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Development of Trypanosoma cruzi invitro assays to i\ dentify compounds suitable \nfor progression in Chagas  disease drug discovery. PLoS Negl. Trop. Dis. 12, e0006612 \(2018\).\ \r:87)/F 4/H/N/Rect[539.373 620.855 544.428 608.444]/Subtype/Link/Type/Annot>> endobj 27 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:24. Ward, A. I. etal. Invivo analysis of Trypanosoma cruzi persistence foci \ at single- cell resolution. mBio 11, e01242-20 \(2020\).\r:88)/F 4/H/N/Rect[545.603 620.855 550.658 608.444]/Subtype/Link/Type/Annot>> endobj 28 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:12. Sanchez- Valdez, F. J., Padilla, A., Wang, W., Orr, D. \n& Tarleton, R. L. S\ pontaneous dormancy protects Trypanosoma cruzi during extended drug exposure. eLife 7, e34039 \(2018\).\r:89)/F 4/H/N/Rect[545.351 587.855 550.658 575.444]/Subtype/Link/Type/Annot>> endobj 29 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:20. Ward, A. I., Olmo, F., Atherton, R. L., Taylor, M. C. \n& Kelly, J. M. Trypan\ osoma cruzi amastigotes that persist in the colon during chronic stage murine infections have a reduced replication rate. Ope\ n Biol. 10, 200261 \(2020\).\r:90)/F 4/H/N/Rect[429.672 521.855 435.103 509.444]/Subtype/Link/Type/Annot>> endobj 30 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:25. Dumoulin, P. C. & Burleigh, B. A. Stress- induced proliferation and cell cycle\ plasticity of intracellular Trypanosoma cruzi amastigotes. mBio 9, e00673-18 \(2018\).\r:80)/F 4/H/N/Rect[190.422 108.155 195.288 98.6352]/Subtype/Link/Type/Annot>> endobj 31 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:12. Sanchez- Valdez, F. J., Padilla, A., Wang, W., Orr, D. \n& Tarleton, R. L. Spo\ ntaneous dormancy protects Trypanosoma cruzi during extended drug exposure. eLife 7, e34039 \(2018\).\r:81)/F 4/H/N/Rect[533.824 88.1551 538.799 78.6352]/Subtype/Link/Type/Annot>> endobj 32 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:23. MacLean, L. M. etal. Development of Trypanosoma cruzi invitro assays to id\ entify compounds suitable \nfor progression in Chagas  disease drug discovery. PLoS Negl. Trop. Dis. 12, e0006612 \(2018\).\r\ :82)/F 4/H/N/Rect[536.472 68.1551 541.338 58.6352]/Subtype/Link/Type/Annot>> endobj 33 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:27. Bustamante, J. M. etal. A modified drug regimen clears active and dormant try\ panosomes in mouse models of Chagas disease. Sci. 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Dumoulin, P. C. & Burleigh, B. A. Stress- induced proliferation and cell cycl\ e plasticity of intracellular Trypanosoma cruzi amastigotes. mBio 9, e00673-18 \(2018\).