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Prostaglandin E2 is the major prostaglandin involved in colorectal carcinogenesis. The biosynthesis of prostaglandin E2 is accomplished by several terminal prostaglandin E synthases through catalytical conversion of the cyclooxygenase product prostaglandin H2. Among the known terminal prostaglandin E synthases, microsomal prostaglandin E synthase type 1 and type 2 were found to be overexpressed in colorectal cancer, however the role and regulation of these enzymes in this tumor entity are yet not fully understood. Here we report that the cyclopentenone prostaglandins 15-deoxy-D12,14-prostaglandin J2 and prostaglandin A2, which have been shown to modulate cell growth and neoplasia, selectively down-regulate microsomal prostaglandin E synthase type 2 mRNA and protein expression in the human colorectal carcinoma cell lines Caco-2 and HCT 116. This effect appeared to be PPARgamma independent and was not found to require G-protein-coupled receptor activation. Instead, inhibition of microsomal prostaglandin E synthase type 2 by cyclopentenone prostaglandins may be mediated by covalent binding of the cyclopentenone ring to cysteine residues on signalling molecules or via a redox-dependent mechanism. Inhibition of microsomal prostaglandin E synthase type 2 was subsequently followed by decreased prostaglandin E synthase activity, which in turn contributed at least in part to the anti-proliferative action of cyclopentenone prostaglandins in HCT 116 cells. Collectively, these data unravel a novel mechanism for the growth-inhibitory effects of cyclopentenone prostaglandins and expose microsomal prostaglandin E synthase type 2 as a new potential target for pharmacological intervention in the treatment of colorectal cancer.
This thesis presents a model for the dynamical description of deconfined quark matter created in ultra-relativistic heavy ion collisions, treating quarks and antiquarks as classical point particles subject to a colour-dependent, Cornell-type potential interaction. The model provides a dynamical handle for hadronization via the recombination of quarks and antiquarks in colour neutral clusters. Gluons are not included explicitly in the model,but are described in an effective manner by the means of the potential interaction. The model includes four different quark flavours (up, down, strange and charm) and uses current masses for the quarks. The dynamical evolution of a system of colour charges subject to the Hamiltonian equations of motion of the model yields the formation of colour neutral clusters of quarks and antiquarks, which are subject only to a small remaining interaction, the strong interquark potential notwithstanding. These clusters can be mapped onto hadrons and hadronic resonances. Thus, the model allows a dynamical description of quarks degrees of freedom in heavy ion collisions, including a recombination scheme for hadronization. The thermal properties of the model turn pout to be very satisfying. The model shows a transition from a confining phase to a deconfined phase with rising temperature, going hand in hand with a softest point in the equation of state and a rise of energy density and pressure to the Stefan-Boltzmann limit of a gas of quarks and antiquarks. Moreover, the potential interaction is screened in the deconfined phase. For the dynamical description of ultra-relativistic heavy ion collision, the qMD model is coupled to UrQMD as a generator for its initial conditions. In this way, a fully dynamical description of the expansion and hadronization of the fireball created in such collisions can be achieved. Non-equilibrium aspects of the expansion dynamics and hadronization by recombination of quarks and antiquarks are discussed in detail, and a comparison with experimental data of collisions at the CERN-SPS is presented. The big advantage of the qMD model is the possibility to study cluster formation, including exotic clusters, and fluctuations in a dynamical manner. As an example, event-by-event fluctuations in electric charge are studied. Such fluctuations have been proposed as a clear criterion to distinguish a deconfined system from a hadrons gas. However, experimental data show hadron gas fluctuation measures even at RHIC, where deconfinement is taken for granted. We will see how the dynamics of quark recombination washes out the quark-gluon plasma signal in the fluctuation criterion. Moreover, we will discuss briefly the problem of entropy at recombination. In a second application, the formation of exotic hadronic clusters, larger than usual mesons and baryons, is studied. Such clusters could provide new measures for the thermalization and homogenization of a deconfined gas of colour charges. Moreover, number estimates for exotic clusters from recombination are considerably lower than corresponding predictions from thermal models, providing a clear difference between statistical hadronization and hadronization via quark recombination. A detailed analysis is provided for pentaquark candidates such as the Theta-Plus. It turns out that the distribution of exotic states over strangeness, isospin, and spin could provide a sensitive measure for thermalization and decorrelation in the deconfined quark phase, if it could be measured.
