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Plasmacytoid dendritic cells (pDCs) play a critical role in bridging the innate and adaptive immune systems. pDCs are specialized type I interferon (IFN) producers, which has implicated them as initiators of autoimmune pathogenesis. However, little is known about the downstream effectors of type I IFN signaling that amplify autoimmune responses. Here, we have used a chemokine reporter mouse to determine the CXCR3 ligand responses in DCs subsets. Following TLR7 stimulation, conventional type 1 and type 2 DCs (cDC1 and cDC2, respectively) uniformly upregulate CXCL10. By contrast, the proportion of chemokine positive pDCs was significantly less, and stable CXCL10+ and CXCL10- populations could be distinguished. CXCL9 expression was induced in all cDC1s, in half of the cDC2 but not by pDCs. The requirement for IFNAR signaling for chemokine reporter expression was interrogated by receptor blocking and deficiency and shown to be critical for CXCR3 ligand expression in Flt3-ligand-derived DCs. Chemokine-producing potential was not concordant with the previously identified markers of pDC heterogeneity. Finally, we show that CXCL10+ and CXCL10- populations are transcriptionally distinct, expressing unique transcriptional regulators, IFN signaling molecules, chemokines, cytokines, and cell surface markers. This work highlights CXCL10 as a downstream effector of type I IFN signaling and suggests a division of labor in pDCs subtypes that likely impacts their function as effectors of viral responses and as drivers of inflammation.

Phenotypically diverse memory CD8(+) T cells are present in the lungs that either re-circulate or reside within the tissue. Understanding the key cellular interactions that regulate the generation and then persistence of these different subsets is of great interest. Recently, DNGR-1(+) dendritic cell (DC) mediated priming was reported to control the generation of lung resident but not circulating memory cells following respiratory viral infection. Here, we report an important role for Ly6C(+) inflammatory monocytes (IMs) in contributing to the persistence of memory CD8(+) T cells but not their generation. Effector CD8(+) T cells expanded and contracted normally in the absence of IMs, but the memory compartment declined significantly over time. Quite unexpectedly, this defect was confined to tissue resident and circulating CXCR3(hi)CX3CR1(lo) memory cells but not CXCR3(hi)CX3CR1(int) and CXCR3(lo)CX3CR1(hi) subsets. Thus, two developmentally distinct innate cells orchestrate the generation and persistence of memory T cell subsets following a respiratory virus infection.

Das Cambridge Crystallographic Data Centre (CCDC) wurde 1965 gegrundet. Das Ziel war die Einrichtung einer Institution, die numerische, chemische und bibliographische Daten von organischen und metallorganischen Kristallstrukturen archiviert. In der Cambridge Structural Database (CSD) sind heute nahezu 700 000 Strukturen hinterlegt, und sie ist ein historisch luckenloses Archiv der niedermolekularen Kristallographie. Fast 40 000 Neueintrage werden jedes Jahr verzeichnet. Da die Rontgenkristallographie ihr einhundertstes Jubilaum feiert – und das CCDC bald sein funfzigstes –, wollen wir in diesem Kurzaufsatz die Anfange des CCDC als eine offentlich geforderte Institution und seine weitere Entwicklung in eine gemeinnutzige Einrichtung nachverfolgen. Wir beschreiben die Entwicklung der CSD und ihres Softwaresystems und betrachten ihre Auswirkungen auf die Forschung in der Strukturchemie, den Materialwissenschaften sowie der Biologie und Medizin. Auserdem diskutieren wir das Finanzierungsmodell des CCDC vor dem Hintergrund der Open-Access- und Open-Data-Debatte.

The Cambridge Crystallographic Data Centre (CCDC) was established in 1965 to record numerical, chemical and bibliographic data relating to published organic and metal-organic crystal structures. The Cambridge Structural Database (CSD) now stores data for nearly 700,000 structures and is a comprehensive and fully retrospective historical archive of small-molecule crystallography. Nearly 40,000 new structures are added each year. As X-ray crystallography celebrates its centenary as a subject, and the CCDC approaches its own 50th year, this article traces the origins of the CCDC as a publicly funded organization and its onward development into a self-financing charitable institution. Principally, however, we describe the growth of the CSD and its extensive associated software system, and summarize its impact and value as a basis for research in structural chemistry, materials science and the life sciences, including drug discovery and drug development. Finally, the article considers the CCDC's funding model in relation to open access and open data paradigms.

Crystal structure determination is the method of choice for the analysis of novel chemical compounds from monatomic metals to proteins and viruses, with some 700,000 crystal structures published so far. Of these, over 500,000 (70%) are carbon-containing organic and metal-organic small molecules, for which experimental three-dimensional (3D) numerical results are stored in the Cambridge Structural Database (CSD), together with two-dimensional chemical structure information and text and numerical fields that record chemical and physical properties. The CSD is fully searchable using an Internet search engine or specialist-distributed software that provides advanced facilities for structure display and data analysis, including many special features for understanding molecular recognition processes such as protein–ligand interactions. Two knowledge bases derived from the CSD provide immediate access to information on intramolecular geometry and intermolecular interactions. CSD information is heavily used in academic and industrial research that relies on knowledge of 3D molecular geometry and intermolecular interactions, for example, in structural chemistry and biology, drug discovery, materials design and development, and in crystallography itself. As a teaching tool, the CSD has a fundamental role to play in illustrating the 3D chemical concepts that are essential for those who study chemistry as a principal or subsidiary subject. © 2011 John Wiley & Sons, Ltd. WIREs Comput Mol Sci 2011 1 368–376 DOI: 10.1002/wcms.35

