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Cet avant-propos rappelle l’origine scientifique de la présente publication sur les liens tissés entre les grands auteurs de la Nouvelle Vague française des années 1960 et la lettre sous toutes ses formes (manuelle, transitionnelle, critique, littéraire, etc.). Constituée autour d’un cycle de journées d’études et d’un colloque organisés entre 2014 et 2021 à l’université de Caen Normandie par le laboratoire de recherche Laslar, cette origine met en lumière le projet d’aborder en une série d’approches variées (historique, esthétique, biographique, etc.), les différentes natures et projections de l’écrit dans l’inspiration et la pratique même des films de la Nouvelle Vague. This foreword recalls the scientific origin of the present publication on the links woven between the great authors of the French New Wave of the 1960s and the letter in all its forms (manual, transitional, critical, literary, etc.). Constituted around a cycle of study days and a colloquium organized between 2014 and 2021 at the University of Caen Normandie by the Laslar research laboratory, this origin highlights the project to address in a series of varied approaches (historical, aesthetic, biographical, etc.), the different natures and projections of the written word in the inspiration and the very practice of New Wave films.

Engineered dynamical maps combining coherent and dissipative transformations of quantum states with quantum measurements, have demonstrated a number of technological applications, and promise to be a crucial tool in quantum thermodynamic processes. Here, we exploit the control on the effective open spin qutrit dynamics of an NV center, to experimentally realize an autonomous feedback process (Maxwell demon) with tunable dissipative strength. The feedback is enabled by random measurement events that condition the subsequent dissipative evolution of the qutrit. The efficacy of the autonomous Maxwell demon is quantified by experimentally characterizing the fluctuations of the energy exchanged by the system with the environment by means of a generalized Sagawa-Ueda-Tasaki relation for dissipative dynamics. This opens the way to the implementation of a new class of Maxwell demons, which could be useful for quantum sensing and quantum thermodynamic devices., Comment: Main text: 13 pages, 5 figures. Supplemental Material: 6 pages, 2 figures

Understanding and predicting charge accumulation and transport in dielectric materials is vital in applications where excess charge can accumulate including semiconductor devices, high-power electronic devices, high voltage DC cabling, high-energy physics facilities, plasma chambers, and spacecraft charging. Excess charge accumulation may result in electrostatic discharge events, which are the leading cause of spacecraft failure due to the space environment. The pulsed electroacoustic method allows you to “pop the hood” and non-destructively directly measure the embedded charge distributions in dielectric materials. Charge transport in disordered dielectric materials, measurements with the pulsed electroacoustic system, and comparison to models will be presented.

The European physical journal / D 74(8), 165 (2020). doi:10.1140/epjd/e2020-100571-8, Lattice gauge theories, which originated from particle physics in the context of Quantum Chromodynamics (QCD), provide an important intellectual stimulus to further develop quantum information technologies. While one long-term goal is the reliable quantum simulation of currently intractable aspects of QCD itself, lattice gauge theories also play an important role in condensed matter physics and in quantum information science. In this way, lattice gauge theories provide both motivation and a framework for interdisciplinary research towards the development of special purpose digital and analog quantum simulators, and ultimately of scalable universal quantum computers. In this manuscript, recent results and new tools from a quantum science approach to study lattice gauge theories are reviewed. Two new complementary approaches are discussed: first, tensor network methods are presented - a classical simulation approach - applied to the study of lattice gauge theories together with some results on Abelian and non-Abelian lattice gauge theories. Then, recent proposals for the implementation of lattice gauge theory quantum simulators in different quantum hardware are reported, e.g., trapped ions, Rydberg atoms, and superconducting circuits. Finally, the first proof-of-principle trapped ions experimental quantum simulations of the Schwinger model are reviewed., Published by Springer, Heidelberg

In ergodic physical systems, time-averaged quantities converge (for large times) to their ensemble-averaged values. Large deviation theory describes rare events where these time averages differ significantly from the corresponding ensemble averages. It allows estimation of the probabilities of these events, and their mechanisms. This theory has been applied to a range of physical systems, where it has yielded new insights into entropy production, current fluctuations, metastability, transport processes, and glassy behaviour. We review some of these developments, identifying general principles. We discuss a selection of dynamical phase transitions, and we highlight some connections between large-deviation theory and optimal control theory., Comment: accepted version, small additions and modifications. 23 pages, "colloquium" article

The stationary behavior of a quantum system is determined by its Hamiltonian and its boundary conditions. All quantum phase transitions (QPT) reported previously were induced by changing the Hamiltonian. In a circular spin model with Heisenberg XY interactions and no magnetic field, we observe an anomaly in quantum phases caused by a qualitative change of the boundary condition. The unexpected anomaly features an infinite number of single-particle levels, in the same pattern as the single-photon-triggered quantum phase transition in the Rabi model. We thank Dr. Z.-M. Wang for his early participation. We acknowledge grant support from the Basque Government (grant IT472-10), the Spanish MICINN (No. FIS2012-36673-C03-03), LightCone Interactive LLC, the National Science Foundation of China (Grants Nos. 11974311 and U1801661), the Fundamental Research Funds for the Central Universities (No. 2018QNA3004), and Zhejiang Provincial Natural Science Foundation of China under Grant No. LD18A040001.