\r:91)/F 4/H/N/Rect[201.907 697.855 207.003 685.444]/Subtype/Link/Type/Annot>> endobj 896 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:26. lvarez, M. G. etal. New scheme of intermittent benznidazole administration i\ n patients chronically infected with Trypanosoma cruzi: clinical, parasitological, and serological assessment after three year\ s of follow- up. Antimicrob. Agents :92)/F 4/H/N/Rect[260.8 510.855 265.851 498.444]/Subtype/Link/Type/Annot>> endobj 897 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:27. Bustamante, J. M. etal. A modified drug regimen clears active and dormant tr\ ypanosomes in mouse models of Chagas disease. Sci. 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P\ rotozoan persister- like cells and drug treatment failure. Nat. Rev. Microbiol. 17, 607 620 \(2019\).\r:96)/F 4/H/N/Rect[190.156 59.8547 195.192 47.4439]/Subtype/Link/Type/Annot>> endobj 901 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:29. Goyal, V. etal. Long- term incidence of relapse and post- kala-azar dermal le\ ishmaniasis after three different visceral leishmaniasis treatment regimens \nin Bihar, India. PLoS Negl. Trop. Dis. 14, e00\ 08429 \(2020\).\r:97)/F 4/H/N/Rect[196.358 59.8547 201.394 47.4439]/Subtype/Link/Type/Annot>> endobj 902 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:30. Gitari, J. W. etal. Leishmaniasis recidivans by Leishmania tropica in Centr\ al Rift Valley region \nin Kenya. Int. J. Infect. Dis. 74, 109 116 \(2018\).\r:98)/F 4/H/N/Rect[202.56 59.8547 207.596 47.4439]/Subtype/Link/Type/Annot>> endobj 903 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:14. Mandell, M. A. & Beverley, S. M. 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Dis. 7, 581 \ 596 \(2007\).\r:114)/F 4/H/N/Rect[490.755 92.8547 495.927 80.4439]/Subtype/Link/Type/Annot>> endobj 919 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 920 0 obj <>stream x}ks+Ir?_E ~7l"ʣJucAMuĽ \UYY rf+6Y'Of?|[~_7V9X)|X,WRn>,Wˇ2[V|ٺ, ٲu*Ke5;Ηy^-+z{o/J}4 D:x.eI?eE8OY'󼺛3rg~D5,V@VEB>E ';& A͉ oMwNpq6:n3JnxI9vܱ&fp}oJ16(жikg%3iusvxsNgY1:C݋S7-ъ0+G˖XQ/zx4˙&Lz֖ 5CExUOVWG8ğ]5׽$>(qZacSwݏj#L Y" 78:2 ejqⶲa*{{lyZG +;vțW"/DYg=hVv~<  )|,iaCu5 ĨM{!H&Wf9W{+?.,no"hc?AX_,kjrY Q'^hMe&S5Y0_POJ &JTMuFqsud' L^w#kA;RL3g$#H/en h5+PLcXwԆFYEHbP'!Մ2`b@aSـ{2xb;uaΊ{9|o#Z{b DP= # A?1$a+WFnU*Wl*^W`vCWJϔ:Y)opUSUFeK/8C̙ʈ\Qug0̊@uZ~xb ¤GoJ=R]G}iO~olƦ=Hy1L8{QƘWLTlNlhn!:Q HYhE-U%F @ /l++挩Ǵ^n/·zK* }t|bd0zU UIg&4ܹn+ YΑ\`C%,`m$'*B={_ ;M;ΧahUzOYP}hVհ ܱkH1UL!3ڏ+ b ?i#xOLns0vX:/Sho|NUܾSJ8_l jYJ-f^ fj9,׼-3rN3tB%r(ͶN\H":`7)[kp*/xi@+vadÎaoߎ<U=Yh!{ M;DYB>o ch"of]}^8uf+[ce^f*휺^&~k`W=\ bL"9M݄]Ʈ %c+Hg۬qtQ16~ =߃ E颽A?y1)_3lVs`G|1&4Zs@9 +OٞU95Vd=FA.fQ24a xCQ:=ً^܈}dVDzZ[mWd%hp ګeMJmF˝2=@SF?R؝&}6e{7Z8AFg90l0Mg*n咗;fhҎgƝ8$$ź({fdƊ)ntR!l*z6D=S`RW[ÒzNr&Kla雪e?_U@WoF}ֺj]4V?A~i9UzmJ-$$fpV`BT{PXQ|,UHr31]z5hGnl V{Z |AM@o{iRVz-;*tQN mf70JL>`j-5`Nʝx./hmE.gRoNf-(|u=qρV@އI!N&EvŸ?)oԞRս5\$U '& zΌI,3i󒲄9y=0yC?Ya(jJx]<e\$ DwR)a Y~~8]t1 .,BY6@|RX@a;c5D@cc4 aO36y6mqhQoM.YܤTgGOФ](ȉ BuQm@=]JnOjV={_ y aLh+$  c~rFh'(]n;Px6AzaVNŽA2*}x|f ǐ;/~toNKV>Dq~ 9z2# ^/HP _EBI{Qͱ}6)EH{XP:xeg%8Z c&琰7˜Ba.ER Z V/t?]