Nucleotide-binding domains (NBDs), roughly 27 kDa in size, are conservative components of the large family of ABC (ATP-binding cassette) transporters, which includes importers, exporters, and receptors. NBDs or ABC-ATPases supply energy for the translocation of a vast variety of substrates across biological membranes. Despite their hydrophilic sequence, many NBDs tend to aggregate and precipitate in solution upon isolation from the complete transporter. The conditions stabilizing an extremely labile NBD component of the E.coli HlyA transporter, HlyB-NBD, were developed. As a result, the pure highly concentrated enzyme was protected from precipitation for months that allowed screening of the unlimited crystallization conditions in the presence of different substrates and performance of the reproducible functional assays. HlyB-NBD was characterized in regard to its uncoupled ATPase activity, oligomeric state, and stability in solution. Comparative analysis of protein stability and ATPase activity in various buffers suggested an inverse relationship between the two. Kinetic analysis of ATPase activity revealed ATP-induced protein dimerization. Gel-filtration experiments with the wild type protein and H662A-mutant of HlyB-NBD provided further evidence of protein dimerization in the presence of ATP. The crystal structures in post- and pre-hydrolysis nucleotide-bound states of HlyB-NBD were determined at 1.6Å and 2.5Å resolution, respectively. While the hydrolytically deficient H662A mutant of HlyB-NBD was crystallized as a stable dimer in the presence of ATP or ATP-Mg2+, with two nucleotide molecules sandwiched between the two monomers, the same protein was shown to be a monomer in the ADP-loaded state. The wild type protein failed to develop crystals with bound ATP, yet formed ADP-bound crystals identical to those of the H662A-mutant. The X-ray structures of HlyB-NBD in various states of the hydrolytic cycle and the functional studies of the enzyme have provided an opportunity to characterize enzyme-substrate complexes and protein-protein interactions between the NBD subunits in great detail. Comparison of the nucleotide-free, the ADP-, and the ATP-loaded states revealed oligomeric and conformational changes of the protein upon substrate binding and resulted in a molecular picture of the catalytic cycle. The correlated results of the structural and functional investigations of HlyB-NBD are discussed with relation to the mechanism of action of ABC transporters.
We present a biologically-inspired system for real-time, feed-forward object recognition in cluttered scenes. Our system utilizes a vocabulary of very sparse features that are shared between and within different object models. To detect objects in a novel scene, these features are located in the image, and each detected feature votes for all objects that are consistent with its presence. Due to the sharing of features between object models our approach is more scalable to large object databases than traditional methods. To demonstrate the utility of this approach, we train our system to recognize any of 50 objects in everyday cluttered scenes with substantial occlusion. Without further optimization we also demonstrate near-perfect recognition on a standard 3-D recognition problem. Our system has an interpretation as a sparsely connected feed-forward neural network, making it a viable model for fast, feed-forward object recognition in the primate visual system.
We demonstrate the occurrence of canonical suppression associated with the conservation of an U(1)-charge in current transport models. For this study a pion gas is simulated within two different transport approaches by incorporating inelastic and volume-limited collisions pi pi leftrightarrow K bar-K for the production of kaon pairs. Both descriptions can dynamically account for the suppression in the yields of rare strange particles in a limited box, being in full accordance with a canonical statistical description.
The transverse momentum dependence of the anisotropic flow v_2 for pi, K, nucleon, Lambda, Xi and Omega is studied for Au+Au collisions at sqrt s_NN = 200 GeV within two independent string-hadron transport approaches (RQMD and UrQMD). Although both models reach only 60% of the absolute magnitude of the measured v_2, they both predict the particle type dependence of v_2, as observed by the RHIC experiments: v_2 exhibits a hadron-mass hierarchy (HMH) in the low p_T region and a number-of-constituent-quark (NCQ) dependence in the intermediate p_T region. The failure of the hadronic models to reproduce the absolute magnitude of the observed v_2 indicates that transport calculations of heavy ion collisions at RHIC must incorporate interactions among quarks and gluons in the early, hot and dense phase. The presence of an NCQ scaling in the string-hadron model results suggests that the particle-type dependencies observed in heavy-ion collisions at intermediate p_T are related to the hadronic cross sections in vacuum rather than to the hadronization process itself, as suggested by quark recombination models.
In November 2005, a survey was begun of the wells in and around Hagia Sophia Church in Istanbul. The long-term goal of the survey is the understanding of the function of the tunnels and the water systems used for Hagia Sophia and its surroundings during the Byzantine and the Ottoman periods. Alternate research methods, such as geophysical research, will be used in future surveys. The 2005 survey examined the channels that run from under the narthex and continue northwards and the southwards of the building as well as channels that run towards the atrium, hippodrome, and garden in the north. The survey resulted in the first photos of the well-bottoms in the history of Hagia Sophia.
Gene trapping is a method of generating murine embryonic stem (ES) cell lines containing insertional mutations in known and novel genes. A number of international groups have used this approach to create sizeable public cell line repositories available to the scientific community for the generation of mutant mouse strains. The major gene trapping groups worldwide have recently joined together to centralize access to all publicly available gene trap lines by developing a user-oriented Website for the International Gene Trap Consortium (IGTC). This collaboration provides an impressive public informatics resource comprising ~45 000 well-characterized ES cell lines which currently represent ~40% of known mouse genes, all freely available for the creation of knockout mice on a non-collaborative basis. To standardize annotation and provide high confidence data for gene trap lines, a rigorous identification and annotation pipeline has been developed combining genomic localization and transcript alignment of gene trap sequence tags to identify trapped loci. This information is stored in a new bioinformatics database accessible through the IGTC Website interface. The IGTC Website (www.genetrap.org) allows users to browse and search the database for trapped genes, BLAST sequences against gene trap sequence tags, and view trapped genes within biological pathways. In addition, IGTC data have been integrated into major genome browsers and bioinformatics sites to provide users with outside portals for viewing this data. The development of the IGTC Website marks a major advance by providing the research community with the data and tools necessary to effectively use public gene trap resources for the large-scale characterization of mammalian gene function.