Colloquium

Neither Labor Law nor Civil Law has yet drawn the legal consequences of the existence of labor relations that unite animals and man. There are no rules protecting animals at work, while their participation in multiple human activities is unequivocal. The use of horses in sports and tourism generates wealth, while the services they provide save or improve lives. While it is easy to "work with animals", it is true that it is never explicitly recognized that animals "work with people". Why? Because animals are subject to the legal regime of property. The case of an animal as versatile as the horse leads us to believe that after having inspired numerous animal protection laws, his participation in society through work could be the first to be recognized. A service provider, transporter, plow, therapist, athlete... he has many roles and is recruited according to his personal skills and physical, intellectual or emotional abilities that make him unique. The social fact that animal labor represents prompts us to claim the specific protection of animals in this context, in light of the emergence of their fundamental right to welfare and, therefore, not to be mistreated. Being well treated in the workplace should be considered as a right of the working population, not as a specific human right. Likewise, the protection and monitoring of the health of the sportsperson must be an imperative that goes beyond the species to which the athlete belongs. This contribution was presented during the Symposium organized by the ADDCDA (Association des Doctorants et Docteurs du Centre de Droit des Affaires) on 11 October 2018 at the University of Toulouse 1 Capitole, on the theme of Sport and Business Law. It is part of the DER2015-69314-P project financed by MINECO, on the legal status of animals. Ni el Derecho del Trabajo ni el Derecho Civil han extraído todavía las consecuencias jurídicas de la existencia de relaciones laborales que unen a los animales y al hombre. No existen normas para la protección de los animales en el trabajo, mientras que su participación en múltiples actividades humanas es inequívoca. El uso de caballos en el deporte y el turismo genera riqueza, mientras que los servicios que prestan salvan o mejoran vidas. Si bien es fácil "trabajar con animales", es cierto que nunca se reconoce explícitamente que los animales "trabajan con personas". ¿Por qué? Porque los animales están sujetos al régimen jurídico de la propiedad. El caso de un animal tan versátil como el caballo, nos lleva a asumir que después de haber inspirado numerosas leyes de protección animal, su participación en la sociedad a través del trabajo podría ser la primera en ser reconocida. Prestador de servicios, transportista, arador, terapeuta, deportista... desempeña muchos papeles y es reclutado de acuerdo a sus competencias personales y habilidades físicas o intelectuales que lo hacen único. El hecho social que representa el trabajo animal nos lleva a reivindicar la protección específica de los animales en este contexto, debido a la emergencia de su derecho fundamental al bienestar y, por eso, a no ser maltratado. Ser bien tratado en el trabajo es un derecho de la población trabajadora, no un derecho humano específico. Análogamente, la protección y vigilancia de la salud del deportista debe ser un imperativo que vaya más allá de la especie a la que pertenece el deportista. Esta ponencia fue presentada en el Coloquio organizado por la ADDCDA (Association des Doctorants et Docteurs du Centre de Droit des Affaires) el 11 de octubre de 2018 en la Universidad de Toulouse 1 Capitole, sobre el tema del Deporte y el Derecho Empresarial. Se enmarca en el proyecto DER2015-69314-P financiado por el MINECO, sobre el estatuto jurídico de los animales.

The Digital Humanities Summer Institute gives students and scholars a chance to broaden their knowledge of the Digital Humanities within a feasible timeframe. The DHSI Colloquium was first founded by Diane Jakacki and Cara Leitch to act as a means of supporting graduates who wanted to be a part of such a gathering. The Colloquium has grown in recent years, to the point where it is now seen as an important part of the field’s conference calendar for emerging and established scholars alike, but it remains a non-threatening space in which students, scholars, and practitioners can share their ideas. This issue is testament to that diversity, as well as the strength of the research being presented at the Colloquium. It includes Scott B. Weingart and Nickoal Eichmann-Kalwara, Mary Borgo, William B. Kurtz, and John Barber. “What’s Under the Big Tent?: A Study of ADHO Conference Abstracts,” which portrays the discipline as one which is dominated by specific groups and practices. Using the Victorian Women Writers Project as a case-study, Mary Borgo treats models for the sustainable growth of TEI-based digital resources. William B. Kurtz details his experiences working on a digital initiative, in this instance, Founders Online: Early Access, and engages with the need for such projects to hold broader public appeal. John Barber’s “Radio Nouspace: Sound, Radio, Digital Humanities,” describes the curation of sound within the context of radio, and how such activity connects to creative digital scholarship. Together, these articles represent the purpose of facilitating a community comprised of divergent interests and perspectives, a community which can often be positively dissonant. Le Digital Humanities Summer Institute (DHSI) offre une chance aux étudiants et érudits d’étoffer leurs connaissances en humanités numériques pendant un délai réalisable. Diane Jakacki et Cara Leitch ont établi le premier colloque du DHSI pour soutenir des diplômés qui voulaient participer à un tel rassemblement. Ces dernières années, le colloque s’est développé jusqu’au point d’être considéré maintenant comme une conférence importante sur le calendrier non seulement pour les érudits émergeants mais aussi pour les érudits établis dans le domaine. Le colloque continue cependant à être un espace non menaçant où les étudiants, les érudits et les professionnels peuvent échanger leurs idées. Ce numéro est un témoignage de cette diversité et de la qualité de la recherche présentée au colloque. Le numéro inclut l’article « What’s Under the Big Tent?: A Study of ADHO Conference Abstracts » par Scott B. Weingart et Nickoal Eichmann-Kalwara, ce qui présente les humanités numériques comme une discipline dominée par des groupes et pratiques spécifiques. En se servant du Victorian Women Writers Project comme étude de cas, Mary Borgo traite des maquettes pour la croissance durable des ressources numériques basées sur la TEI. William B. Kurtz détaille les expériences qu’il a acquises en travaillant sur l’initiative numérique Founders Online: Early Access ainsi que l’importance que de tels projets constituent un facteur attractif pour un plus large public. Dans le texte de John Barber, « Radio Nouspace: Sound, Radio, Digital Humanities », il s’agit du traitement de sons radiophoniques et du lien entre cette activité et l’érudition numérique créative. Tous ces articles correspondent au but de faciliter une communauté composée des intérêts et perspectives divergents qui peut souvent être véritablement dissonante. Mots-clés: Digital Humanities; DHSI Special Issue; Digital Humanities Summer

Rotation of molecules embedded in He nanodroplets is explored by a combination of fs laser-induced alignment experiments and angulon quasiparticle theory. We demonstrate that at low fluence of the fs alignment pulse, the molecule and its solvation shell can be set into coherent collective rotation lasting long enough to form revivals. With increasing fluence, however, the revivals disappear -- instead, rotational dynamics as rapid as for an isolated molecule is observed during the first few picoseconds. Classical calculations trace this phenomenon to transient decoupling of the molecule from its He shell. Our results open novel opportunities for studying non-equilibrium solute-solvent dynamics and quantum thermalization., Comment: 6+7 pages; 4+1 figures; 1 table

Este artículo explora las características formales y temáticas de la obra dramática de Fernán González de Eslava para mostrar la influencia del debate medieval en la producción del autor. A través del análisis de diversos coloquios de temas teológico, histórico y filosófico, se profundiza en el estudio del uso que González de Eslava le dio al debate para la transmisión de la doctrina y la persuasión de la audiencia. This paper explores the formal characteristics and the themes of the dramatic work of Fernán González de Eslava. The discussion is focus on the influence of medieval debate in the author’s dramatic production. Through the analysis of different pieces the paper shows how the debate was used by Gonzalez de Eslava as a tool to educate and persuade the audience in to the religious Christian doctrine.