΀u@ž}5ʩ$ u` a"n\CW~^qvY5Fݩa{!*/TYB1R ])Ixh8pA5u^ ;X'LϚA&o@/r}eŊȬq&X[RauhB&wFEq31* @Z sږxX\ 2Lσ}{V<`1-lS\i׉Oc^s˩T7A1۳Rj߿R~PGE6{a#az}1Y( ~PCu0D*4^I#Lo7뒸%an1lD'~!s9[DJ4+*?fabL듔cHp̋NB[7!ù {ߑܝzia #m6}>Xm~W\* . t:ޜ"ת GFr0ʭ/?}?L#xq*dd~CRϢ??ΗWG-2c#@IP&q!=W{T ؗn J$=n#n%&m޸z0 & KF&Trx VqlG50biԨp ɸ\{O!2,5` mìX=f̷?Se&R0jp =|'x-Qdv@S(~3v=nL\ ̹k8VL2ܼgzDBHjK%ƩCYk8;$7}wb]Fei,#:kQm1 pPm>pېL"-HXyU?bn1^iܫײ6eyQDgVuȩx}w6;f܂lec[u~5Ss{,q<+L rk((mZkeSBb/ޱC^GW2[6u۬6W*yϸG[Rkυj,Z 2Szf d6CܤLJ#mV-DsEvkn ^@d CpPn>6|(@q8/.ÎajRXABL4^Mh~܇DE^pvAMaz_ [`r b[Q3ĦՑU^ 9nLu&s/"@l"YOdqO\>1j͙0J0F2%.+EH Y~B.$XDf rq ̡'d-68U[kX7ZDNrث[0GBc`3渊H"IA>p:ng /l\ض7#6HТ5~M䯻n-%}k* t9\8>mXXZ:Q6Df /|>gA= 0kt_VwgE" b먒=cҿə{ȩy6T8d!~!M2 oiq5HL=6JXB}PM܀v:0uf eٓm (3 Cʸ *ؐ6u*Z'Cr>qx<l@F;sMU#kY9Xڢu5:ldqkutwaPǹ3a<(!2v\jW zy (_YA[ڶعYCg,=D> Pkƞ+?0o+~F\ ТuerTCys\j8d'ׁ)~3gfcQ{3 ;WqX@re-]p|8Yjp_0' Xnl6a9nɍ\ D$#'VNwcyٔ@ 2wJԱةg|t YQ]Nj>޻`;'Ɖ\=S:gYol_:1Co :UUB_PFuۚq{faլzRy5w2 XvQDX0mYZ2`j}-K<72ؚ=Nbc6ѡR=Y)nE"c?lLl3xmX4L͊,vJvxW..̌O)x bݲ:ue4aULLiT„ }n;p}'FRBx!inV˲ZxTaHe{U,fRYjxf-{d[yl0Eg߽lx`l.q¢6V^NR'^!_Fu?9&#ZK6,DdS1 vъaԢpɮ[v7hUɛDj)lW+*_gM.r*ڪ|U*\N0EM~lx쿰 j L<Ty8ғ-.=Mnlρԩ߿݁ȃq =zh+3tQd`S~{q_뼳}s =߳<O:DZ&lIy;FyB՟#k5,۳Lf: `|"B,5*~XbKEʲG̱9RsIzXIn6"ch*Lm~xe_N)zbhL0}˝8ν<ĩ7G _bttƁ)d}^AꧻS QD!~I6l'(,}=lVO l2Z?׆V 9ظ+) ~!CG ( ;yN8:9@5*xP;Qd0 h{y{bܽzɮ/m,iۢPE&ub^竦FQVBJ~ʚ~L=oWoA$7F%e)=KzJtm".Rm.s@ē\AC:m,Kz]~Ntqk`VI9q;їO\Kq<hr} P'ml~^ɶ>"#Tα3}yD$GsǤLrr1ZiQiQ|] jzoeSK]n YWF—&Q}:\lMfr,n{;G9&af!05c^e?Л*k5 OG~3p¾}1#z!:\V,b O8+:c<(v=xgb75psCDip q>}UL4R*mrZ10s`ґGc.fp6`82 1$gL,|(/٦УnaH Lw l+\5jE􈤇;|lݹ;`HfcEhd!F;AB4c!6f'LpL]m-O͆`4Q<$<3f9zXN'FK89B3&B?n#G`$.2kzf!.lx dХyyܗ+Y}،ŵnix VNqǐ6FQVþ4B|5-MxmR;tȵ8sC j벻V3KUJ91"_'08'q$FqcTBP.d@a"Mh\Òvv囏ʝVa81cߏ˶C;y@gb'(%]b..Q3MƂ i%9uS hYҕ!K6ðfn[#[/Đ$ƓN;pD`pn{lbܷĘ,|7Mj!(ҲăYe0c;{I$TXb-ݎcvTlg3ˑ\ ĥ=j9pg>n=ٛ0dH2 Lџut9>n9yJ 3L[c{'xB%Z3 #ݼolTag3&w2Y+ Յ$ØXێgd x\A)qj0'b5S ZVw {T1 Ww/s72X>8pgۃ ?I7\lzXK8;9ѕW]zmRe[kUqUHa F!ߵV_=-YU5 |rJO?3b $g}*#16@IĦYǒJy~4PpAt+ٜv0 P/<+n >:tYR1~ 7!yy+=G !<^4p; %򑄍<`A8f#n|vl&KI3YLq(ZB*~S|gW!ܣ:J %٥&ggPHf)V{uvAG:o?oH>S?V/՘ci}h)8[u[UnVFZZ67k7 W*-ZL[3z)׿eUPS~?~VZ_t8t_ endstream endobj 921 0 obj <> endobj 922 0 obj [923 0 R 924 0 R 925 0 R 926 0 R 927 0 R 928 0 R 929 0 R 930 0 R 931 0 R 932 0 R 933 0 R 934 0 R 935 0 R 936 0 R 937 0 R 938 0 R] endobj 923 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:43. Caridha, D. etal. Route map for the discovery and pre- clinical development o\ f new drugs and treatments for cutaneous leishmaniasis. Int. J. Parasitol. Drugs Drug Resist. 11, 106 117 \(2019\).\r:115)/F 4/H/N/Rect[237.333 730.855 242.59 718.444]/Subtype/Link/Type/Annot>> endobj 924 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:44. Steverding, D. The history of leishmaniasis. Parasit. Vectors 10, 82 \(2017\ \).\r:116)/F 4/H/N/Rect[174.242 653.855 179.443 641.444]/Subtype/Link/Type/Annot>> endobj 925 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:45. Meleney, H. E. The histopathology of kala- azar \nin the hamster, monkey and ma\ n. Am. J. Pathol. 