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Meurer, Sabine ; Pioch, Sylke ; Pabst, Tatjana ; Opitz, Nils ; Schmidt, Peter M. ; Beckhaus, Tobias ; Wagner, Kristina ; Matt, Simone ; Gegenbauer, Kristina ; Geschka, Sandra ; Karas, Michael ; Stasch, Johannes-Peter ; Schmidt, Harald H. H. W. ; Müller-Esterl, Werner
Background: Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and down-regulation of its major intracellular receptor, the alpha/beta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of sGC's heme and responsiveness to NO.
Results: sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here we show that oxidation-induced down-regulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand, BAY 58-2667, prevented sGC ubiquitination and stabilized both alpha and beta subunits.
Conclusion: Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC.
Maynard, Daniel S. ; Bialic-Murphy, Lalasia ; Zohner, Constantin ; Averill, Colin ; Hoogen, Johan van den ; Ma, Haozhi ; Mo, Lidong ; Smith, Gabriel Reuben ; Acosta, Alicia T. R. ; Aubin, Isabelle ; Berenguer, Erika ; Boonman, Coline C. F. ; Catford, Jane A. ; Cerabolini, Bruno E. L. ; Dias, Arildo S. ; González-Melo, Andrés ; Hietz, Peter ; Lusk, Christopher H. ; Mori, Akira S. ; Niinemets, Ülo ; Pillar, Valério D. ; Pinho, Bruno X. ; Rosell, Julieta A. ; Schurr, Frank ; Sheremetev, Serge N. ; Silva, Ana Carolina Feldenheimer da ; Sosinski, Ênio ; Bodegom, Peter M. van ; Weiher, Evan ; Bönisch, Gerhard ; Kattge, Jens ; Crowther, Thomas Ward
Due to massive energetic investments in woody support structures, trees are subject to unique physiological, mechanical, and ecological pressures not experienced by herbaceous plants. Despite a wealth of studies exploring trait relationships across the entire plant kingdom, the dominant traits underpinning these unique aspects of tree form and function remain unclear. Here, by considering 18 functional traits, encompassing leaf, seed, bark, wood, crown, and root characteristics, we quantify the multidimensional relationships in tree trait expression. We find that nearly half of trait variation is captured by two axes: one reflecting leaf economics, the other reflecting tree size and competition for light. Yet these orthogonal axes reveal strong environmental convergence, exhibiting correlated responses to temperature, moisture, and elevation. By subsequently exploring multidimensional trait relationships, we show that the full dimensionality of trait space is captured by eight distinct clusters, each reflecting a unique aspect of tree form and function. Collectively, this work identifies a core set of traits needed to quantify global patterns in functional biodiversity, and it contributes to our fundamental understanding of the functioning of forests worldwide.
Adamczewski-Musch, Jörn ; Akishin, Pavel G. ; Becker, Karl-Heinz ; Bendarouach, Jordan ; Deveaux, Christina Anna ; Dürr, Michael ; Eschke, Jürgen ; Förtsch, Jörg ; Heep, Julian ; Höhne, Claudia ; Ivanishchev, Dmitry ; Kampert, Karl-Heinz ; Kočenda, Leonid M. ; Kravtsov, Peter ; Kres, Ievgenii ; Lebedev, Semen ; Lebedeva, Elena ; Linev, Sergey ; Mahmoud, Tariq ; Malaev, Mikhail ; Michel, Jan ; Miftakhov, Nail ; Niebur, Wolfgang ; Otto, Jan-Hendrik ; Ovcharenko, Egor ; Patel, Vivek ; Pauly, Christian ; Pfeifer, Dennis ; Riabov, Yuri G. ; Roshchin, Evgeny ; Samsonov, Vladimir ; Tarasenkova, Olga ; Traxler, Michael ; Tyts, D. ; Vznuzdaev, Marat ; Weber, Adrian Amatus ; Zumbruch, Peter W.
The Compressed Baryonic Matter (CBM) experiment is a dedicated heavy ion collision experiment at the FAIR facility. It will be one of the first HEP experiments which works in a triggerless mode: data received in the DAQ from the detectors will not be associated with events by a hardware trigger anymore. All raw data within a giventime period will be collected continuously in containers, so-called time-slices. The task of the reconstruction algorithms is to create events out of this raw data stream. In this contribution, the optimization of the reconstruction software in the RICH detector to the free-streaming data flow is presented. The implementation of ring reconstruction algorithms which use time measurements of the hits as an additional parameter is discussed.
