Mouse-Human Experimental Epigenetic Analysis Unmasks Dietary Targets and Genetic Liability for Diabetic Phenotypes
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- Juliet Booker
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1 C M Ru Mu-Hu Ex E Ay U Dy T G Ly D Py M L. Muu,,, Mu M. S,,, Aw E. J,,, X L,, H K, P M, Yuyu L, V Ruz,, Ax D, M Hu, C L, M MCy,,, E Näu, Ju R. Z, G. W W,, Aw P. F,, * D M, J H Uvy S M, N W S, B, MD, USA C E, J H Uvy S M, N W S, B, MD, USA D Pyy, J H Uvy S M, N W S, B, MD, USA C M Oy R, J H Uvy S M, N W S, B, MD, USA L Iu B Dv, N W S, B, MD, USA D M H, J H B S Pu H, N W S, B, MD, USA D Mu M Suy K Iu, S, Sw D P, J H Uvy S M, N W S, B, MD, USA W Tu C Hu G, Uvy Ox, Rv Dv, Ox OX BN, UK Ox C D, Ey M, Uvy Ox, Cu H, O R, H, Ox OX LI, UK Ox NIHR B R C, Cu H, O R, H, Ox OX LI, UK D C S, Dy H, K Iu, S, Sw C- u ://x.././... SUMMARY U u v y (TD), w v -u yu u, v u, TD v y TD u y. B w y u y u, w y y DNA-y. W u -Rux--Y y, y w y v. T v w TD, y w w y GWAS. Fu y w v u w u, uy v u u y -. INTRODUCTION Ty u (TD) w y ww v. TD u ww, u v y (C., ). Au TD, y -w u (MCy, ), y y % w u (A., ). T w y, u w ww v, u v. A x, w y Rux--Y y (RYGB) y u u v u v TD- (M., ). E, uy -DNA u- u v, u DNA y, u u uy v xu (B., ). E y u y u, w (Cu., ), vy u (S., ). M u x vy y w vu v, w.% x y z (Sz W Gu Py G Cu, ).% TD (G L G Cu., ). T uy, v u, v u y u. Hwv, u v w, u u u uy, u C M,, Juy, ª Ev I.
2 T. G-w S Mu DMR Tu Ay v <. v <. Ay D W F u GTT ITT vu u v DMR y, u y/ y. S T S u u DMR. u, uy, w u uy u u uvy y (DNA ). A u v v y u u u -y, u v, u (w yy u ) (Hu., ; Lu., ; Mñ., ). T v y TD u. Su v u y w TD (Dy., ). S v u uy u y RYGB (K., ). Tw u x DNA y x TD u u v TCFL u (Rö., ; T., ). Fy, uy x y u u vuy u y u v y v RYGB (B., ). H, w uz w y vv y TD u. W x u - uy x u y. W u y yz u u v y u. T u u - -RYGB w u y-u u. T - x w vuy, w v uvv y w u u, v u u, y y uy v. W y - y- u -w uy (GWAS) TD y u y-v y w u TD. A u, w y u w u, u - v wu x y y v w. RESULTS A DNA My Mu Ay Pu y H-F D T DNA y, w u v -uu y- v y (CHARM), w u y v CG u. CG u. I y x u u, w u y y (DMR) w u (T ). A x, w y -- vu w--, w u yy vy yuv xy (P, Fu A). PEPCK, u P, yz - u, u, w u y u, yy y (B., ). I - vu w- y, v DMR w w yz y y y w, u, u u -uuv (ITT/GTT AUC) vu (T T S). O x u GTT- DMR F, w u y y. M DMR u w y w, w y ux y v y (Fu S). W y x DNA y u w u y x u v u. W u w y u w w y w ITT y (T S). P u uvy DNA y u y u. G Oy Mu DMR W y v DNA y w v u y. T -w y DMR w w y v u/y wy u u y, w vu <. (T S). Ex y- yy DMR y --, w v wy w v yy DMR, w y wy w y yy DMR. Iy u- y w uu y y y TD (H, ). Sy, w w v wu w yu (R., ). T wy, wv, v vuy w y w y -u y y. C M,, Juy, ª Ev I.
