Bauer,F

JACC Cardiovasc Interv. 2012 Apr 25;: 22560979

Transfemoral Aortic Valve Replacement With the Edwards SAPIEN and Edwards SAPIEN XT Prosthesis Using Exclusively Local Anesthesia and Fluoroscopic Guidance: Feasibility and 30-Day Outcomes.

Eric Durand, Bogdan Borz, Matthieu Godin, Christophe Tron, Pierre-Yves Litzler, Jean-Paul Bessou, Karim Bejar, Chiara Fraccaro, Carlos Sanchez-Giron, Jean-Nicolas Dacher, Fabrice Bauer, Alain Cribier, Hélène Eltchaninoff

Department of Cardiology, University Hospital of Rouen, INSERM U 1096, Hospital Charles Nicolle, Rouen, France.

OBJECTIVES: The authors report the feasibility and 30-day outcomes of transfemoral aortic valve replacement (TAVR), using the Edwards SAPIEN (Edwards Lifesciences, Irvine, California) and Edwards SAPIEN XT (Edwards Lifesciences) prosthesis, implanted using exclusively local anesthesia and fluoroscopic guidance. BACKGROUND: Transfemoral TAVR is often managed with general anesthesia. However, a simplified percutaneous approach using local anesthesia has become more popular because it offers multiple advantages in an elderly and fragile population. METHODS: Between May 2006 and January 2011, the authors prospectively evaluated 151 consecutive patients (logistic euroSCORE: 22.8 ± 11.8%) who underwent TAVR (SAPIEN: n = 78, SAPIEN XT: n = 73) using only local anesthesia and fluoroscopic guidance. The primary endpoint was a combination of all-cause mortality, major stroke, life-threatening bleeding, stage 3 acute kidney injury (AKI), periprocedural myocardial infarction (MI), major vascular complication, and repeat procedure for valve-related dysfunction at 30 days. RESULTS: Transarterial femoral approach was surgical in all SAPIEN procedures and percutaneous in 97.3% of SAPIEN XT, using the ProStar vascular closure device, and was well tolerated in all cases. Conversion to general anesthesia was required in 3.3%(SAPIEN cases) and was related to complications. Vasopressors were required in 5.5%. Procedural success was 95.4%. The combined-safety endpoint was reached in 15.9%, including overall mortality (6.6%), major stroke (2.0%), life-threatening bleeding (7.9%), stage 3 AKI (0.7%), periprocedural MI (1.3%), major vascular complication (7.9%), and repeat procedure for valve-related dysfunction (2.0%) at 30 days. A permanent pacemaker was required in 5.3%. CONCLUSIONS: This single-center, prospective registry demonstrated the feasibility and safety of a simplified transfemoral TAVR performed using only local anesthesia and fluoroscopic guidance in high surgical risk patients with severe aortic stenosis.

Phys Rev Lett. 2012 Mar 16;108 (11):111803 22540463

Search for the Standard Model Higgs Boson in the Diphoton Decay Channel with 4.9 fb^{-1} of pp Collision Data at sqrt[s]=7 TeV with ATLAS.

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Fakultät für Mathematik und Physik, Albert-Ludwigs-Universität, Freiburg i.Br., Germany.

A search for the standard model Higgs boson is performed in the diphoton decay channel. The data used correspond to an integrated luminosity of 4.9 fb^{-1} collected with the ATLAS detector at the Large Hadron Collider in proton-proton collisions at a center-of-mass energy of sqrt[s]=7 TeV. In the diphoton mass range 110-150 GeV, the largest excess with respect to the background-only hypothesis is observed at 126.5 GeV, with a local significance of 2.8 standard deviations. Taking the look-elsewhere effect into account in the range 110-150 GeV, this significance becomes 1.5 standard deviations. The standard model Higgs boson is excluded at 95% confidence level in the mass ranges of 113-115 GeV and 134.5-136 GeV.

Phys Rev Lett. 2012 Mar 16;108 (11):111802 22540462

Search for the Higgs Boson in the H→WW^{(*)}→l^{+}νl^{-}ν[over ¯] Decay Channel in pp Collisions at sqrt[s]=7 TeV with the ATLAS Detector.