Recent studies of the genetics of speciation in Drosophila have focused on two problems: ( i ) identifying and characterizing the genes that cause reproductive isolation, and ( ii ) determining the evolutionary forces that drove the divergence of these “speciation genes.” Here, I review this work. I conclude that speciation genes correspond to ordinary loci having normal functions within species. These genes fall into several functional classes, although a role in transcriptional regulation could prove particularly common. More important, speciation genes are typically very rapidly evolving, and this divergence is often driven by positive Darwinian selection. Finally, I review recent work in Drosophila pseudoobscura on the possible role of meiotic drive in the evolution of the genes that cause postzygotic isolation.

With the completion of the human genome and the growing number of diverse genomes being sequenced, a new age of evolutionary research is currently taking shape. The myriad of technological breakthroughs in biology that are leading to the unification of broad scientific fields such as molecular biology, biochemistry, physics, mathematics, and computer science are now known as systems biology. Here, I present an overview, with an emphasis on eukaryotes, of how the postgenomics era is adopting comparative approaches that go beyond comparisons among model organisms to shape the nascent field of evolutionary systems biology.

The Rhagoletis pomonella sibling species complex is a model for sympatric speciation by means of host plant shifting. However, genetic variation aiding the sympatric radiation of the group in the United States may have geographic roots. Inversions on chromosomes 1-3 affecting diapause traits adapting flies to differences in host fruiting phenology appear to exist in the United States because of a series of secondary introgression events from Mexico. Here, we investigate whether these inverted regions of the genome may have subsequently evolved to become more recalcitrant to introgression relative to collinear regions, consistent with new models for chromosomal speciation. As predicted by the models, gene trees for six nuclear loci mapping to chromosomes other than 1-3 tended to have shallower node depths separating Mexican and U.S. haplotypes relative to an outgroup sequence than nine genes residing on chromosomes 1-3. We discuss the implications of secondary contact and differential introgression with respect to sympatric host race formation and speciation in Rhagoletis , reconciling some of the seemingly dichotomous views of Mayr, Dobzhansky, and Bush concerning modes of divergence.

Genomes hold within them the record of the evolution of life on Earth. But genome fusions and horizontal gene transfer (HGT) seem to have obscured sufficiently the gene sequence record such that it is difficult to reconstruct the phylogenetic tree of life. HGT among prokaryotes is not random, however. Some genes (informational genes) are more difficult to transfer than others (operational genes). Furthermore, environmental, metabolic, and genetic differences among organisms restrict HGT, so that prokaryotes preferentially share genes with other prokaryotes having properties in common, including genome size, genome G+C composition, carbon utilization, oxygen utilization/sensitivity, and temperature optima, further complicating attempts to reconstruct the tree of life. A new method of phylogenetic reconstruction based on gene presence and absence, called conditioned reconstruction, has improved our prospects for reconstructing prokaryotic evolution. It is also able to detect past genome fusions, such as the fusion that appears to have created the first eukaryote. This genome fusion between a deep branching eubacterium, possibly an ancestor of the cyanobacterium and a proteobacterium, with an archaeal eocyte (crenarchaea), appears to be the result of an early symbiosis. Given new tools and new genes from relevant organisms, it should soon be possible to test current and future fusion theories for the origin of eukaryotes and to discover the general outlines of the prokaryotic tree of life.

The cichlid fishes of Lake Malawi are famously diverse. However, phylogenetic and population genetic studies of their history have been difficult because of the great amount of genetic variation that is shared between species. We apply a recently developed method for fitting the “isolation with migration” divergence model to a data set of specially designed compound loci to develop portraits of cichlid species divergence. Outgroup sequences from a cichlid from Lake Tanganyika permit model parameter estimates in units of years and effective population sizes. Estimated speciation times range from 1,000 to 17,000 years for species in the genus Tropheops . These exceptionally recent dates suggest that Malawi cichlids as a group experience a very active and dynamic diversification process. Current effective population size estimates range form 2,000 to near 40,000, and to >120,000 for estimates of ancestral population sizes. It appears that very recent speciation and gene flow are among the reasons why it has been difficult to discern the phylogenetic history of Malawi cichlids.

Ernst Mayr used the geography of closely related species in various stages of increasing divergence to “animate” the process of geographic, or allopatric, speciation. This approach was applied to a wide set of taxa, and a seminal paper by Mayr used it to explore speciation patterns in tropical sea urchins. Since then, taxonomic information in several of these genera has been augmented by detailed molecular phylogenies. We compare Mayr's animation with the phylogenies of eight sea urchin genera placed by Mayr into four speciation groups. True to Mayr's predictions, early-stage genera have on average lower species divergence and more polytypic species than genera in later stages. For six of these genera, we also have information about the evolution of the gamete recognition protein bindin, which is critical to reproductive isolation. These comparisons show that later-stage genera with many sympatric species tend to be those with rapid bindin evolution. By contrast, early-stage genera with few sympatric species are not necessarily earlier in the divergence process; they happen to be those with slow rates of bindin evolution. These results show that the rate of speciation in sea urchins does not only depend on the steady accumulation of genome divergence over time, but also on the rate of evolution of gamete recognition proteins. The animation method used by Mayr is generally supported by molecular phylogenies. However, the existence of multiple rates in the acquisition of reproductive isolation complicates placement of different genera in an evolutionary series.

The genetic factors contributing to complex trait variation may reside in regulatory, rather than protein-coding portions of the genome. Within noncoding regions, SNPs in regulatory elements are more likely to contribute to phenotypic variation than those in nonregulatory regions. Thus, it is important to be able to identify and annotate noncoding regulatory elements. DNA conservation among diverged species successfully identifies noncoding regulatory regions. However, because rapidly evolving regulatory regions will not generally be conserved across species, these will not detected by using purely conservation-based methods. Here we describe additional approaches that can be used to identify putative regulatory elements via signatures of nonneutral evolution. An examination of the pattern of polymorphism both within and between populations of Drosophila melanogaster , as well as divergence with its sibling species Drosophila simulans , across 24.2 kb of noncoding DNA identifies several nonneutrally evolving regions not identified by conservation. Because different methods tag different regions, it appears that the methods are complementary. Patterns of variation at different elements are consistent with the action of selective sweeps, balancing selection, or population differentiation. Together with regions conserved between D. melanogaster and Drosophila pseudoobscura , we tag 5.3 kb of noncoding DNA as potentially regulatory. Ninety-seven of the 408 common noncoding SNPs surveyed are within putatively regulatory regions. If these methods collectively identify the majority of functional noncoding polymorphisms, genotyping only these SNPs in an association mapping framework would reduce genotyping effort for noncoding regions 4-fold.