3 A B Fu. G-w S My C R D-Iu Oy CBL/ M (A) Tw -w DMR yy y u -. E y v y vu u, w u y v. T u. (B) By w () u (AUC) w y y -w v. E, w y x P w yz y. D x DMR uy v CHARM. T y x x. My R M A G Ex Su W y u DMR y DMR (Fu A T S). T -w y DMR v FDR vu... I w u u wu uu, w x u DMR w v u w. u. M u w - u w u CHARM. N u y DMR w y y u yu. E CG w y y CHARM. Au w u v, u u u w u -y -- u u u, w u uv PCR (PCR) z x u y- u u y w W w v x (y) F/, C, C, w x y- w-y y AQ C (T S). T x w y w -- w-- vv x y, w u uv PCR x x -w DMR (Fu B). W u PCR x RNA y w yz y CHARM. O x, w RNA x y (Fu B). C M,, Juy, ª Ev I.
4 A B Fu. R Mu My C A M A G Ex C (A) My v CHARM y w -w DMR u u yu. R x CG y yu. F w yu, y x y, vu CG x x. Pu DNA y y v %, %, %, %, % y. (B) G x -w u y DMR. RNA v w z - S RNA u y (C T [- ] C T [w- ]). E C T w u. * <., ** <.. T -w CHARM DMR w ; + y- yy -, vy. S Fu S w- x T S T S yu u u, vy. Fu, w w DNA y w vuy u -w x (Xu., ). W w v w - y - x (Fu SA SB). T u vy C M,, Juy, ª Ev I.
5 u y v DMR (K., ). T, w w uy DMR w, DMR, y y v u x. Mu DMR R Evuy Hu A Tu W y uy v DMR x - v u wu v u v u. T, w y v u y u vuy v, w CHARM y u uuu u u, x-, u- u, w u -RYGB. W x u y DMR u u vu. W v vy v w DMR u vu u DMR -- vu w-- u y ( <, Fu SA, v ), w w u y y yu u. Nx, w u y wu u, w u -w u y DMR, u u (), u v Ov UCSC (H., ), u CHARM w. T y (.%), u u y, CHARM, y v, CG y v vu. O v DMR, (.%) w y ( <.) w (T S). T u w w yz y RYGB uy ( u ). A v u u y v u u u, w (%) y w -- u, u u y --, wu v y u v v. W v u y u u, w y (u v ), u u, w / (%) y u y vu <., / (%) vu <. (Fu SB). A y v w w y u, GTT, / ITT u u. Fu, y w - -/- RYGB (.., y uy v v), u uy y vu w w uy y vu,.., w y u v w y uy ( =. ). I Fu, w w v y u u, u u DMR, y w u DMR, v u uy y v v v y. T v w : ADRBK (,,, Fu A) KCNA (u v, - uy,, Fu B). W w u DNA y w vuy u u -w x vu (A., ). A w u u, w w y v w y- y y- x (Fu SA SB, ). W u-u u u DNA TD u (Dy., ), w % ( =., =. ) u DMR u y w w u TD u y ( =., Fu SC), u uv DMR u TD. Fy, w v u u y DMR u v u, w.% (T S). G R L A w Ov R Hu Mu My C W u GWAS TD u w y w u z u y- DMR. GWAS uy w DIAGRAM (D G R M-Ay) TD -w -y, GWAS u, TD, (://www. -u.). W y x w w y- DMR TD y u GWAS v u DMR. W u y DMR y GWAS (GWAS vu u w <, vu.., T S). Gv u y v, u y y u y TCFL. W u y u TCFL u, w v x y u TD y u (N., ). W u x x uy w vv GWAS. G -w GWAS (uuy SNP) w y (-) DMR y C M,, Juy, ª Ev I.