The analysis of doxorubicin-loaded poly(butyl cyanoacrylate) nanoparticles in in vitro glioma models
(2005)
The use of doxorubicin for the treatment of glioma tumours would be an important approach in the chemotherapy treatment since doxorubicin is a very effective neoplastic agent. However, one problem faced by the use of doxorubicin for the treatment of brain tumours is the fact that doxorubicin is a substrate of an efflux pump protein, P-glycoprotein (P-gp), which is located on the luminal side of the brain capillary endothelium and in many tumour cells, which acts pumping out of the cell such substrate, and blocking its transport into the cell. A strategy to enhance the doxorubicin delivery into the brain would be the use of nanoparticles. This work showed, that the treatment of doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles decreased the viability of the three glioma cell lines, the GS-9L, the RG-2, and the F-98 cell lines significantly in comparison to doxorubicin in solution, indicating an improvement of the nanoparticles-bound doxorubicin transport into the cells. The modification of the nanoparticles surface with different surfactants may even enhance the delivery of the drug into the cells. Searching for an improvement of the doxorubicin internalization, the nanoparticles surface was modified using polysorbate 80, poloxamer 188 and poloxamine 908 surfactants. The poloxamer 188 and polaxamine 908 surfactant modified nanoparticles did not show a significant enhancement of the doxorubicin internalization. Contrary, the treatment of polysorbate 80 surfactant modified nanoparticles led in some cases to a significant decrease of cancer cell viability. The use of doxorubicin in the three glioma cell lines allowed the measurement of different responses towards doxorubicin treatment. The different responses were due to the entry of various amounts of doxorubicin into the glioma cells, which express the P-glycoprotein in their cellular membrane. A higher level of the P-gp expression correlated with a weaker response towards the doxorubicin treatment. The GS-9L cell line showed a significant higher level of P-gp expression than the F-98, and RG-2 cell lines, and consequently, the GS-9L cell line presented the highest resistance to doxorubicin with the highest viability values after doxorubicin treatment. Due to the fact that the transport of doxorubicin is governed by the activity of the P-gp in the studied glioma cells, the use of poloxamer 185 as a P-gp inhibitor resulted in an enhancement of the uptake as well as of the accumulation of doxorubicin into the cells. The effect of poloxamer 185 on the doxorubicin uptake was significant marked in the case of doxorubicin-resistance cells, as the GS-9L cell line. In some cases, the presence of the nanoparticles formulation showed also an influence on such uptake improvement. The use of a P-gp inhibitor in combination with chemotherapeutic agents leads to encouraging results. Because of the wide spectrum of substances acting as P-gp inhibitors, the exact inhibitory mechanisms remain still unclear. For instance in our results the evaluation of a described P-gp inhibitor, polysorbate 80 did not show an important improvement in the doxorubicin uptake in the P-gp-expressing cell line, GS-9L. On the other hand, the Polysorbate 80-Dox-PBCA nanoparticles formulation decreased in greater extend the viability of the glioma cells than the poloxamer185-Dox-PBCA nanoparticles. Although, the P-gp inhibition was undoubtedly higher in the presence of poloxamer 185, polysorbate 80 showed a main effect on the disruption of the cellular membrane, resulting in an important cellular viability decrease. It seems that poloxamer 185 presents a direct effect on the functionality of the P-gp protein, which would be of great importance in the sensitization of resistant cancer cells. The range of concentration of poloxamer 185 is very important to yield an inhibitory effect on the P-gp-mediated transport mechanism. The accumulation of Rhodamine-123 (Rho-123), a known P-gp substrate, increased in a range of concentration from 0.001 % to 0.01, whereas at 0.1 % poloxamer 185 the accumulation significantly decreased. A maximal Rho-123 accumulation was reached at 0.01 % poloxamer 185.
Several observables of unbound nucleons which are to some extent sensitive to the medium modifications of nucleon-nucleon elastic cross sections in neutron-rich intermediate energy heavy ion collisions are investigated. The splitting effect of neutron and proton effective masses on cross sections is discussed. It is found that the transverse flow as a function of rapidity, the Q_zz as a function of momentum, and the ratio of halfwidths of the transverse to that of longitudinal rapidity distribution R_t/l are very sensitive to the medium modifications of the cross sections. The transverse momentum distribution of correlation functions of two-nucleons does not yield information on the in-medium cross section.
Elliptic flow analysis at RHIC with the Lee-Yang Zeroes method in a relativistic transport approach
(2006)
The Lee-Yang zeroes method is applied to study elliptic flow (v_2) in Au+Au collisions at sqrt s =200 A GeV, with the UrQMD model. In this transport approach, the true event plane is known and both the nonflow effects and event-by-event v_2 fluctuations exist. Although the low resolutions prohibit the application of the method for most central and peripheral collisions, the integral and differential elliptic flow from the Lee-Yang zeroes method agrees with the exact v_2 values very well for semi-central collisions.