One of Ernst Mayr's legacies is the consensus that the allopatry model is the predominant mode of speciation in most sexually reproducing lineages. In this model, reproductive isolation develops as a pleiotropic byproduct of the genetic divergence that develops among physically isolated populations. Presently, there is no consensus concerning which, if any, evolutionary process is primarily responsible for driving the specific genetic divergence that leads to reproductive isolation. Here, we focus on the hypothesis that inter-locus antagonistic coevolution drives rapid genetic divergence among allopatric populations and thereby acts as an important “engine” of speciation. We assert that only data from studies of experimental evolution, rather than descriptive patterns of molecular evolution, can provide definitive evidence for this hypothesis. We describe and use an experimental approach, called hemiclonal analysis, that can be used in the Drosophila melanogaster laboratory model system to simultaneously screen nearly the entire genome for both standing genetic variation within a population and the net-selection gradient acting on the variation. Hemiclonal analysis has four stages: ( i ) creation of a laboratory “island population”; ( ii ) cytogenetic cloning of nearly genome-wide haplotypes to construct hemiclones; ( iii ) measurement of additive genetic variation among hemiclones; and ( iv ) measurement of the selection gradient acting on phenotypic variation among hemiclones. We apply hemiclonal analysis to test the hypothesis that there is ongoing antagonistic coevolution between the sexes in the D. melanogaster laboratory model system and then discuss the relevance of this analysis to natural systems.

Converging experimental evidence indicates that CD4+regulatory T cells control progression of autoimmune insulitis in nonobese diabetic (NOD) mice. Here, we studied the nature of these regulatory T cells and their mode of action in diabetes-prone NODRag-/-or severe combined immunodeficient (SCID) mice harboring a transgenic T cell receptor derived from the diabetogenic T cell clone BDC2.5. We first show that diabetes onset is prevented in such mice by infusion of polyclonal CD4+T cells expressingl-selectin (CD62L) but not prevented or only marginally prevented by CD4+CD25+T cells. Similarly, we found with a cotransfer model that CD4+CD62L+T cells but not CD4+CD25+T cells inhibited diabetes transfer into NOD SCID recipients by transgenic NOD BDC2.5 SCID cells. Unexpectedly, cotransfer of transgenic NOD BDC2.5 SCID cells and spleen cells from WT diabetic NOD mice did not induce diabetes, whereas each individual population did so. Data are presented arguing for the role of CD4+CD62L+T cells present within the polyclonal diabetogenic population in mediating this apparently paradoxical effect. Collectively, these data confirm the central role of CD4+CD62L+regulatory T cells in controlling disease onset in a well defined transgenic model of autoimmune diabetes and suggest the intervention of homeostatic mechanisms as part of their mode of action.

DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, are being evaluated as prophylactic vaccines and therapeutic treatments for infectious diseases, allergies, and cancer; plasmids encoding normal human proteins are likewise being tested as vaccines and treatments for autoimmune diseases. Examples of in vivo prophylaxis and immunotherapy, based on different types of immune responses (humoral and cellular), in a variety of disease models and under evaluation in early phase human clinical trials are presented. Viral vectors continue to show better levels of expression than those achieved by DNA plasmid vectors. We have focused our clinical efforts, at this time, on the use of recombinant viral vectors for both vaccine as well as cytokine gene transfer studies. We currently have four clinical programs in cancer immunotherapy. Two nonspecific immunotherapy programs are underway that apply adenoviral vectors for the transfer of cytokine genes into tumors in situ . An adenovirus-IFNγ construct (TG1042) is currently being tested in phase II clinical trials in cutaneous lymphoma. A similar construct, adenovirus-IL2 (TG1024), also injected directly into solid tumors, is currently being tested in patients with solid tumors (about one-half of which are melanoma). Encouraging results are seen in both programs. Two cancer vaccine immunotherapy programs focus on two cancer-associated antigens: human papilloma virus E6 and E7 proteins and the epithelial cancer-associated antigen MUC1. Both are encoded by a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] and both are coexpressed with IL-2. Encouraging results seen in both of these programs are described.

Our recent clinical trials demonstrate that autologous cell transfer after lymphodepleting chemotherapy can cause the regression of large, vascularized tumors in patients with refractory metastatic melanoma. Eighteen of 35 patients treated with tumor-reactive lymphocyte cultures experienced an objective clinical response (>50% reduction in tumor), including four complete responders. In some patients, tumor regression was accompanied by a large in vivo expansion of the administered antitumor lymphocytes, which persisted in peripheral blood at >70% of total lymphocytes for many months after transfer. The cells capable of mediating tumor regression consisted of heterogeneous lymphocyte populations with high avidity for tumor antigens that were derived from tumor-infiltrating lymphocytes cultured for limited times in vitro . The success of this treatment likely results from the ability to infuse large numbers of activated antitumor lymphocytes into an appropriate host homeostatic environment depleted of regulatory T cells. These studies are elucidating the requirements for successful immunotherapy of patients with advanced metastatic disease and are leading to additional clinical trials with gene-modified lymphocytes.

One's present repertoire of antibodies encodes the history of one's past immunological experience. Can the present autoantibody repertoire be consulted to predict resistance or susceptibility to the future development of an autoimmune disease? Here, we developed an antigen microarray chip and used bioinformatic analysis to study a model of type 1 diabetes developing in nonobese diabetic male mice in which the disease was accelerated and synchronized by exposing the mice to cyclophosphamide at 4 weeks of age. We obtained sera from 19 individual mice, treated the mice to induce cyclophosphamide-accelerated diabetes (CAD), and found, as expected, that 9 mice became severely diabetic, whereas 10 mice permanently resisted diabetes. We again obtained serum from each mouse after CAD induction. We then analyzed, by using rank-order and superparamagnetic clustering, the patterns of antibodies in individual mice to 266 different antigens spotted on the chip. A selected panel of 27 different antigens (10% of the array) revealed a pattern of IgG antibody reactivity in the pre-CAD sera that discriminated between the mice resistant or susceptible to CAD with 100% sensitivity and 82% specificity (P= 0.017). Surprisingly, the set of IgG antibodies that was informative before CAD induction did not separate the resistant and susceptible groups after the onset of CAD; new antigens became critical for post-CAD repertoire discrimination. Thus, at least for a model disease, present antibody repertoires can predict future disease, predictive and diagnostic repertoires can differ, and decisive information about immune system behavior can be mined by bioinformatic technology. Repertoires matter.

