Delay of phagosome maturation by a mycobacterial lipid is reversed by nitric oxide.

Mycobacterium tuberculosis is a facultative intracellular pathogen that inhibits phagosome maturation in macrophages thereby securing survival and growth. Mycobacteria reside in an early endocytic compartment of near-neutral pH where they upregulate production of complex glycolipids such as trehalose dimycolate. Here, we report that trehalose dimycolate coated onto beads increased the bead retention in early phagosomes, i.e. at a similar stage as viable mycobacteria. Thus, a single mycobacterial lipid sufficed to divert phagosome maturation and likely contributes to mycobacterial survival in macrophages. Previous studies showed that activated macrophages promote maturation of mycobacterial phagosomes and eliminate mycobacteria through bactericidal effectors including nitric oxide generated by inducible nitric-oxide synthase. We show that deceleration of bead phagosome maturation by trehalose dimycolate was abolished in immune-activated wild type, but not in activated nitric-oxide synthase-deficient macrophages, nor when hydroxyl groups of trehalose dimycolate were chemically modified by reactive nitrogen intermediates. Thus, specific host defence effectors of activated macrophages directly target a specific virulence function of mycobacteria

TapA acts as specific chaperone in TasA filament formation by strand complementation

Studying mechanisms of bacterial biofilm generation is of vital importance to understanding bacterial cell–cell communication, multicellular cohabitation principles, and the higher resilience of microorganisms in a biofilm against antibiotics. Biofilms of the nonpathogenic, gram-positive soil bacterium Bacillus subtilis serve as a model system with biotechnological potential toward plant protection. Its major extracellular matrix protein components are TasA and TapA. The nature of TasA filaments has been of debate, and several forms, amyloidic and non-Thioflavin T-stainable have been observed. Here, we present the three-dimensional structure of TapA and uncover the mechanism of TapA-supported growth of nonamyloidic TasA filaments. By analytical ultracentrifugation and NMR, we demonstrate TapA-dependent acceleration of filament formation from solutions of folded TasA. Solid-state NMR revealed intercalation of the N-terminal TasA peptide segment into subsequent protomers to form a filament composed of β-sandwich subunits. The secondary structure around the intercalated N-terminal strand β0 is conserved between filamentous TasA and the Fim and Pap proteins, which form bacterial type I pili, demonstrating such construction principles in a gram-positive organism. Analogous to the chaperones of the chaperone-usher pathway, the role of TapA is in donating its N terminus to serve for TasA folding into an Ig domain-similar filament structure by donor-strand complementation. According to NMR and since the V-set Ig fold of TapA is already complete, its participation within a filament beyond initiation is unlikely. Intriguingly, the most conserved residues in TasA-like proteins (camelysines) of Bacillaceae are located within the protomer interface

TapA acts as specific chaperone in TasA filament formation by strand complementation

Studying mechanisms of bacterial biofilm generation is of vital importance to understanding bacterial cell–cell communication, multicellular cohabitation principles, and the higher resilience of microorganisms in a biofilm against antibiotics. Biofilms of the nonpathogenic, gram-positive soil bacterium Bacillus subtilis serve as a model system with biotechnological potential toward plant protection. Its major extracellular matrix protein components are TasA and TapA. The nature of TasA filaments has been of debate, and several forms, amyloidic and non-Thioflavin T-stainable have been observed. Here, we present the three-dimensional structure of TapA and uncover the mechanism of TapA-supported growth of nonamyloidic TasA filaments. By analytical ultracentrifugation and NMR, we demonstrate TapA-dependent acceleration of filament formation from solutions of folded TasA. Solid-state NMR revealed intercalation of the N-terminal TasA peptide segment into subsequent protomers to form a filament composed of β-sandwich subunits. The secondary structure around the intercalated N-terminal strand β0 is conserved between filamentous TasA and the Fim and Pap proteins, which form bacterial type I pili, demonstrating such construction principles in a gram-positive organism. Analogous to the chaperones of the chaperone-usher pathway, the role of TapA is in donating its N terminus to serve for TasA folding into an Ig domain-similar filament structure by donor-strand complementation. According to NMR and since the V-set Ig fold of TapA is already complete, its participation within a filament beyond initiation is unlikely. Intriguingly, the most conserved residues in TasA-like proteins (camelysines) of Bacillaceae are located within the protomer interface

Testing thermal reprocessing in active galactic nuclei accretion discs

The thermal reprocessing hypothesis in active galactic nuclei (AGN), where extreme ultraviolet/X-ray photons are reprocessed by the accretion disc into optical/UV photons, predicts wavelength-dependent time-delays between the optical continuum at different wavelengths. Recent photometric monitoring by Sergeev et al. has shown that the time-delay is observed in 14 AGN, and generally seen to increase with increasing wavelength, as predicted in the reprocessing scenario. We fit the observed time-delays and optical spectral energy distribution using a disc reprocessing model. The model delivers estimates for the nuclear reddening, the product of black hole mass and accretion rate, and the distance to each object. However, the distances at face value give H 0 = 44 ± 5 km s −1 Mpc −1 – a factor of 1.6 smaller than generally accepted. We discuss the implications of this on the reprocessing model.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72494/1/j.1365-2966.2007.12098.x.pd