6 - (Fu A). T u y x y ( =.) (Fu S) w y y wy y GWAS. Sy, x y, y y y GWAS y u-y u-u y wy (Fu B). Gv u, w u u u y DMR w u y w TD. W yz DMR v SNP TD y w u. A y DMR v GWAS TD w w vu y w vv TD, y, y, w u DMR w w TD. T u y vuy v y u u SNP-v uy DIAGRAM y. I, - y v DMR y v w SNP ( x w uu >.) v w TD ( <., T ; Ex Pu). W w v DMR v w DIAGRAM SNP (T S). I, y v w y y-u y w, u w TD- SNP v y v u y RYGB uy. T SNP u y x u.% TD y, u y -w DIAGRAM (M., ). Ev xu GWAS-v (TCFL), w x.% v, u x u.% v TD uy. T u, v u y u TD. I : My HF LwF G + K : My L O P Suy O P Suy G + KCNA My G + Mu Hu A B : HF LwF A My : L O P Suy O P Suy ADRBK Fu. Ov My C Hu Mu A Tu (A B) Tw -w DMR u u y ( ) v A (A) K (B) w w y u u ( ). F y, y v vu u u, w u y v. y x, y vu. Bw y w v y. S Fu S u v T S T S v u DMR u w DIAGRAM v DMR, vy. C M,, Juy, ª Ev I.
7 A B CARA TMCC G-w GWAS G - DMR G y Fuy v C- DMR w TD G-w u DMR Fu. D R I w Ey Cv Gy A G I T Suy (A B) G u QIAGEN Iuy IPA (Iuy Sy), w u y. (A) G w -w TD DIAGRAM -y w y v - DMR. G w w. (B) S w TD- y v - DMR, w w w y -v u-y -w DMR uy w. G x w-u. S Fu S u y (A). u v u y y v. N - TD GWAS, SNP v, w u - y- DMR, y u w GWAS uy. T u w GWAS-v TD u DMR v w GWAS SNP, u y y. W yz y w DNA y v u TD y vv vy. U uy v u u y (Hz., ), w u DMR u u (w v y). W u v CHARM w.%.% u,.% ( v, =. ).% ( v, =. ) y.% ( v, =. ) % ( v, =. ) u GWAS- v u, vy (T S). Tu, y- yu y u. N w vuy w TD u v GWAS. Fu Ay G I y C- S My I u - y u y, u, TD,, w uy y v. W w w y y v RYGB. A RYGB, v y v u u y u u vy, w yz u u u wu y v TD- y- y. W x y x y uu u u-u u u y. T u u v y u, y u y. W y v T-L y, y x RNA x v u. I -, yy - y w w, yy w vx. S u u w u u v (Fu B). P C M,, Juy, ª Ev I.
8 T. Mu-Hu DMR w G TD R L A G Rv DMR D TSS RYGB v DIAGRAM vu T,.E- T I,.E- A v +.E- E I +.E- T v. P v x, +. T +. A,. DIAGRAM GWAS. u L I, +. M v +. BC v x +. (C) R w, +. F I, +. Su v +. T I, +. Tx x, -. Gz I, +. T I +. B I,. D v +. K C, +. C I, +. C x, +. N I,. P +. P v +. Px, +. Hx, +. C v +. Ev x +. Sw u u y, DMR v, (TSS), w y ( ) -RYGB uy v w u y v (RYGB v), vu TD. S T S u w u T S v DMR v w. u u vy Du. DISCUSSION I u, w -w DMR w -u y y y. O, v y u y, y. Ty DMR v w SNP y x v w u TD. T w DNA y v v v w y v w TD. Ou v yu w - u, y u, v TD y y uy TD y u y. I uy, w w u vu y u y GWAS u, w u u u DMR u vy. A w w uuv SNP w w - uy y x u y vy y w SNP y GWAS (Y., ), u u v y y. T uu SNP y u.% TD v, w w y uy y y y. W v w u y y u-u u u y, u. S u y uu wy v u w u u (%) (T., ), u uuy w u y u vy. T w u u u v y- x : M, P, T w yy -- u, x u,, w w vx uu y, x u u u, w wu w u y v y. W vuy u u, v v uv y. M w v u (SRF), w w u u (J., ). Sy, PLEKHO y w AKT/PIK (Z., ), wy w vv u. W u u, w u u v v w (Gu., ), wu y- x w y vv w. I w v -w GWAS, y wu v y GWAS. Sy, y u C M,, Juy, ª Ev I.
