Zafar, Capital of Himyar, Sixth Preliminary Report, February–March 2006

Die Grabungsmannschaft der Universität Heidelberg untersucht Zafar – Hauptstadt der himyarischen Stammeskonföderation – seit 1998. Dieses interdisziplinäre Projekt erbrachte Funde in der Kunstgeschichte, Botanik und Chronologi

A Viable Business Model for Innovations with Digital Healthcare Applications in Germany

Germany established laws to quickly introduce digital innovations in healthcare by forcing statutory insurances to reimburse companies producing digital applications. This could enhance the well-being of patients. For example, an application in psychotherapy can cut the waiting time for a psychotherapist in Germany. However, such enhancements will reach the patients only if companies offering digital applications have a viable business model to survive. Our analysis of the business model of a company offering a recognized digital application shows that such business models are not easy to develop. The analysis is transferrable to other countries, if they establish similar laws. First, we describe the legal framework for digital healthcare applications set up in Germany. We also describe the conditions that must be met for such an application to be recognized by the relevant body so that statutory insurances must pay for it. This is followed by a discussion of the reimbursement amount. Then, we develop the business model of a producer of a specific digital healthcare application. Although the possibility of reimbursement for accepted applications constitutes a competitive advantage, underestimating costs from the approval process and marketing may be dangerous. The same is true for relying on revenues from reimbursement

Electron Microprobe Analysis and X-ray Diffraction Methods in Archaeometry: Investigations on Pre-Islamic Beads from the Sultanate of Oman

Beads from graves of the Samad Assemblage, Sultanate of Oman and from an ancient crafts quarter of the old kingdom of Ruhana, in Sri Lanka, were investigated using electron analysis and X-ray powder diffraction. Both experimental methods were optimized toward non-destructive analysis

Exploring RNA polymerase regulation by NMR spectroscopy

RNA synthesis is a central process in all organisms, with RNA polymerase (RNAP) as the key enzyme. Multisubunit RNAPs are evolutionary related and are tightly regulated by a multitude of transcription factors. Although Escherichia coli RNAP has been studied extensively, only little information is available about its dynamics and transient interactions. This information, however, are crucial for the complete understanding of transcription regulation in atomic detail. To study RNAP by NMR spectroscopy we developed a highly efficient procedure for the assembly of active RNAP from separately expressed subunits that allows specific labeling of the individual constituents. We recorded [(1)H,(13)C] correlation spectra of isoleucine, leucine, and valine methyl groups of complete RNAP and the separately labeled β’ subunit within reconstituted RNAP. We further produced all RNAP subunits individually, established experiments to determine which RNAP subunit a certain regulator binds to, and identified the β subunit to bind NusE

Regulation of foamy virus protease activity by viral RNA

No abstract available

Thermotoga maritima NusG : domain interaction mediates autoinhibition and thermostability

NusG, the only universally conserved transcription factor, comprises an N- and a C-terminal domain (NTD, CTD) that are flexibly connected and move independently in Escherichia coli and other organisms. In NusG from the hyperthermophilic bacterium Thermotoga maritima (tmNusG), however, NTD and CTD interact tightly. This closed state stabilizes the CTD, but masks the binding sites for the interaction partners Rho, NusE and RNA polymerase (RNAP), suggesting that tmNusG is autoinhibited. Furthermore, tmNusG and some other bacterial NusGs have an additional domain, DII, of unknown function. Here we demonstrate that tmNusG is indeed autoinhibited and that binding to RNAP may stabilize the open conformation. We identified two interdomain salt bridges as well as Phe336 as major determinants of the domain interaction. By successive weakening of this interaction we show that after domain dissociation tmNusG-CTD can bind to Rho and NusE, similar to the Escherichia coli NusG-CTD, indicating that these interactions are conserved in bacteria. Furthermore, we show that tmNusG-DII interacts with RNAP as well as nucleic acids with a clear preference for double stranded DNA. We suggest that tmNusG-DII supports tmNusG recruitment to the transcription elongation complex and stabilizes the tmNusG:RNAP complex, a necessary adaptation to high temperatures

