Showing papers by "University of Würzburg published in 2009"
TL;DR: This review considers current knowledge about the epidemiology and transmission of H. pylori, as well as the role of this infectious agent in the pathogenesis of upper gastrointestinal tract disease.
Abstract: H. pylori is one of the most common bacterial infections in human beings, and its discovery 20 years ago altered the diagnosis and treatment of gastroduodenal disease. This review considers current knowledge about the epidemiology and transmission of H. pylori, as well as the role of this infectious agent in the pathogenesis of upper gastrointestinal tract disease. Diagnostic approaches, indications for therapy, and measures of therapeutic efficacy are reviewed.
2,817 citations
Institut Gustave Roussy1, French Institute of Health and Medical Research2, University of Paris-Sud3, Icahn School of Medicine at Mount Sinai4, University of Texas Southwestern Medical Center5, Thomas Jefferson University6, McMaster University7, University of Massachusetts Medical School8, LSU Health Sciences Center New Orleans9, Roswell Park Cancer Institute10, Boston Children's Hospital11, University of Gothenburg12, University of Freiburg13, Buck Institute for Research on Aging14, University of California, San Francisco15, Centre national de la recherche scientifique16, National Institutes of Health17, Technion – Israel Institute of Technology18, University of Leicester19, University of Chieti-Pescara20, Istituto Superiore di Sanità21, University of North Carolina at Chapel Hill22, New York University23, University of Pennsylvania24, Howard Hughes Medical Institute25, Yale University26, University of Ulm27, University of Burgundy28, Aix-Marseille University29, Pasteur Institute30, University of Strasbourg31, Johns Hopkins University32, University of Zurich33, University of Tokyo34, Weizmann Institute of Science35, University of Michigan36, University College London37, Duke University38, University of Graz39, Ghent University40, Trinity College, Dublin41, University of Amsterdam42, University of Lyon43, University of Rome Tor Vergata44, University of Göttingen45, Stony Brook University46, Kyoto University47, Merck & Co.48, Austrian Academy of Sciences49, National University of Singapore50, University of Chicago51, Royal College of Surgeons in Ireland52, La Trobe University53, University of Buenos Aires54, University of Padua55, University of Lisbon56, University of Cambridge57, University of Würzburg58, University of Geneva59, University of Bern60, Rockefeller University61, University of Lausanne62, Osaka University63, University of California, San Diego64, University of Glasgow65, Harvard University66, Karolinska Institutet67
TL;DR: A nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls is provided and the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells is emphasized.
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells
2,218 citations
University of Helsinki1, Mexican Social Security Institute2, University of New Mexico3, National Taiwan University4, Central Manchester University Hospitals NHS Foundation Trust5, State University of Campinas6, Telethon Institute for Child Health Research7, Chulalongkorn University8, University of the Philippines9, Royal Women's Hospital10, Queen Mary University of London11, University of Alberta12, University of Manitoba13, University of Würzburg14, Katholieke Universiteit Leuven15, Hull York Medical School16, GlaxoSmithKline17, University of Tampere18
TL;DR: The HPV- 16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes.
1,569 citations
TL;DR: A new, free software is introduced calculating a large spectrum of network indices, visualizing bipartite networks and generating null models, and enables ecologists to readily contrast their findings with null model expectations for many different questions, thus separating statistical inevitability from ecological process.
Abstract: Many analyses of ecological networks in recent years have introduced new indices to describe network properties. As a consequence, tens of indices are available to address similar questions, differing in specific detail, sensitivity in detecting the property in question, and robustness with respect to network size and sampling intensity. Furthermore, some indices merely reflect the number of species participating in a network, but not their interrelationship, requiring a null model approach. Here we introduce a new, free software calculating a large spectrum of network indices, visualizing bipartite networks and generating null models. We use this tool to explore the sensitivity of 26 network indices to network dimensions, sampling intensity and singleton observations. Based on observed data, we investigate the interrelationship of these indices, and show that they are highly correlated, and heavily influenced by network dimensions and connectance. Finally, we re-evaluate five common hypotheses about network properties, comparing 19 pollination networks with three differently complex null models: 1. The number of links per species ("degree") follow (truncated) power law distributions. 2. Generalist pollinators interact with specialist plants, and vice versa (dependence asymmetry). 3. Ecological networks are nested. 4. Pollinators display complementarity, owing to specialization within the network. 5. Plant-pollinator networks are more robust to extinction than random networks. Our results indicate that while some hypotheses hold up against our null models, others are to a large extent understandable on the basis of network size, rather than ecological interrelationships. In particular, null model pattern of dependence asymmetry and robustness to extinction are opposite to what current network paradigms suggest. Our analysis, and the tools we provide, enables ecologists to readily contrast their findings with null model expectations for many different questions, thus separating statistical inevitability from ecological process.