We propose to measure correlations of heavy-flavor hadrons to address the status of thermalization at the partonic stage of light quarks and gluons in high-energy nuclear collisions, shown on the example of azimuthal correlations of D-Dbar pairs. We show that hadronic interactions at the late stage can not disturb these correlations significantly. Thus, a decrease or the complete absence of these initial correlations indicates frequent interactions of heavy-flavor quarks in the partonic stage. Therefore, early thermalization of light quarks is likely to be reached. PACS numbers: 25.75.-q
In this paper we derive a formula for the energy loss due to elastic N to N particle scattering in models with extra dimensions that are compactified on a radius R. In contrast to a previous derivation we also calculate additional terms that are suppressed by factors of frequency over compactification radius. In the limit of a large compactification radius R those terms vanish and the standard result for the non compactified case is recovered.
The pion source as seen through HBT correlations at RHIC energies is investigated within the UrQMD approach. We find that the calculated transverse momentum, centrality, and system size dependence of the Pratt-HBT radii R_L and R_S are reasonably well in line with experimental data. The predicted R_O values in central heavy ion collisions are larger as compared to experimental data. The corresponding quantity sqrt R_O^2-R_S^2 of the pion emission source is somewhat larger than experimental estimates.
Gravitational radiation from ultra high energy cosmic rays in models with large extra dimensions
(2006)
The effects of classical gravitational radiation in models with large extra dimensions are investigated for ultra high energy cosmic rays (CRs). The cross sections are implemented into a simulation package (SENECA) for high energy hadron induced CR air showers. We predict that gravitational radiation from quasi-elastic scattering could be observed at incident CR energies above 10^9 GeV for a setting with more than two extra dimensions. It is further shown that this gravitational energy loss can alter the energy reconstruction for CR energies E_CR > 5 10^9 GeV.
No black holes at IceCube
(2006)
Background: Depression is a disorder with high prevalence in primary health care and a significant burden of illness. The delivery of health care for depression, as well as other chronic illnesses, has been criticized for several reasons and new strategies to address the needs of these illnesses have been advocated. Case management is a patient-centered approach which has shown efficacy in the treatment of depression in highly organized Health Maintenance Organization (HMO) settings and which might also be effective in other, less structured settings. Methods/Design: PRoMPT (PRimary care Monitoring for depressive Patients Trial) is a cluster randomised controlled trial with General Practice (GP) as the unit of randomisation. The aim of the study is to evaluate a GP applied case-management for patients with major depressive disorder. 70 GPs were randomised either to intervention group or to control group with the control group delivering usual care. Each GP will include 10 patients suffering from major depressive disorder according to the DSM-IV criteria. The intervention group will receive treatment based on standardized guidelines and monthly telephone monitoring from a trained practice nurse. The nurse investigates the patient's status concerning the MDD criteria, his adherence to GPs prescriptions, possible side effects of medication, and treatment goal attainment. The control group receives usual care – including recommended guidelines. Main outcome measure is the cumulative score of the section depressive disorders (PHQ-9) from the German version of the Prime MD Patient Health Questionnaire (PHQ-D). Secondary outcome measures are the Beck-Depression-Inventory, self-reported adherence (adapted from Moriskey) and the SF-36. In addition, data are collected about patients' satisfaction (EUROPEP-tool), medication, health care utilization, comorbidity, suicide attempts and days out of work. The study comprises three assessment times: baseline (T0) , follow-up after 6 months (T1) and follow-up after 12 months (T2). Discussion: Depression is now recognized as a disorder with a high prevalence in primary care but with insufficient treatment response. Case management seems to be a promising intervention which has the potential to bridge the gap of the usually time-limited and fragmented provision of care. Case management has been proven to be effective in several studies but its application in the private general medical practice setting remains unclear.
Background: Diabetes model projects in different regions of Germany including interventions such as quality circles, patient education and documentation of medical findings have shown improvements of HbA1c levels, blood pressure and occurrence of hypoglycaemia in before-after studies (without control group). In 2002 the German Ministry of Health defined legal regulations for the introduction of nationwide disease management programs (DMP) to improve the quality of care in chronically ill patients. In April 2003 the first DMP for patients with type 2 diabetes was accredited. The evaluation of the DMP is essential and has been made obligatory in Germany by the Fifth Book of Social Code. The aim of the study is to assess the effectiveness of DMP by example of type 2 diabetes in the primary care setting of two German federal states (Rheinland-Pfalz and Sachsen-Anhalt). Methods/Design: The study is three-armed: a prospective cluster-randomized comparison of two interventions (DMP 1 and DMP 2) against routine care without DMP as control group. In the DMP group 1 the patients are treated according to the current situation within the German-Diabetes-DMP. The DMP group 2 represents diabetic care within ideally implemented DMP providing additional interventions (e.g. quality circles, outreach visits). According to a sample size calculation a sample size of 200 GPs (each GP including 20 patients) will be required for the comparison of DMP 1 and DMP 2 considering possible drop-outs. For the comparison with routine care 4000 patients identified by diabetic tracer medication and age (> 50 years) will be analyzed. Discussion: This study will evaluate the effectiveness of the German Diabetes-DMP compared to a Diabetes-DMP providing additional interventions and routine care in the primary care setting of two different German federal states.
