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Recent advances in complement research have revolutionized our understanding of its role in immune responses. The immunomodulatory features of complement in infections by intracellular pathogens, e.g., viruses, are attracting increasing attention. Thereby, local production and activation of complement by myeloid-derived cells seem to be crucial. We could recently show that C3, a key player of the complement cascade, is required for effective defense against the intracellular bacterium Chlamydia psittaci . Avian zoonotic strains of this pathogen cause life-threatening pneumonia with systemic spread in humans; closely related non-avian strains are responsible for less severe diseases of domestic animals with economic loss. To clarify how far myeloid- and non-myeloid cell-derived complement contributes to immune response and resulting protection against C. psittaci , adoptive bone marrow transfer experiments focusing on C3 were combined with challenge experiments using a non-avian (BSL 2) strain of this intracellular bacterium. Surprisingly, our data prove that for C. psittaci -induced pneumonia in mice, non-myeloid-derived, circulating/systemic C3 has a leading role in protection, in particular on the development of pathogen-specific T- and B- cell responses. In contrast, myeloid-derived and most likely locally produced C3 plays only a minor, mainly fine-tuning role. The work we present here describes authentic, although less pronounced, antigen directed immune responses.

The zoonotic intracellular bacterium Chlamydia psittaci causes life-threatening pneumonia in humans. During mouse lung infection, complement factor C3 and the anaphylatoxin C3a augment protection against C. psittaci by a so far unknown mechanism. To clarify how complement contributes to the early, innate and the late, specific immune response and resulting protection, this study addresses the amount of C3, the timing when its presence is required as well as the anaphylatoxin receptor(s) mediating its effects and the complement-dependent migration of dendritic cells. Challenge experiments with C. psittaci on various complement KO mice were combined with transient decomplementation by pharmacological treatment, as well as the analysis of in vivo dendritic cells migration. Our findings reveal that a plasma concentration of C3 close to wildtype levels was required to achieve full protection. The diminished levels of C3 of heterozygote C3 +/− mice permitted already relative effective protection and improved survival as compared to C3 −/− mice, but overall recovery of these animals was delayed. Complement was in particular required during the first days of infection. However, additionally, it seems to support protection at later stages. Migration of CD103 + dendritic cells from the infected lung to the draining lymph node—as prerequisite of antigen presentation—depended on C3 and C3aR and/or C5aR. Our results provide unique mechanistic insight in various aspects of complement-dependent immune responses under almost identical, rather physiological experimental conditions. Our study contributes to an improved understanding of the role of complement, and C3a in particular, in infections by intracellular bacteria.

Chlamydia trachomatis causes most bacterial sexually transmitted diseases worldwide. Different major outer membrane proteins (MOMPs) define various serovars of this intracellular pathogen: In women, D to L3 can cause urethritis, cervicitis, salpingitis, and oophoritis, and, thus, infertility. Protective immunity might be serovar-specific since chlamydial infection does not appear to induce an effective acquired immunity and reinfections occur. A better understanding of induced cross-serovar protection is essential for the selection of suitable antigens in vaccine development. In our mouse lung infection screening model, we evaluated the urogenital serovars D, E, and L2 in this regard. Seven weeks after primary infection or mock-infection, respectively, mice were infected a second time with the identical or one of the other serovars. Body weight and clinical score were monitored for 7 days. Near the peak of the second lung infection, bacterial load, myeloperoxidase, IFN-γ, and TNF-α in lung homogenate, as well as chlamydia-specific IgG levels in blood were determined. Surprisingly, compared with mice that were infected then for the first time, almost independent of the serovar combination used, all acquired parameters of disease were similarly diminished. Our reinfection study suggests that efficient cross-serovar protection could be achieved by a vaccine combining chlamydial antigens that do not include nonconserved MOMP regions.

