Showing papers by "University of Basel published in 2004"
TL;DR: This review offers guidance in establishing the diagnosis correctly and an algorithm summarizing the appropriate medical and surgical options for prosthetic joints infections.
Abstract: Modern techniques have reduced the frequency of infections that are associated with prosthetic joints, but such infections continue to pose difficult problems in clinical management. Advances in understanding biofilms and the pathogenesis of microbial interactions with the implant have led to more rational approaches to therapy. This review offers guidance in establishing the diagnosis correctly and an algorithm summarizing the appropriate medical and surgical options.
2,617 citations
TL;DR: Two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
Abstract: The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. mTORC2 is not upstream of the mTORC1 effector S6K. Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
2,059 citations
TL;DR: It is shown that treatment of plants with flg22, a peptide representing the elicitor-active epitope of flagellin, induces the expression of numerous defence-related genes and triggers resistance to pathogenic bacteria in wild-type plants, but not in plants carrying mutations in the flageLLin receptor gene FLS2.
Abstract: Plants and animals recognize microbial invaders by detecting pathogen-associated molecular patterns (PAMPs) such as flagellin. However, the importance of flagellin perception for disease resistance has, until now, not been demonstrated. Here we show that treatment of plants with flg22, a peptide representing the elicitor-active epitope of flagellin, induces the expression of numerous defence-related genes and triggers resistance to pathogenic bacteria in wild-type plants, but not in plants carrying mutations in the flagellin receptor gene FLS2. This induced resistance seems to be independent of salicylic acid, jasmonic acid and ethylene signalling. Wild-type and fls2 mutants both display enhanced resistance when treated with crude bacterial extracts, even devoid of elicitor-active flagellin, indicating the existence of functional perception systems for PAMPs other than flagellin. Although fls2 mutant plants are as susceptible as the wild type when bacteria are infiltrated into leaves, they are more susceptible to the pathogen Pseudomonas syringae pv. tomato DC3000 when it is sprayed on the leaf surface. Thus, flagellin perception restricts bacterial invasion, probably at an early step, and contributes to the plant's disease resistance.
1,639 citations
TL;DR: The small RNA profile of cells infected by Epstein-Barr virus is recorded and it is shown that EBV expresses several microRNA (miRNA) genes, which are identified viral regulators of host and/or viral gene expression.
Abstract: RNA silencing processes are guided by small RNAs that are derived from double-stranded RNA. To probe for function of RNA silencing during infection of human cells by a DNA virus, we recorded the small RNA profile of cells infected by Epstein-Barr virus (EBV). We show that EBV expresses several microRNA (miRNA) genes. Given that miRNAs function in RNA silencing pathways either by targeting messenger RNAs for degradation or by repressing translation, we identified viral regulators of host and/or viral gene expression.
1,608 citations
TL;DR: This work found that in the case of decisions from experience, people make choices as if they underweight the probability of rare events, and explored the impact of two possible causes of this underweighting—reliance on relatively small samples of information and overweighting of recently sampled information.
Abstract: When people have access to information sources such as newspaper weather forecasts, drug-package inserts, and mutual-fund brochures, all of which provide convenient descriptions of risky prospects, they can make decisions from description. When people must decide whether to back up their computer's hard drive, cross a busy street, or go out on a date, however, they typically do not have any summary description of the possible outcomes or their likelihoods. For such decisions, people can call only on their own encounters with such prospects, making decisions from experience. Decisions from experience and decisions from description can lead to dramatically different choice behavior. In the case of decisions from description, people make choices as if they overweight the probability of rare events, as described by prospect theory. We found that in the case of decisions from experience, in contrast, people make choices as if they underweight the probability of rare events, and we explored the impact of two possible causes of this underweighting--reliance on relatively small samples of information and overweighting of recently sampled information. We conclude with a call for two different theories of risky choice.
1,421 citations
TL;DR: Experiments demonstrate that a wide set of unsymmetric linear systems can be solved and high performance is consistently achieved for large sparse unsympetric matrices from real world applications.