Grosskinsky, Sonja ; Schott, Melanie ; Brenner, Christiane ; Cutler, Sally J. ; Kraiczy, Peter ; Zipfel, Peter F. ; Simon, Markus M. ; Wallich, Reinhard
Borrelia recurrentis, the etiologic agent of louse-borne relapsing fever in humans, has evolved strategies, including antigenic variation, to evade immune defence, thereby causing severe diseases with high mortality rates. Here we identify for the first time a multifunctional surface lipoprotein of B. recurrentis, termed HcpA, and demonstrate that it binds human complement regulators, Factor H, CFHR-1, and simultaneously, the host protease plasminogen. Cell surface bound factor H was found to retain its activity and to confer resistance to complement attack. Moreover, ectopic expression of HcpA in a B. burgdorferi B313 strain, deficient in Factor H binding proteins, protected the transformed spirochetes from complement-mediated killing. Furthermore, HcpA-bound plasminogen/plasmin endows B. recurrentis with the potential to resist opsonization and to degrade extracellular matrix components. Together, the present study underscores the high virulence potential of B. recurrentis. The elucidation of the molecular basis underlying the versatile strategies of B. recurrentis to escape innate immunity and to persist in human tissues, including the brain, may help to understand the pathological processes underlying louse-borne relapsing fever.
Tedersoo, Leho ; Mikryukov, Vladimir ; Zizka, Alexander ; Bahram, Mohammad ; Hagh-Doust, Niloufar ; Anslan, Sten ; Prylutskyi, Oleh ; Delgado-Baquerizo, Manuel ; Maestre, Fernando T. ; Pärn, Jaan ; Öpik, Maarja ; Moora, Mari ; Zobel, Martin ; Espenberg, Mikk ; Mander, Ülo ; Khalid, Abdul Nasir ; Corrales, Adriana ; Agan, Ahto ; Vasco-Palacios, Aída ; Saitta, Alessandro ; Rinaldi, Andrea C. ; Verbeken, Annemieke ; Sulistyo, Bobby P. ; Tamgnoue, Boris ; Furneaux, Brendan ; Ritter, Camila Duarte ; Nyamukondiwa, Casper ; Sharp, Cathy ; Marín, César ; Gohar, Daniyal ; Klavina, Darta ; Sharmah, Dipon ; Dai, Dong Qin ; Nouhra, Eduardo ; Biersma, Elisabeth Machteld ; Rähn, Elisabeth ; Cameron, Erin K. ; De Crop, Eske ; Otsing, Eveli ; Davydov, Evgeny A. ; Albornoz, Felipe E. ; Brearley, Francis Q. ; Buegger, Franz ; Zahn, Geoffrey ; Bonito, Gregory ; Hiiesalu, Inga ; Barrio, Isabel C. ; Heilmann-Clausen, Jacob ; Ankuda, Jelena ; Kupagme, John Y. ; Maciá-Vicente, Jose G. ; Djeugap Fovo, Joseph ; Geml, József ; Alatalo, Juha M. ; Alvarez-Manjarrez, Julieta ; Põldmaa, Kadri ; Runnel, Kadri ; Adamson, Kalev ; Bråthen, Kari Anne ; Pritsch, Karin ; Tchan, Kassim I. ; Armolaitis, Kęstutis ; Hyde, Kevin D. ; Newsham, Kevin K. ; Panksep, Kristel ; Lateef, Adebola A. ; Tiirmann, Liis ; Hansson, Linda ; Lamit, Louis J. ; Saba, Malka ; Tuomi, Maria ; Gryzenhout, Marieka ; Bauters, Marijn ; Piepenbring, Meike ; Wijayawardene, Nalin ; Soulemane Yorou, Nourou ; Kurina, Olavi ; Mortimer, Peter E. ; Meidl, Peter ; Kohout, Petr ; Nilsson, R. Henrik ; Puusepp, Rasmus ; Drenkhan, Rein ; Garibay Orijel, Roberto ; Godoy, Roberto ; Alkahtani, Saad ; Rahimlou, Saleh ; Dudov, Sergey V. ; Põlme, Sergei ; Ghosh, Soumya ; Mundra, Sunil ; Ahmed, Talaat ; Netherway, Tarquin ; Henkel, Terry W. ; Roslin, Tomas ; Nteziryayo, Vincent ; Fedosov, Vladimir E. ; Onipchenko, Vladimir G. ; Erandi Yasanthika, W. A. ; Lim, Young Woon ; Soudzilovskaia, Nadejda A. ; Antonelli, Alexandre ; Kõljalg, Urmas ; Abarenkov, Kessy