1,222 citations
TL;DR: A dual-systems perspective of impulse and self-control is outlined and a framework for the prediction of self- control outcomes is suggested that combines three elements that may enable a more precise prediction ofSelf-control outcomes than they do when studied in isolation.
Abstract: Though human beings embody a unique ability for planned behavior, they also often act impulsively. This insight may be important for the study of self-control situations in which people are torn between their long-term goals to restrain behavior and their immediate impulses that promise hedonic fulfillment. In the present article, we outline a dual-systems perspective of impulse and self-control and suggest a framework for the prediction of self-control outcomes. This framework combines three elements that, considered jointly, may enable a more precise prediction of self-control outcomes than they do when studied in isolation: impulsive precursors of behavior, reflective precursors, and situational or dispositional boundary conditions. The theoretical and practical utility of such an approach is demonstrated by drawing on recent evidence from several domains of self-control such as eating, drinking, and sexual behavior.
1,055 citations
Queen Mary University of London1, Pompeu Fabra University2, Spanish National Research Council3, University of Würzburg4, University of Leeds5, Helmholtz Centre for Environmental Research - UFZ6, University of Birmingham7, Temuco Catholic University8, Alfred Wegener Institute for Polar and Marine Research9, University of York10, Aarhus University11, Imperial College London12, University of Sheffield13
TL;DR: A number of 'dead ends' and 'fruitful avenues' are suggested for future research into ecological networks by suggesting a new catalogue of evermore complete, taxonomically resolved, and quantitative data.
Abstract: Summary 1. A fundamental goal of ecological network research is to understand how the complexity observed in nature can persist and how this affects ecosystem functioning. This is essential for us to be able to predict, and eventually mitigate, the consequences of increasing environmental perturbations such as habitat loss, climate change, and invasions of exotic species. 2. Ecological networks can be subdivided into three broad types: ‘traditional’ food webs, mutualistic networks and host‐parasitoid networks. There is a recent trend towards cross-comparisons among network types and also to take a more mechanistic, as opposed to phenomenological, perspective. For example, analysis of network configurations, such as compartments, allows us to explore the role of co-evolution in structuring mutualistic networks and host‐parasitoid networks, and of body size in food webs. 3. Research into ecological networks has recently undergone a renaissance, leading to the production of a new catalogue of evermore complete, taxonomically resolved, and quantitative data. Novel topological patterns have been unearthed and it is increasingly evident that it is the distribution of interaction strengths and the configuration of complexity, rather than just its magnitude, that governs network stability and structure. 4. Another significant advance is the growing recognition of the importance of individual traits and behaviour: interactions, after all, occur between individuals. The new generation of high-quality networks is now enabling us to move away from describing networks based on species-averaged data and to start exploring patterns based on individuals. Such refinements will enable us to address more general ecological questions relating to foraging theory and the recent metabolic theory of ecology. 5. We conclude by suggesting a number of ‘dead ends’ and ‘fruitful avenues’ for future research into ecological networks.
867 citations
TL;DR: This critical review provides an overview on the formation of pi-stacks of functional dyes in solution, aiming to acquaint young researchers with this topical research field and to stimulate further advance in supramolecular dye chemistry.