1, 147 168 \(1925\).\r:117)/F 4/H/N/Rect[180.692 653.855 185.894 641.444]/Subtype/Link/Type/Annot>> endobj 926 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:46. Domnguez- Asenjo, B. etal. Bioluminescent imaging identifies thymus, as over\ looked colonized organ, \nin a chronic model of Leishmania donovani mouse visceral leishmaniasis. ACS Infect. Dis. 7, 871 \ 883 \(2021\).\r:118)/F 4/H/N/Rect[314.096 609.855 319.191 597.444]/Subtype/Link/Type/Annot>> endobj 927 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:47. Feilij, H., Muller, L. & Cappa, S. M. G. Direct micromethod for diagnosis of a\ cute and congenital Chagas  disease. J. Clin. Microbiol. 18, 327 330 \(1983\).\r:119)/F 4/H/N/Rect[471.218 664.855 476.319 652.444]/Subtype/Link/Type/Annot>> endobj 928 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:48. Silva, A. E. etal. Acute Chagas  disease in postrenal transplant and treatmen\ t with benzonidazole. \nAnn. Diagn. Pathol. 14, 199 203 \(2010\).\r:120)/F 4/H/N/Rect[536.308 653.855 541.61 641.444]/Subtype/Link/Type/Annot>> endobj 929 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:49. Lewis, M. D. & Kelly, J. M. Putting infection dynamics at the heart of Chagas \ disease. Trends Parasitol. 32, 899 911 \(2016\).\r:121)/F 4/H/N/Rect[512.43 631.855 517.643 619.444]/Subtype/Link/Type/Annot>> endobj 930 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:49. Lewis, M. D. & Kelly, J. M. Putting infection dynamics at the heart of Chagas\ disease. Trends Parasitol. 32, 899 911 \(2016\).\r:122)/F 4/H/N/Rect[393.022 565.855 398.164 553.444]/Subtype/Link/Type/Annot>> endobj 931 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:Fig. 2 | Efficacy studies. Whole- body images of mice \(ventral \(V\) and dors\ al \(D\)\) infected with bioluminescent Trypanosoma cruzi, taken with an IVIS system. a | Untreated mice. \nb | Mice treate\ d with benznidazole \(100 mg kg"1\) from :123)/F 4/H/N/Rect[513.117 510.855 517.542 498.444]/Subtype/Link/Type/Annot>> endobj 932 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:50. Lewis, M. D. etal. Bioluminescence imaging of chronic Trypanosoma cruzi inf\ ections reveals tissue- specific parasite dynamics and heart disease in the absence \nof locally persistent infection. Cell. Mi\ crobiol. 16, 1285 1300 \(2014\).\r:124)/F 4/H/N/Rect[408.564 477.855 413.713 465.444]/Subtype/Link/Type/Annot>> endobj 933 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:1. Field, M. C. etal. Anti- trypanosomatid drug discovery: an ongoing challenge\ and a continuing need. Nat. Rev. Microbiol. 15, 217 231 \(2017\).\r:126)/F 4/H/N/Rect[389.977 367.855 392.642 355.444]/Subtype/Link/Type/Annot>> endobj 934 0 obj <>/BS<>/Border[0 0 0]/F 4/H/N/Rect[529.984 213.855 552.756 201.444]/Subtype/Link/Type/Annot>> endobj 935 0 obj <>/BS<>/Border[0 0 0]/F 4/H/N/Rect[353.197 202.974 469.918 190.444]/Subtype/Link/Type/Annot>> endobj 936 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:Fig. 3 | New anti-trypanosomatid drugs and targets. 