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Undrus, G Unel, Y Unno, D Urbaniec, G Usai, M Uslenghi, L Vacavant, V Vacek, B Vachon, S Vahsen, J Valenta, P Valente, S Valentinetti, S Valkar, E Valladolid Gallego, S Vallecorsa, J A Valls Ferrer, H van der Graaf, E van der Kraaij, R Van Der Leeuw, E van der Poel, D van der Ster, N van Eldik, P van Gemmeren, Z van Kesteren, I van Vulpen, M Vanadia, W Vandelli, G Vandoni, A Vaniachine, P Vankov, F Vannucci, F Varela Rodriguez, R Vari, E W Varnes, D Varouchas, A Vartapetian, K E Varvell, V I Vassilakopoulos, F Vazeille, G Vegni, J J Veillet, C Vellidis, F Veloso, R Veness, S Veneziano, A Ventura, D Ventura, M Venturi, N Venturi, V Vercesi, M Verducci, W Verkerke, J C Vermeulen, A Vest, M C Vetterli, I Vichou, T Vickey, O E Vickey Boeriu, G H A Viehhauser, S Viel, M Villa, M Villaplana Perez, E Vilucchi, M G Vincter, E Vinek, V B Vinogradov, M Virchaux, J Virzi, O Vitells, M Viti, I Vivarelli, F Vives Vaque, S Vlachos, D Vladoiu, M Vlasak, N Vlasov, A Vogel, P Vokac, G Volpi, M Volpi, G Volpini, H von der Schmitt, J von Loeben, H von Radziewski, E von Toerne, V Vorobel, A P Vorobiev, V Vorwerk, M Vos, R Voss, T T Voss, J H Vossebeld, N Vranjes, M Vranjes Milosavljevic, V Vrba, M Vreeswijk, T Vu Anh, R Vuillermet, I Vukotic, W Wagner, P Wagner, H Wahlen, J Wakabayashi, J Walbersloh, S Walch, J Walder, R Walker, W Walkowiak, R Wall, P Waller, A Walz, C Wang, H Wang, J Wang, J C Wang, R Wang, S M Wang, A Warburton, C P Ward, M Warsinsky, R Wastie, P M Watkins, A T Watson, I J Watson, M F Watson, G Watts, S Watts, A T Waugh, B M Waugh, J Weber, M Weber, M S Weber, P Weber, A R Weidberg, P Weigell, J Weingarten, C Weiser, H Wellenstein, P S Wells, M Wen, T Wenaus, S Wendler, Z Weng, T Wengler, S Wenig, N Wermes, M Werner, P Werner, M Werth, M Wessels, C Weydert, K Whalen, S J Wheeler-Ellis, S P Whitaker, A White, M J White, S R Whitehead, D Whiteson, D Whittington, F Wicek, D Wicke, F J Wickens, W Wiedenmann, M Wielers, P Wienemann, C Wiglesworth, L A M Wiik, L A M Wiik-Fuchs, P A Wijeratne, A Wildauer, M A Wildt, I Wilhelm, H G Wilkens, J Z Will, E Williams, H H Williams, W Willis, S Willocq, J A Wilson, M G Wilson, A Wilson, I Wingerter-Seez, S Winkelmann, F Winklmeier, M Wittgen, M W Wolter, H Wolters, W C Wong, G Wooden, B K Wosiek, J Wotschack, M J Woudstra, K W Wozniak, K Wraight, C Wright, M Wright, B Wrona, S L Wu, X Wu, Y Wu, E Wulf, R Wunstorf, B M Wynne, S Xella, M Xiao, S Xie, Y Xie, C Xu, D Xu, G Xu, B Yabsley, S Yacoob, M Yamada, H Yamaguchi, A Yamamoto, K Yamamoto, S Yamamoto, T Yamamura, T Yamanaka, J Yamaoka, T Yamazaki, Y Yamazaki, Z Yan, H Yang, U K Yang, Y Yang, Z Yang, S Yanush, Y Yao, Y Yasu, G V Ybeles Smit, J Ye, S Ye, M Yilmaz, R Yoosoofmiya, K Yorita, R Yoshida, K Yoshihara, C Young, S Youssef, D Yu, J Yu, L Yuan, A Yurkewicz, B Zabinski, V G Zaets, R Zaidan, A M Zaitsev, Z Zajacova, Yo K Zalite, L Zanello, P Zarzhitsky, A Zaytsev, C Zeitnitz, M Zeller, M Zeman, A Zemla, C Zendler, O Zenin, T Zeniš, Z Zenonos, S Zenz, D Zerwas, G Zevi Della Porta, Z Zhan, D Zhang, H Zhang, J Zhang, X Zhang, Z Zhang, L Zhao, T Zhao, Z Zhao, A Zhemchugov, S Zheng, J Zhong, B Zhou, N Zhou, Y Zhou, C G Zhu, H Zhu, J Zhu, Y Zhu, X Zhuang, V Zhuravlov, D Zieminska, R Zimmermann, S Zimmermann, M Ziolkowski, R Zitoun, L Zivković, V V Zmouchko, G Zobernig, A Zoccoli, Y Zolnierowski, A Zsenei, M Zur Nedden, V Zutshi, L Zwalinski

