A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection.This work was supported by the Australian Research Council (DP0771859) and the National Health and Medical Research Council (#459412, #635510)

Spontaneous Development of Psoriasis in a New Animal Model Shows an Essential Role for Resident T Cells and Tumor Necrosis Factor-α

Psoriasis is a common T cell–mediated autoimmune disorder where primary onset of skin lesions is followed by chronic relapses. Progress in defining the mechanism for initiation of pathological events has been hampered by the lack of a relevant experimental model in which psoriasis develops spontaneously. We present a new animal model in which skin lesions spontaneously developed when symptomless prepsoriatic human skin was engrafted onto AGR129 mice, deficient in type I and type II interferon receptors and for the recombination activating gene 2. Upon engraftment, resident human T cells in prepsoriatic skin underwent local proliferation. T cell proliferation was crucial for development of a psoriatic phenotype because blocking of T cells led to inhibition of psoriasis development. Tumor necrosis factor-α was a key regulator of local T cell proliferation and subsequent disease development. Our observations highlight the importance of resident T cells in the context of lesional tumor necrosis factor-α production during development of a psoriatic lesion. These findings underline the importance of resident immune cells in psoriasis and will have implications for new therapeutic strategies for psoriasis and other T cell–mediated diseases

Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes

Arenaviruses such as Lassa virus (LASV) cause significant morbidity and mortality in endemic areas. Using a glycoprotein (GP) exchange strategy, we have recently developed live-attenuated arenavirus vaccine prototypes (rLCMV/VSVG) based on lymphocytic choriomeningitis virus (LCMV), a close relative of LASV. rLCMV/VSVG induced long-term CD8+ T cell immunity against wild-type virus challenge and exhibited a stably attenuated phenotype in vivo. Here we elucidated the innate and adaptive immune requirements for the control of rLCMV/VSVG. Infection of RAG−/− mice resulted in persisting viral RNA in blood but not in overt viremia. The latter was only found in mice lacking both RAG and IFN type I receptor. Conversely, absence of IFN type II signaling or NK cells on an RAG-deficient background had only minor effects on vaccine virus load or none at all. rLCMV/VSVG infection of wild-type mice induced less type I IFN than did wild-type LCMV, and type I as well as type II IFNs were dispensable for the induction of virus-specific memory CD8 T cells and virus-neutralizing antibodies by rLCMV/VSVG. In conclusion, the adaptive immune systems are essential for elimination of rLCMV/VSVG, and type I but not type II IFN plays a major contributive role in lowering rLCMV/VSVG loads in vivo, attesting to the attenuation profile of the vaccine. Nevertheless, IFNs are not required for the induction of potent vaccine responses. These results provide a better understanding of the immunobiology of rLCMV/VSVG and will contribute to the further development of GP exchange vaccines for combating arenaviral hemorrhagic fever

Improving Simulations of MPI Applications Using A Hybrid Network Model with Topology and Contention Support

Proper modeling of collective communications is essential for understanding the behavior of medium-to-large scale parallel applications, and even minor deviations in implementation can adversely affect the prediction of real-world performance. We propose a hybrid network model extending LogP based approaches to account for topology and contention in high-speed TCP networks. This model is validated within SMPI, an MPI implementation provided by the SimGrid simulation toolkit. With SMPI, standard MPI applications can be compiled and run in a simulated network environment, and traces can be captured without incurring errors from tracing overheads or poor clock synchronization as in physical experiments. SMPI provides features for simulating applications that require large amounts of time or resources, including selective execution, ram folding, and off-line replay of execution traces. We validate our model by comparing traces produced by SMPI with those from other simulation platforms, as well as real world environments.Une bonne modélisation des communications collective est indispensable à la compréhension des performances des applications parallèles et des différences, même minimes, dans leur implémentation peut drastiquement modifier les performances escomptées. Nous proposons un modèle réseau hybrid étendant les approches de type LogP mais permettant de rendre compte de la topologie et de la contention pour les réseaux hautes performances utilisant TCP. Ce modèle est mis en oeuvre et validé au sein de SMPI, une implémentation de MPI fournie par l'environnement SimGrid. SMPI permet de compiler et d'exécuter sans modification des applications MPI dans un environnement simulé. Il est alors possible de capturer des traces sans l'intrusivité ni les problème de synchronisation d'horloges habituellement rencontrés dans des expériences réelles. SMPI permet également de simuler des applications gourmandes en mémoire ou en temps de calcul à l'aide de techniques telles l'exécution sélective, le repliement mémoire ou le rejeu hors-ligne de traces d'exécutions. Nous validons notre modèle en comparant les traces produites à l'aide de SMPI avec celles de traces d'exécution réelle. Nous montrons le gain obtenu en les comparant également à celles obtenues avec des modèles plus classiques utilisés dans des outils concurrents

Notch1 and Jagged1 are expressed after CNS demyelination, but are not a major rate-determining factor during remyelination

The reasons for the eventual failure of repair mechanisms in multiple sclerosis are unknown. The presence of precursor and immature oligodendrocytes in some non-repairing lesions suggests a mechanism in which these cells either receive insufficient differentiation signals or are exposed to differentiation inhibitors. Jagged signalling via Notch receptors on oligodendrocyte precursor cells (OPCs) inhibits their differentiation during development and the finding that both notch and jagged are expressed in multiple sclerosis lesions has fostered the view that this signalling pathway may explain remyelination failure. In this study, we show that Notch1 is expressed on adult OPCs and that there are multiple cellular sources of its ligand Jagged1 in a rodent model of remyelination. However, despite their expression, the lesions undergo complete remyelination. To establish whether Notch-jagged signalling regulates the rate of remyelination we compared their expression profiles in young animals with those in older animals, where remyelination occurs more slowly, but could find no correlation between expression and remyelination rate. Finally we found that OPC-targeted Notch1 ablation in cuprizone-treated Plp-creER Notch1lox/lox transgenic mice yielded no significant differences in remyelination parameters between knock-out and control mice. Thus, in contrast to developmental myelination, adult expression of Notch1 and Jagged1 neither prevents nor plays a major rate-determining role in remyelination. More generally, the re-expression of developmentally expressed genes following injury in the adult does not per se imply similar functio