Abstract: This critical review provides an overview on the formation of π-stacks of functional dyes in solution, aiming to acquaint young researchers with this topical research field and to stimulate further advance in supramolecular dye chemistry. Different mathematical models that have been proposed and applied for the description of aggregation equilibria of π-systems in solution are discussed. The factors that have significant impact on the structural features of aggregates and the thermodynamics of π–π stacking such as electrostatic interactions, size and geometry of the dye molecules are covered in this review. A comparison of the binding strength is made for different classes of functional π-conjugated systems, from simple benzene to more extended polycyclic hydrocarbon molecules, including triphenylenes and hexabenzocoronenes, heteroaromatic porphyrins and phthalocyanines, quadrupolar naphthalene and perylene bisimides, dipolar or even zwitterionic merocyanines and squaraines, and some macrocyclic dyes. Solvent effects on binding constants are analysed by linear free energy relationships with various solvent polarity scales (98 references with multiple entries).
852 citations
TL;DR: It is demonstrated that SLAC1 represents the slow, deactivating, weak voltage-dependent anion channel of guard cells controlled by phosphorylation/dephosphorylation.
Abstract: In response to drought stress the phytohormone ABA (abscisic acid) induces stomatal closure and, therein, activates guard cell anion channels in a calcium-dependent as well as-independent manner. Two key components of the ABA signaling pathway are the protein kinase OST1 (open stomata 1) and the protein phosphatase ABI1 (ABA insensitive 1). The recently identified guard cell anion channel SLAC1 appeared to be the key ion channel in this signaling pathway but remained electrically silent when expressed heterologously. Using split YFP assays, we identified OST1 as an interaction partner of SLAC1 and ABI1. Upon coexpression of SLAC1 with OST1 in Xenopus oocytes, SLAC1-related anion currents appeared similar to those observed in guard cells. Integration of ABI1 into the SLAC1/OST1 complex, however, prevented SLAC1 activation. Our studies demonstrate that SLAC1 represents the slow, deactivating, weak voltage-dependent anion channel of guard cells controlled by phosphorylation/dephosphorylation.
756 citations
TL;DR: The data identify polyP as a new class of mediator having fundamental roles in platelet-driven proinflammatory and procoagulant disorders, including Hermansky-Pudlak Syndrome patients, who lack platelet polyP.
737 citations
Mayo Clinic1, Spanish National Research Council2, Masaryk University3, University of Turin4, Catholic Medical Center5, Emory University6, Alexandra Hospital7, Memorial Sloan Kettering Cancer Center8, University of Würzburg9, University of Arkansas for Medical Sciences10, University of Bologna11, Free University of Berlin12, Royal Prince Alfred Hospital13, Lund University14, Cedars-Sinai Medical Center15
TL;DR: Consensus guidelines for the use of the serum immunoglobulin-free light chain assay are provided, in the diagnosis and management of clonal PCD.
Abstract: The serum immunoglobulin-free light chain (FLC) assay measures levels of free κ and λ immunoglobulin light chains. There are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL). Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL, oligosecretory myeloma and nearly two-thirds of patients who had previously been deemed to have non-secretory myeloma. In AL patients, serial FLC measurements outperform PEL and immunofixation. In oligosecretory myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. In contrast, there are no data to support using FLC assay in place of 24-h urine PEL for monitoring or for serial measurements in PCD with measurable disease by serum or urine PEL. This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD.
699 citations
TL;DR: The data confirm that the quantum transport through the (helical) edge channels is dissipationless and that the contacts lead to equilibration between the counterpropagating spin states at the edge, which agree quantitatively with the theory of the quantum spin Hall effect.
Abstract: Nonlocal transport through edge channels holds great promise for low-power information processing. However, edge channels have so far only been demonstrated to occur in the quantum Hall regime, at high magnetic fields. We found that mercury telluride quantum wells in the quantum spin Hall regime exhibit nonlocal edge channel transport at zero external magnetic field. The data confirm that the quantum transport through the (helical) edge channels is dissipationless and that the contacts lead to equilibration between the counterpropagating spin states at the edge. The experimental data agree quantitatively with the theory of the quantum spin Hall effect. The edge channel transport paves the way for a new generation of spintronic devices for low-power information processing.
TL;DR: Myocardial fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe aortic stenosis and was not reversible after AVR over the 9 months of follow-up examined in this study.