Solution Structure of Human Proguanylin: The role of a hormone prosequence

The endogenous ligand of guanylyl cyclase C, guanylin, is produced as the 94-amino-acid prohormone proguanylin, with the hormone guanylin located at the COOH terminus of the prohormone. The solution structure of proguanylin adopts a new protein fold and consists of a three-helix bundle, a small three-stranded {beta}-sheet of two NH2-terminal strands and one COOH-terminal strand, and an unstructured linker region. The sequence corresponding to guanylin is fixed in its bioactive topology and is involved in interactions with the NH2-terminal {beta}-hairpin: the hormone region (residues 80–94) partly wraps around the first 4 NH2-terminal residues that thereby shield parts of the hormone surface. These interactions provide an explanation for the negligible bioactivity of the prohormone as well as the important role of the NH2-terminal residues in the disulfide-coupled folding of proguanylin. Since the ligand binding region of guanylyl cyclase C is predicted to be located around an exposed {beta}-strand, the intramolecular interactions observed between guanylin and its prosequence may be comparable with the guanylin/receptor interaction

AZT resistance alters enzymatic properties and creates an ATP-binding site in SFVmac reverse transcriptase

BACKGROUND: The replication of simian foamy virus from macaques can be inhibited by the nucleoside reverse transcriptase inhibitor azidothymidine (AZT, zidovudine). Four substitutions in the protease-reverse transcriptase (PR-RT) protein (K211I, I224T, S345T, E350K) are necessary to obtain highly AZT resistant and fully replication competent virus. AZT resistance is based on the excision of the incorporated AZTMP in the presence of ATP. I224T is a polymorphism which is not essential for AZT resistance per se, but is important for regaining efficient replication of the resistant virus. RESULTS: We constructed PR-RT enzymes harboring one to four amino acid substitutions to analyze them biochemically and to determine their ability to remove the incorporated AZTMP. S345T is the only single substitution variant exhibiting significant AZTMP excision activity. Although K211I alone showed no AZTMP excision activity, excision efficiency doubled when K211I was present in combination with S345T and E350K. K211I also decreased nucleotide binding affinity and increased fidelity. NMR titration experiments revealed that a truncated version of the highly AZT resistant mt4 variant, comprising only the fingers-palm subdomains was able to bind ATP with a K(D)-value of ca. 7.6 mM, whereas no ATP binding could be detected in the corresponding wild type protein. We could show by NMR spectroscopy that S345T is responsible for ATP binding, probably by making a tryptophan residue accessible. CONCLUSION: Although AZT resistance in SFVmac is based on excision of the incorporated AZTMP like in HIV-1, the functions of the resistance substitutions in SFVmac PR-RT appear to be different. No mutation resulting in an aromatic residue like F/Y215 in HIV, which is responsible for π-π-stacking interactions with ATP, is present in SFVmac. Instead, S345T is responsible for creating an ATP binding site, probably by making an already existing tryptophan more accessible, which in turn can interact with ATP. This is in contrast to HIV-1 RT, in which an ATP binding site is present in the WT RT but differs from that of the AZT resistant enzyme. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12977-015-0147-7) contains supplementary material, which is available to authorized users

Forecasting US bond default ratings allowing for previous and initial state dependence in an ordered probit model

In this paper we investigate the ability of a number of different ordered probit models to predict ratings based on firm-specific data on business and financial risks. We investigate models based on momentum, drift and ageing and compare them against alternatives that take into account the initial rating of the firm and its previous actual rating. Using data on US bond issuing firms rated by Fitch over the years 2000 to 2007 we compare the performance of these models in predicting the rating in-sample and out-of-sample using root mean squared errors, Diebold-Mariano tests of forecast performance and contingency tables. We conclude that initial and previous states have a substantial influence on rating prediction