1,324 citations
TL;DR: In addition to their adhesive functions, cell-adhesion molecules modulate signal-transduction pathways by interacting with molecules such as receptor tyrosine kinases, components of the WNT signalling pathway and RHO-family GTPases, which have a crucial role in tumour progression.
Abstract: In addition to their adhesive functions, cell-adhesion molecules modulate signal-transduction pathways by interacting with molecules such as receptor tyrosine kinases, components of the WNT signalling pathway and RHO-family GTPases. So, changes in the expression of cell-adhesion molecules affect not only the adhesive repertoire of a cell, but also its signal-transduction status. Conversely, signalling pathways can modulate the function of cell-adhesion molecules, altering the interactions between cells and their environment. Recent experimental evidence indicates that such processes have a crucial role in tumour progression, in particular during invasion and metastasis.
1,295 citations
TL;DR: At a coarse scale, the treelines of the world's mountains seem to follow a common isotherm, but the evidence for this has been indirect so far, so this work aims at underpinning this with facts.
Abstract: Aim At a coarse scale, the treelines of the world`s mountains seem to follow a common isotherm, but the evidence for this has been indirect so far. Here we aim at underpinning this with facts. Location We present the results of a data-logging campaign at 46 treeline sites between 68degrees N and 42degrees S. Methods We measured root-zone temperatures with an hourly resolution over 1-3 years per site between 1996 and 2003. Results Disregarding taxon-, landuse- or fire-driven tree limits, high altitude climatic treelines are associated with a seasonal mean ground temperature of 6.7 degreesC (+/-0.8 SD; 2.2 K amplitude of means for different climatic zones), a surprisingly narrow range. Temperatures are higher (7-8 degreesC) in the temperate and Mediterranean zone treelines, and are lower in equatorial treelines (5-6 degreesC) and in the subarctic and boreal zone (6-7 degreesC). While air temperatures are higher than soil temperatures in warm periods, and are lower than soil temperatures in cold periods, daily means of air and soil temperature are almost the same at 6-7 degreesC, a physics driven coincidence with the global mean temperature at treeline. The length of the growing season, thermal extremes or thermal sums have no predictive value for treeline altitude on a global scale. Some Mediterranean (Fagus spp.) and temperate South Hemisphere treelines (Nothofagus spp.) and the native treeline in Hawaii (Metrosideros) are located at substantially higher isotherms and represent genus-specific boundaries rather than boundaries of the life-form tree. In seasonal climates, ground temperatures in winter (absolute minima) reflect local snow pack and seem uncritical. Main conclusions The data support the hypothesis of a common thermal threshold for forest growth at high elevation, but also reflect a moderate region and substantial taxonomic influence.
1,227 citations
TL;DR: It is shown that elongation factor Tu, the most abundant bacterial protein, acts as a PAMP in Arabidopsis thaliana and other Brassicaceae, and an N-acetylated peptide comprising the first 18 amino acids, termed elf18, is fully active as inducer of defense responses.
Abstract: Innate immunity is based on the recognition of pathogen-associated molecular patterns (PAMPs). Here, we show that elongation factor Tu (EF-Tu), the most abundant bacterial protein, acts as a PAMP in Arabidopsis thaliana and other Brassicaceae. EF-Tu is highly conserved in all bacteria and is known to be N-acetylated in Escherichia coli. Arabidopsis plants specifically recognize the N terminus of the protein, and an N-acetylated peptide comprising the first 18 amino acids, termed elf18, is fully active as inducer of defense responses. The shorter peptide, elf12, comprising the acetyl group and the first 12 N-terminal amino acids, is inactive as elicitor but acts as a specific antagonist for EF-Tu-related elicitors. In leaves of Arabidopsis plants, elf18 induces an oxidative burst and biosynthesis of ethylene, and it triggers resistance to subsequent infection with pathogenic bacteria.
854 citations
TL;DR: Current concepts on the molecular composition and function of GABA(B) receptors are reviewed and ongoing drug-discovery efforts are discussed, which are expected to broaden the spectrum of therapeutic applications.