Aims: This paper is a review of the literature on problem-related drinking of alcohol among medical doctors, and it deals with the epidemiology and results. Methods: A search of computer literature databases - PubMed and ETOH - was performed to locate articles reporting problem-related drinking among doctors, using population-based samples of doctors within the last two decades. Results: In the light of different definitions of problem-related drinking, there was found a breadth of prevalence of problem-related drinking - from heavy drinking and hazardous drinking (12%-16%) to misuse and dependence (6%-8%) - within the population-based samples of doctors. An increased risk was positively related to male doctors and doctors of the age of 40-45 years and older, and to some factors of work, lifestyle and health. Conclusion: For the future, it seems necessary to sensitise the research for problem-related drinking of doctors in Germany, e.g. initiating a representative survey, analysing the drinking of alcohol in the context of health, life-style and work-related factors.
Celiac disease
(2006)
Celiac disease is a chronic intestinal disease caused by intolerance to gluten. It is characterized by immune-mediated enteropathy, associated with maldigestion and malabsorption of most nutrients and vitamins. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. The main symptoms are: stomach pain, gas, and bloating, diarrhea, weight loss, anemia, edema, bone or joint pain. Prevalence for clinically overt celiac disease varies from 1:270 in Finland to 1:5000 in North America. Since celiac disease can be asymptomatic, most subjects are not diagnosed or they can present with atypical symptoms. Furthermore, severe inflammation of the small bowel can be present without any gastrointestinal symptoms. The diagnosis should be made early since celiac disease causes growth retardation in untreated children and atypical symptoms like infertility or neurological symptoms. Diagnosis requires endoscopy with jejunal biopsy. In addition, tissue-transglutaminase antibodies are important to confirm the diagnosis since there are other diseases which can mimic celiac disease. The exact cause of celiac disease is unknown but is thought to be primarily immune mediated (tissue-transglutaminase autoantigen); often the disease is inherited. Management consists in life long withdrawal of dietary gluten, which leads to significant clinical and histological improvement. However, complete normalization of histology can take years.
Prostaglandin E2 (PGE2) plays an important role in bone development and metabolism. To interfere therapeutically in the PGE2 pathway, however, knowledge about the involved enzymes (cyclooxygenases) and receptors (PGE2 receptors) is essential. We therefore examined the production of PGE2 in cultured growth plate chondrocytes in vitro and the effects of exogenously added PGE2 on cell proliferation. Furthermore, we analysed the expression and spatial distribution of cyclooxygenase (COX)-1 and COX-2 and PGE2 receptor types EP1, EP2, EP3 and EP4 in the growth plate in situ and in vitro. PGE2 synthesis was determined by mass spectrometry, cell proliferation by DNA [3H]-thymidine incorporation, mRNA expression of cyclooxygenases and EP receptors by RT-PCR on cultured cells and in homogenized growth plates. To determine cellular expression, frozen sections of rat tibial growth plate and primary chondrocyte cultures were stained using immunohistochemistry with polyclonal antibodies directed towards COX-1, COX-2, EP1, EP2, EP3, and EP4. Cultured growth plate chondrocytes transiently secreted PGE2 into the culture medium. Although both enzymes were expressed in chondrocytes in vitro and in vivo, it appears that mainly COX-2 contributed to PGE2-dependent proliferation. Exogenously added PGE2 stimulated DNA synthesis in a dose-dependent fashion and gave a bell-shaped curve with a maximum at 10-8 M. The EP1/EP3 specific agonist sulprostone and the EP1-selective agonist ONO-D1-004 increased DNA synthesis. The effect of PGE2 was suppressed by ONO-8711. The expression of EP1, EP2, EP3, and EP4 receptors in situ and in vitro was observed; EP2 was homogenously expressed in all zones of the growth plate in situ, whereas EP1 expression was inhomogenous, with spared cells in the reserve zone. In cultured cells these four receptors were expressed in a subset of cells only. The most intense staining for the EP1 receptor was found in polygonal cells surrounded by matrix. Expression of receptor protein for EP3 and EP4 was observed also in rat growth plates. In cultured chrondrocytes, however, only weak expression of EP3 and EP4 receptor was detected. We suggest that in growth plate chondrocytes, COX-2 is responsible for PGE2 release, which stimulates cell proliferation via the EP1 receptor.
Herman P. Schwan [1915–2005] was a distinguished scientist and engineer, and a founding father of the field of biomedical engineering. A man of integrity, Schwan influenced the lives of many, including his wife and children, and his many students and colleagues. Active in science until nearly the end of his life, he will be very much missed by his family and many colleagues.
