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Tatsuya Suzuki, Toru Okamoto, Hiroshi Katoh, Yukari Sugiyama, Shinji Kusakabe, Makoto Tokunaga, Junki Hirano, Yuka Miyata, Takasuke Fukuhara, Masahito Ikawa, Takashi Satoh, Sachiyo Yoshio, Ryosuke Suzuki, Masayuki Saijo, David C. S. Huang, Tatsuya Kanto, Shizuo Akira, Yoshiharu Matsuura
Infection with flaviviruses requires BCLXL for cell survival
www.plospathogens.org
www.plospathogens.org
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2.0749 0 Td
(supporting)Tj
4.6035 0 Td
(the)Tj
1.4683 0 Td
(therapeutic)Tj
4.7337 0 Td
(use)Tj
1.5307 0 Td
(of)Tj
1.0148 0 Td
(induc-)Tj
-33.8964 -1.2983 Td
(tion)Tj
1.8425 0 Td
(of)Tj
1.0148 0 Td
(cell)Tj
1.5591 0 Td
(death)Tj
2.4264 0 Td
(by)Tj
1.1849 0 Td
(mitochondria-mediated)Tj
9.7908 0 Td
(apoptosis)Tj
3.9912 0 Td
(to)Tj
1.0204 0 Td
(eliminate)Tj
3.9515 0 Td
(unnecessary)Tj
5.0966 0 Td
(cells.)Tj
-30.682 -1.2983 Td
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1.1112 0 Td
(this)Tj
1.6725 0 Td
(study,)Tj
2.6191 0 Td
(we)Tj
1.3267 0 Td
(showed)Tj
3.2484 0 Td
(that)Tj
1.7802 0 Td
(cells)Tj
1.9219 0 Td
(infected)Tj
3.4185 0 Td
(with)Tj
1.9956 0 Td
(flaviviruses)Tj
4.6771 0 Td
(including)Tj
4.0421 0 Td
(JEV,)Tj
2.0409 0 Td
(DENV)Tj
2.9537 0 Td
(and)Tj
-34.0041 -1.3039 Td
(ZIKV)Tj
2.5285 0 Td
(specifically)Tj
4.5694 0 Td
(induced)Tj
3.4696 0 Td
(apoptosis)Tj
3.9855 0 Td
(by)Tj
1.1849 0 Td
(inhibition)Tj
4.2236 0 Td
(of)Tj
1.0148 0 Td
(BCLX)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 434.1543 640.7433 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(L)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 440.3338 642.3874 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(through)Tj
3.4469 0 Td
(the)Tj
1.4683 0 Td
(suppression)Tj
4.9833 0 Td
(of)Tj
1.0148 0 Td
(MCL1)Tj
-34.9452 -1.2982 Td
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4.6884 0 Td
(Furthermore,)Tj
5.6183 0 Td
(we)Tj
1.3266 0 Td
(showed)Tj
3.2485 0 Td
(that)Tj
1.7801 0 Td
(host)Tj
1.9106 0 Td
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3.1577 0 Td
(synthesis)Tj
3.821 0 Td
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0.8504 0 Td
(impaired)Tj
3.8438 0 Td
(in)Tj
1.0374 0 Td
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-33.2047 -1.2983 Td
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3.7927 0 Td
(with)Tj
1.9956 0 Td
(flaviviruses,)Tj
4.8982 0 Td
(leading)Tj
3.1351 0 Td
(to)Tj
1.0262 0 Td
(the)Tj
1.4683 0 Td
(decay)Tj
2.4831 0 Td
(of)Tj
1.0148 0 Td