Fakultät für Mathematik und Physik, Albert-Ludwigs-Universität, Freiburg im Breisgau, Germany.

A search for the Higgs boson has been performed in the H→WW^{(*)}→ℓ^{+}νℓ^{-}ν[over ¯] channel (ℓ=e/μ) with an integrated luminosity of 2.05 fb^{-1} of pp collisions at sqrt[s]=7 TeV collected with the ATLAS detector at the Large Hadron Collider. No significant excess of events over the expected background is observed and limits on the Higgs boson production cross section are derived for a Higgs boson mass in the range 110 GeV<m_{H}<300 GeV. The observations exclude the presence of a standard model Higgs boson with a mass 145<m_{H}<206 GeV at 95% confidence level.

Int J Pharm. 2012 Apr 15;: 22525086

Differential efficacy of DOTAP enantiomers for siRNA delivery in vitro.

Megan Cavanaugh Terp, Finn Bauer, Yasuro Sugimoto, Bo Yu, Robert W Brueggemeier, L James Lee, Robert J Lee

Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA; NSF Nanoscale Science and Engineering Center (NSEC) for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.

DOTAP, as a racemic mixture, is a cationic lipid and a widely used transfection reagent. In this study, the effect of DOTAP's stereochemical structure on transfection efficiency was evaluated in vitro. Racemic and enantiomerically pure DOTAP were used in lipoplex formulations to deliver siRNA to MCF-7 cells, targeting the aromatase enzyme. At the 50nM siRNA concentration and lipid-to-RNA charge ratios of 4 and 5, the R enantiomer of DOTAP was found to perform better than either the S- or the racemic agent. In addition, at 10nM siRNA concentration and a charge ratio of 3, the R- lipoplex formulation silenced aromatase by ∼50% whereas the S and racemic formulations caused no significant target downregulation. Differences in lipid packing were modeled using membrane simulations. The results showed that, when combined with cholesterol, pure R-DOTAP and S-DOTAP enantiomers had 105% and 115% of lipid density relative to racemic DOTAP, respectively. These findings suggest an important role of lipid chirality in future development of lipid based siRNA delivery systems.

Arch Cardiovasc Dis. 2012 Mar ;105 (3):132-40 22520795

Prospective analysis of 30-day safety and performance of transfemoral transcatheter aortic valve implantation with Edwards SAPIEN XT versus SAPIEN prostheses.

Hélène Eltchaninoff, Eric Durand, Bogdan Borz, Matthieu Godin, Christophe Tron, Pierre-Yves Litzler, Jean-Paul Bessou, Karim Bejar, Chiara Fraccaro, Carlos Sanchez-Giron, Jean-Nicolas Dacher, Fabrice Bauer, Alain Cribier

Department of Cardiology, Hospital Charles-Nicolle, University Hospital of Rouen, 1, rue de Germont, 76031 Rouen cedex, France; University of Rouen, Inserm U1096, 76183 Rouen, France.