High-throughput gene trapping is a random approach for inducing insertional mutations across the mouse genome. This approach uses gene trap vectors that simultaneously inactivate and report the expression of the trapped gene at the insertion site, and provide a DNA tag for the rapid identification of the disrupted gene. Gene trapping has been used by both public and private institutions to produce libraries of embryonic stem (ES) cells harboring mutations in single genes. Presently,~ 66% of the protein coding genes in the mouse genome have been disrupted by gene trap insertions. Among these, however, genes encoding signal peptides or transmembrane domains (secretory genes) are underrepresented because they are not susceptible to conventional trapping methods. Here, we describe a high-throughput gene trapping strategy that effectively targets secretory genes. We used this strategy to assemble a library of ES cells harboring mutations in 716 unique secretory genes, of which 61% were not trapped by conventional trapping, indicating that the two strategies are complementary. The trapped ES cell lines, which can be ordered from the International Gene Trap Consortium (http://www.genetrap.org), are freely available to the scientific community.
Background: Murine leukemia virus (MLV) vector particles can be pseudotyped with a truncated variant of the human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) and selectively target gene transfer to human cells expressing both CD4 and an appropriate co-receptor. Vector transduction mimics the HIV-1 entry process and is therefore a safe tool to study HIV-1 entry. Results: Using FLY cells, which express the MLV gag and pol genes, we generated stable producer cell lines that express the HIV-1 envelope gene and a retroviral vector genome encoding the green fluorescent protein (GFP). The BH10 or 89.6 P HIV-1 Env was expressed from a bicistronic vector which allowed the rapid selection of stable cell lines. A codon-usage-optimized synthetic env gene permitted high, Rev-independent Env expression. Vectors generated by these producer cells displayed different sensitivity to entry inhibitors. Conclusion: These data illustrate that MLV/HIV-1 vectors are a valuable screening system for entry inhibitors or neutralizing antisera generated by vaccines.
One of the dangers of harmonisation and unification processes taking place within the framework of the EU is that they may result in the codification of the lowest common denominator. This is precisely what is threatening to happen in respect of assignment. Referring the transfer of receivables by way of assignment to the law of the assignor’s residence, as article 13 of the Proposal does, would be opting for the most conservative solution and would for many Member States be a step backward rather than forward. A conflict rule referring assignment to the law of the assignor's residence is too rigid to do justice to the dynamic nature of assignments in cross-border transactions and it is unjustly one-sided. It offers no real advantages when compared to other conflict rules; it even has serious disadvantages which make the conflict rule unsuitable for efficient assignment-based cross-border transactions. It is not unconceivable that this conflict rule would even be contrary to the fundamental freedoms of the ECTreaty. The Community legislators in particular should be careful not to needlessly adopt rules which create insurmountable obstacles for cross-border business where choice-of-law by the parties would perfectly do. Community legislation has a special responsibility to create a smooth legal environment for single market transactions.
This Paper will look at the changing nature of asset management, and will examine the nature of the European framework for collective investment undertakings, enshrined in the UCITS Directive2 in that light. This question whether the UCITS Directive in its current form remains an appropriate European response to the changing investment management landscape is an issue with which the European Commission is actively engaging through its Green Paper on the Enhancement of the EU Framework for Investment Funds, published in July 2005.3 But before considering these important questions, it is necessary to begin with an idea of what a collective investment, more specifically a UCITS actually is and how it fits conceptually in the broader world of pooled investments.....
We analyze the degree of contract completeness with respect to staging of venture capital investments using a hand-collected German data set of contract data from 464 rounds into 290 entrepreneurial firms. We distinguish three forms of staging (pure milestone financing, pure round financing and mixes). Thereby, contract completeness reduces when going from pure milestone financing via mixes to pure round financing. We show that the decision for a specific form of staging is determined by the expected distribution of bargaining power between the contracting parties when new funding becomes necessary and the predictability of the development process. To be more precise, parties choose the more complete contracts the lower the entrepreneur's expected bargaining power - the maximum level depending on the predictability of the development process. JEL Classification: G24, G32, D86, D80, G34
This paper investigates whether the stock market reacts to unsolicited ratings for a sample of S&P rated firms from January 1996 to December 2005. We first analyze the stock market reaction associated with the assignment of an initial unsolicited rating. We find evidence that this reaction is negative and particularly accentuated for Japanese firms. A comparison between S&P’s initial unsolicited ratings with previously published ratings of two Japanese rating agencies for a Japanese subsample shows that ratings assigned by S&P are systematically worse. Further, we find that the stock market does not react to the transition from an unsolicited to a solicited rating. Comparison of the upgrades in the sample with a matched-sample of upgrades of solicited ratings reveals that the price reactions are no different. In addition, abnormal returns are worse for firms whose rating remained unchanged after the solicitation compared to those for upgraded firms. Finally, we find that Japanese firms are less likely to receive an upgrade. Our findings suggest that unsolicited ratings are biased downwards, that the capital market therefore expects upgrades of formerly unsolicited ratings and punishes firms whose ratings remain unchanged. All these effects seem to be more pronounced for Japanese firms.