Gelingendes Leben - Krise als Chance für Person & Gesellschaft. Band II

• Peter Antes, Rel.wiss. • Petra Bahr, Theol. / Journ. • Matthias Beck Med./JS, AT • Gottfried Biewer, Bildungswiss., AT • Aladin El-Mafaalani, Pol.wiss.• Johannes Eurich, Diak.wiss. • Mario Feigel, Med. CH • Heike Gramkow, Manag.Dir. • Heinrich Greving, Heilpäd. • Udo Hahn, Theol.• Maria-C. Hallwachs, Stud., Beratg. schon betroffen • Walter Hirche, Min. a.D./Präs. Dt. UNESCO • Wolfgang Jantzen †, Soz. • Jochen-C. Kaiser, Hist. • Karl-J. Kemmelmeyer, Präs. Musikrat • Hermes Kick, Med.-Ethik • Waldemar Kippes Redemptorist JN • Ferdinand Klein, SoPäd., SK • Berthold Krüger, bpb • Christian Larsen, Arzt, CH • Ulrich Lilie Präs. Diak.W • Christian Lindmeier, SoPäd., DGfE • Ralf Meister, Bischof • Bertolt Meyer, Org.- u. Wirtschaftspsych, schon betroffen, CH • Peter Neher, Präs. Caritas • Ekkehard Nuissl, Dir. Dt. Inst. EB, DIE • Ulrich Pohl, Vorst. Bethel • Hartmann Römer, Physiker • David Roth, Lt. Hospiz • Hartmut Schlegel SoPäd. • Joachim Schoss, Unternehmer, schon betroffen, CH • Walter Surböck Med., AT• Karl-H. Steinmetz, Trad. Europ. Med., AT • Rudolf Tippelt, Bildg. Forschg. • Inge Wasserberg, Inklu.Beratg. • Walter Thirring †, Phys. CERN, C

WW domain sequence activity relationships identified using ligand recognition propensities of 42 WW domains

WW domains mediate protein–protein interactions in a number of different cellular functions by recognizing proline-containing peptide sequences. We determined peptide recognition propensities for 42 WW domains using NMR spectroscopy and peptide library screens. As potential ligands, we studied both model peptides and peptides based on naturally occurring sequences, including phosphorylated residues. Thirty-two WW domains were classified into six groups according to detected ligand recognition preferences for binding the motifs PPx(Y/poY), (p/φ)P(p,g)PPpR, (p/φ)PPRgpPp, PPLPp, (p/ξ)PPPPP, and (poS/poT)P (motifs according to modified Seefeld Convention 2001). In addition to these distinct binding motifs, group-specific WW domain consensus sequences were identified. For PPxY-recognizing domains, phospho-tyrosine binding was also observed. Based on the sequences of the PPx(Y/poY)-specific group, a profile hidden Markov model was calculated and used to predict PPx(Y/poY)-recognition activity for WW domains, which were not assayed. PPx(Y/poY)-binding was found to be a common property of NEDD4-like ubiquitin ligases

Long-term neurocognitive function and quality of life after multimodal therapy in adult glioma patients: a prospective long-term follow-up

PURPOSE: Multimodal therapies have significantly improved prognosis in glioma. However, in particular radiotherapy may induce long-term neurotoxicity compromising patients' neurocognition and quality of life. The present prospective multicenter study aimed to evaluate associations of multimodal treatment with neurocognition with a particular focus on hippocampal irradiation. METHODS: Seventy-one glioma patients (WHO grade 1-4) were serially evaluated with neurocognitive testing and quality of life questionnaires. Prior to (baseline) and following further treatment (median 7.1 years [range 4.6-11.0] after baseline) a standardized computerized neurocognitive test battery (NeuroCog FX) was applied to gauge psychomotor speed and inhibition, verbal short-term memory, working memory, verbal and non-verbal memory as well as verbal fluency. Mean ipsilateral hippocampal radiation dose was determined in a subgroup of 27 patients who received radiotherapy according to radiotherapy plans to evaluate its association with neurocognition. RESULTS: Between baseline and follow-up mean performance in none of the cognitive domains significantly declined in any treatment modality (radiotherapy, chemotherapy, combined radio-chemotherapy, watchful-waiting), except for selective attention in patients receiving chemotherapy alone. Apart from one subtest (inhibition), mean ipsilateral hippocampal radiation dose > 50 Gy (Dmean) as compared to  50 Gy numerically deteriorated in 4/8 domains. CONCLUSIONS: Multimodal glioma therapy seems to affect neurocognition less than generally assumed. Even patients with unilateral hippocampal irradiation with > 50 Gy showed no profound cognitive decline in this series