Fungi play pivotal roles in ecosystem functioning, but little is known about their global patterns of diversity, endemicity, vulnerability to global change drivers and conservation priority areas. We applied the high-resolution PacBio sequencing technique to identify fungi based on a long DNA marker that revealed a high proportion of hitherto unknown fungal taxa. We used a Global Soil Mycobiome consortium dataset to test relative performance of various sequencing depth standardization methods (calculation of residuals, exclusion of singletons, traditional and SRS rarefaction, use of Shannon index of diversity) to find optimal protocols for statistical analyses. Altogether, we used six global surveys to infer these patterns for soil-inhabiting fungi and their functional groups. We found that residuals of log-transformed richness (including singletons) against log-transformed sequencing depth yields significantly better model estimates compared with most other standardization methods. With respect to global patterns, fungal functional groups differed in the patterns of diversity, endemicity and vulnerability to main global change predictors. Unlike α-diversity, endemicity and global-change vulnerability of fungi and most functional groups were greatest in the tropics. Fungi are vulnerable mostly to drought, heat, and land cover change. Fungal conservation areas of highest priority include wetlands and moist tropical ecosystems.
Friess, Helmut ; Langrehr, Jan M. ; Oettle, Helmut ; Raedle, Jochen ; Niedergethmann, Marco ; Dittrich, Christian ; Hossfeld, Dieter K. ; Stöger, Herbert ; Neyns, Bart ; Herzog, Peter ; Piedbois, Pascal ; Dobrowolski, Frank ; Scheithauer, Werner ; Hawkins, Robert ; Katz, Frieder ; Balcke, Peter ; Vermorken, Jan ; Van Belle, Simon ; Davidson, Neville ; Esteve, Albert Abad ; Castellano, Daniel ; Kleeff, Jörg ; Tempia-Caliera, Adrien A. ; Kovar, Andreas ; Nippgen, Johannes
Background Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. Methods A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. Results Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. Conclusion There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.
Lal, Dennis ; Ruppert, Ann-Kathrin ; Trucks, Holger ; Schulz, Herbert ; Kovel, Carolien G. de ; Kasteleijn-Nolst Trenité, Dorothée G. ; Sonsma, Anja C. M. ; Koeleman, Bobby P. ; Lindhout, Dick ; Weber, Yvonne G. ; Lerche, Holger ; Kapser, Claudia ; Schankin, Christoph Josef ; Kunz, Wolfram S. ; Surges, Rainer ; Elger, Christian Erich ; Gaus, Verena ; Schmitz, Bettina ; Helbig, Ingo ; Muhle, Hiltrud ; Stephani, Ulrich ; Klein, Karl Martin ; Rosenow, Felix ; Neubauer, Bernd Axel ; Reinthaler, Eva Maria ; Zimprich, Fritz ; Feucht, Martha ; Møller, Rikke S. ; Hjalgrim, Helle ; Jonghe, Peter De ; Suls, Arvid ; Lieb, Wolfgang ; Franke, Andre ; Strauch, Konstantin ; Gieger, Christian ; Schurmann, Claudia ; Schminke, Ulf ; Nürnberg, Peter ; Sander, Thomas
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
Grottenthaler, Julia M. ; Werner, Christoph R. ; Steurer, Martina ; Spengler, Ulrich ; Berg, Thomas ; Engelmann, Cornelius ; Wedemeyer, Heiner ; Hahn, Thomas von ; Stremmel, Wolfgang ; Pathil-Warth, Anita ; Seybold, Ulrich ; Schott, Eckart ; Blessin, Usha ; Sarrazin, Christoph ; Welker, Martin-Walter ; Harrer, Ellen ; Scholten, Stefan ; Hinterleitner, Clemens ; Lauer, Ulrich Manfred ; Malek, Nisar Peter ; Berg, Christoph Peter
Objectives: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.