Abstract: Background In this prospective follow-up study, the effect of myocardial fibrosis on myocardial performance in symptomatic severe aortic stenosis was investigated, and the impact of fibrosis on clinical outcome after aortic valve replacement (AVR) was estimated. Methods and results Fifty-eight consecutive patients with isolated symptomatic severe aortic stenosis underwent extensive baseline characterization before AVR. Standard and tissue Doppler echocardiography and cardiac magnetic resonance imaging (late-enhancement imaging for replacement fibrosis) were performed at baseline and 9 months after AVR. Endomyocardial biopsies were obtained intraoperatively to determine the degree of myocardial fibrosis. Patients were analyzed according to the severity of interstitial fibrosis in cardiac biopsies (severe, n=21; mild, n=15; none, n=22). The extent of histologically determined cardiac fibrosis at baseline correlated closely with New York Heart Association functional class and markers of longitudinal systolic function (all P Conclusions Myocardial fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe aortic stenosis and was not reversible after AVR over the 9 months of follow-up examined in this study. Because markers of longitudinal systolic function appear to indicate sensitively both the severity of myocardial fibrosis and the clinical outcome, they may prove valuable for preoperative risk assessment in patients with aortic stenosis.
TL;DR: The syntheses and comprehensive characterization of 14 organic semiconductors based on perylene bisimide (PBI) dyes that are equipped with up to four halogen substituent in the bay area of the perylene core and five different highly fluorinated imide substituents are described, making them suitable for a wide range of practical applications.
Abstract: The syntheses and comprehensive characterization of 14 organic semiconductors based on perylene bisimide (PBI) dyes that are equipped with up to four halogen substituents in the bay area of the perylene core and five different highly fluorinated imide substituents are described. The influence of the substituents on the LUMO level and the solid state packing of PBIs was examined by cyclic voltammetry and single crystal structure analyses of seven PBI derivatives, respectively. Top-contact/bottom-gate organic thin film transistor (OTFT) devices were constructed by vacuum deposition of these PBIs on SiO2 gate dielectrics that had been pretreated with n-octadecyl triethoxysilane in vapor phase (OTS-V) or solution phase (OTS-S). The electrical characterization of all devices was accomplished in a nitrogen atmosphere as well as in air, and the structural features of thin films were explored by grazing incidence X-ray diffraction (GIXD) and atomic force microscopy (AFM). Several of those PBIs that bear only hydr...
University of Nebraska Medical Center1, Carlos III Health Institute2, University of Oxford3, University of Oslo4, Oregon Health & Science University5, National Institutes of Health6, University of British Columbia7, University of Würzburg8, Bosch9, University of Arizona10, University of Barcelona11, Emory University12
TL;DR: A new algorithm using GCET1, CD10, BCL6, MUM1, and FOXP1 was derived that closely approximated the GEP classification with 93% concordance and will facilitate risk stratification of DLBCL patients and futureDLBCL research using archival materials.
Abstract: Purpose: Hans and coworkers previously developed an immunohistochemical algorithm with ∼80% concordance with the gene expression profiling (GEP) classification of diffuse large B-cell lymphoma (DLBCL) into the germinal center B-cell–like (GCB) and activated B-cell–like (ABC) subtypes. Since then, new antibodies specific to germinal center B-cells have been developed, which might improve the performance of an immunostain algorithm. Experimental Design: We studied 84 cases of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP)–treated DLBCL (47 GCB, 37 ABC) with GCET1, CD10, BCL6, MUM1, FOXP1, BCL2, MTA3, and cyclin D2 immunostains, and compared different combinations of the immunostaining results with the GEP classification. A perturbation analysis was also applied to eliminate the possible effects of interobserver or intraobserver variations. A separate set of 63 DLBCL cases treated with rituximab plus CHOP (37 GCB, 26 ABC) was used to validate the new algorithm. Results: A new algorithm using GCET1, CD10, BCL6, MUM1, and FOXP1 was derived that closely approximated the GEP classification with 93% concordance. Perturbation analysis indicated that the algorithm was robust within the range of observer variance. The new algorithm predicted 3-year overall survival of the validation set [GCB (87%) versus ABC (44%); P Conclusion: Our new algorithm is significantly more accurate than the Hans9 algorithm and will facilitate risk stratification of DLBCL patients and future DLBCL research using archival materials. (Clin Cancer Res 2009;15(17):5494–502)
TL;DR: Different in vitro collagen-based cell invasion models are evaluated, employing either pepsinized or non-pepsinized collagen extracts, and their structure to connective tissue in vivo is compared, and it is shown that, depending on the collagen source, in vitro models yield homogeneous fibrillar texture with a quite narrow range of pore size variation, whereas all in vivo scaffolds comprise a range from low- to high-density fibrilar networks and heterogeneous p
TL;DR: Adrenocortical carcinoma (ACC) is a rare malignancy, and it was only in 2004 that the International Union Against Cancer (UICC) defined TNM criteria and published the first staging classification.