9 A Gu U () Ovx.E-.E-.E- *** ** *** Iu () C.E-.E- * C.E- *** Mu DNA P M T T Gz B Gu U () Hu DNA Mu G Δ Hu G Δ Kw.E-.E-.E- ** Iu ().E- Fu. Ovx RNA- M Kw S G T-L Ay (A B) S v TD-SNP v DMR w y vx (A) w w RNA (B). Gu u,, w y w-wy ANOVA y B w: * <., ** <., *** <.. (C) DNA y x v -- u vu w-- u (.., Y yy/w x -- w- ). B w. x. T u y u w u - y w GWAS u SNP wu v w. R w u y w DNA y u (Lu., ), y u u y u. Ou u u- u, wv, y y v w u vy u v u u. T w y y u, v w w TD, DNA y v u v u. I u y w wy w (Fu ). F x, PRC, u y, w TD y -w DIAGRAM u, u w y y -w DIAGRAM. I, wv, u y FOXO, u, u, y w y y u u y. FOXO u u y TCFL, GWAS u. Fu, v uy uy w u w w vv TD, u y w vuy w y TD w vv w y u y (Fu B). S, u FASN APP, w u y. T y u u GWAS uy (ENCODE P Cu, ; J., ; N., ), u u uu v uy y y - u y. T w, u, y GWAS w y. Ay, w w y u y uy uy, uy,, u-. Ou u y uy x TD-v y vy. Cu y y u v uy v v x v y (N, ). T uy y v y y y u u, u vu. T y v w wz xu u -. T y y, u u SNP u wu y -w. T u u y u y, u y TD, vv y, u u wy,, v u. EXPERIMENTAL PROCEDURES F u ( u), Su Ex Pu. C M,, Juy, ª Ev I.
10 Mu S P A w v y Iu A C U C T J H Uvy S M. M CBL/ w u C Rv. M w - w-. D w v w, w. A uy, w v uz, u w. I Gu Iu T T C (w w ) w w u u. A w v ( ) u. F u, w v u. Su w u x. Mu Hy I A y y w u C (BD B) u vuy u (By F, ; L., ). Mu Py Ay I Mu y w u u C (S) u w vuy (S., ). P I I P u CHARM w vuy (Hu., ). F u, w w -- w--, u, y, -u w u. T-L Tu T T-L w u w S M v (S) w vx u L (L T) v uu. C Cuu Gu U Ay T-L (ATCC) w uu, u u y w w vx. C C T uy w v y R E C S. A v w. C w RYGB uy ( =,, vy) ( w) w ( = ). Fu u u u T S. Hu S Suy Suuu A Tu B A RYGB w Rux w. Suuu ( ) w ( w) u. B w RYGB uy ( u) v yy ( u). B u RYGB uy w v u y. CHARM DNA My Ay G DNA w u w MPu DNA u (E) w uu. G DNA w, w MBC, -u,, yz CHARM y (L-A., ). T y y v u w (://.. v.u/). Suu, z, w vuy (J., ). Bu Pyu G DNA w u PCR u. DNA y w uuy y yu w PSQ HS (B) vuy (M., ). Ay y %, %, %, %, % y w u xu u SI- w- DNA. Quv PCR Ay V w PB (W S, ) yz y I DNA T. RNA w x w TRIz (L T), DNA w w Qu Rv T K (QIAGEN), PCR w w F SYBR G (A By) HT F R-T PCR y (A By). RNA v w z - S RNA v. GO A W yz GO u GO (E., ). E w u y u y u y. W-G G Ex Ay W- x u u u uy w w GEO (B., ). T u w y, u w u u uy v (RMA) Ay R y (Bu). T x w DMR, (FC) x w v vu w DMR, vu w u P. E w Hu Mu DMR T Ov UCSC w u DMR u u, y Bu (Lw., ). F DMR, w -v u DMR u DMR (T S), w u u DMR v w vu v, u v w. E w -u u -v DMR, DMR y w, y u u w. C-S S Ay W y u DMR ( FDR < %) v (u, GTT, ITT, w, ) y x v v - DMR, u DMR w y u. T w v u u u u y Bu (Lw., ). T DMR w u CHARM u w. W u vu vu u - vu -RYGB uy u u vu, u w <., vu w DMR. DIAGRAM GWAS Ay W GWAS u u-u DMR y uy v u DIAGRAM -y (:// -u./w.; S GWAS: Suy S w). W v uy v M M. (M., ) Wy. (Wy., ) u G-v C M,, Juy, ª Ev I.