Autoimmune T and B cell responses to CNS antigen(s) are thought to drive the pathogenesis of multiple sclerosis (MS), and thus are logical targets for therapy. Indeed, several immunomodulatory agents, including IFN-β1b, IFN-β1a, glatiramer acetate, and mitoxantrone, have had beneficial clinical effects in different forms of MS. However, because the available treatments are only partially effective, MS therapy needs to be further improved. Selective (antigen-specific) immunotherapies are especially appealing because in theory they combine maximal efficacy with minimal side effects. Indeed, several innovative immunotherapies have been successfully applied in experimental autoimmune encephalomyelitis. For example, autoreactive T cells can be selectively targeted by means of antigen, T cell receptor, or activation markers. However, experimental autoimmune encephalomyelitis is far from being a perfect approximation of MS because MS is more heterogeneous and the target antigen(s) is (are) not known. Further advances in MS therapy will depend on our growing understanding of the pathogenesis of this still incurable disease.

Studies in experimental models (1953–1956) demonstrated that acquired donor-specific allotolerance in immunologically immature or irradiated animals is strongly associated with donor leukocyte chimerism. Bone marrow transplantation in immune-deficient or cytoablated human recipients was a logical extension (1968). In contrast, clinical (1959) and then experimental organ transplantation was systematically accomplished in the apparent absence of leukocyte chimerism. Consequently, it was assumed for many years that success with organ and bone marrow transplantation involved fundamentally different mechanisms. With the discovery in 1992 of small numbers of donor leukocytes in the tissues or blood of long-surviving organ recipients (microchimerism), we concluded that organ engraftment was a form of leukocyte chimerism-dependent partial tolerance. In this initially controversial paradigm, alloengraftment after both kinds of transplantation is the product of a double immune reaction in which responses, each to the other, of coexisting donor and recipient immune systems results in variable reciprocal clonal exhaustion, followed by peripheral clonal deletion. It was proposed with Rolf Zinkernagel that the individual alloresponses are the equivalent of the MHC-restricted T cell recognition of, and host response to, intracellular parasites and that the mechanisms of immune responsiveness, or nonresponsiveness, are governed by the migration and localization of the respective antigens. Elucidation of the mechanisms of nonresponsiveness (clonal exhaustion-deletion and immune ignorance) and their regulation removed much of the historical mystique of transplantation. The insight was then applied to improve the timing and dosage of immunosuppression of current human transplant recipients.

By using data from three bibliographic databases in biology, physics, and mathematics, respectively, networks are constructed in which the nodes are scientists, and two scientists are connected if they have coauthored a paper. We use these networks to answer a broad variety of questions about collaboration patterns, such as the numbers of papers authors write, how many people they write them with, what the typical distance between scientists is through the network, and how patterns of collaboration vary between subjects and over time. We also summarize a number of recent results by other authors on coauthorship patterns.

A crossmapping technique is introduced for visualizing multiple and overlapping relations among entity types in collections of journal articles. Groups of entities from two entity types are crossplotted to show correspondence of relations. For example, author collaboration groups are plotted on the x axis against groups of papers (research fronts) on the y axis. At the intersection of each pair of author group/research front pairs a circular symbol is plotted whose size is proportional to the number of times that authors in the group appear as authors in papers in the research front. Entity groups are found by agglomerative hierarchical clustering using conventional similarity measures. Crossmaps comprise a simple technique that is particularly suited to showing overlap in relations among entity groups. Particularly useful crossmaps are: research fronts against base reference clusters, research fronts against author collaboration groups, and research fronts against term co-occurrence clusters. When exploring the knowledge domain of a collection of journal papers, it is useful to have several crossmaps of different entity pairs, complemented by research front timelines and base reference cluster timelines.

Usage data at a high-traffic web site can expose information about external events and surges in popularity that may not be accessible solely from analyses of content and link structure. We consider sites that are organized around a set of items available for purchase or download, consider, for example, an e-commerce site or collection of online research papers, and we study a simple indicator of collective user interest in an item, the batting average, defined as the fraction of visits to an item's description that result in an acquisition of that item. We develop a stochastic model for identifying points in time at which an item's batting average experiences significant change. In experiments with usage data from the Internet Archive, we find that such changes often occur in an abrupt, discrete fashion, and that these changes can be closely aligned with events such as the highlighting of an item on the site or the appearance of a link from an active external referrer. In this way, analyzing the dynamics of item popularity at an active web site can help characterize the impact of a range of events taking place both on and off the site.

From an informed critique of existing methods to the development of original tools, cartographic engagement can provide a unique perspective on knowledge domain visualization. Along with a discussion of some principles underlying a cartographically informed visualization methodology, results of experiments involving several thousand conference abstracts will be sketched and their plausibility reflected on.

Recent developments in question-answering systems have demonstrated that approaches based on propositional analysis of source text, in conjunction with formal inference systems, can produce substantive improvements in performance over surface-form approaches. [Voorhees, E. M. (2002) in Eleventh Text Retrieval Conference , eds. Voorhees, E. M. & Buckland, L. P., http://trec.nist.gov/pubs/trec11/t11_proceedings.html ]. However, such systems are hampered by the need to create broad-coverage knowledge bases by hand, making them difficult to adapt to new domains and potentially fragile if critical information is omitted. To demonstrate how this problem might be addressed, the Syntagmatic Paradigmatic model, a memory-based account of sentence processing, is used to autonomously extract propositional knowledge from unannotated text. The Syntagmatic Paradigmatic model assumes that people store a large number of sentence instances. When trying to interpret a new sentence, similar sentences are retrieved from memory and aligned with the new sentence by using String Edit Theory. The set of alignments can be considered an extensional interpretation of the sentence. Extracting propositional information in this way not only permits the model to answer questions for which the relevant facts are explicitly stated in the text but also allows the model to take advantage of “inference by coincidence,” where implicit inference occurs as an emergent property of the mechanism. To illustrate the potential of this approach, the model is tested for its ability to determine the winners of tennis matches as reported on the Association of Tennis Professionals web site.