Abstract: BACKGROUND:
Adrenocortical carcinoma (ACC) is a rare malignancy, and it was only in 2004 that the International Union Against Cancer (UICC) defined TNM criteria and published the first staging classification. However, to date, the prognostic value of the proposed classification has not been evaluated.
METHODS:
The German ACC Registry comprising 492 patients was searched for patients who were diagnosed between 1986 and 2007 with detailed information on primary diagnosis and a minimum follow-up of 6 months. Patients were assigned to UICC tumor stage, and disease-specific survival (DSS) was assessed. In addition, the contribution of potential risk factors for DSS was evaluated.
RESULTS:
In total, 416 patients with a mean follow-up of 36 months met the inclusion criteria (stage I, n = 23 patients; stage II, n = 176 patients; stage III, n = 67 patients; stage IV, n = 150 patients). Kaplan-Meier analysis revealed a stage-dependent DSS. However, DSS in patients with stage II ACC did not differ significantly from DSS in patients with stage III ACC (hazard ratio, 1.38; 95% confidence interval, 0.89-2.16). Furthermore, patients who had stage IV ACC without distant metastases had an improved DSS compared with patients who had metastatic disease (P = .004). An analysis of different potential risk factors for defining stage III ACC revealed important roles in DSS for tumor infiltration in surrounding tissue, venous tumor thrombus (VTT), and positive lymph nodes; whereas tumor invasion in adjacent organs carried a prognosis similar to that of infiltration in surrounding tissue only.
CONCLUSIONS:
The 2004 UICC staging classification for ACC has significant limitations. On the basis of the current analysis, a revised classification with superior prognostic accuracy is proposed (the European Network for the Study of Adrenal Tumors classification). In this system, stage III ACC is defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or VTT; and stage IV ACC is restricted to patients with distant metastasis. Cancer 2009. © 2009 American Cancer Society.
TL;DR: A paradigm shift in the treatment of selected B-cell malignancies is anticipated, moving from targeting primarily the malignant cells toward combining cytotoxic drugs with agents that interfere with the microenvironment's proactive role.
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TL;DR: In this paper, the authors found that the positive impact of sustainability orientation vanishes with business experience, and suggested measures to nourish an evidently existing potential for sustainable entrepreneurship, based on survey data collected from students and alumni of a German technical university.
Abstract: Do individuals who are concerned by issues of sustainability also exhibit strong entrepreneurial intentions? Given that existing imperfections in the market create numerous opportunities for entrepreneurship connected with sustainable development, adding individual sustainability orientation to models of entrepreneurial intention could increase their explanatory power. Based on survey data collected from students and alumni of a German technical university, we provide evidence that entering sustainability orientation into the equation is actually meaningful. However, our findings suggest that the positive impact of sustainability orientation vanishes with business experience. Consequently, we suggest measures to nourish an evidently existing potential for sustainable entrepreneurship.
TL;DR: On the basis of pH-tunable spectral overlap of donors and acceptors, the donor-loaded polymerized vesicles display pH-dependent fluorescence resonance energy transfer from the encapsulated donors to the bilayer dye membrane, providing ultrasensitive pH information on their aqueous environment with fluorescence colour changes covering the whole visible light range.
Abstract: Water-soluble, self-assembled nanocapsules composed of a functional bilayer membrane and enclosed guest molecules can provide smart (that is, condition responsive) sensors for a variety of purposes. Owing to their outstanding optical and redox properties, perylene bisimide chromophores are interesting building blocks for a functional bilayer membrane in a water environment. Here, we report water-soluble perylene bisimide vesicles loaded with bispyrene-based energy donors in their aqueous interior. These loaded vesicles are stabilized by in situ photopolymerization to give nanocapsules that are stable over the entire aqueous pH range. On the basis of pH-tunable spectral overlap of donors and acceptors, the donor-loaded polymerized vesicles display pH-dependent fluorescence resonance energy transfer from the encapsulated donors to the bilayer dye membrane, providing ultrasensitive pH information on their aqueous environment with fluorescence colour changes covering the whole visible light range. At pH 9.0, quite exceptional white fluorescence could be observed for such water-soluble donor-loaded perylene vesicles.
