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Peter Hortschansky, Hubertus Haas, Eva M Huber, Michael Groll, Axel A Brakhage
The CCAAT binding complex (CBC), consisting of a heterotrimeric core structure, is highly conserved in eukaryotes and constitutes an important general transcriptional regulator. Scope of the review. In this review we discuss the scientific history and the current state of knowledge of the multiple gene regulatory functions, protein motifs and structure of the CBC in fungi with a special focus on Aspergillus species. Major conclusions and general significance. Initially identified as a transcriptional activator of respiration in Saccharomyces cerevisiae, in other fungal species the CBC was found to be involved in highly diverse pathways, but a general rationale for its involvement was missing...
December 8, 2016: Biochimica et Biophysica Acta
Gerard H Bode, Gregory Coué, Christian Freese, Karin E Pickl, Maria Sanchez-Purrà, Berta Albaiges, Salvador Borrós, Ewoud C van Winden, Leto-Aikaterini Tziveleka, Zili Sideratou, Johan F Engbersen, Smriti Singh, Krystyna Albrecht, Jürgen Groll, Martin Möller, Andy J G Pötgens, Christoph Schmitz, Eleonore Fröhlich, Christian Grandfils, Frank M Sinner, C James Kirkpatrick, Harry W M Steinbusch, Hans-Georg Frank, Ronald E Unger, Pilar Martinez-Martinez
Targeted delivery of drugs across endothelial barriers remains a formidable challenge, especially in the case of the brain, where the blood-brain barrier severely limits entry of drugs into the central nervous system. Nanoparticle-mediated transport of peptide/protein-based drugs across endothelial barriers shows great potential as a therapeutic strategy in a wide variety of diseases. Functionalizing nanoparticles with peptides allows for more efficient targeting to specific organs. We have evaluated the hemocompatibilty, cytotoxicity, endothelial uptake, efficacy of delivery and safety of liposome, hyperbranched polyester, poly(glycidol) and acrylamide-based nanoparticles functionalized with peptides targeting brain endothelial receptors, in vitro and in vivo...
November 21, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
Eva M Huber, Wolfgang Heinemeyer, Gerjan de Bruin, Herman S Overkleeft, Michael Groll
Inhibition of the immunoproteasome subunit β5i alleviates autoimmune diseases in preclinical studies and represents a promising new anti-inflammatory therapy. However, the lack of structural data on the human immunoproteasome still hampers drug design. Here, we systematically determined the potency of seven α' β' epoxyketone inhibitors with varying N-caps and P3-stereochemistry for mouse/human β5c/β5i and found pronounced differences in their subunit and species selectivity. Using X-ray crystallography, the compounds were analyzed for their modes of binding to chimeric yeast proteasomes that incorporate key parts of human β5c, human β5i or mouse β5i and the neighboring β6 subunit...
December 1, 2016: EMBO Journal
Jodi M Lestner, Andreas H Groll, Ghaith Aljayyoussi, Nita L Seibel, Aziza Shad, Corina Gonzalez, Lauren V Wood, Paul F Jarosinski, Thomas J Walsh, William W Hope
Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited pharmacokinetic (PK) data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. Our objective was to describe the pharmacokinetics of LAmB in children aged 1 to 17 years with suspected or documented IFD. Thirty-five children were treated with LAmB at doses of 2.5 to 10 mg kg(-1) daily. Samples were taken at baseline and at 0...
December 2016: Antimicrobial Agents and Chemotherapy
R A Vindas Bolaños, S M Cokelaere, J M Estrada McDermott, K E M Benders, U Gbureck, S G M Plomp, H Weinans, J Groll, P R van Weeren, J Malda
OBJECTIVE: To investigate the effect of decellularized cartilage-derived matrix (CDM) scaffolds, by itself and as a composite scaffold with a calcium phosphate (CaP) base, for the repair of osteochondral defects. It was hypothesized that the chondral defects would heal with fibrocartilaginous tissue and that the composite scaffold would result in better bone formation. METHODS: After an 8-week pilot experiment in a single horse, scaffolds were implanted in eight healthy horses in osteochondral defects on the medial trochlear ridge of the femur...
August 20, 2016: Osteoarthritis and Cartilage
Bo-Tao Xin, Gerjan de Bruin, Eva M Huber, Andrej Besse, Bogdan I Florea, Dmitri V Filippov, Gijsbert A van der Marel, Alexei F Kisselev, Mario van der Stelt, Christoph Driessen, Michael Groll, Herman S Overkleeft
This work reports the development of highly potent and selective inhibitors of the β5c catalytic activity of human constitutive proteasomes. The work describes the design principles, large hydrophobic P3 residue and small hydrophobic P1 residue, that led to the synthesis of a panel of peptide epoxyketones; their evaluation and the selection of the most promising compounds for further analyses. Structure-activity relationships detail how in a logical order the β1c/i, β2c/i, and β5i activities became resistant to inhibition as compounds were diversified stepwise...