BACKGROUND A new generation of balloon-expandable valves (e.g. Edwards SAPIEN XT) enables the use of a decreased sheath size using the NovaFlex™ delivery system for transfemoral transcatheter aortic valve implantation (TAVI). However, there are few data analysing the efficacy and safety of this new prosthesis. AIMS To evaluate periprocedural and 30-day clinical outcomes using the Edwards SAPIEN XT compared with the first-generation Edwards SAPIEN prosthesis. METHODS Between May 2006 and October 2011, consecutive high-risk or non-operable patients with severe aortic stenosis had TAVI using an Edwards SAPIEN or SAPIEN XT prosthesis. Valve Academic Research Consortium endpoints were used. RESULTS Of 250 patients who underwent TAVI, 190 were performed transfemorally (78 SAPIEN and 112 SAPIEN XT). Transfemoral access was possible more often using SAPIEN XT (112/123 [91.1%] vs 78/127 [61.4%]; P<0.001). Mean logistic EuroSCORE was significantly lower in the SAPIEN XT group (18.1±11.0% vs 27.3±11.1%; P<0.0001), and the iliofemoral artery minimal lumen diameter was smaller (6.7±1.2 vs 8.5±1.3mm; P<0.0001). Device success was similar in both groups (95.5% for SAPIEN XT and 93.6% for SAPIEN), as was the 30-day combined safety endpoint (15.2% and 17.9%, respectively). At 30days, prosthesis performance was similar in both groups. CONCLUSIONS Short-term safety and performance analysis of the latest generation of balloon-expandable valve, the SAPIEN XT, seem similar to the previous generation. However, transfemoral implantation is more often possible, related to sheath size reduction.

PLoS One. 2012 ;7 (3):e32148 22403629

Common Variants in the Type 2 Diabetes KCNQ1 Gene Are Associated with Impairments in Insulin Secretion During Hyperglycaemic Glucose Clamp.

Molecular Genetics, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

BACKGROUND Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. METHODOLOGY The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. PRINCIPAL FINDINGS We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. CONCLUSIONS Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.

Phys Rev Lett. 2012 Jan 27;108 (4):041805 22400827

Search for New Phenomena in tt[over ¯] Events with Large Missing Transverse Momentum in Proton-Proton Collisions at sqrt[s]=7 TeV with the ATLAS Detector.

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A T H Arce, J P Archambault, S Arfaoui, J-F Arguin, E Arik, M Arik, A J Armbruster, O Arnaez, C Arnault, A Artamonov, G Artoni, D Arutinov, S Asai, R Asfandiyarov, S Ask, B Asman, L Asquith, K Assamagan, A Astbury, A Astvatsatourov, G Atoian, B Aubert, E Auge, K Augsten, M Aurousseau, N Austin, G Avolio, R Avramidou, D Axen, C Ay, G Azuelos, Y Azuma, M A Baak, G Baccaglioni, C Bacci, A M Bach, H Bachacou, K Bachas, G Bachy, M Backes, M Backhaus, E Badescu, P Bagnaia, S Bahinipati, Y Bai, D C Bailey, T Bain, J T Baines, O K Baker, M D Baker, S Baker, E Banas, P Banerjee, Sw Banerjee, D Banfi, A Bangert, V Bansal, H S Bansil, L Barak, S P Baranov, A Barashkou, A Barbaro Galtieri, T Barber, E L Barberio, D Barberis, M Barbero, D Y Bardin, T Barillari, M Barisonzi, T Barklow, N Barlow, B M Barnett, R M Barnett, A Baroncelli, G Barone, A J Barr, F Barreiro, J Barreiro Guimarães da Costa, P Barrillon, R Bartoldus, A E Barton, D Bartsch, V Bartsch, R L Bates, L Batkova, J R Batley, A 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Blondel, W Blum, U Blumenschein, G J Bobbink, V B Bobrovnikov, S S Bocchetta, A Bocci, C R Boddy, M Boehler, J Boek, N Boelaert, S Böser, J A Bogaerts, A Bogdanchikov, A Bogouch, C Bohm, V Boisvert, T Bold, V Boldea, N M Bolnet, M Bona, V G Bondarenko, M Bondioli, M Boonekamp, G Boorman, C N Booth, S Bordoni, C Borer, A Borisov, G Borissov, I Borjanovic, S Borroni, K Bos, D Boscherini, M Bosman, H Boterenbrood, D Botterill, J Bouchami, J Boudreau, E V Bouhova-Thacker, C Bourdarios, N Bousson, A Boveia, J Boyd, I R Boyko, N I Bozhko, I Bozovic-Jelisavcic, J Bracinik, A Braem, P Branchini, G W Brandenburg, A Brandt, G Brandt, O Brandt, U Bratzler, B Brau, J E Brau, H M Braun, B Brelier, J Bremer, R Brenner, S Bressler, D Breton, D Britton, F M Brochu, I Brock, R Brock, T J Brodbeck, E Brodet, F Broggi, C Bromberg, G Brooijmans, W K Brooks, G Brown, H Brown, P A Bruckman de Renstrom, D Bruncko, R Bruneliere, S Brunet, A Bruni, G Bruni, M Bruschi, T Buanes, F Bucci, J Buchanan, N J 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J Zhu, Y Zhu, X Zhuang, V Zhuravlov, D Zieminska, R Zimmermann, S Zimmermann, M Ziolkowski, R Zitoun, L Zivković, V V Zmouchko, G Zobernig, A Zoccoli, Y Zolnierowski, A Zsenei, M Zur Nedden, V Zutshi, L Zwalinski