(labile)Tj
2.3471 0 Td
(proteins)Tj
3.5092 0 Td
(such)Tj
2.0636 0 Td
(as)Tj
1.0148 0 Td
(MCL1.)Tj
3.016 0 Td
(Treatment)Tj
-31.7647 -1.3039 Td
(with)Tj
1.9956 0 Td
(inhibitors)Tj
4.1442 0 Td
(for)Tj
1.3833 0 Td
(BCLX)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 299.622 601.7385 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(L)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 303.6472 603.3826 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(,)Tj
0.4422 0 Td
(as)Tj
1.0147 0 Td
(well)Tj
1.8199 0 Td
(as)Tj
1.0148 0 Td
(deficiency)Tj
4.2689 0 Td
(of)Tj
1.0148 0 Td
(BCLX)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 423.7228 601.7385 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(L)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 429.959 603.3826 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(gene,)Tj
2.3073 0 Td
(induced)Tj
3.464 0 Td
(BAX/BAK-dependent)Tj
-28.7658 -1.2982 Td
(apoptosis)Tj
3.9912 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.4683 0 Td
(infected)Tj
3.4243 0 Td
(cells.)Tj
2.143 0 Td
(Finally,)Tj
3.1691 0 Td
(engulfment)Tj
4.8132 0 Td
(of)Tj
1.0148 0 Td
(virus-infected)Tj
5.7485 0 Td
(cells)Tj
1.9219 0 Td
(by)Tj
1.1848 0 Td
(macrophages)Tj
5.4992 0 Td
(was)Tj
-35.4101 -1.2983 Td
(significantly)Tj
5.0854 0 Td
(enhanced)Tj
4.0818 0 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.4684 0 Td
(inhibition)Tj
4.2292 0 Td
(of)Tj
1.0148 0 Td
(BCLX)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 394.9228 575.7165 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(L)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 401.159 577.4173 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(without)Tj
3.3278 0 Td
(an)Tj
1.2019 0 Td
(increase)Tj
3.4752 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(production)Tj
4.7168 0 Td
(of)Tj
-35.3194 -1.3039 Td
(pro-inflammatory)Tj
7.4551 0 Td
(cytokines,)Tj
4.2236 0 Td
(which)Tj
2.6475 0 Td
(led)Tj
1.423 0 Td
(to)Tj
1.0205 0 Td
(the)Tj
1.474 0 Td
(suppression)Tj
4.9775 0 Td
(of)Tj
1.0148 0 Td
(viral)Tj
1.9956 0 Td
(dissemination.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 533.9905 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Results)Tj
/F13 1 Tf
0 -1.4976 Td
(Inhibition)Tj
4.5071 0 Td
(of)Tj
1.063 0 Td
(BCLX)Tj
ET
Q
q
1 j
1 J
0 w
8.9997 0 0 7.999 297.411 513.9779 cm
BT
/F13 1 Tf
1 TL
-0.0044 Tc
0 0 Td
(L)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 305.0078 516.0188 cm
BT
/F13 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(accelerates)Tj