TL;DR: This review shows that researchers of plant-animal mutualisms have made substantial progress in the understanding of the processes behind the patterns observed in mutualistic networks, but are still far from a thorough, integrative mechanistic understanding.
TL;DR: A new noninvasive brain-actuated wheelchair that relies on a P300 neurophysiological protocol and automated navigation, showing a great adaptation as well as a high robustness and low variability of the system.
Abstract: This paper describes a new noninvasive brain-actuated wheelchair that relies on a P300 neurophysiological protocol and automated navigation. When in operation, the user faces a screen displaying a real-time virtual reconstruction of the scenario and concentrates on the location of the space to reach. A visual stimulation process elicits the neurological phenomenon, and the electroencephalogram (EEG) signal processing detects the target location. This location is transferred to the autonomous navigation system that drives the wheelchair to the desired location while avoiding collisions with obstacles in the environment detected by the laser scanner. This concept gives the user the flexibility to use the device in unknown and evolving scenarios. The prototype was validated with five healthy participants in three consecutive steps: screening (an analysis of three different groups of visual interface designs), virtual-environment driving, and driving sessions with the wheelchair. On the basis of the results, this paper reports the following evaluation studies: 1) a technical evaluation of the device and all functionalities; 2) a users' behavior study; and 3) a variability study. The overall result was that all the participants were able to successfully operate the device with relative ease, thus showing a great adaptation as well as a high robustness and low variability of the system.
TL;DR: Real-time monitoring of G-protein-coupled receptor (GPCR) signaling in native cells suggests that the receptor for thyroid stimulating hormone remains active after internalization, challenging the current model for GPCR signaling.
Abstract: G-protein–coupled receptors (GPCRs) are generally thought to signal to second messengers like cyclic AMP (cAMP) from the cell surface and to become internalized upon repeated or prolonged stimulation. Once internalized, they are supposed to stop signaling to second messengers but may trigger nonclassical signals such as mitogen-activated protein kinase (MAPK) activation. Here, we show that a GPCR continues to stimulate cAMP production in a sustained manner after internalization. We generated transgenic mice with ubiquitous expression of a fluorescent sensor for cAMP and studied cAMP responses to thyroid-stimulating hormone (TSH) in native, 3-D thyroid follicles isolated from these mice. TSH stimulation caused internalization of the TSH receptors into a pre-Golgi compartment in close association with G-protein αs-subunits and adenylyl cyclase III. Receptors internalized together with TSH and produced downstream cellular responses that were distinct from those triggered by cell surface receptors. These data suggest that classical paradigms of GPCR signaling may need revision, as they indicate that cAMP signaling by GPCRs may occur both at the cell surface and from intracellular sites, but with different consequences for the cell.
TL;DR: Several major enhancements have been included into VBFNLO, including the implementation of anomalous gauge boson couplings has been extended to all triboson and VBF $VVjj processes, and semileptonic decay modes of the vector bosons are now available for many processes.
TL;DR: It is found that cGMP passes through gap junctions into the oocyte, where it inhibits the hydrolysis of cAMP by the phosphodiesterase PDE3A, and causes a decrease in oocyte cAMP, leading to the resumption of meiosis.
Abstract: Mammalian oocytes are arrested in meiotic prophase by an inhibitory signal from the surrounding somatic cells in the ovarian follicle. In response to luteinizing hormone (LH), which binds to receptors on the somatic cells, the oocyte proceeds to second metaphase, where it can be fertilized. Here we investigate how the somatic cells regulate the prophase-to-metaphase transition in the oocyte, and show that the inhibitory signal from the somatic cells is cGMP. Using FRET-based cyclic nucleotide sensors in follicle-enclosed mouse oocytes, we find that cGMP passes through gap junctions into the oocyte, where it inhibits the hydrolysis of cAMP by the phosphodiesterase PDE3A. This inhibition maintains a high concentration of cAMP and thus blocks meiotic progression. LH reverses the inhibitory signal by lowering cGMP levels in the somatic cells (from ∼2 μM to ∼80 nM at 1 hour after LH stimulation) and by closing gap junctions between the somatic cells. The resulting decrease in oocyte cGMP (from ∼1 μM to ∼40 nM) relieves the inhibition of PDE3A, increasing its activity by ∼5-fold. This causes a decrease in oocyte cAMP (from ∼700 nM to ∼140 nM), leading to the resumption of meiosis.