August 11, 2016: Journal of Medicinal Chemistry
Tariq M Hassan, M Selim Asmer, Nadeem Mazhar, Tariq Munshi, Tanya Tran, Dianne L Groll
Despite their rigorous training, studies have shown that physicians experience higher rates of mental illness, substance abuse, and suicide compared to the general population. An online questionnaire was sent to a random sample of physicians across Canada to assess physicians' knowledge of the incidence of mental illness among physicians and their attitudes towards disclosure and treatment in a hypothetical situation where one developed a mental illness. We received 139 responses reflecting mostly primary care physicians and nonsurgical specialists...
2016: Psychiatry Journal
Eva M Huber, Wolfgang Heinemeyer, Xia Li, Cassandra S Arendt, Mark Hochstrasser, Michael Groll
Biogenesis of the 20S proteasome is tightly regulated. The N-terminal propeptides protecting the active-site threonines are autocatalytically released only on completion of assembly. However, the trigger for the self-activation and the reason for the strict conservation of threonine as the active site nucleophile remain enigmatic. Here we use mutagenesis, X-ray crystallography and biochemical assays to suggest that Lys33 initiates nucleophilic attack of the propeptide by deprotonating the Thr1 hydroxyl group and that both residues together with Asp17 are part of a catalytic triad...
2016: Nature Communications
M Meininger, T Schmitz, T Wagner, A Ewald, U Gbureck, J Groll, C Moseke
Surface acoustic wave (SAW) biosensors are highly sensitive for mass binding and are therefore used to detect protein-protein and protein-antibody interactions. Whilst the standard surface of the chips is a thin gold film, measurements on implant- or bone-like surfaces could significantly enhance the range of possible applications for this technique. The aim of this study was to establish methods to coat biosensor chips with Ti, TiN, and silver-doped TiN using physical vapor deposition as well as with hydroxyapatite by electrophoresis...
April 1, 2016: Materials Science & Engineering. C, Materials for Biological Applications
Elke R Duell, Manuel Glaser, Camille Le Chapelain, Iris Antes, Michael Groll, Eva M Huber
The epipolythiodioxopiperazine (ETP) gliotoxin mediates toxicity via its reactive thiol groups and thereby contributes to virulence of the human pathogenic fungus Aspergillus fumigatus. Self-intoxication of the mold is prevented either by reversible oxidation of reduced gliotoxin or by irreversible conversion to bis(methylthio)gliotoxin. The latter is produced by the S-methyltransferase TmtA and attenuates ETP biosynthesis. Here, we report the crystal structure of TmtA in complex with S-(5'-adenosyl)-l-homocysteine...
April 15, 2016: ACS Chemical Biology
Justine S van Eenennaam, Yuzhu Wei, Katja C F Grolle, Edwin M Foekema, AlberTinka J Murk
Unusually large amounts of marine snow, including Extracellular Polymeric Substances (EPS), were formed during the 2010 Deepwater Horizon oil spill. The marine snow settled with oil and clay minerals as an oily sludge layer on the deep sea floor. This study tested the hypothesis that the unprecedented amount of chemical dispersants applied during high phytoplankton densities in the Gulf of Mexico induced high EPS formation. Two marine phytoplankton species (Dunaliella tertiolecta and Phaeodactylum tricornutum) produced EPS within days when exposed to the dispersant Corexit 9500...
March 15, 2016: Marine Pollution Bulletin
Klaus M Beier, Umut C Oezdemir, Eliza Schlinzig, Anna Groll, Elena Hupp, Tobias Hellenschmidt
The Berlin Project for Primary Prevention of Child Sexual Abuse by Juveniles (PPJ) offers diagnostic and therapeutic help to 12-to-18-year-old juveniles with a sexual preference for the prepubescent and/or early pubescent body of children and who apply for treatment on a voluntary basis. The project goal is to prevent primary or recurrent child sexual abuse as well as primary or recurrent use of child abuse images. Treatment aims to enable affected juveniles to obtain control over their conflictual sexual behaviors...
February 2016: Child Abuse & Neglect
Susanne Meininger, Sourav Mandal, Alok Kumar, Jürgen Groll, Bikramjit Basu, Uwe Gbureck
UNLABELLED: Strontium ions (Sr(2+)) are known to prevent osteoporosis and also encourage bone formation. Such twin requirements have motivated researchers to develop Sr-substituted biomaterials for orthopaedic applications. The present study demonstrates a new concept of developing Sr-substituted Mg3(PO4)2 - based biodegradable scaffolds. In particular, this work reports the fabrication, mechanical properties with an emphasis on strength reliability as well as in vitro degradation of highly biodegradable strontium-incorporated magnesium phosphate cements...