4.7008 0 Td
(cell)Tj
1.6299 0 Td
(death)Tj
2.5559 0 Td
(upon)Tj
2.3953 0 Td
(infection)Tj
3.9544 0 Td
(with)Tj
2.0787 0 Td
(flaviviruses)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 499.011 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Firstly,)Tj
2.9706 0 Td
(to)Tj
1.0262 0 Td
(examine)Tj
3.6 0 Td
(the)Tj
1.4683 0 Td
(roles)Tj
2.1316 0 Td
(of)Tj
1.0148 0 Td
(BAX/BAK-dependent)Tj
8.9915 0 Td
(apoptosis)Tj
3.9911 0 Td
(during)Tj
2.9254 0 Td
(flavivirus-infected)Tj
7.4437 0 Td
(cells,)Tj
-35.5632 -1.3039 Td
(we)Tj
1.3266 0 Td
(generated)Tj
4.1328 0 Td
(BAX)Tj
2.1374 0 Td
(and)Tj
1.7347 0 Td
(BAK)Tj
2.1544 0 Td
(double-knockout)Tj
7.1149 0 Td
(\(BAX/BAKDKO\))Tj
7.2396 0 Td
(Huh7)Tj
2.5228 0 Td
(cell)Tj
1.5591 0 Td
(lines)Tj
2.0636 0 Td
(\(clones)Tj
3.0727 0 Td
(#29)Tj
-35.0586 -1.2982 Td
(and)Tj
1.7291 0 Td
(#47\))Tj
1.9842 0 Td
(and)Tj
1.7348 0 Td
(infected)Tj
3.4186 0 Td
(with)Tj
1.9955 0 Td
(Japanese)Tj
3.6907 0 Td
(encephalitis)Tj
4.9606 0 Td
(virus)Tj
2.1997 0 Td
(\(JEV\))Tj
2.4945 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1A)Tj
2.194 0 Td
(Fig)Tj
0 g
(\).)Tj
2.0466 0 Td
(Although)Tj
4.0025 0 Td
(Huh7)Tj
2.5228 0 Td
(cells)Tj
-34.9736 -1.2983 Td
(induced)Tj
3.4582 0 Td
(cell)Tj
1.5534 0 Td
(death)Tj
2.4207 0 Td
(at)Tj
0.9468 0 Td
(4)Tj
0.6917 0 Td
(days)Tj
1.9899 0 Td
(post-infection)Tj
5.8166 0 Td
(with)Tj
1.9899 0 Td
(JEV,)Tj
2.0353 0 Td
(BAX/BAKDKO)Tj
6.5537 0 Td
(cells)Tj
1.9105 0 Td
(exhibited)Tj
3.9231 0 Td
(a)Tj
0.6463 0 Td
(complete)Tj
-33.9361 -1.2983 Td
(resistant)Tj
3.5829 0 Td
(to)Tj
1.0262 0 Td
(mitochondria)Tj
5.7146 0 Td
(mediated)Tj
3.9458 0 Td
(apoptosis)Tj
3.9855 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(],)Tj
2.0806 0 Td
(suggesting)Tj
4.3993 0 Td
(that)Tj
1.7802 0 Td
(cells)Tj
1.9218 0 Td
(infected)Tj
3.4186 0 Td
(with)Tj
1.9956 0 Td
(JEV)Tj
-33.8511 -1.3039 Td
(induce)Tj
2.9366 0 Td
(mitochondria-mediated)Tj
9.7908 0 Td
(apoptosis)Tj
3.9912 0 Td
(at)Tj
0.9524 0 Td
(4)Tj
0.6917 0 Td
(days)Tj
2.0012 0 Td
(post-infection.)Tj
6.0491 0 Td
(However,)Tj
4.0762 0 Td
(BAX/BAKDKO)Tj
-30.4892 -1.2982 Td
(cells)Tj
1.9218 0 Td
(also)Tj
1.7632 0 Td
(exhibited)Tj
3.9288 0 Td
(cell)Tj
1.559 0 Td
(death)Tj
2.4321 0 Td
(at)Tj
0.9525 0 Td
(5)Tj
0.6973 0 Td
(and)Tj
1.7291 0 Td
(6)Tj
0.6973 0 Td
(days)Tj
1.9956 0 Td
(post-infection.)Tj
6.0491 0 Td
(The)Tj
1.7858 0 Td
(BAX/BAK-independent)Tj
9.8078 0 Td
(cell)Tj
-35.3194 -1.2983 Td
(death)Tj
2.4321 0 Td
(might)Tj
2.5965 0 Td
(be)Tj
1.1508 0 Td
(induced)Tj