A first step in identifying the content of a document is determining which topics that document addresses. We describe a generative model for documents, introduced by Blei, Ng, and Jordan [Blei, D. M., Ng, A. Y. & Jordan, M. I. (2003) J. Machine Learn. Res. 3, 993-1022], in which each document is generated by choosing a distribution over topics and then choosing each word in the document from a topic selected according to this distribution. We then present a Markov chain Monte Carlo algorithm for inference in this model. We use this algorithm to analyze abstracts from PNAS by using Bayesian model selection to establish the number of topics. We show that the extracted topics capture meaningful structure in the data, consistent with the class designations provided by the authors of the articles, and outline further applications of this analysis, including identifying “hot topics” by examining temporal dynamics and tagging abstracts to illustrate semantic content.

A review of data mining and analysis techniques that can be used for the mapping of knowledge domains is given. Literature mapping techniques can be based on authors, documents, journals, words, and/or indicators. Most mapping questions are related to research assessment or to the structure and dynamics of disciplines or networks. Several mapping techniques are demonstrated on a data set comprising 20 years of papers published in PNAS. Data from a variety of sources are merged to provide unique indicators of the domain bounded by PNAS. By using funding source information and citation counts, it is shown that, on an aggregate basis, papers funded jointly by the U.S. Public Health Service (which includes the National Institutes of Health) and non-U.S. government sources outperform papers funded by other sources, including by the U.S. Public Health Service alone. Grant data from the National Institute on Aging show that, on average, papers from large grants are cited more than those from small grants, with performance increasing with grant amount. A map of the highest performing papers over the 20-year period was generated by using citation analysis. Changes and trends in the subjects of highest impact within the PNAS domain are described. Interactions between topics over the most recent 5-year period are also detailed.

We are interested in tracking changes in large-scale data by periodically creating an agglomerative clustering and examining the evolution of clusters (communities) over time. We examine a large real-world data set: the NEC CiteSeer database, a linked network of >250,000 papers. Tracking changes over time requires a clustering algorithm that produces clusters stable under small perturbations of the input data. However, small perturbations of the CiteSeer data lead to significant changes to most of the clusters. One reason for this is that the order in which papers within communities are combined is somewhat arbitrary. However, certain subsets of papers, called natural communities, correspond to real structure in the CiteSeer database and thus appear in any clustering. By identifying the subset of clusters that remain stable under multiple clustering runs, we get the set of natural communities that we can track over time. We demonstrate that such natural communities allow us to identify emerging communities and track temporal changes in the underlying structure of our network data.

The World Wide Web provides a unprecedented opportunity to automatically analyze a large sample of interests and activity in the world. We discuss methods for extracting knowledge from the web by randomly sampling and analyzing hosts and pages, and by analyzing the link structure of the web and how links accumulate over time. A variety of interesting and valuable information can be extracted, such as the distribution of web pages over domains, the distribution of interest in different areas, communities related to different topics, the nature of competition in different categories of sites, and the degree of communication between different communities or countries.

Representations of scientific knowledge must reflect the dynamic nature of knowledge construction and the evolving networks of relations between scientific concepts. In this article, we describe initial work toward dynamic, visual methods and tools that support the construction, communication, revision, and application of scientific knowledge. Specifically, we focus on tools to capture and explore the concepts that underlie collaborative science activities, with examples drawn from the domain of human-environment interaction. These tools help individual researchers describe the process of knowledge construction while enabling teams of collaborators to synthesize common concepts. Our visualization approach links geographic visualization techniques with concept-mapping tools and allows the knowledge structures that result to be shared through a Web portal that helps scientists work collectively to advance their understanding. Our integration of geovisualization and knowledge representation methods emphasizes the process through which abstract concepts can be contextualized by the data, methods, people, and perspectives that produced them. This contextualization is a critical component of a knowledge structure, without which much of the meaning that guides the sharing of concepts is lost. By using the tools we describe here, human-environment scientists are given a visual means to build concepts from data (individually and collectively) and to connect these concepts to each other at appropriate levels of abstraction.

We present a method for creating a network of gene co-occurrences from the literature and partitioning it into communities of related genes. The way in which our method identifies communities makes it likely that the component genes of each community will be related by their function. The method processes a large database of article abstracts, synthesizing information from many sources to shed light on groups of genes that have been shown to interact. It is a tool to be used by researchers in the biomedical sciences to swiftly search for known interactions and to provide insight into unexplored connections. The partitioning procedure is designed to be particularly applicable to large networks in which individual nodes may play a role in more than one community. In this paper, we explain the details of the method, in particular the partitioning process. We also apply the method to produce communities of genes related to colon cancer and show that the results are useful.

Scientific research is highly dynamic. New areas of science continually evolve;others gain or lose importance, merge or split. Due to the steady increase in the number of scientific publications it is hard to keep an overview of the structure and dynamic development of one's own field of science, much less all scientific domains. However, knowledge of hot topics, emergent research frontiers, or change of focus in certain areas is a critical component of resource allocation decisions in research labs, governmental institutions, and corporations. This paper demonstrates the utilization of Kleinberg's burst detection algorithm, co-word occurrence analysis, and graph layout techniques to generate maps that support the identification of major research topics and trends. The approach was applied to analyze and map the complete set of papers published in the Proceedings of the National Academy of Sciences (PNAS) in the years 1982-2001. Six domain experts examined and commented on the resulting maps in an attempt to reconstruct the evolution of major research areas covered by PNAS.

The 500 different species of venomous cone snails (genus Conus ) use small, highly structured peptides (conotoxins) for interacting with prey, predators, and competitors. These peptides are produced by translating mRNA from many genes belonging to only a few gene superfamilies. Each translation product is processed to yield a great diversity of different mature toxin peptides (≈50,000–100,000), most of which are 12–30 aa in length with two to three disulfide crosslinks. In vitro , forming the biologically relevant disulfide configuration is often problematic, suggesting that in vivo mechanisms for efficiently folding the diversity of conotoxins have been evolved by the cone snails. We demonstrate here that the correct folding of a Conus peptide is facilitated by a posttranslationally modified amino acid, γ-carboxyglutamate. In addition, we show that multiple isoforms of protein disulfide isomerase are major soluble proteins in Conus venom duct extracts. The results provide evidence for the type of adaptations required before cone snails could systematically explore the specialized biochemical world of “microproteins” that other organisms have not been able to systematically access. Almost certainly, additional specialized adaptations for efficient microprotein folding are required.

