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We argue two alternative routes that lead entrepreneurial start-ups to acquisition outcomes instead of liquidation. On one hand, acquisitions can come about through the control route with external financers such as venture capitalists (VCs). VCs take control through their board seats along with other contractual rights that can bring about changes in a start-up necessary to successfully attract a strategic acquirer. Consistent with this view, we show that VCs often replace the founding entrepreneur as CEO long before an acquisition exit. On the other hand, acquisitions can come about through advice and support provided to the start-up, such as that provided by an incubator or technology park. Based on a sample of 251 Crunchbase companies in the U.S. over the years 2007 to 2014, we present evidence that is strongly consistent with these propositions. Further, we show that the data indicate a tension between VC-backing of start-ups resident in technology parks insofar as such start-ups are slower to become, and less likely to be, acquired.
Kieffer, Tara L. ; De Meyer, Sandra ; Bartels, Doug J. ; Sullivan, James C. ; Zhang, Eileen Z. ; Tigges, Ann ; Dierynck, Inge ; Spanks, Joan ; Dorrian, Jennifer ; Jiang, Min ; Adiwijaya, Bambang ; Ghys, Anne ; Beumont, Maria ; Kauffman, Robert S. ; Adda, Nathalie ; Jacobson, Ira M. ; Sherman, Kenneth E. ; Zeuzem, Stefan ; Kwong, Ann D. ; Picchio, Gaston
Background: In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR.
Methods: Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.
Results: Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients.
Conclusions: A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment.
Rieke, Johanna Magdalena ; Zhang, Rong ; Braun, Doreen ; Yilmaz, Öznur ; Japp, Anna S. ; Lopes, Filipa M. ; Pleschka, Michael ; Hilger, Alina Christine ; Schneider, Sophia ; Newman, William G. ; Schneider, Sophia ; Newman, William G. ; Beaman, Glenda M. ; Nordenskjöld, Agneta ; Ebert, Anne-Karoline ; Promm, Martin ; Rösch, Wolfgang H. ; Stein, Raimund ; Hirsch, Karin ; Schäfer, Frank-Mattias ; Schmiedeke, Eberhard ; Boemers, Thomas M. ; Lacher, Martin ; Kluth, Dietrich ; Gosemann, Jan-Hendrik ; Anderberg, Magnus ; Barker, Gillian ; Holmdahl, Gundela ; Läckgren, Göran ; Keene, David ; Cervellione, Raimondo M. ; Giorgio, Elisa ; Di Grazia, Massimo ; Feitz, Wouter F. J. ; Marcelis, Carlo L. M. ; Rooij, Iris Antonia Leonarda Martina van ; Bökenkamp, Arend ; Beckers, Goedele M. A. ; Keegan, Catherine E. ; Sharma, Amit ; Dakal, Tikam Chand ; Wittler, Lars ; Grote, Phillip ; Zwink, Nadine ; Jenetzky, Ekkehart ; Brusco, Alfredo ; Thiele, Holger ; Ludwig, Michael ; Schweizer, Ulrich ; Woolf, Adrian S. ; Odermatt, Benjamin ; Reutter, Heiko
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Hitzel, Juliane ; Lee, Eunjee ; Zhang, Yi ; Bibli, Sofia Iris ; Li, Xiaogang ; Zukunft, Sven ; Pflüger, Beatrice ; Hu, Jiong ; Schürmann, Christoph ; Vasconez, Andrea Estefania ; Oo, James A. ; Kratzer, Adelheid ; Kumar, Sandeep ; Rezende Felipe, Flávia Figueiredo de ; Josipovic, Ivana ; Thomas, Dominique Jeanette ; Giral, Hector ; Schreiber, Yannick ; Geisslinger, Gerd ; Fork, Christian ; Yang, Xia ; Sigala, Fragiska ; Romanoski, Casey E. ; Kroll, Jens ; Jo, Hanjoong ; Landmesser, Ulf ; Lusis, Aldons J. ; Namgaladze, Dmitry ; Fleming, Ingrid ; Leisegang, Matthias ; Zhu, Jianhui ; Brandes, Ralf
Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
Madey, Richard ; Zhang, Wei-Ming ; Anderson, Bryon D. ; Baldwin, Alan Richard ; Elaasar, Mostafa ; Flanders, Bruce S. ; Keane, Declan ; Pairsuwan, Weerapong ; Varga, J. ; Watson, John W. ; Westfall, Gary D. ; Hartnack, Christoph ; Stöcker, Horst ; Frankel, Kenneth A.
Inclusive neutron spectra were measured at 0°, 4°, 8°, 15°, 30°, and 42° from Nb-Nb and Au-Au collisions at 800 MeV/nucleon. A peak that originates from neutron evaporation from the projectile appears in the spectra at angles out to 8°. The shapes and magnitudes of the spectra are compared with those calculated from models of nucleus-nucleus collisions. The differential cross sections for Au-Au collisions are about four times those for Nb-Nb collisions. The predictions of the Vlasov-Uehling-Uhlenbeck (VUU) and QMD theories agree with the angular distributions of the differential cross sections except at small angles; the VUU prediction overestimates the angular distributions from a few degrees to about 20°, whereas the QMD prediction underestimates the angular distributions below 8°. The Firestreak model overestimates the angular distribution for Nb-Nb collisions and underestimates it for Au-Au collisions. Also, the VUU and QMD models agree with the measured double-differential cross sections in more angular and energy regions than the Firestreak and intranuclear cascade models; however, none of the models can account for the peaks at small angles (θ≤15°).
Zhang, Rong ; Gehlen, Jan ; Kawalia, Amit ; Melissari, Maria-Theodora ; Dakal, Tikam Chand ; Menon, Athira M. ; Höfele, Julia ; Riedhammer, Korbinian ; Waffenschmidt, Lea ; Fabian, Julia ; Breuer, Katinka ; Kalanithy, Jeshurun ; Hilger, Alina Christine ; Sharma, Amit ; Hölscher, Alice ; Boemers, Thomas M. ; Pauly, Markus ; Leutner, Andreas ; Fuchs, Jörg ; Seitz, Guido ; Ludwikowski, Barbara ; Gomez, Barbara ; Hubertus, Jochen ; Heydweiller, Andreas ; Kurz, Ralf ; Leonhardt, Johannes ; Kosch, Ferdinand ; Holland-Cunz, Stefan ; Münsterer, Oliver ; Ure, Beno ; Schmiedeke, Eberhard ; Neser, Jörg ; Degenhardt, Petra ; Märzheuser, Stefanie ; Kleine, Katharina ; Schäfer, Mattias ; Spychalski, Nicole ; Deffaa, Oliver J. ; Gosemann, Jan-Hendrik ; Lacher, Martin ; Heilmann-Heimbach, Stefanie ; Zwink, Nadine ; Jenetzky, Ekkehart ; Ludwig, Michael ; Grote, Phillip ; Schumacher, Johannes ; Thiele, Holger ; Reutter, Heiko
Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.