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The information that suc\ h studies provide can facilitate the m:128)/F 4/H/N/Rect[186.495 224.855 190.933 212.444]/Subtype/Link/Type/Annot>> endobj 952 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:8. Kande Betu Ku Mesu, V. etal. Oral fexinidazole \nfor stage 1 or early stage 2 \ African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open- label, cohort study. Lancet Glob. He\ alth 9, e999 e1008 \(2021\).\r:129)/F 4/H/N/Rect[288.928 158.974 291.482 146.444]/Subtype/Link/Type/Annot>> endobj 953 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:51. Wittlin, S. & Mser, P. From magic bullet to magic bomb: reductive bioactivati\ on of antiparasitic agents. ACS Infect. Dis. 7, 2777 2786 \(2021\).\r:130)/F 4/H/N/Rect[248.114 125.855 253.21 113.444]/Subtype/Link/Type/Annot>> endobj 954 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:52. Wall, R. J. etal. Clinical and veterinary trypanocidal benzoxaboroles target \ CPSF3. Proc. Natl Acad. Sci. USA 115, 9616 9621 \(2018\).\r:131)/F 4/H/N/Rect[253.139 59.8547 258.234 47.4439]/Subtype/Link/Type/Annot>> endobj 955 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:Fig. 3 | New anti-trypanosomatid drugs and targets. There has been great pr\ ogress in drug discovery and development for kinetoplastid diseases, and shown are some examples of new chemical entities in dev\ elopment, including their mode of act:132)/F 4/H/N/Rect[401.773 202.855 406.32 190.444]/Subtype/Link/Type/Annot>> endobj 956 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:53. Wyllie, S. etal. Cyclin- dependent kinase 12 is a drug target for visceral le\ ishmaniasis. Nature 560, 192 197 \(2018\).\r:133)/F 4/H/N/Rect[400.268 147.855 405.689 135.444]/Subtype/Link/Type/Annot>> endobj 957 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:54. Wyllie, S. etal. Preclinical candidate for the treatment of visceral leishman\ iasis that acts through proteasome inhibition. Proc. Natl Acad. Sci. USA 116, 9318 9323 \(2019\).\r:134)/F 4/H/N/Rect[486.757 114.855 492.044 102.444]/Subtype/Link/Type/Annot>> endobj 958 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:55. Thomas, M. etal. Scaffold- hopping strategy on a series of proteasome inhibit\ ors led to a preclinical candidate for the treatment of visceral leishmaniasis. J. Med. Chem. 64, 5905 5930 \(2021\).\r:135)/F 4/H/N/Rect[493.336 114.855 498.623 102.444]/Subtype/Link/Type/Annot>> endobj 959 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:56. Khare, S. etal. Proteasome inhibition for treatment \nof leishmaniasis, Chagas\ disease and sleeping sickness. Nature 537, 229 233 \(2016\).