Abstract: GABA(B) receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABA(B) receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABA(B) system. This led to the surprising discovery that GABA(B) receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABA(B) receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABA(B) receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABA(B) receptors and the receptors for gamma-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABA(B) receptor polymorphisms to epilepsy. Significantly, the cloning of GABA(B) receptors enabled identification of the first allosteric GABA(B) receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABA(B) receptors and discuss ongoing drug-discovery efforts.
815 citations
TL;DR: It is concluded that anti-EpCam therapies, if proven to be successful, will have broad applications in a wide variety of carcinomas.
TL;DR: A method is presented that can find the global minimum of very complex condensed matter systems based on the simple principle of exploring the configurational space as fast as possible and of avoiding revisiting known parts of this space.
Abstract: A method is presented that can find the global minimum of very complex condensed matter systems. It is based on the simple principle of exploring the configurational space as fast as possible and of avoiding revisiting known parts of this space. Even though it is not a genetic algorithm, it is not based on thermodynamics. The efficiency of the method depends strongly on the type of moves that are used to hop into new local minima. Moves that find low-barrier escape-paths out of the present minimum generally lead into low energy minima.
TL;DR: The genome of the filamentous ascomycete Ashbya gossypii provided compelling evidence that the evolution of S. cerevisiae included a whole genome duplication orfusion of two related species and showed which of the duplicated genes lost one copy and which retained both copies.
Abstract: We have sequenced and annotated the genome of the filamentous ascomycete Ashbya gossypii. With a size of only 9.2 megabases, encoding 4718 protein-coding genes, it is the smallest genome of a free-living eukaryote yet characterized. More than 90% of A. gossypii genes show both homology and a particular pattern of synteny with Saccharomyces cerevisiae. Analysis of this pattern revealed 300 inversions and translocations that have occurred since divergence of these two species. It also provided compelling evidence that the evolution of S. cerevisiae included a whole genome duplication or fusion of two related species and showed, through inferred ancient gene orders, which of the duplicated genes lost one copy and which retained both copies.
TL;DR: It is proposed that the local action of this novel-type guanylate cyclase might constitute a general regulatory principle in bacterial growth and development.
Abstract: Pole development is coordinated with the Caulobacter crescentus cell cycle by two-component signaling proteins. We show that an unusual response regulator, PleD, is required for polar differentiation and is sequestered to the cell pole only when it is activated by phosphorylation. Dynamic localization of PleD to the cell pole provides a mechanism to temporally and spatially control the signaling output of PleD during development. Targeting of PleD to the cell pole is coupled to the activation of a C-terminal guanylate cyclase domain, which catalyzes the synthesis of cyclic di-guanosine monophosphate. We propose that the local action of this novel-type guanylate cyclase might constitute a general regulatory principle in bacterial growth and development.
TL;DR: This paper showed that ERRα is an effector of the transcriptional coactivator PGC-1α and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis.
Abstract: Estrogen-related receptor α (ERRα) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERRα is an effector of the transcriptional coactivator PGC-1α [peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERRα compromises the ability of PGC-1α to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERRα is sufficient to elicit both responses. ERRα binding sites are present in the transcriptional control regions of ERRα/PGC-1α-induced genes and contribute to the transcriptional response to PGC-1α. The ERRα-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERRα activity could be linked to pathological changes in metabolic disease, such as diabetes.
TL;DR: The findings show that some AMF species present in natural ecosystems are maintained under organic farming but severely depressed under conventional Farming, indicating a potentially severe loss of ecosystem function under conventional farming.