11 u u v % v SNP. W w DMR GWAS u u w y. T w DMR LD GWAS (C-T J, ), y y (-) TD w -w y DIAGRAM -y uy w u QIAGEN Iuy IPA (Iuy Sy). ACCESSION NUMBERS T GEO y GSE. SUPPLEMENTAL INFORMATION Su I u Su Ex Pu, u u, u w ://x.././... AUTHOR CONTRIBUTIONS M.L.M. u y x. M.M.S. y u u w P.M., Y.L., M.H.. X.L. u u u u u v G.W.W.. A.E.J. y. A.D., C.L., M.M. MAGENTA y. H.K., E.N., J.R.Z. v u y RYGB. A.P.F. w v u y x w w M.L.M., A.E.J., M.M. J.R.Z. ACKNOWLEDGMENTS T w w u y NIH D P Aw DP ES A.P.F, y NIDDK R DK G.W.W, y Nv-N Fu S Cuy Cu E.N. J.R.Z., y Eu R Cu J.R.Z. W A Ru. Rv: S, Rv: Nv, A: D, Pu: Juy, REFERENCES A, P., Lv, M., I, B., S, L., T, M.R., Ly, V., Tu, T., G, L.; B Suy Gu (). Hy y y uv B Suy. D,. A, E., M, N., Kuyé, A., Bwz, P.J., Pv, M., C, M., L-Cá, S., Eu, A., Lu, J., Hé, P.,. (). A u RNA u CCL u u y. D,. B, R., K, H., Ru, M., Y, J., K, F.R., K, A., Näu, E., Z, J.R. (). W y uy u y y. C R,. B, T., W, S.E., Lux, P., Ev, C., K, I.F., Tvy, M., M, K.A., Py, K.H., S, P.M., H, M.,. (). NCBI GEO: v u u. Nu A R. (D u), D D. B, E.G., H, R.E., A, B., F, C. (). Du y: PCK y. T E. M.,. By, M.N., F, D.S. (). H-y v y : uu uy. J. C B.,. B, H.T., F, M.D., F, A.P. (). A u. T G.,. C, L., M, D.J., Z, P.Z. (). T ww y y u uu v. N. Rv. E.,. C-T, L., J, A.E. (). R: Iy w w. ://u.// R. Cu, H., Cuz-C, M., G, F.M., Hu, D.F., K, D.R., Bu, S., Wu, Y., H, X., Pw, N.R., F, A.P. (). L IGF :. S,. Dy, T., Vv, P., Sö, S., H, E., N, E., O, A.H., K, C.L., W, C.B., E, L., Rö, T.,. (). G-w DNA y y u y - u u. PLS G.,. E, E., Nv, R., S, I., L, D., Y, Z. (). GO: vy vuz GO. BMC B,. ENCODE P Cu (). A y DNA u. Nu,. G L G Cu, W, C.J., S, E.M., Su, S., P, G.M., Gu, S., K, S., G, A., C, J., Buv, M.L., M, S.,. (). Dvy w v. N. G.,. Gu, P., L M-Bu, Y., T, J.F. (). Pv v u u u IRS- y. B,. H, A.S., K, D., B, R., B, G.P., B, G., Cw, H., D, M., Fuy, T.S., H, R.A., Hu, F.,. (). T UCSC G Bw D: u. Nu A R. (D u), D D. Hz, D., A, B.J., L, T.I., Lu, A., S-Aé, V., Sv, A.A., H, H.A., Yu, R.A. (). Su- y. C,. H, G.S. (). E uu y. C,. Hu, E.A., A, W.P., K, D.C., C, B.C., M, C.J., N, H.H., W, J.K., Ky, K.T. (). DNA y y u u xu u. BMC B,. Hu, M.A., D, P.B., H, J.F. (). Gu u x u AMP y u u x -. D,. J, A.E., Mu, P., L, H., L, J.T., F, M.D., F, A.P., Izy, R.A. (). Bu u y y y y u. I. J. E.,. J, W., G, A.B., B, T., Hy, R.R., C, T.P., K, E.Y., E, M., Fz, C., S, A., S, A.,. (). I SRF vy u u u u u. J. C. Iv.,. J, L., R, S., W, R.K., Du, R.H., MGv, D.P., Hu, K.Y., L, J.C., Su, L.P., S, Y., A, C.A.,.; I IBD G Cu (IIBDGC) (). H- v u y w. Nu,. K, K., D, A., W, B., N, K., Z, R., C, P., K, J., Ay, M.J., J, H., E, L.I.,. (). E y u u. Nu,. C M,, Juy, ª Ev I.