\r:136)/F 4/H/N/Rect[426.954 103.855 432.361 91.4439]/Subtype/Link/Type/Annot>> endobj 960 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:54. Wyllie, S. etal. Preclinical candidate for the treatment of visceral leishma\ niasis that acts through proteasome inhibition. Proc. Natl Acad. Sci. USA 116, 9318 9323 \(2019\).\r:137)/F 4/H/N/Rect[462.766 59.8547 467.817 47.4439]/Subtype/Link/Type/Annot>> endobj 961 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:55. Thomas, M. etal. Scaffold- hopping strategy on a series of proteasome inhibi\ tors led to a preclinical candidate for the treatment of visceral leishmaniasis. J. Med. 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Thomas, M. etal. Scaffold- hopping strategy on a series of proteasome inhib\ itors led to a preclinical candidate for the treatment of visceral leishmaniasis. J. Med. Chem. 64, 5905 5930 \(2021\).\r:16\ 8)/F 4/H/N/Rect[201.911 334.855 207.174 322.444]/Subtype/Link/Type/Annot>> endobj 1005 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:64. Shalev- Benami, M. etal. Atomic resolution snapshot of Leishmania ribosome \ inhibition by the aminoglycoside paromomycin. Nat. Commun. 8, 1589 \(2017\).\r:169)/F 4/H/N/Rect[274.132 191.855 279.227 179.444]/Subtype/Link/Type/Annot>> endobj 1006 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:Box 1 | New genetic methods: mechanism of action determination\rDetermining the m\ echanism of action and molecular targets of compounds identified via phenotypic screening can \nbe vital. The information that s\ uch studies provide can facilitate the:170)/F 4/H/N/Rect[174.709 81.8547 179.124 69.4439]/Subtype/Link/Type/Annot>> endobj 1007 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:65. Riley, J. etal. Development of a fluorescence- based Trypanosoma cruzi CYP\ 51 inhibition assay for effective compound triaging in drug discovery programmes for Chagas disease. PLoS Negl. Trop. Dis. 9\ , e0004014 \(2015\).\r:171)/F 4/H/N/Rect[403.787 730.974 408.808 718.444]/Subtype/Link/Type/Annot>> endobj 1008 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:66. Wall, R. J. etal. The Qi site of cytochrome b is a promiscuous drug targe\ t in Trypanosoma cruzi and Leishmania donovani. ACS Infect. Dis. 6, 515 528 \(2020\).\r:172)/F 4/H/N/Rect[463.046 730.974 468.067 718.444]/Subtype/Link/Type/Annot>> endobj 1009 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:54. Wyllie, S. etal. 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Chem. 55, 140 152 \(2012\).\r:186)/F 4/H/N/Rect[445.12 125.974 450.182 113.444]/Subtype/Link/Type/Annot>> endobj 1023 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 1024 0 obj <>stream x}Y#IKa!dI6B\;#h-L223x$ɪ\IngB Еdv;?3ST__7V9}X*isr~6Kr٪ QV"_:YWŢXUU-E[׫bYf~}͋Xf֟mRl,J=fVxgߘ_~ͯѲY^7{κEc_wGu#Vm[:" Wg>KBte-Y߱4`y\8ēDǀ& j/HѮ.7 Ȇ'v^pS|}4ajiDWM6ǡ?e-QJS#%n~waoiLŷ2_zCխGkIK=LT3l1_9!C8}ɀЛ"h\oFoy7JsC8َ %\-i4ΗM9^#| VfDh|iCsZ+M_m^+x$ ޯUԁdyryF,ɳ'TF]p/~$BMi098)ސ4A<݈f^UxT Ρ=AzمmGXs1;RRDnc苊6u|o ENg!ORPU1qH/lujoR0@*_Kybh<^@tx.iЧb\ϸX~G"9{51^ko2_0 Eb=Ȧ'-|ٳXҊZ7TҒ6)֪,ȢeZR:BDBfm57,և,xZEq35Dy1%\B;H rQuS8 pN T)Ʉ"Sxl% '#z9 @IsȥٞaA1{ YGEP3jC6F|m³8eS3|,ʊnjY絪y꺺`DSL^x\Qt[tzj}COWۜw3U#fsf]O51KpbCc>CPQD-7$%=OXDs[a#X)ir6 kH+tIj1H#)Zƌ1ެyÖp ΃,:67P2#>"N.