TL;DR: This review summarizes the current knowledge of platelet Ca2+ homeostasis with a focus on the newly identified Ca2- entry mechanisms.
TL;DR: Treatment of Fabry cardiomyopathy with recombinant α-galactosidase A should best be started before myocardial fibrosis has developed to achieve long-term improvement in myocardIAL morphology and function and exercise capacity.
Abstract: Background— Enzyme replacement therapy with recombinant α-galactosidase A reduces left ventricular hypertrophy and improves regional myocardial function in patients with Fabry disease during short-term treatment. Whether enzyme replacement therapy is effective in all stages of Fabry cardiomyopathy during long-term follow-up is unknown. Methods and Results— We studied 32 Fabry patients over a period of 3 years regarding disease progression and clinical outcome under enzyme replacement therapy. Regional myocardial fibrosis was assessed by magnetic resonance imaging late-enhancement technique. Echocardiographic myocardial mass was calculated with the Devereux formula, and myocardial function was quantified by ultrasonic strain-rate imaging. In addition, exercise capacity was measured by bicycle stress test. All measurements were repeated at yearly intervals. At baseline, 9 patients demonstrated at least 2 fibrotic left ventricular segments (severe myocardial fibrosis), 11 had 1 left ventricular segment affec...
University of Cambridge1, Monash University2, Centre national de la recherche scientifique3, University of Bonn4, Harish-Chandra Research Institute5, University of Paris6, University of Turin7, Center for Theoretical Studies, University of Miami8, KEK9, University of Barcelona10, Spanish National Research Council11, University of Montpellier12, CERN13, Stanford University14, University of Edinburgh15, Fermilab16, ETH Zurich17, University of Southampton18, University of Zaragoza19, University of Würzburg20, Moscow State University21, Durham University22, Sapienza University of Rome23, Paul Scherrer Institute24
TL;DR: Extensions of the conventions of the first SLHA are proposed to include various generalisations: the minimal supersymmetric standard model with violation of CP, R-parity, and flavour, as well as the simplest next-to-minimal model.
TL;DR: The function of Bruchpilot seems responsible for effectively clustering Ca2+ channels beneath the T-bar density late in a protracted AZ formation process, potentially through a direct molecular interaction with intracellular Ca 2+ channel domains.
Abstract: Synaptic vesicles fuse at active zone (AZ) membranes where Ca2+ channels are clustered and that are typically decorated by electron-dense projections. Recently, mutants of the Drosophila melanogaster ERC/CAST family protein Bruchpilot (BRP) were shown to lack dense projections (T-bars) and to suffer from Ca2+ channel–clustering defects. In this study, we used high resolution light microscopy, electron microscopy, and intravital imaging to analyze the function of BRP in AZ assembly. Consistent with truncated BRP variants forming shortened T-bars, we identify BRP as a direct T-bar component at the AZ center with its N terminus closer to the AZ membrane than its C terminus. In contrast, Drosophila Liprin-α, another AZ-organizing protein, precedes BRP during the assembly of newly forming AZs by several hours and surrounds the AZ center in few discrete punctae. BRP seems responsible for effectively clustering Ca2+ channels beneath the T-bar density late in a protracted AZ formation process, potentially through a direct molecular interaction with intracellular Ca2+ channel domains.
TL;DR: In this paper, the authors analyzed the crying patterns of 30 French and 30 German newborns with respect to their melody and intensity contours, and found that the French group preferentially produced cries with a rising melody contour, whereas the German group preferred to produce falling contours.
TL;DR: The present study describes a new tool for the delimitation and identification of the internal transcribed spacer 2 (ITS2) based on hidden Markov models (HMMs) and verifies annotations by comparison to a conserved structural motif in the 5.8S/28S rRNA regions.