Systemic autoimmunity such as systemic lupus erythematosus (SLE) is associated with the loss of B-cell tolerance, B-cell dysregulation and autoantibody production. While some autoantibodies may contribute to the pathology seen with SLE, numerous studies have shown that dysregulation of T-cell function is another critical aspect driving disease. The positive results obtained in clinical trials using T-cell- or B-cell-specific treatments have suggested that cooperation between T and B cells probably underlies disease progression in many patients. A similar cooperative mechanism seemed to explain SLE developing in mice overexpressing the B-cell-activating factor from the tumor necrosis factor family (BAFF). However, surprisingly, T-cell-deficient BAFF transgenic (Tg) mice develop SLE similar to T-cell-sufficient BAFF Tg mice, and the disease was linked to innate activation of B cells and production of proinflammatory autoantibody isotypes. In conclusion, dysregulated innate activation of B cells alone can drive disease independently of T cells, and as such this aspect represents a new pathogenic mechanism in autoimmunity.

The Cambridge Crystallographic Data Centre (CCDC) was established in 1965 to record numerical, chemical and bibliographic data relating to published organic and metal–organic crystal structures. The Cambridge Structural Database (CSD) now stores data for nearly 700 000 structures and is a comprehensive and fully retrospective historical archive of small-molecule crystallography. Nearly 40 000 new structures are added each year. As X-ray crystallography celebrates its centenary as a subject, and the CCDC approaches its own 50th year, this article traces the origins of the CCDC as a publicly funded organization and its onward development into a self-financing charitable institution. Principally, however, we describe the growth of the CSD and its extensive associated software system, and summarize its impact and value as a basis for research in structural chemistry, materials science and the life sciences, including drug discovery and drug development. Finally, the article considers the CCDC’s funding model in relation to open access and open data paradigms.

Multiple-solvent crystal structure determination (MSCS) allows the position and orientation of bound solvent fragments to be identified by determining the structure of protein crystals soaked in organic solvents. We have extended this technique by the determination of high-resolution crystal structures of thermolysin (TLN), generated from crystals soaked in 2% to 100% isopropanol. The procedure causes only minor changes to the conformation of the protein, and an increasing number of isopropanol interaction sites could be identified as the solvent concentration is increased. Isopropanol occupies all four of the main subsites in the active site, although this was only observed at very high concentrations of isopropanol for three of the four subsites. Analysis of the isopropanol positions shows little correlation with interaction energy computed using a molecular mechanics force field, but the experimentally determined positions of isopropanol are consistent with the structures of known protein-ligand complexes of TLN. Proteins 1999;37:628–640. ©1999 Wiley-Liss, Inc.

The function of our immune system is undeniably intertwined with the ability of immune cells to migrate to and interact with each other. Chemokines serve as critical extracellular mediators of this migration. Chemokine receptors are seven transmembrane G protein-coupled receptors, which are associated with cell surface- or extracellular matrix-associated glycosaminoglycans. Chemokines constitute the largest family of cytokines, consisting of ~50 endogenous chemokine ligands in humans and mice. Through coordinated interaction with their receptors, chemokines have a critical role in all immune cell movement, such as the migration required for immune cell development and organ homeostasis, to inflammation and cellular interaction for the development of effector function and to the pathological recruitment of immune cells in disease.1, 2

We report on a girl with Floating-Harbor syndrome, trigonocephaly due to metopic suture synostosis, preauricular pit, hypoplastic thumb, subluxated radial head, and Sprengel deformity. A review suggests that trigonocephaly may be an important craniofacial manifestation in this syndrome that is recognizable in infancy. With time, this finding appears to become less noticeable, and the face develops a triangular shape, accentuated by a broad and bulbous nose.

RPM2 is a Saccharomyces cerevisiae nuclear gene required for normal cell growth yet the only known function of Rpm2p is as a protein subunit of yeast mitochondrial RNase P, an enzyme responsible for the 5′ maturation of mitochondrial tRNAs. Since mitochondrial protein synthesis in S. cerevisiae is not essential for viability, RPM2 must provide another function in addition to its known role as a mitochondrial tRNA processing enzyme. During a search for RPM2 homologues from Kluyveromyces lactis, we recovered a K. lactis gene that compensates for the essential function but not the RNase P function of RPM2. We have named this gene SEF1 (Suppressor of the Essential Function). DNA sequence analysis of SEF1 reveals it contains a Zn(2)-Cys(6) binuclear cluster motif found in a growing number of yeast transcription factors. The SEF1 homologue of S. cerevisiae also compensates for the essential function of RPM2. The two proteins share 49% identity and 72% amino acid sequence similarity. The SEF1 sequence has been deposited in the GenBank data library under accession number U92898. © 1998 John Wiley & Sons, Ltd.