Fakultät für Mathematik und Physik, Albert-Ludwigs-Universität, Freiburg i.Br., Germany.

A search for new phenomena in tt[over ¯] events with large missing transverse momentum in proton-proton collisions at a center-of-mass energy of 7 TeV is presented. The measurement is based on 1.04 fb^{-1} of data collected with the ATLAS detector at the LHC. Contributions to this final state may arise from a number of standard model extensions. The results are interpreted in terms of a model where new top-quark partners are pair produced and each decay to an on-shell top (or antitop) quark and a long-lived undetected neutral particle. The data are found to be consistent with standard model expectations. A limit at 95% confidence level is set excluding a cross section times branching ratio of 1.1 pb for a top-partner mass of 420 GeV and a neutral particle mass less than 10 GeV. In a model of exotic fourth generation quarks, top-partner masses are excluded up to 420 GeV and neutral particle masses up to 140 GeV.

Phys Rev Lett. 2012 Jan 27;108 (4):041804 22400826

Measurement of the ZZ Production Cross Section and Limits on Anomalous Neutral Triple Gauge Couplings in Proton-Proton Collisions at sqrt[s]=7 TeV with the ATLAS Detector.

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Ward, M Warsinsky, P M Watkins, A T Watson, M F Watson, G Watts, S Watts, A T Waugh, B M Waugh, J Weber, M Weber, M S Weber, P Weber, A R Weidberg, P Weigell, J Weingarten, C Weiser, H Wellenstein, P S Wells, M Wen, T Wenaus, S Wendler, Z Weng, T Wengler, S Wenig, N Wermes, M Werner, P Werner, M Werth, M Wessels, C Weydert, K Whalen, S J Wheeler-Ellis, S P Whitaker, A White, M J White, S R Whitehead, D Whiteson, D Whittington, D Wicke, F J Wickens, W Wiedenmann, M Wielers, P Wienemann, C Wiglesworth, L A M Wiik, P A Wijeratne, A Wildauer, M A Wildt, I Wilhelm, H G Wilkens, J Z Will, E Williams, H H Williams, W Willis, S Willocq, J A Wilson, M G Wilson, A Wilson, I Wingerter-Seez, S Winkelmann, F Winklmeier, M Wittgen, M W Wolter, H Wolters, W C Wong, G Wooden, B K Wosiek, J Wotschack, M J Woudstra, K Wraight, C Wright, M Wright, B Wrona, S L Wu, X Wu, Y Wu, E Wulf, R Wunstorf, B M Wynne, S Xella, M Xiao, S Xie, Y Xie, C Xu, D Xu, G Xu, B Yabsley, S Yacoob, M Yamada, H Yamaguchi, A Yamamoto, K Yamamoto, S Yamamoto, T Yamamura, T Yamanaka, J Yamaoka, T Yamazaki, Y Yamazaki, Z Yan, H Yang, U K Yang, Y Yang, Z Yang, S Yanush, Y Yasu, G V Ybeles Smit, J Ye, S Ye, M Yilmaz, R Yoosoofmiya, K Yorita, R Yoshida, C Young, S Youssef, D Yu, J Yu, L Yuan, A Yurkewicz, V G Zaets, R Zaidan, A M Zaitsev, Z Zajacova, Yo K Zalite, L Zanello, P Zarzhitsky, A Zaytsev, C Zeitnitz, M Zeller, M Zeman, A Zemla, C Zendler, O Zenin, T Zeniš, Z Zenonos, S Zenz, D Zerwas, G Zevi Della Porta, Z Zhan, D Zhang, H Zhang, J Zhang, X Zhang, Z Zhang, L Zhao, T Zhao, Z Zhao, A Zhemchugov, S Zheng, J Zhong, B Zhou, N Zhou, Y Zhou, C G Zhu, H Zhu, J Zhu, Y Zhu, X Zhuang, V Zhuravlov, D Zieminska, R Zimmermann, S Zimmermann, M Ziolkowski, R Zitoun, L Zivković, V V Zmouchko, G Zobernig, A Zoccoli, Y Zolnierowski, A Zsenei, M Zur Nedden, V Zutshi, L Zwalinski