In this paper, we propose a model of credit rating agencies using the global games framework to incorporate information and coordination problems. We introduce a refined utility function of a credit rating agency that, additional to reputation maximization, also embeds aspects of competition and feedback effects of the rating on the rated firms. Apart from hinting at explanations for several hypotheses with regard to agencies' optimal rating assessments, our model suggests that the existence of rating agencies may decrease the incidence of multiple equilibria. If investors have discretionary power over the precision of their private information, we can prove that public rating announcements and private information collection are complements rather than substitutes in order to secure uniqueness of equilibrium. In this respect, rating agencies may spark off a virtuous circle that increases the efficiency of the market outcome.
Background: Cancer gene therapy will benefit from vectors that are able to replicate in tumor tissue and cause a bystander effect. Replication-competent murine leukemia virus (MLV) has been described to have potential as cancer therapeutics, however, MLV infection does not cause a cytopathic effect in the infected cell and viral replication can only be studied by immunostaining or measurement of reverse transcriptase activity. Results: We inserted the coding sequences for green fluorescent protein (GFP) into the proline-rich region (PRR) of the ecotropic envelope protein (Env) and were able to fluorescently label MLV. This allowed us to directly monitor viral replication and attachment to target cells by flow cytometry. We used this method to study viral replication of recombinant MLVs and split viral genomes, which were generated by replacement of the MLV env gene with the red fluorescent protein (RFP) and separately cloning GFP-Env into a retroviral vector. Co-transfection of both plasmids into target cells resulted in the generation of semi-replicative vectors, and the two color labeling allowed to determine the distribution of the individual genomes in the target cells and was indicative for the occurrence of recombination events. Conclusions: Fluorescently labeled MLVs are excellent tools for the study of factors that influence viral replication and can be used to optimize MLV-based replication-competent viruses or vectors for gene therapy.
Using data of US domestic mergers and acquisitions transactions, this paper shows that acquirers have a preference for geographically proximate target companies. We measure the ‘home bias’ against benchmark portfolios of hypothetical deals where the potential targets consist of firms of similar size in the same four-digit SIC code that have been targets in other transactions at about the same time or firms that have been listed at a stock exchange at that time. There is a strong and consistent home bias for M&A transactions in the US, which is significantly declining during the observation period, i.e. between 1990 and 2004. At the same time, the average distances between target and acquirer increase articulately. The home bias is stronger for small and relatively opaque target companies suggesting that local information is the decisive factor in explaining the results. Acquirers that diversify into new business lines also display a stronger preference for more proximate targets. With an event study we show that investors react relatively better to proximate acquisitions than to distant ones. That reaction is more important and becomes significant in times when the average distance between target and acquirer becomes larger, but never becomes economically significant. We interpret this as evidence for the familiarity hypothesis brought forward by Huberman (2001): Acquirers know about the existence of proximate targets and are more likely to merge with them without necessarily being better informed. However, when comparing the best and the worst deals, we are able to show a dramatic difference in distances and home bias: The most successful deals display on average a much stronger home bias and distinctively smaller distance between acquirer and target than the least successful deals. Proximity in M&A transactions therefore is a necessary but not sufficient condition for success. The paper contributes to the growing literature on the role of distance in financial decisions.
The 5'-terminal cloverleaf (CL)-like RNA structures are essential for the initiation of positive- and negative-strand RNA synthesis of entero- and rhinoviruses. SLD is the cognate RNA ligand of the viral proteinase 3C (3Cpro), which is an indispensable component of the viral replication initiation complex. The structure of an 18mer RNA representing the apical stem and the cGUUAg D-loop of SLD from the first 5'-CL of BEV1 was determined in solution to a root-mean-square deviation (r.m.s.d.) (all heavy atoms) of 0.59 A (PDB 1Z30). The first (antiG) and last (synA) nucleotide of the D-loop forms a novel ‘pseudo base pair’ without direct hydrogen bonds. The backbone conformation and the base-stacking pattern of the cGUUAg-loop, however, are highly similar to that of the coxsackieviral uCACGg D-loop (PDB 1RFR) and of the stable cUUCGg tetraloop (PDB 1F7Y) but surprisingly dissimilar to the structure of a cGUAAg stable tetraloop (PDB 1MSY), even though the cGUUAg BEV D-loop and the cGUAAg tetraloop differ by 1 nt only. Together with the presented binding data, these findings provide independent experimental evidence for our model [O. Ohlenschläger, J. Wöhnert, E. Bucci, S. Seitz, S. Häfner, R. Ramachandran, R. Zell and M. Görlach (2004) Structure, 12, 237–248] that the proteinase 3Cpro recognizes structure rather than sequence.
We have isolated the human protein SNEV as downregulated in replicatively senescent cells. Sequence homology to the yeast splicing factor Prp19 suggested that SNEV might be the orthologue of Prp19 and therefore might also be involved in pre-mRNA splicing. We have used various approaches including gene complementation studies in yeast using a temperature sensitive mutant with a pleiotropic phenotype and SNEV immunodepletion from human HeLa nuclear extracts to determine its function. A human–yeast chimera was indeed capable of restoring the wild-type phenotype of the yeast mutant strain. In addition, immunodepletion of SNEV from human nuclear extracts resulted in a decrease of in vitro pre-mRNA splicing efficiency. Furthermore, as part of our analysis of protein–protein interactions within the CDC5L complex, we found that SNEV interacts with itself. The self-interaction domain was mapped to amino acids 56–74 in the protein's sequence and synthetic peptides derived from this region inhibit in vitro splicing by surprisingly interfering with spliceosome formation and stability. These results indicate that SNEV is the human orthologue of yeast PRP19, functions in splicing and that homo-oligomerization of SNEV in HeLa nuclear extract is essential for spliceosome assembly and that it might also be important for spliceosome stability.