ƌ$jbu2F S!JĄ3RmcwUd Fp3+vsΕƒ^VSuď;48HZ"wfLZpO> ?c@ʠx` XEip=O)O V30:Y=L 1P==nzJ&FE|bpE?btþhAz'_K{o+mBn7'+;faPKALJD8-Ȳ[}mQvYIHN7$G^rBy|QDȪ^l>Y+2'KהK8Ԓ|\6]LY_| q欧A9-di(MoTƄ!Xh=׿W>].)Z2 b9*WXS( -I/[|.˩]%j8쇍4dر&tFѩzgSRoA&b?@E#&}Mb&̝W-U",2 YG]e/:5}6 yZY_x>̀祥PU3wW֫f7*:gukAG2.ri4Fd\p=+ûg[qhHbOho*hWڞ <j0cf(h„UABO<4v8:x틉Ðz qY{:PwvQT$3^ *&hfN{?d`=: MK,9!>N W"6~0MݕqM+xXNlr$aCXi $> 5xpt')! 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WT@-"GV~mvui ޶5\bT3DY״R FDtӪ 0NUe02]D$ٱ}\66=yE[sdno^Z@75ӎa-*x6SsbD>Uj n)P0DwOVkL3WyQϗ_h5#Zѷ+ɣP=+P}Ҥq+teIX^yz{8͇+ &7f%*P9{_%<DВ~4utJ@<₎3_n&;1 ěemN?_ s,+fFNӯw"$_߄USu ,xkͪݨF+& \~t)yWo_7C38z#Kt]b6΀s&e=M lY/B#Ba ۬4 4C`]YBBgPC?Im8PBUt .idHE $rg"g|Dc_c2$ZqkOHEL0!+ U|t"VLML4yVQ)dCGgBy$tYSi=:?uU k.wVSYh_2+Ԩ>[n?bk,^Gڰ- ;o'i zi4H伄سfԹ ~6Ϝ9Ag}<5y,W6/n s,jRY=kȩΨoLN 'lɠiIp@M)ü4GؓX/pQ:G`|:H &=<}3xEKL]d>s\p մbT1t+Z0C!qQz^*Ď4iS5"N9y$ɽ';q&쾓6xKpuYU 2K9h-yPfS_?ٌz8>+&a;iϰ B˟꩒V^6ϢO ʂȧH GVpȊ9jyTbQFUp--ufMY‰q YJ p9]1٪+I^!aj\b57۰?ˎ$i~-Ϯ(dI,3 *AX ZK-w&KA _YźA>FCEϪHCBvC|nzDkrgB ~6,iƿPo)?mj)TQ&bQ5/𫏧8i 0! KEQٕlU&X*H. 2=>#4dd> A޳mԡX'F#ж`w9:%gOINAK$0f- x`й`ҸCO~!N$~bӮ`fƖۋi2 &Qt1ط1$1PY4VthnūO$ɣ',\9TzuJڹOD=ў(Ѕc߾!M5ׁ_M0?B4P'm< mKG`L0(V]IrP^QEնDHZӛBGXo߈4,~Z35+IH[BdA'rP)p@A†-ݗt"BһE $FLzNꮣR3R5?L+>_y6Yk 6ގ8H"n"Xp0}\ot4$C?gṇ}+Ee'ENq'DrdF"' % BTzJm{-e%`^ ƚul$&Lio{DmILd-tT !Qah&,b{XF]X]QwMY˻)4ZձDѳ8ܭpLG5]`.QR#"OFQ")Fx+n-(\]Qݽ,)l[,&#.1?b g>cp!υ6&ח{Zsc[Vle'Wե-f>9!!Vn}¬oS.V&SlL4n 6o6s|v[<> endobj 1026 0 obj <> endobj 1027 0 obj [1028 0 R 1029 0 R 1030 0 R 1031 0 R 1032 0 R 1033 0 R 1034 0 R 1035 0 R 1036 0 R 1037 0 R 1038 0 R 1039 0 R 1040 0 R 1041 0 R 1042 0 R 1043 0 R 1044 0 R 1045 0 R 1046 0 R 1047 0 R 1048 0 R 1049 0 R 1050 0 R 1051 0 R 1052 0 R 1053 0 R] endobj 1028 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:72. Ames, B. N., Lee, F. D. & Durston, W. E. An improved bacterial test system for\ the detection and classification of mutagens and carcinogens. Proc. Natl Acad. Sci. 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Nature 559, 498 506 \(2018\).\r:190)/F 4/H/N/Rect[334.665 389.855 339.761 377.444]/Subtype/Link/Type/Annot>> endobj 1032 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:74. Peniche, A. G. etal. Development of an ex vivo lymph node explant model for i\ dentification of novel molecules active against Leishmania major. Antimicrob. Agents Chemother. 58, 78 87 \(2014\).\r:191)/F 4/H/N/Rect[224.282 345.855 229.378 333.444]/Subtype/Link/Type/Annot>> endobj 1033 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:75. Domnguez- Asenjo, B. etal. Ex vivo phenotypic screening of two small repurpo\ sing drug collections identifies nifuratel as a potential new treatment against visceral and cutaneous leishmaniasis. \nACS Inf\ ect. Dis. 7, 2390 2401 \(2021\).