Fakultät für Mathematik und Physik, Albert-Ludwigs-Universität, Freiburg i.Br., Germany.

A measurement of the ZZ production cross section in proton-proton collisions at sqrt[s]=7 TeV using data corresponding to an integrated luminosity of 1.02 fb^{-1} recorded by the ATLAS experiment at the LHC is presented. Twelve events containing two Z boson candidates decaying to electrons and/or muons are observed, with an expected background of 0.3±0.3(stat)_{-0.3}^{+0.4}(syst) events. The cross section measured in a phase-space region with good detector acceptance and for dilepton masses within the range 66 to 116 GeV is σ_{ZZ→ℓ^{+}ℓ^{-}ℓ^{+}ℓ^{-}}^{fid}=19.4_{-5.2}^{+6.3}(stat)_{-0.7}^{+0.9}(syst)±0.7(lumi) fb. The resulting total cross section for on-shell ZZ production, σ_{ZZ}^{tot}=8.5_{-2.3}^{+2.7}(stat)_{-0.3}^{+0.4}(syst)±0.3(lumi) pb, is consistent with the standard model expectation of 6.5_{-0.2}^{+0.3} pb calculated at the next-to-leading order in QCD. Limits on anomalous neutral triple gauge boson couplings are derived.

G3 (Bethesda). 2012 Jan ;2 (1):131-41 22384390

Many Saccharomyces cerevisiae Cell Wall Protein Encoding Genes Are Coregulated by Mss11, but Cellular Adhesion Phenotypes Appear Only Flo Protein Dependent.

Michael C Bester, Dan Jacobson, Florian F Bauer

Institute for Wine Biotechnology, Faculty of Agricultural and Forestry Sciences, Stellenbosch University, 7600 Stellenbosch, South Africa.

The outer cell wall of the yeast Saccharomyces cerevisiae serves as the interface with the surrounding environment and directly affects cell-cell and cell-surface interactions. Many of these interactions are facilitated by specific adhesins that belong to the Flo protein family. Flo mannoproteins have been implicated in phenotypes such as flocculation, substrate adhesion, biofilm formation, and pseudohyphal growth. Genetic data strongly suggest that individual Flo proteins are responsible for many specific cellular adhesion phenotypes. However, it remains unclear whether such phenotypes are determined solely by the nature of the expressed FLO genes or rather as the result of a combination of FLO gene expression and other cell wall properties and cell wall proteins. Mss11 has been shown to be a central element of FLO1 and FLO11 gene regulation and acts together with the cAMP-PKA-dependent transcription factor Flo8. Here we use genome-wide transcription analysis to identify genes that are directly or indirectly regulated by Mss11. Interestingly, many of these genes encode cell wall mannoproteins, in particular, members of the TIR and DAN families. To examine whether these genes play a role in the adhesion properties associated with Mss11 expression, we assessed deletion mutants of these genes in wild-type and flo11Δ genetic backgrounds. This analysis shows that only FLO genes, in particular FLO1/10/11, appear to significantly impact on such phenotypes. Thus adhesion-related phenotypes are primarily dependent on the balance of FLO gene expression.

