to single-queen eusocial species, to multiple-queen eusocial species. Specifically, between-year variation in population sex ratio was low (6.6% of total possible variation) in solitary species, which is consistent with the view that in solitary species, sex ratio can vary only in response to fluctuations in ecological factors such as food availability. In contrast, we found significantly higher (19.5%) between-year variation in population sex ratio in multiple-queen eusocial species, which supports the view that in these species, sex ratio can also fluctuate in response to temporal changes in social factors such as queen number and queen-worker control over sex ratio, as well as factors influencing caste determination. The simultaneous adjustment of sex ratio in response to temporal fluctuations in ecological and social factors seems to preclude the existence of a single sex ratio optimum. The absence of such an optimum may reflect an additional cost associated with the evolution of complex breeding systems in Hymenoptera societies.