3.464 0 Td
(by)Tj
1.1848 0 Td
(necrosis)Tj
3.481 0 Td
(or)Tj
1.0998 0 Td
(pyroptosis)Tj
4.3823 0 Td
(rather)Tj
2.6419 0 Td
(than)Tj
2.0296 0 Td
(apoptosis)Tj
3.9911 0 Td
(as)Tj
1.0148 0 Td
(previously)Tj
4.3484 0 Td
(reported)Tj
-33.8171 -1.3039 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(1A)Tj
0 g
(\))Tj
1.7178 0 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(].)Tj
-2.3414 -1.2983 Td
(Recent)Tj
2.9593 0 Td
(clinical)Tj
3.0784 0 Td
(studies)Tj
2.9877 0 Td
(showed)Tj
3.2485 0 Td
(that)Tj
1.7801 0 Td
(survival)Tj
3.3336 0 Td
(of)Tj
1.0148 0 Td
(chronic)Tj
3.2938 0 Td
(lymphocytic)Tj
5.159 0 Td
(leukaemia)Tj
4.2917 0 Td
(\(CLL\))Tj
2.6362 0 Td
(is)Tj
-34.9793 -1.2983 Td
(largely)Tj
2.8573 0 Td
(dependent)Tj
4.4617 0 Td
(on)Tj
1.2755 0 Td
(BCL2)Tj
2.4775 0 Td
([)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
(],)Tj
2.075 0 Td
(and)Tj
1.7291 0 Td
(that)Tj
1.7801 0 Td
(loss)Tj
1.6951 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(single)Tj
/F7 1 Tf
2.5341 0 Td
[()-2()13()]TJ
/F6 1 Tf
1.8596 0 Td
(allele)Tj
2.2393 0 Td
(attenuates)Tj
4.269 0 Td
(MYC-induced)Tj
-30.9201 -1.3039 Td
(lymphoma)Tj
/F7 1 Tf
4.5467 0 Td
[()12( )]TJ
1.0148 0 Td
[()-13()15()3()]TJ
/F6 1 Tf
1.8198 0 Td
([)Tj
0.83 0.64 0.02 0 k
(23)Tj
0 g
(].)Tj
2.075 0 Td
(In)Tj
1.1111 0 Td
(addition,)Tj
3.8211 0 Td
(selective)Tj
3.5433 0 Td
(inhibition)Tj
4.2236 0 Td
(of)Tj
1.0148 0 Td
(MCL1)Tj
2.7893 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.126 0 Td
(shown)Tj
2.8459 0 Td
(to)Tj
1.0262 0 Td
(induce)Tj
-33.4996 -1.2982 Td
(apoptosis)Tj
3.9911 0 Td
(in)Tj
1.0318 0 Td
(acute)Tj
2.3301 0 Td
(myelogenous)Tj
5.5048 0 Td
(leukaemia)Tj
4.2916 0 Td
(cell)Tj
1.5591 0 Td
(lines)Tj
2.0636 0 Td
(without)Tj
3.3335 0 Td
(signs)Tj
2.2224 0 Td
(of)Tj
1.0148 0 Td
(toxicity)Tj
3.1974 0 Td
(to)Tj
1.0262 0 Td
(normal)Tj
3.1464 0 Td
(human)Tj
-34.7128 -1.2983 Td
(haematopoietic)Tj
6.3665 0 Td
(progenitor)Tj
4.4957 0 Td
(cells)Tj
1.9219 0 Td
([)Tj
0.83 0.64 0.02 0 k
(24)Tj
0 g
(].)Tj
2.075 0 Td
(It)Tj
0.8617 0 Td
(had)Tj
1.7064 0 Td
(been)Tj
2.126 0 Td
(reported)Tj
3.6567 0 Td
(that)Tj
1.7801 0 Td
(cellular)Tj
3.1351 0 Td
(stress)Tj
2.3981 0 Td
(such)Tj
2.058 0 Td
(as)Tj
1.0148 0 Td
(ER)Tj
1.4116 0 Td
(stress,)Tj
-35.0076 -1.2983 Td
(DNA)Tj
2.3754 0 Td
(damage)Tj
3.3222 0 Td
(and)Tj
1.7347 0 Td
(innate)Tj
2.7383 0 Td
(immune)Tj
3.6226 0 Td
(response)Tj
3.7361 0 Td
(affects)Tj
2.7382 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4684 0 Td
(expression)Tj
4.4617 0 Td
(of)Tj
1.0148 0 Td
(BCL2)Tj