Abstract: Previous work has shown considerably en- hanced soil fertility in agroecosystems managed by organic farming as compared to conventional farming. Arbuscular mycorrhizal fungi (AMF) play a crucial role in nutrient acquisition and soil fertility. The objective of this study was to investigate the diversity of AMF in the context of a long-term study in which replicated field plots, at a single site in Central Europe, had been cultivated for 22 years according to two "organic" and two "conventional" farming systems. In the 23rd year, the field plots, carrying an 18-month-old grass-clover stand, were examined in two ways with respect to AMF diversity. Firstly, AMF spores were isolated and morphologically identified from soil samples. The study revealed that the AMF spore abundance and species diversity was sig- nificantly higher in the organic than in the conventional systems. Furthermore, the AMF community differed in the conventional and organic systems: Glomus species were similarly abundant in all systems but spores of Acaulos- pora and Scutellospora species were more abundant in the organic systems. Secondly, the soils were used to establish AMF-trap cultures using a consortium of Plantago lanceolata, Trifolium pratense and Lolium perenne as host plants. The AMF spore community developing in the trap cultures differed: after 12 months, two species of the Acaulosporaceae (A. paulinae and A. longula) were consistently found to account for a large part of the spore community in the trap cultures from the organic systems but were found rarely in the ones from the conventional systems. The findings show that some AMF species present in natural ecosystems are maintained under organic farming but severely depressed under conven- tional farming, indicating a potentially severe loss of ecosystem function under conventional farming.
TL;DR: Features of trauma memories in post‐traumatic stress disorder (PTSD), including characteristics of unintentional re‐experiencing symptoms and intentional recall of trauma narratives are described, and implications for treatment are discussed.
Abstract: The article describes features of trauma memories in post‐traumatic stress disorder (PTSD), including characteristics of unintentional re‐experiencing symptoms and intentional recall of trauma narratives. Re‐experiencing symptoms are usually sensory impressions and emotional responses from the trauma that appear to lack a time perspective and a context. The vast majority of intrusive memories can be interpreted as re‐experiencing of warning signals, i.e., stimuli that signalled the onset of the trauma or of moments when the meaning of the event changed for the worse. Triggers of re‐experiencing symptoms include stimuli that have perceptual similarity to cues accompanying the traumatic event. Intentional recall of the trauma in PTSD may be characterised by confusion about temporal order, and difficulty in accessing important details, both of which contribute to problematic appraisals. Recall tends to be disjointed. When patients with PTSD deliberately recall the worst moments of the trauma, they often do n...
TL;DR: It is found that the eukaryotic-like serine/threonine protein kinase G from pathogenic mycobacteria was secreted within macrophage phagosomes, inhibiting phagosome-lysosome fusion and mediating intracellular survival of myc Cobacteria.
Abstract: Pathogenic mycobacteria resist lysosomal delivery after uptake into macrophages, allowing them to survive intracellularly. We found that the eukaryotic-like serine/threonine protein kinase G from pathogenic mycobacteria was secreted within macrophage phagosomes, inhibiting phagosome-lysosome fusion and mediating intracellular survival of mycobacteria. Inactivation of protein kinase G by gene disruption or chemical inhibition resulted in lysosomal localization and mycobacterial cell death in infected macrophages. Besides identifying a target for the control of mycobacterial infections, these findings suggest that pathogenic mycobacteria have evolved eukaryotic-like signal transduction mechanisms capable of modulating host cell trafficking pathways.
TL;DR: Molecular dynamics simulations for the potassium channel KcsA show that the carbonyl groups coordinating the ion in the narrow pore are indeed very dynamic (‘liquid-like’) and that their intrinsic electrostatic properties control ion selectivity.
Abstract: Potassium channels are essential for maintaining a normal ionic balance across cell membranes. Central to this function is the ability of such channels to support transmembrane ion conduction at nearly diffusion-limited rates while discriminating for K+ over Na+ by more than a thousand-fold. This selectivity arises because the transfer of the K+ ion into the channel pore is energetically favoured, a feature commonly attributed to a structurally precise fit between the K+ ion and carbonyl groups lining the rigid and narrow pore. But proteins are relatively flexible structures that undergo rapid thermal atomic fluctuations larger than the small difference in ionic radius between K+ and Na+. Here we present molecular dynamics simulations for the potassium channel KcsA, which show that the carbonyl groups coordinating the ion in the narrow pore are indeed very dynamic ('liquid-like') and that their intrinsic electrostatic properties control ion selectivity. This finding highlights the importance of the classical concept of field strength. Selectivity for K+ is seen to emerge as a robust feature of a flexible fluctuating pore lined by carbonyl groups.