Diversification of cytochrome P450 monooxygenases (P450s) is thought to result from antagonistic interactions between plants and their herbivorous enemies. However, little direct evidence demonstrates the relationship between selection by plant toxins and adaptive changes in herbivore P450s. Here we show that the furanocoumarin-metabolic activity of CYP6B proteins in two species of swallowtail caterpillars is associated with the probability of encountering host plant furanocoumarins. Catalytic activity was compared in two closely related CYP6B4 and CYP6B17 groups in the polyphagous congeners Papilio glaucus and Papilio canadensis . Generally, P450s from P. glaucus , which feeds occasionally on furanocoumarin-containing host plants, display higher activities against furanocoumarins than those from P. canadensis , which normally does not encounter furanocoumarins. These P450s in turn catalyze a larger range of furanocoumarins at lower efficiency than CYP6B1, a P450 from Papilio polyxenes , which feeds exclusively on furanocoumarin-containing host plants. Reconstruction of the ancestral CYP6B sequences using maximum likelihood predictions and comparisons of the sequence and geometry of their active sites to those of contemporary CYP6B proteins indicate that host plant diversity is directly related to P450 activity and inversely related to substrate specificity. These predictions suggest that, along the lineage leading to Papilio P450s, the ancestral, highly versatile CYP6B protein presumed to exist in a polyphagous species evolved through time into a more efficient and specialized CYP6B1-like protein in Papilio species with continual exposure to furanocoumarins. Further diversification of Papilio CYP6Bs has likely involved interspersed events of positive selection in oligophagous species and relaxation of functional constraints in polyphagous species.

The insect chemoreceptor superfamily in Drosophila melanogaster is predicted to consist of 62 odorant receptor (Or) and 68 gustatory receptor (Gr) proteins, encoded by families of 60 Or and 60 Gr genes through alternative splicing. We include two previously undescribed Or genes and two previously undescribed Gr genes; two previously predicted Or genes are shown to be alternative splice forms. Three polymorphic pseudogenes and one highly defective pseudogene are recognized. Phylogenetic analysis reveals deep branches connecting multiple highly divergent clades within the Gr family, and the Or family appears to be a single highly expanded lineage within the superfamily. The genes are spread throughout the Drosophila genome, with some relatively recently diverged genes still clustered in the genome. The Gr5a gene on the X chromosome, which encodes a receptor for the sugar trehalose, has transposed from one such tandem cluster of six genes at cytological location 64, as has Gr61a , and all eight of these receptors might bind sugars. Analysis of intron evolution suggests that the common ancestor consisted of a long N-terminal exon encoding transmembrane domains 1-5 followed by three exons encoding transmembrane domains 6-7. As many as 57 additional introns have been acquired idiosyncratically during the evolution of the superfamily, whereas the ancestral introns and some of the older idiosyncratic introns have been lost at least 48 times independently. Altogether, these patterns of molecular evolution suggest that this is an ancient superfamily of chemoreceptors, probably dating back at least to the origin of the arthropods.

All animals detect osmotic and mechanical stimuli, but the molecular basis for these responses is incompletely understood. The vertebrate transient receptor potential channel vanilloid subfamily 4 (TRPV4) (VR-OAC) cation channel has been suggested to be an osmo/mechanosensory channel. To assess its function in vivo , we expressed TRPV4 in Caenorhabditis elegans sensory neurons and examined its ability to generate behavioral responses to sensory stimuli. C. elegans ASH neurons function as polymodal sensory neurons that generate a characteristic escape behavior in response to mechanical, osmotic, or olfactory stimuli. These behaviors require the TRPV channel OSM-9 because osm-9 mutants do not avoid nose touch, high osmolarity, or noxious odors. Expression of mammalian TRPV4 in ASH neurons of osm-9 worms restored avoidance responses to hypertonicity and nose touch, but not the response to odorant repellents. Mutations known to reduce TRPV4 channel activity also reduced its ability to direct nematode avoidance behavior. TRPV4 function in ASH required the endogenous C. elegans osmotic and nose touch avoidance genes ocr-2, odr-3, osm-10 , and glr-1 , indicating that TRPV4 is integrated into the normal ASH sensory apparatus. The osmotic and mechanical avoidance responses of TRPV4-expressing animals were different in their sensitivity and temperature dependence from the responses of wild-type animals, suggesting that the TRPV4 channel confers its characteristic properties on the transgenic animals' behavior. These results provide evidence that TRPV4 can function as a component of an osmotic/mechanical sensor in vivo .

Disease resistance of plants involves two distinct forms of chemical communication with the pathogen: recognition and defense. Both are essential components of a highly complex, multifaceted defense response, which begins with non-self recognition through the perception of pathogen-derived signal molecules and results in the production, inter alia, of antibiotically active compounds (phytoalexins) and cell wall-reinforcing material around the infection site. To elucidate the molecular details and the genomic basis of the underlying chains of events, we used two different experimental systems: suspension-cultured cells of Petroselinum crispum (parsley) and wild-type as well as mutant plants of Arabidopsis thaliana . Particular emphasis was placed on the structural and functional identification of signal and defense molecules, and on the mechanisms of signal perception, intracellular signal transduction and transcriptional reprogramming, including the structural and functional characterization of the responsible cis-acting gene promoter elements and transacting regulatory proteins. Comparing P. crispum and A. thaliana allows us to distinguish species-specific defense mechanisms from more universal responses, and furthermore provides general insights into the nature of the interactions. Despite the complexity of the pathogen defense response, it is experimentally tractable, and knowledge gained so far has opened up a new realm of gene technology-assisted strategies for resistance breeding of crop plants.

Numerous plant species have been known for decades that respond to herbivore attacks by systemically synthesizing defensive chemicals to protect themselves from predators. The nature of systemic wound signals remained obscure until 1991, when an 18-aa peptide called systemin was isolated from tomato leaves and shown to be a primary signal for systemic defense. More recently, two new hydroxyproline-rich, glycosylated peptide defense signals have been isolated from tobacco leaves, and three from tomato leaves. Because of their origins in plants, small sizes, hydroxyproline contents (tomato systemin is proline-rich), and defense-signaling activities, the new peptides are included in a functionally defined family of signals collectively called systemins. Here, we review structural and biological properties of the systemin family, and discuss their possible roles in systemic wound signaling.