2.4774 0 Td
(protein)Tj
3.1578 0 Td
(family)Tj
-34.1232 -1.3039 Td
([)Tj
0.83 0.64 0.02 0 k
(25)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(27)Tj
0 g
(].)Tj
3.5432 0 Td
(Therefore,)Tj
4.3937 0 Td
(we)Tj
1.3266 0 Td
(speculated)Tj
4.405 0 Td
(that)Tj
1.7745 0 Td
(virus)Tj
2.2053 0 Td
(infection)Tj
3.7928 0 Td
(alters)Tj
2.3527 0 Td
(the)Tj
1.4684 0 Td
(expression)Tj
4.4673 0 Td
(of)Tj
1.0148 0 Td
(BCL2)Tj
2.4775 0 Td
(proteins)Tj
-33.2218 -1.2982 Td
(through)Tj
3.4412 0 Td
(the)Tj
1.474 0 Td
(induction)Tj
4.1329 0 Td
(of)Tj
1.0148 0 Td
(cellular)Tj
3.1407 0 Td
(stress.)Tj
2.6192 0 Td
(BH3-only)Tj
4.1499 0 Td
(proteins)Tj
3.515 0 Td
(are)Tj
1.4513 0 Td
(known)Tj
3.0047 0 Td
(to)Tj
1.0205 0 Td
(exhibit)Tj
2.9763 0 Td
(specific)Tj
3.1918 0 Td
(inter-)Tj
-35.1323 -1.2983 Td
(actions)Tj
3.0557 0 Td
(with)Tj
2.0012 0 Td
(pro-survival)Tj
5.0797 0 Td
(BCL2)Tj
2.4774 0 Td
(proteins,)Tj
3.7418 0 Td
(including)Tj
4.0421 0 Td
(BCL2,)Tj
2.6986 0 Td
(BCLX)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 455.3574 276.3212 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(L)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 459.3826 278.022 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(,)Tj
0.4422 0 Td
(BCLW)Tj
2.9706 0 Td
(and)Tj
1.7292 0 Td
(MCL1)Tj
2.7892 0 Td
([)Tj
0.83 0.64 0.02 0 k
(28)Tj
0 g
(].)Tj
-33.868 -1.3039 Td
(BIM)Tj
2.0296 0 Td
(and)Tj
1.7348 0 Td
(PUMA)Tj
3.0897 0 Td
(bind)Tj
2.0693 0 Td
(to)Tj
1.0261 0 Td
(all)Tj
1.1452 0 Td
(pro-survival)Tj
5.0854 0 Td
(BCL2)Tj
2.4774 0 Td
(proteins;)Tj
3.7361 0 Td
(BAD)Tj
2.2223 0 Td
(binds)Tj
2.432 0 Td
(selectively)Tj
4.2406 0 Td
(to)Tj
1.0262 0 Td
(BCL2,)Tj
-32.3147 -1.2982 Td
(BCLX)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 224.3338 250.3559 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(L)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 230.57 252 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(and)Tj
1.7291 0 Td
(BCLW;)Tj
3.1918 0 Td
(and)Tj
1.7291 0 Td
(NOXA)Tj
3.0444 0 Td
(binds)Tj
2.4321 0 Td
(specifically)Tj
4.5694 0 Td
(to)Tj
1.0261 0 Td
(MCL1)Tj
2.7893 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1B)Tj
2.092 0 Td
(Fig)Tj
0 g
(\).)Tj
2.0466 0 Td
(To)Tj
1.3379 0 Td
(investigate)Tj
4.4617 0 Td
(the)Tj
1.4684 0 Td
(roles)Tj
-34.9736 -1.2982 Td
(of)Tj
1.0148 0 Td
(pro-survival)Tj
5.0796 0 Td
(BCL2)Tj
2.4774 0 Td
(proteins)Tj
3.515 0 Td
(in)Tj
1.0374 0 Td
(cells)Tj
1.9219 0 Td
(infected)Tj
3.4186 0 Td
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