12 K, H., Ny, C., L, S., Bè, R., Y, J., K, A., Z, J.R., Näu, E. (). A y PDK, IL B, IL, TNF Rux- Y y. Su. O. R. D.,. L-A, C., Ay, M.J., Owy, J.M., F, A.P. (). Cv -uu y v y (CHARM). Cu. P. Hu. G. C,. Lw, M., G, R., Cy, V. (). y: R w w. B,. L, W.C., R, K.L., T, D. (). I uu u u y. M M. B.,. Lu, Y., Ay, M.J., Pyuv, L., F, M.D., H, E., Ru, A., Ru, L., Av, N., Tu, M., R, M.,. (). Ew DNA y y u. N. B.,. MCy, M.I. (). G, y, y. N. E. J. M.,. M, F., S, A., Cè, F., W O, W.A., F, A., C, R., S, M., S, R., M, P., M, J.C., M, L. (). C uy MS-HRM yu u u APC CDKNA y. PLS ONE,. M, G., Puz, S., D G, A., Gu, C., I, A., L, L., N, G., P, A., C, M., G, G., Ru, F. (). B uy vu v y y. N. E. J. M.,. Mñ, C.M., Izy, R.A., Ku, W.E., T, K., Gu, R.E., F, A.P., Tu, M.A. (). Mu -y y u u. G B., R. M, A.P., V, B.F., Tv, T.M., F, T., Sè, A.V., S, V., Sw, R.J., K, H., G, H., M, A.,.; W Tu C C Cu; M-Ay Gu Iu- Cu (MAGIC) Iv; G Iv AN T (GIANT) Cu; A G Ey Nw Ty D (AGEN-TD) Cu; Su A Ty D (SATD) Cu; DIA G R A M-y (DIAGRAM) Cu (). L- y v u yy y. N. G.,. N, D.L., Gz, E., Z, W., Du, S., D, M.E., Cx, N.J. (). T- SNP y QTL: vy GWAS. PLS G.,. N, E., J, P.A., Pyv, A., Vv, P., P, M., Sv, M.K., Pu, P., R-M, R., P, N.L., A, P.,. (). A DNA y x u u u w y. D,. N, D. (). A y vy: v v u. I Fu,. R, R., H, L., D, A.L., Nv, M.J., Huy, S.M., H, K.E., M, K.J., Fy, K.N. (). M v u: w y u vy u. D,. Rö, T., Vv, P., Dvå, C., Dy, T., H, E., O, A.H., N, E., T, A., D N, M., E, K.F.,. (). A x x v u -w DNA y u u. PLS G.,. Sz W Gu Py G Cu (). B z-. Nu,. S, S., Ky, T.K., J, P.A. (). E. C,. S, A., Ev, J.G., P, S., H, D., L, H.F. (). Iu u y y u y. Dv. C,. T, X., Gu, A., C, A., Pw, A.M., K, S., Vu, J.V., N, S.M., Su, J., Cz, M.P. (). A RNA - MAPK/NIK v u PPAR,, u-v x. P. N. A. S. USA,. T, G., A, D., K, J.D., R, M., Duv, T., N, B., W, J., F, Y., Lvy-L, E., G, B., H, A. (). G-w uvy v y - DNA y v u. Hu. M. G.,. W, X., S, B. (). A PCR uv x y. Nu A R.,. Wy, N.R., Y, J., G, M.E., V, P.M. (). T u ROC uv. PLS G.,. Xu, H., B, G.T., Y, Q., T, G., Y, D., Cu, C.J., S, J., N, A., R, J.S., T, L.A., C, H. (). C y u v y- u. J. C. Iv.,. Y, J., By, B., MEvy, B.P., G, S., H, A.K., Ny, D.R., M, P.A., H, A.C., M, N.G., My, G.W.,. (). C SNP x y u. N. G.,. Z, L., W, Y., X, F., W, S., X, G., L, Y., Y, X., Lu, K., W, R., F, J.,. (). CKIP- u y TRAF- A v. C R.,. C M,, Juy, ª Ev I.
Fuzzy Reasoning and Optimization Based on a Generalized Bayesian Network
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