Immune Requirements of Post-Exposure Immunization with Modified Vaccinia Ankara of Lethally Infected Mice

Current prophylactic vaccines work via the induction of B and T cell mediated memory that effectively control further replication of the pathogen after entry. In the case of therapeutic or post-exposure vaccinations the situation is far more complex, because the pathogen has time to establish itself in the host, start producing immune-inhibitory molecules and spread into distant organs. So far it is unclear which immune parameters have to be activated in order to thwart an existing lethal infection. Using the mousepox model, we investigated the immunological mechanisms responsible for a successful post-exposure immunization with modified vaccinia Ankara (MVA). In contrast to intranasal application of MVA, we found that intravenous immunization fully protected mice infected with ectromelia virus (ECTV) when applied three days after infection. Intravenous MVA immunization induced strong innate and adaptive immune responses in lethally infected mice. By using various gene-targeted and transgenic mouse strains we show that NK cells, CD4 T cells, CD8 T cells and antibodies are essential for the clearance of ECTV after post-exposure immunization. Post-exposure immunization with MVA is an effective measure in a murine model of human smallpox. MVA activates innate and adaptive immune parameters and only a combination thereof is able to purge ECTV from its host. These data not only provide a basis for therapeutic vaccinations in the case of the deliberate release of pathogenic poxviruses but possibly also for the treatment of chronic infections and cancer

Floquet prethermalization with lifetime exceeding 90s in a bulk hyperpolarized solid

We report the observation of long-lived Floquet prethermal states in a bulk solid composed of dipolar-coupled $^{13}$C nuclei in diamond at room temperature. For precessing nuclear spins prepared in an initial transverse state, we demonstrate pulsed spin-lock Floquet control that prevents their decay over multiple-minute long periods. We observe Floquet prethermal lifetimes $T_2'\approx$90.9s, extended >60,000-fold over the nuclear free induction decay times. The spins themselves are continuously interrogated for $\sim$10min, corresponding to the application of $\approx$5.8M control pulses. The $^{13}$C nuclei are optically hyperpolarized by lattice Nitrogen Vacancy (NV) centers; the combination of hyperpolarization and continuous spin readout yields significant signal-to-noise in the measurements. This allows probing the Floquet thermalization dynamics with unprecedented clarity. We identify four characteristic regimes of the thermalization process, discerning short-time transient processes leading to the prethermal plateau, and long-time system heating towards infinite temperature. This work points to new opportunities possible via Floquet control in networks of dilute, randomly distributed, low-sensitivity nuclei. In particular, the combination of minutes-long prethermal lifetimes and continuous spin interrogation opens avenues for quantum sensors constructed from hyperpolarized Floquet prethermal nuclei.Comment: 5 pages, 5 figures. SI: 2 pages, 4 figure

Development of the American College of Rheumatology Electronic Clinical Quality Measures for Gout

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143639/1/acr23500.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143639/2/acr23500-sup-0001-AppendixS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143639/3/acr23500_am.pd

Adapting Wine Grape Ripening to Global Change Requires a Multi-Trait Approach

In winegrowing regions around the world increasing temperature associated with climate change is responsible for earlier harvests and is implicated in undesirably high sugar concentrations at harvest. Determining the suitability of grapevine varieties in existing or new winegrowing areas has often been based on temperature, without considering other factors. The purpose of this study was to quantify key berry sugar accumulation traits and characterize their plasticity in response to several climate variables. Data was collected from 36 different cultivars over 7 years (2012-2018) from an experimental vineyard in Bordeaux, France. Sugar amounts were obtained through weekly berry sampling starting at mid-veraison and continuing until after technological maturity. The variation in sugar accumulation traits for all cultivars, when considered together, were well explained by cultivar, year, and their interaction, highlighting the relative roles of genetic variation and phenotypic plasticity. Sugar accumulation traits were affected by antecedent and concurrent climate factors such as photosynthetically active radiation, temperature, and vine water status, whether before, or after mid-veraison. In addition, other traits such as berry weight at mid-veraison and date of mid-veraison had an important influence on sugar accumulation traits. More notably, the relative importance of these factors varied significantly by cultivar. The specific physiological mechanisms driving the plasticity of these traits remain to be identified. Adaptation to climate change cannot be based on temperature alone and crop responses cannot be generalized across genotypes, even within species.COntinental To coastal Ecosystems: evolution, adaptability and governanc

Realization of logically labeled effective pure states for bulk quantum computation

We report the first use of "logical labeling" to perform a quantum computation with a room-temperature bulk system. This method entails the selection of a subsystem which behaves as if it were at zero temperature - except for a decrease in signal strength - conditioned upon the state of the remaining system. No averaging over differently prepared molecules is required. In order to test this concept, we execute a quantum search algorithm in a subspace of two nuclear spins, labeled by a third spin, using solution nuclear magnetic resonance (NMR), and employing a novel choice of reference frame to uncouple nuclei.Comment: PRL 83, 3085 (1999). Small changes made to improve readability and remove ambiguitie