Chlamydia trachomatis is the most frequent sexually-transmitted disease-causing bacterium. Urogenital serovars of this intracellular pathogen lead to urethritis and cervicitis. Ascending infections result in pelvic inflammatory disease, salpingitis, and oophoritis. One of 200 urogenital infections leads to tubal infertility. Serovars A–C cause trachoma with visual impairment. There is an urgent need for a vaccine. We characterized a new five-component subunit vaccine in a mouse vaccination-lung challenge infection model. Four recombinant Pmp family-members and Ctad1 from C. trachomatis serovar E, all of which participate in adhesion and binding of chlamydial elementary bodies to host cells, were combined with the mucosal adjuvant cyclic-di-adenosine monophosphate. Intranasal application led to a high degree of cross-serovar protection against urogenital and ocular strains of C. trachomatis, which lasted at least five months. Critical evaluated parameters were body weight, clinical score, chlamydial load, a granulocyte marker and the cytokines IFN-γ/TNF-α in lung homogenate. Vaccine antigen-specific antibodies and a mixed Th1/Th2/Th17 T cell response with multi-functional CD4+ and CD8+ T cells correlate with protection. However, serum-transfer did not protect the recipients suggesting that circulating antibodies play only a minor role. In the long run, our new vaccine might help to prevent the feared consequences of human C. trachomatis infections.

Introduction The nature of information used in medicine has changed. In the past, we were limited to routine clinical data and published clinical trials. Today, we deal with massive, multiple data streams and easy access to new tests, ideas, and capabilities to process them. Whereas in the past getting information for decision‐making was a challenge, now, it is how to analyze, evaluate and prioritize all that is readily available through the multitude of data‐collecting devices. Clinicians must become adept with the tools needed to deal with the era of big data, requiring a major change in how we learn to make decisions. Major change is often met with resistance and questions about value. A Learning Health System is an enabler to encourage the development of such tools and demonstrate value in improved decision‐making. Methods We describe how we are developing a Biomedical Informatics program to help our medical institution's evolution as an academic Learning Health System, including strategy, training for house staff and examples of the role of informatics from operations to research. Results We described an array of learning health system implementations and educational programs to improve healthcare and prepare a cadre of physicians with basic information technology skills. The programs have been well accepted with, for example, increasing interest and enrollment in the educational programs. Conclusions We are now in an era when large volumes of a wide variety of data are readily available. The challenge is not so much in the acquisition of data, but in assessing the quality, relevance and value of the data. The data we can get may not be the data we need. In the past, sources of data were limited, and trial results published in journals were the major source of evidence for decision making. The advent of powerful analytics systems has changed the concept of evidence. Clinicians will have to develop the skills necessary to work in the era of big data. It is not reasonable to expect that all clinicians will also be data scientists. However, understanding the role of AI and predictive analytics, and how to apply them, will become progressively more important. Programs such as the one being implemented at Wake Forest fill that need.

Petrochronology is a rapidly emerging branch of Earth science that links time (ages or rates) with specific rock-forming processes and their physical conditions. It is founded in petrology and geochemistry, which define a petrogenetic context or delimit a specific process, to which chronometric data are then linked. This combination informs Earth's petrogenetic processes better than petrology or geochronology alone. This volume and the accompanying short courses address three broad categories of inquiry. Conceptual approaches chapters include petrologic modeling of multi-component chemical and mineralogic systems, and development of methods that include diffusive alteration of mineral chemistry. Methods chapters address four main analytical techniques, specifically EPMA, LA-ICP-MS, SIMS and TIMS. Mineral-specific chapters explore applications to a wide range of minerals, including zircon (metamorphic, igneous, and detrital/Hadean), baddeleyite, REE minerals (monazite, allanite, xenotime and apatite), titanite, rutile, garnet, and major igneous minerals (olivine, plagioclase and pyroxenes).

[...]I told mom that the place we found was 'as quirky as corporate could get!' It worked well for her. The scientific basis of medical practice, and all its gleaming accomplishments from the cutting and measuring of things (science's Latin root, 'scire', derives from 'to cut, divide'), needs to find its place in the complete picture of lived human experience. [...]our advocacy for experiences for our students steeped in embodied word and image-qualitative symbols-that allow them to thicken and enliven their quantitative understanding of the world in which they will live and practise.