TL;DR: The results suggest that genetic variation in TLR2 is a major determinant of the susceptibility to asthma and allergies in children of farmers.
Abstract: Background The finding that the prevalence of asthma and allergies is less frequent in children raised on animal farms has led to the conjecture that exposure to microbial products modifies immune responses. The toll-like receptors (TLRs) represent an evolutionarily conserved family of innate immunity receptors with microbial molecules as ligands. Objectives We reasoned that polymorphisms in genes encoding TLRs might modulate the protective effects observed in farming populations. Methods Farmers' and nonfarmers' children living in rural areas in Austria and Germany and who were enrolled in the cross-sectional ALEX study were genotyped for single nucleotide polymorphisms in the TLR2 and TLR4 genes. The frequencies of asthma, allergic rhinitis, and atopic sensitization were compared between the genotypes in relation to exposure to farming and endotoxin. Results Among farmers' children, those carrying a T allele in TLR2/−16934 compared with children with genotype AA were significantly less likely to have a diagnosis of asthma (3% vs 13%, P = .012), current asthma symptoms (3% vs 16%, P = .004), atopic sensitization (14% vs 27%, P = .023), and current hay fever symptoms (3% vs 14%, P = .01). The association between TLR2/−16934 and asthma among children of farmers was independent of atopy. No such association was found among children from the same rural communities but not living on farms. Conclusion Our results suggest that genetic variation in TLR2 is a major determinant of the susceptibility to asthma and allergies in children of farmers.
TL;DR: A mathematical model of a THA was developed to determine the optimal combination of cup inclination, cup anteversion, and stem antetorsion for maximizing ROM and minimizing the risk for cup–neck impingement.
TL;DR: In this article, the evolution of the European Cenozoic Rift System (ECRIS) and the Alpine orogen is discussed on the base of a set of palaeotectonic maps and two retro-deformed lithospheric transects which extend across the Western and Central Alps and the Massif Central and the Rhenish Massif, respectively.
TL;DR: It is reported that selection of highly proliferative stem cells followed by treatment with retinoic acid generated essentially pure precursors that markers identified as Pax-6-positive radial glial cells went on to generate neurons with remarkably uniform biochemical and electrophysiological characteristics.
Abstract: Although it has long been known that cultured embryonic stem cells can generate neurons, the lineage relationships with their immediate precursors remain unclear. We report here that selection of highly proliferative stem cells followed by treatment with retinoic acid generated essentially pure precursors that markers identified as Pax-6-positive radial glial cells. As they do in vivo, these cells went on to generate neurons with remarkably uniform biochemical and electrophysiological characteristics.
TL;DR: The authors of as mentioned in this paper show that the volume of the lithosphere is not necessarily preserved during rifting as advocated by conventional stretching models, and that the structural style of rifts is controlled by the rheological structure of the upper and lower lithosphere, the availability of crustal discontinuities that can be tensionally reactivated, the mode (orthogonal or oblique) and amount of extension, and the lithological composition of pre- and syn-rift sediments.
TL;DR: A transition from stick-slip to continuous sliding is observed for atomically modulated friction by means of a friction force microscope and the results are compared to a recently discussed concept called superlubricity.
Abstract: A transition from stick-slip to continuous sliding is observed for atomically modulated friction by means of a friction force microscope. When the stick-slip instabilities cease to exist, a new regime of ultralow friction is encountered. The transition is described in the framework of the Tomlinson model using a parameter eta which relates the strength of the lateral atomic surface potential and the stiffness of the contact under study. Experimentally, this parameter can be tuned by varying the normal load on the contact. We compare our results to a recently discussed concept called superlubricity.
TL;DR: The data indicate that PI3Kgamma is an essential component of a complex controlling PDE3B phosphodiesterase-mediated cAMP destruction, and participates in two distinct signaling pathways: a kinase-dependent activity that controls PKB/Akt as well as MAPK phosphorylation and contributes to TAC-induced cardiac remodeling.
