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Lue Sun, Takashi Moritake, Kazuya Ito, Yoshitaka Matsumoto, Hironobu Yasui, Hidehiko Nakagawa, Aki Hirayama, Osamu Inanami, Koji Tsuboi
Metabolic analysis of radioresistant medulloblastoma stem-like clones and potential therapeutic targets
www.plosone.org
www.plosone.org
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(32)Tj
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(second)Tj
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(kinase)Tj
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(activity)Tj
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(lactate)Tj
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(parental)Tj
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4.3936 0 Td
(intervention)Tj
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(modified)Tj
3.8494 0 Td
(multiple)Tj
3.566 0 Td
(steps)Tj
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1.0148 0 Td
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(mitochondria)Tj
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(morphology,)Tj
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(development)Tj
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3.0897 0 Td
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7.1263 0 Td
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11.9999 0 0 11.9999 200.0125 379.2755 cm
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7.4999 0 0 6.6659 521.2346 277.6251 cm
BT
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ET
Q
q
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1 J
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(PBS)Tj
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3.3392 0 Td
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(made)Tj
-33.046 -1.2983 Td
(using)Tj
2.3867 0 Td
(an)Tj
1.2019 0 Td
(ultra-microtome)Tj
6.8881 0 Td
(and)Tj
1.7292 0 Td
(imaged)Tj
3.1577 0 Td
(using)Tj
2.3868 0 Td
(a)Tj
0.6576 0 Td
(JEM-1400)Tj
4.2633 0 Td
(transmission)Tj
5.3631 0 Td
(electron)Tj
3.4639 0 Td
(microscope)Tj
-31.4983 -1.2982 Td
(\(JEOL\).)Tj
3.3108 0 Td
(At)Tj
1.2019 0 Td
(least)Tj
1.9785 0 Td
(50)Tj
1.1736 0 Td
(mitochondria)Tj
5.7203 0 Td
(in)Tj
1.0318 0 Td
(each)Tj
2.0296 0 Td
(sample)Tj
3.0217 0 Td
(were)Tj
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(analyzed)Tj
3.7021 0 Td
(by)Tj
1.1792 0 Td
(ImageJ)Tj
3.033 0 Td
(software)Tj
3.5887 0 Td
(\(NIH,)Tj
-33.0971 -1.304 Td
(USA\).)Tj
2.6815 0 Td
(Mitochondria)Tj
5.7883 0 Td
(circularity)Tj
4.3087 0 Td
(was)Tj
1.6951 0 Td
(calculated)Tj
4.2065 0 Td
(from)Tj
2.2054 0 Td
(the)Tj
1.4683 0 Td
(equation)Tj
3.7361 0 Td
(C)Tj
0.8844 0 Td
(=)Tj
0.7993 0 Td
(4)Tj
/F12 1 Tf
[()]TJ
/F5 1 Tf
(/)Tj
/F12 1 Tf
[()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 500.8818 506.2677 cm
BT
/F5 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 504.4535 501.7889 cm
BT
/F5 1 Tf
1 TL
-0.004 Tc
0 0 Td
(,)Tj
0.4478 0 Td
(where)Tj
2.6476 0 Td
(S)Tj
0.6973 0 Td
(is)Tj
0.8447 0 Td
(the)Tj
-35.0813 -1.2982 Td
(mitochondria)Tj
5.7203 0 Td
(area)Tj
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(and)Tj
1.7291 0 Td
(L)Tj
0.7597 0 Td
(is)Tj
0.8447 0 Td
(the)Tj
1.4684 0 Td
(mitochondria)Tj
5.7203 0 Td
(perimeter.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 461.537 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Measurement)Tj
6.2693 0 Td
(of)Tj
1.0488 0 Td
(CD133-positive)Tj
6.9686 0 Td
(ratio)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 444.5291 cm
BT
/F5 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Cells)Tj
2.1599 0 Td
(were)Tj
2.1203 0 Td
(trypsinized,)Tj
4.8983 0 Td
(washed)Tj
3.1748 0 Td
(with)Tj
2.0012 0 Td
(PBS)Tj
1.8312 0 Td
(containing)Tj
4.5297 0 Td
(2%)Tj
1.4513 0 Td
(FBS,)Tj
2.0296 0 Td
(and)Tj
1.7292 0 Td
(2)Tj
/F10 1 Tf
[()]TJ
/F5 1 Tf
(10)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 479.2251 449.0078 cm