February 2016: Acta Biomaterialia
Rachel L Wattier, Christopher C Dvorak, Jill A Hoffman, Ava A Brozovich, Ibrahim Bin-Hussain, Andreas H Groll, Elio Castagnola, Katherine M Knapp, Theoklis E Zaoutis, Britt Gustafsson, Lillian Sung, David Berman, Natasha B Halasa, Mark J Abzug, Aristea Velegraki, Tanvi S Sharma, Brian T Fisher, William J Steinbach
BACKGROUND: Invasive mold infections (IMIs) are a leading cause of mortality in immunocompromised children, yet there has never been an international epidemiologic investigation of pediatric IMIs. METHODS: This international, prospective cohort study was performed to characterize the epidemiology, antifungal therapy, and outcomes of pediatric IMIs. Children (≤18 years) with proven or probable IMIs were enrolled between August 2007 and May 2011 at 22 sites. Risk factors, underlying diagnoses, and treatments were recorded...
December 2015: Journal of the Pediatric Infectious Diseases Society
Christian Dubiella, Regina Baur, Haissi Cui, Eva M Huber, Michael Groll
Clinically applied proteasome inhibitors induce cell death by concomitant blockage of constitutive and immunoproteasomes. In contrast, selective immunoproteasome inhibition is less cytotoxic and has the potential to modulate chronic inflammation and autoimmune diseases. In this study, we rationally designed decarboxylated peptides that covalently target a non-catalytic cysteine of the immunoproteasome subunit β5i with α-chloroacetamide-containing sidechains. The enhanced isoform specificity decreased cytotoxic effects and the compound suppressed the production of inflammatory cytokines...
December 21, 2015: Angewandte Chemie
Fernanda Abilleira, Clarice Brum, Andrea von Groll, Pedro Eduardo da Silva
INTRODUCTION: Reports of Mycobacterium tuberculosis resistant to multiple drugs are increasing globally and laboratories are becoming increasingly aware of the need for drug susceptibility testing. In recent years, due to the long time required by conventional drug susceptibility testing, new approaches have been proposed for faster detection of drug resistance, such as the nitrate reductase assay, considered fast and inexpensive, making it a good diagnostic tool for low resource countries...
April 2015: Biomédica: Revista del Instituto Nacional de Salud
M S Valença, J L R Scaini, F S Abileira, C V Gonçalves, A von Groll, P E A Silva
SETTING: Tuberculosis (TB) in prisons is a challenge for the public health system. Active and passive case screening are important tools for TB case detection. OBJECTIVE: To characterise TB in a southern Brazil prison in terms of epidemiological variables, diagnostic approaches and clinical isolate genotypes. DESIGN: Inmates of a southern Brazilian prison were assessed using active and passive TB case screening. Sputum microscopy, culture, drug susceptibility testing and genotyping were performed...
October 2015: International Journal of Tuberculosis and Lung Disease
Veronika Haslbeck, Adrian Drazic, Julia M Eckl, Ferdinand Alte, Martin Helmuth, Grzegorz Popowicz, Werner Schmidt, Frank Braun, Matthias Weiwad, Gunter Fischer, Gerd Gemmecker, Michael Sattler, Frank Striggow, Michael Groll, Klaus Richter
Protein phosphatase 5 (PP5) is an evolutionary conserved serine/threonine phosphatase. Its dephosphorylation activity modulates a diverse set of cellular factors including protein kinases and the microtubule-associated tau protein involved in neurodegenerative disorders. It is auto-regulated by its heat-shock protein (Hsp90)-interacting tetratricopeptide repeat (TPR) domain and its C-terminal α-helix. In the present study, we report the identification of five specific PP5 activators [PP5 small-molecule activators (P5SAs)] that enhance the phosphatase activity up to 8-fold...
April 20, 2015: Bioscience Reports
Gernot Hochleitner, Tomasz Jüngst, Toby D Brown, Kathrin Hahn, Claus Moseke, Franz Jakob, Paul D Dalton, Jürgen Groll
The aim of this study was to explore the lower resolution limits of an electrohydrodynamic process combined with direct writing technology of polymer melts. Termed melt electrospinning writing, filaments are deposited layer-by-layer to produce discrete three-dimensional scaffolds for in vitro research. Through optimization of the parameters (flow rate, spinneret diameter, voltage, collector distance) for poly-ϵ-caprolactone, we could direct-write coherent scaffolds with ultrafine filaments, the smallest being 817 ± 165 nm...
September 2015: Biofabrication
Lena Keller, Alberto Plaza, Christian Dubiella, Michael Groll, Marcel Kaiser, Rolf Müller
In our screening efforts to identify unique scaffolds from myxobacteria for the drug discovery process, we used LC-SPE-NMR-MS techniques to isolate six linear peptides, termed macyranone A-F, from Cystobacter fuscus MCy9118. The macyranones are characterized by a rare 2-methylmalonamide moiety and an α-amino ketone fragment including an α',β'-epoxyketone in macyranone A. Gene disruption experiments confirmed the biosynthetic gene cluster of the macyranones as PKS/NRPS hybrid. Detailed in silico and phylogenetic analysis unraveled that the biosynthesis involves two conspicuous amide bond formations accomplished by an amidotransferase and a unique condensation domain...
July 1, 2015: Journal of the American Chemical Society
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