TL;DR: This work describes a signaling mechanism linking an environmental sensor to ribosome biogenesis, and shows that regulation of RP gene transcription via TOR and PKA in yeast involves the Forkhead-like transcription factor FHL1 and the two cofactors IFH1 and CRF1.
TL;DR: Results suggest that the spherical AFM tip is large enough to measure the aggregate dynamic elastic modulus of cartilage, whereas the sharp AFMtip depicts the elastic properties of its fine structure.
TL;DR: Results suggest that the indirect effects of CO2 on plant and soil water relations may contribute substantially to experimentally induced CO2-effects, and also reflect local humidity conditions.
Abstract: Atmospheric CO2 enrichment may stimulate plant growth directly through (1) enhanced photosynthesis or indirectly, through (2) reduced plant water consumption and hence slower soil moisture depletion, or the combination of both. Herein we describe gas exchange, plant biomass and species responses of five native or semi-native temperate and Mediterranean grasslands and three semi-arid systems to CO2 enrichment, with an emphasis on water relations. Increasing CO2 led to decreased leaf conductance for water vapor, improved plant water status, altered seasonal evapotranspiration dynamics, and in most cases, periodic increases in soil water content. The extent, timing and duration of these responses varied among ecosystems, species and years. Across the grasslands of the Kansas tallgrass prairie, Colorado shortgrass steppe and Swiss calcareous grassland, increases in aboveground biomass from CO2 enrichment were relatively greater in dry years. In contrast, CO2-induced aboveground biomass increases in the Texas C3/C4 grassland and the New Zealand pasture seemed little or only marginally influenced by yearly variation in soil water, while plant growth in the Mojave Desert was stimulated by CO2 in a relatively wet year. Mediterranean grasslands sometimes failed to respond to CO2-related increased late-season water, whereas semiarid Negev grassland assemblages profited. Vegetative and reproductive responses to CO2 were highly varied among species and ecosystems, and did not generally follow any predictable pattern in regard to functional groups. Results suggest that the indirect effects of CO2 on plant and soil water relations may contribute substantially to experimentally induced CO2-effects, and also reflect local humidity conditions. For landscape scale predictions, this analysis calls for a clear distinction between biomass responses due to direct CO2 effects on photosynthesis and those indirect CO2 effects via soil moisture as documented here.
TL;DR: It is inferred that, in solution, the two DGC domains of a dimer align in a two-fold symmetric way to catalyze c-diGMP synthesis and sets an upper limit for the concentration of this second messenger in the cell.
Abstract: Recent discoveries suggest that a novel second messenger, bis-(3′→5′)-cyclic di-GMP (c-diGMP), is extensively used by bacteria to control multicellular behavior. Condensation of two GTP to the dinucleotide is catalyzed by the widely distributed diguanylate cyclase (DGC or GGDEF) domain that occurs in various combinations with sensory and/or regulatory modules. The crystal structure of the unorthodox response regulator PleD from Caulobacter crescentus, which consists of two CheY-like receiver domains and a DGC domain, has been solved in complex with the product c-diGMP. PleD forms a dimer with the CheY-like domains (the stem) mediating weak monomer–monomer interactions. The fold of the DGC domain is similar to adenylate cyclase, but the nucleotide-binding mode is substantially different. The guanine base is H-bonded to Asn-335 and Asp-344, whereas the ribosyl and α-phosphate moieties extend over the β2-β3-hairpin that carries the GGEEF signature motif. In the crystal, c-diGMP molecules are crosslinking active sites of adjacent dimers. It is inferred that, in solution, the two DGC domains of a dimer align in a two-fold symmetric way to catalyze c-diGMP synthesis. Two mutually intercalated c-diGMP molecules are found tightly bound at the stem–DGC interface. This allosteric site explains the observed noncompetitive product inhibition. We propose that product inhibition is due to domain immobilization and sets an upper limit for the concentration of this second messenger in the cell.