\r:192)/F 4/H/N/Rect[230.574 345.855 235.669 333.444]/Subtype/Link/Type/Annot>> endobj 1034 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:76. da Silva Lara, L. etal. 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A., Harris, A., Qaiser, Z., Croft, S. L. & \nSeifert, K. Pharmacodynam\ ics and biodistribution \nof single- dose liposomal amphotericin B at different stages of experimental visceral leishmaniasis. \ Antimicrob. Agents Chemother. 61, e:203)/F 4/H/N/Rect[410.742 576.855 416.053 564.444]/Subtype/Link/Type/Annot>> endobj 1045 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:81. Van Bocxlaer, K. etal. Topical treatment for cutaneous leishmaniasis: dermato\ - pharmacokinetic lead optimization of benzoxaboroles. Antimicrob. Agents Chemother. 62, e02419-17 \(2018\).\r:204)/F 4/H/N/Rect[537.817 444.855 542.868 432.444]/Subtype/Link/Type/Annot>> endobj 1046 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:83. Van Bocxlaer, K., Yardley, V., Murdan, S. & Croft, S. L. Topical formulations \ of miltefosine for cutaneous leishmaniasis in a BALB/c mouse model. J. Pharm. Pharmacol. 68, 862 872 \(2016\).\r:205)/F 4/H/N/Rect[545.608 444.855 550.658 432.444]/Subtype/Link/Type/Annot>> endobj 1047 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:84. Fairlamb, A. H. & Horn, D. Melarsoprol resistance \nin African trypanosomiasis.\ Trends Parasitol. 34, 481 492 \(2018\).\r:206)/F 4/H/N/Rect[459.804 334.855 464.967 322.444]/Subtype/Link/Type/Annot>> endobj 1048 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:85. Carter, N. S. & Fairlamb, A. H. Arsenical- resistant trypanosomes lack an unus\ ual adenosine transporter. Nature 361, 173 176 \(1993\).\r:207)/F 4/H/N/Rect[485.118 323.855 490.347 311.444]/Subtype/Link/Type/Annot>> endobj 1049 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:88. Graf, F. E. etal. Chimerization at the AQP2-AQP3 locus is the genetic basis o\ f melarsoprol- pentamidine cross- resistance in clinical Trypanosoma brucei gambiense isolates. Int. J. Parasitol. 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A third generation vaccine for human visceral leishmaniasis \ and post kala azar dermal leishmaniasis: first- in-human trial of ChAd63-KH. \nPLoS Negl. Trop. 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Host- directed therapies for infectious diseases: current \ status, recent progress, and future prospects. Lancet Infect. Dis. 16, e47 e63 \(2016\).\r:268)/F 4/H/N/Rect[542.992 411.855 550.658 399.444]/Subtype/Link/Type/Annot>> endobj 1153 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevMicro_777.indd:113. Zumla, A. etal. Host- directed therapies for infectious diseases: current\ status, recent progress, and future prospects. Lancet Infect. 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