Many animals show intimate interactions with bacterial symbionts that provision hosts with limiting nutrients. The best studied such association is that between aphids and Buchnera aphidicola , which produces essential amino acids that are rare in the phloem sap diet. Genomic studies of Buchnera have provided a new means for inferring metabolic capabilities of the symbionts and their likely contributions to hosts. Despite evolutionary reduction of genome size, involving loss of most ancestral genes, Buchnera retains capabilities for biosynthesis of all essential amino acids. In contrast, most genes duplicating amino acid biosynthetic capabilities of hosts have been eliminated. In Buchnera of many aphids, genes for biosynthesis of leucine and tryptophan have been transferred from the chromosome to distinctive plasmids, a feature interpreted as a mechanism for overproducing these amino acids through gene amplification. However, the extent of plasmid-associated amplification varies between and within species, and plasmid-borne genes are sometimes fewer in number than single copy genes on the (polyploid) main chromosome. This supports the broader interpretation of the plasmid location as a means of achieving regulatory control of gene copy number and/or transcription. Buchnera genomes have eliminated most regulatory sequences, raising the question of the extent to which gene expression is moderated in response to changing demands imposed by host nutrition or other factors. Microarray analyses of the Buchnera transcriptome reveal only slight changes in expression of nutritionrelated genes in response to shifts in host diet, with responses less dramatic than those observed for the related nonsymbiotic species, Escherichia coli .

Tissue stem cells form the cellular base for organ homeostasis and repair. Stem cells have the unusual ability to renew themselves over the lifetime of the organ while producing daughter cells that differentiate into one or multiple lineages. Difficult to identify and characterize in any tissue, these cells are nonetheless hotly pursued because they hold the potential promise of therapeutic reprogramming to grow human tissue in vitro , for the treatment of human disease. The mammalian skin epithelium exhibits remarkable turnover, punctuated by periods of even more rapid production after injury due to burn or wounding. The stem cells responsible for supplying this tissue with cellular substrate are not yet easily distinguishable from neighboring cells. However, in recent years a significant body of work has begun to characterize the skin epithelial stem cells, both in tissue culture and in mouse and human skin. Some epithelial cells cultured from skin exhibit prodigious proliferative potential; in fact, for >20 years now, cultured human skin has been used as a source of new skin to engraft onto damaged areas of burn patients, representing one of the first therapeutic uses of stem cells. Cell fate choices, including both self-renewal and differentiation, are crucial biological features of stem cells that are still poorly understood. Skin epithelial stem cells represent a ripe target for research into the fundamental mechanisms underlying these important processes.

We recently showed that a rare cell from murine bone marrow, which we termed multipotent adult progenitor cells (MAPCs), can be expanded for >120 population doublings. Mouse (m)MAPCs differentiate into mesenchymal lineage cells as well as endothelium and endoderm, and, when injected in the blastocyst, mMAPCs contribute to most if not all somatic cell lineages including the different cell types of the brain. Our results, reported herein, demonstrate that mMAPCs can also be induced to differentiate into cells having anatomical and electrophysiological characteristics similar to those of midbrain neurons. Differentiation to a neuronal phenotype was achieved by coculturing mMAPCs with astrocytes, suggesting that neuronal differentiation may require astrocyte-derived factors similar to what is required for the differentiation of embryonic stem cells and neural stem cells to neurons. Differentiation of mMAPCs to neuron-like cells follows similar developmental steps as described for embryonic stem cells and neural stem cells. MAPCs therefore may constitute a source of cells for treatment of central nervous system disorders. ispartof: pages:11854-60 ispartof: Proceedings of the National Academy of Sciences of the United States of America vol:100 issue:Suppl 1 pages:11854-60 ispartof: Arthur M Sackler Colloquium of the National-Academy-of-Sciences on Regenerative Medicine location:CA, IRVINE date:18 Oct - 22 Oct 2002 status: published

We have tested the ability of bone marrow (BM) cells (BMCs) to form hepatocytes in liver injury models. We used three models: ( i ) carbon tetrachloride (CCl 4 ) treatment, ( ii ) albumin-urokinase transgenic mouse [TgN(Alb1Plau)], and ( iii ) hepatitis B transgenic mouse [TgN(Alb1HBV)]. As a nonselective liver injury model, irradiated C57BL/6 (B6) mice were transplanted with BMCs from GFP transgenic mouse [TgN(ActbEGFP)] or β-galactosidase transgenic mouse [TgN(MtnLacZ)] followed by the administration of CCl 4 . Irradiated TgN(Alb1HBV) and TgN(Alb1Plau) were also transplanted with BMCs from TgN(ActbEGFP) or TgN(MtnLacZ). Approximately 1.5 × 10 6 hepatocytes per liver were analyzed for GFP-positive cells, and the whole livers were inspected for β-galactosidase expression. No GFP-positive hepatocytes and no gross blue staining of the livers with 5-bromo-4-chloro-3-indolyl β- d -galactoside in any of the 18 recipient mice analyzed were detected. The livers from female animals with gender-mismatched BM transplantation were also tested with Y chromosome fluorescent in situ hybridization analysis to detect donor-derived cells. A total of five isolated hepatocytes were positive for Y chromosome in 4.1 × 10 5 hepatocytes analyzed. Our results demonstrate that there is little or no contribution of BMCs to the replacement of injured livers in these models. We conclude that BM-derived cells cannot generally lead to a cure of liver damage.

In mammalian epidermis, the level of β-catenin signaling regulates lineage selection by stem cell progeny. High levels of β-catenin stimulate formation of hair follicles, whereas low levels favor differentiation into interfollicular epidermis and sebocytes. In transgenic mouse epidermis, overexpression of β-catenin leads to formation of hair follicle tumors, whereas overexpression of N-terminally truncated Lef1, which blocks β-catenin signaling, results in spontaneous sebaceous tumors. Accompanying overexpression of β-catenin is up-regulation of Sonic hedgehog (SHH) and its receptor, Patched (PTCH/Ptch). In ΔNLef1 tumors Ptch mRNA is up-regulated in the absence of SHH. We now show that PTCH is up-regulated in both human and mouse sebaceous tumors and is accompanied by overexpression of Indian hedgehog (IHH). In normal sebaceous glands IHH is expressed in differentiated sebocytes and the transcription factor GLI1 is activated in sebocyte progenitors, suggesting a paracrine signaling mechanism. PTCH1 and IHH are up-regulated during human sebocyte differentiation in vitro and inhibition of hedgehog signaling inhibits growth and stimulates differentiation. Overexpression of ΔNLef1 up-regulates IHH and stimulates proliferation of undifferentiated sebocytes. We present a model of the interactions between β-catenin and hedgehog signaling in the epidermis in which SHH promotes proliferation of progenitors of the hair lineages whereas IHH stimulates proliferation of sebocyte precursors.