Methods: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).
Results: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.
Conclusion: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
Lévesque, C. André ; Brouwer, Henk ; Cano, Liliana ; Hamilton, John P. ; Holt, Carson ; Huitema, Edgar ; Raffaele, Sylvain ; Robideau, Gregg P. ; Thines, Marco ; Win, Joe ; Zerillo, Marcelo M. ; Beakes, Gordon W. ; Boore, Jeffrey L. ; Busam, Dana ; Dumas, Bernard ; Ferriera, Steve ; Fürstenberg, Susan ; Gachon, Claire M. M. ; Gaulin, Elodie ; Govers, Francine ; Grenville-Briggs, Laura ; Horner, Neil ; Hostetler, Jessica ; Jiang, Rays H. Y. ; Johnson, Justin ; Krajaejun, Theerapong ; Lin, Haining ; Meijer, Harold J. G. ; Moore, Barry ; Morris, Paul ; Phuntmart, Vipaporn ; Puiu, Daniela ; Shetty, Jyoti ; Stajich, Jason E. ; Tripathy, Sucheta ; Wawra, Stephan ; West, Pieter van ; Whitty, Brett R. ; Coutinho, Pedro M. ; Henrissat, Bernard ; Martin, Frank ; Thomas, Paul D. ; Tyler, Brett M. ; Vries, Ronald Peter de ; Kamoun, Sophien ; Yandell, Mark ; Tisserat, Ned ; Buell, C. Robin
Background: Pythium ultimum (P. ultimum) is a ubiquitous oomycete plant pathogen responsible for a variety of diseases on a broad range of crop and ornamental species. Results: The P. ultimum genome (42.8 Mb) encodes 15,290 genes and has extensive sequence similarity and synteny with related Phytophthora species, including the potato blight pathogen Phytophthora infestans. Whole transcriptome sequencing revealed expression of 86% of genes, with detectable differential expression of suites of genes under abiotic stress and in the presence of a host. The predicted proteome includes a large repertoire of proteins involved in plant pathogen interactions although surprisingly, the P. ultimum genome does not encode any classical RXLR effectors and relatively few Crinkler genes in comparison to related phytopathogenic oomycetes. A lower number of enzymes involved in carbohydrate metabolism were present compared to Phytophthora species, with the notable absence of cutinases, suggesting a significant difference in virulence mechanisms between P. ultimum and more host specific oomycete species. Although we observed a high degree of orthology with Phytophthora genomes, there were novel features of the P. ultimum proteome including an expansion of genes involved in proteolysis and genes unique to Pythium. We identified a small gene family of cadherins, proteins involved in cell adhesion, the first report in a genome outside the metazoans. Conclusions: Access to the P. ultimum genome has revealed not only core pathogenic mechanisms within the oomycetes but also lineage specific genes associated with the alternative virulence and lifestyles found within the pythiaceous lineages compared to the Peronosporaceae.
Kashani, Kianoush ; Al-Khafaji, Ali ; Ardiles, Thomas ; Artigas, Antonio ; Bagshaw, Sean M. ; Bell, Max ; Bihorac, Azra ; Birkhahn, Robert ; Cely, Cynthia M. ; Chawla, Lakhmir S. ; Davison, Danielle L. ; Feldkamp, Thorsten ; Forni, Lui G. ; Gong, Michelle Ng ; Gunnerson, Kyle J. ; Haase, Michael ; Hackett, James ; Honore, Patrick M. ; Hoste, Eric A. J. ; Joannes-Boyau, Olivier ; Joannidis, Michael ; Kim, Patrick ; Koyner, Jay L. ; Laskowitz, Daniel T. ; Lissauer, Matthew E. ; Marx, Gernot ; McCullough, Peter A. ; Mullaney, Scott ; Ostermann, Marlies ; Rimmelé, Thomas ; Shapiro, Nathan I. ; Shaw, Andrew D. ; Shi, Jing ; Sprague, Amy M. ; Vincent, Jean-Louis ; Vinsonneau, Christophe ; Wagner, Ludwig ; Walker, Michael G. ; Wilkerson, R. Gentry ; Zacharowski, Kai ; Kellum, John A.
Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2].[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2].[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2].[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration: ClinicalTrials.gov number NCT01209169.