Am J Hum Genet. 2012 Mar 9;90 (3):410-25 22325160

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.

Richa Saxena, Clara C Elbers, Yiran Guo, Inga Peter, Tom R Gaunt, Jessica L Mega, Matthew B Lanktree, Archana Tare, Berta Almoguera Castillo, Yun R Li, Toby Johnson, Marcel Bruinenberg, Diane Gilbert-Diamond, Ramakrishnan Rajagopalan, Benjamin F Voight, Ashok Balasubramanyam, John Barnard, Florianne Bauer, Jens Baumert, Tushar Bhangale, Bernhard O Böhm, Peter S Braund, Paul R Burton, Hareesh R Chandrupatla, Robert Clarke, Rhonda M Cooper-DeHoff, Errol D Crook, George Davey-Smith, Ian N Day, Anthonius de Boer, Mark C H de Groot, Fotios Drenos, Jane Ferguson, Caroline S Fox, Clement E Furlong, Quince Gibson, Christian Gieger, Lisa A Gilhuijs-Pederson, Joseph T Glessner, Anuj Goel, Yan Gong, Struan F A Grant, Diederick E Grobbee, Claire Hastie, Steve E Humphries, Cecilia E Kim, Mika Kivimaki, Marcus Kleber, Christa Meisinger, Meena Kumari, Taimour Y Langaee, Debbie A Lawlor, Mingyao Li, Maximilian T Lobmeyer, Anke-Hilse Maitland-van der Zee, Matthijs F L Meijs, Cliona M Molony, David A Morrow, Gurunathan Murugesan, Solomon K Musani, Christopher P Nelson, Stephen J Newhouse, Jeffery R O'Connell, Sandosh Padmanabhan, Jutta Palmen, Sanjey R Patel, Carl J Pepine, Mary Pettinger, Thomas S Price, Suzanne Rafelt, Jane Ranchalis, Asif Rasheed, Elisabeth Rosenthal, Ingo Ruczinski, Sonia Shah, Haiqing Shen, Günther Silbernagel, Erin N Smith, Annemieke W M Spijkerman, Alice Stanton, Michael W Steffes, Barbara Thorand, Mieke Trip, Pim van der Harst, Daphne L van der A, Erik P A van Iperen, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Bruce H R Wolffenbuttel, Taylor Young, M Hadi Zafarmand, Joseph M Zmuda, Michael Boehnke, David Altshuler, Mark McCarthy, W H Linda Kao, James S Pankow, Thomas P Cappola, Peter Sever, Neil Poulter, Mark Caulfield, Anna Dominiczak, Denis C Shields, Deepak L Bhatt, Li Zhang, Sean P Curtis, John Danesh, Juan P Casas, Yvonne T van der Schouw, N Charlotte Onland-Moret, Pieter A Doevendans, Gerald W Dorn 2nd, Martin Farrall, Garret A FitzGerald, Anders Hamsten, Robert Hegele, Aroon D Hingorani, Marten H Hofker, Gordon S Huggins, Thomas Illig, Gail P Jarvik, Julie A Johnson, Olaf H Klungel, William C Knowler, Wolfgang Koenig, Winfried März, James B Meigs, Olle Melander, Patricia B Munroe, Braxton D Mitchell, Susan J Bielinski, Daniel J Rader, Muredach P Reilly, Stephen S Rich, Jerome I Rotter, Danish Saleheen, Nilesh J Samani, Eric E Schadt, Alan R Shuldiner, Roy Silverstein, Kandice Kottke-Marchant, Philippa J Talmud, Hugh Watkins, Folkert W Asselbergs, Paul I W de Bakker, Jeanne McCaffery, Cisca Wijmenga, Marc S Sabatine, James G Wilson, Alex Reiner, Donald W Bowden, Hakon Hakonarson, David S Siscovick, Brendan J Keating

Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA. rsaxena@chgr.mgh.harvard.edu

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.

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