We estimate the effect of pension reforms on households' expectations of retirement outcomes and private wealth accumulation decisions exploiting a decade of intense Italian pension reforms as a source of exogenous variation in expected pension wealth. The Survey of Household Income and Wealth, a large random sample of the Italian population, elicits expectations of the age at which workers expect to retire and of the ratio of pension benefits to pre-retirement income between 1989 and 2002. We find that workers have revised expectations in the direction suggested by the reform and that there is substantial offset between private wealth and perceived pension wealth, particularly by workers that are better informed about their pension wealth. Klassifikation: E21, H55
We present a multivariate generalization of the mixed normal GARCH model proposed in Haas, Mittnik, and Paolella (2004a). Issues of parametrization and estimation are discussed. We derive conditions for covariance stationarity and the existence of the fourth moment, and provide expressions for the dynamic correlation structure of the process. These results are also applicable to the single-component multivariate GARCH(p, q) model and simplify the results existing in the literature. In an application to stock returns, we show that the disaggregation of the conditional (co)variance process generated by our model provides substantial intuition, and we highlight a number of findings with potential significance for portfolio selection and further financial applications, such as regime-dependent correlation structures and leverage effects. Klassifikation: C32, C51, G10, G11
We model the impact of bank mergers on loan competition, reserve holdings and aggregate liquidity. A merger changes the distribution of liquidity shocks and creates an internal money market, leading to financial cost efficiencies and more precise estimates of liquidity needs. The merged banks may increase their reserve holdings through an internalization effect or decrease them because of a diversification effect. The merger also affects loan market competition, which in turn modifies the distribution of bank sizes and aggregate liquidity needs. Mergers among large banks tend to increase aggregate liquidity needs and thus the public provision of liquidity through monetary operations of the central bank. Klassifikation: D43, G21, G28, L13
When a spot market monopolist has a position in a corresponding futures market, he has an incentive to deviate from the spot market optimum to make this position more profitable. Rational futures market makers take this into account when setting prices. We show that the monopolist, by randomizing his futures market position, can strategically exploit his market power at the expense of other futures market participants. Furthermore, traders without market power can manipulate futures prices by hiding their orders behind the monopolist's strategic trades. The moral hazard problem stemming from spot market power thus provides a venue for strategic trading and manipulation that parallels the adverse selection problem stemming from inside information. Klassifikation: D82, G13
We study a set of German open-end mutual funds for a time period during which this industry emerged from its infancy. In those years, the distribution channel for mutual funds was dominated by the brick-and-mortar retail networks of the large universal banks. Using monthly observations from 12/1986 through 12/1998, we investigate if cross-sectional return differences across mutual funds affect their market shares. Although such a causal relation has been established in highly competitive markets, such as the United States, the rigid distribution system in place in Germany at the time may have caused retail performance and investment performance to uncouple. In fact, although we observe stark differences in investment performance across mutual funds (and over time), we find no evidence that cross-sectional performance differences affect the market shares of these funds. Klassifikation: G 23
Large banks often sell part of their loan portfolio in the form of collateralized debt obligations (CDO) to investors. In this paper we raise the question whether credit asset securitization affects the cyclicality (or commonality) of bank equity values. The commonality of bank equity values reflects a major component of systemic risks in the banking market, caused by correlated defaults of loans in the banks' loan books. Our simulations take into account the major stylized fact of CDO transactions, the non-proportional nature of risk sharing that goes along with tranching. We provide a theoretical framework for the risk transfer through securitization that builds on a macro risk factor and an idiosyncratic risk factor, allowing an identification of the types of risk that the individual tranche holders bear. This allows conclusions about the risk positions of issuing banks after risk transfer. Building on the strict subordination of tranches, we first evaluate the correlation properties both within and across risk classes. We then determine the effect of securitization on the systematic risk of all tranches, and derive its effect on the issuing bank's equity beta. The simulation results show that under plausible assumptions concerning bank reinvestment behaviour and capital structure choice, the issuing intermediary's systematic risk tends to rise. We discuss the implications of our findings for financial stability supervision. Klassifikation: G28
In this paper, we consider expected value, variance and worst-case optimization of nonlinear models. We present algorithms for computing optimal expected values, and variance, based on iterative Taylor expansions. We establish convergence and consider the relative merits of policies beaded on expected value optimization and worst-case robustness. The latter is a minimax strategy and ensures optimal cover in view of the worst-case scenario(s) while the former is optimal expected performance in a stochastic setting. Both approaches are used with a macroeconomic policy model to illustrate relative performances, robustness and trade-offs between the strategies. Klassifikation: C61, E43