BT
/F5 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(6)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 485.0078 444.5291 cm
BT
/F5 1 Tf
1 TL
-0.004 Tc
0 0 Td
(cells)Tj
1.9218 0 Td
(were)Tj
2.1203 0 Td
(suspended)Tj
-32.5414 -1.2982 Td
(in)Tj
1.0318 0 Td
(80)Tj
/F10 1 Tf
1.1735 0 Td
[()]TJ
/F5 1 Tf
(l)Tj
0.9752 0 Td
(of)Tj
1.0148 0 Td
(PBS)Tj
1.8311 0 Td
(with)Tj
2.0013 0 Td
(2%)Tj
1.4513 0 Td
(FBS)Tj
1.8028 0 Td
(prior)Tj
2.2564 0 Td
(to)Tj
1.0205 0 Td
(addition)Tj
3.5999 0 Td
(of)Tj
1.0148 0 Td
(20)Tj
/F10 1 Tf
1.1736 0 Td
[()]TJ
/F5 1 Tf
(l)Tj
0.9694 0 Td
(FcR)Tj
1.7915 0 Td
(blocking)Tj
3.685 0 Td
(reagent)Tj
3.1804 0 Td
(\(Miltenyi)Tj
3.9628 0 Td
(Biotec)Tj
-33.9361 -1.2983 Td
(Inc.,)Tj
1.9842 0 Td
(Tokyo,)Tj
3.0218 0 Td
(Japan\))Tj
2.8232 0 Td
(and)Tj
1.7292 0 Td
(10)Tj
/F10 1 Tf
1.1678 0 Td
[()]TJ
/F5 1 Tf
(l)Tj
0.9751 0 Td
(of)Tj
1.0148 0 Td
(phycoerythrin)Tj
5.9131 0 Td
(\(PE\)-conjugated)Tj
6.7917 0 Td
(anti-human)Tj
4.9776 0 Td
(CD133/1)Tj
3.8494 0 Td
(mouse)Tj
-34.2479 -1.3039 Td
(IgG1)Tj
2.2167 0 Td
(antibody)Tj
3.7644 0 Td
(\(Miltenyi)Tj
3.9571 0 Td
(Biotec\).)Tj
3.2825 0 Td
(After)Tj
2.2847 0 Td
(incubation)Tj
4.5524 0 Td
(for)Tj
1.3833 0 Td
(30)Tj
1.1736 0 Td
(min)Tj
1.8538 0 Td
(at)Tj
0.9524 0 Td
(4C)Tj
1.7518 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(dark)Tj
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(cells)Tj
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(were)Tj
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(washed)Tj
3.1748 0 Td
(twice)Tj
2.3187 0 Td
(with)Tj
1.9956 0 Td
(2%)Tj
1.457 0 Td
(FBS)Tj
1.8028 0 Td
(in)Tj
1.0318 0 Td
(PBS)Tj
1.8369 0 Td
(and)Tj
1.7291 0 Td
(propidium)Tj
4.5411 0 Td
(iodide)Tj
2.7439 0 Td
(\(PI\))Tj
1.7971 0 Td
(\(Sigma-Aldrich\))Tj
6.7577 0 Td
(was)Tj
1.7008 0 Td
(added)Tj
2.6588 0 Td
(to)Tj
1.0262 0 Td
(a)Tj
-36.5723 -1.2982 Td
(final)Tj
2.0012 0 Td
(concentration)Tj
5.8224 0 Td
(of)Tj
1.0148 0 Td
(1)Tj
/F10 1 Tf
0.6916 0 Td
[()]TJ
/F5 1 Tf
(g/ml)Tj
2.5909 0 Td
(to)Tj
1.0261 0 Td
(detect)Tj
2.6135 0 Td
(dead)Tj
2.1317 0 Td
(cells.)Tj
2.1486 0 Td
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1.7802 0 Td
(cells)Tj
1.9218 0 Td
(were)Tj
2.1203 0 Td
(filtered)Tj
3.067 0 Td
(through)Tj
3.4469 0 Td
(a)Tj
0.652 0 Td
(35-)Tj
/F10 1 Tf
[()]TJ
/F5 1 Tf
(m)Tj
2.846 0 Td
(cell)Tj
-35.875 -1.3039 Td
(strainer)Tj
3.2938 0 Td
(and)Tj
1.7292 0 Td
(at)Tj
0.9524 0 Td
(least)Tj
1.9842 0 Td
(3)Tj
/F10 1 Tf
[()]TJ
/F5 1 Tf
(10)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 299.5653 370.9984 cm
BT
/F5 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 305.348 366.5196 cm
BT
/F5 1 Tf
1 TL
-0.004 Tc
0 0 Td
(cells)Tj
1.9162 0 Td
(were)Tj
2.1259 0 Td
(analyzed)Tj
3.7021 0 Td
(by)Tj
1.1792 0 Td
(flow)Tj
1.9445 0 Td
(cytometry)Tj
4.2746 0 Td
(\(FACSCalibur\).)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 339.2503 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Tumor)Tj
3.085 0 Td
(sphere)Tj
3.241 0 Td
(assay)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 322.2425 cm
BT
/F5 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Cells)Tj
2.1599 0 Td
(were)Tj
2.1203 0 Td
(cultured)Tj
3.566 0 Td
(in)Tj
1.0375 0 Td
(serum-free)Tj
4.5807 0 Td
(medium)Tj
3.6057 0 Td
(\(SFM\))Tj
2.7949 0 Td
(composed)Tj
4.3087 0 Td
(of)Tj
1.0148 0 Td
(Dulbecco's)Tj
4.5864 0 Td
(Modified)Tj
3.9231 0 Td
(Eagle)Tj
-33.698 -1.2982 Td
(Medium/Nutrient)Tj
7.4777 0 Td
(Mixture)Tj
3.4639 0 Td
(F-12)Tj
2.0523 0 Td
(\(DMEM/)Tj
3.9798 0 Td
(F12;)Tj
1.9275 0 Td
(GIBCO,)Tj
3.4866 0 Td
(Life)Tj
1.7405 0 Td
(Technologies\),)Tj
6.0945 0 Td
(20)Tj
1.1735 0 Td
(ng/ml)Tj
2.6249 0 Td
(epider-)Tj
-34.0212 -1.2983 Td
(mal)Tj
1.7177 0 Td
(growth)Tj
3.0728 0 Td
(factor)Tj
2.5455 0 Td
(\(EGF;)Tj
2.5965 0 Td
(\(Sigma-Aldrich\),)Tj
6.9845 0 Td
(20)Tj
1.1735 0 Td
(ng/ml)Tj
2.6306 0 Td
(basic)Tj
2.211 0 Td
(fibroblast)Tj
4.0025 0 Td
(growth)Tj
3.0784 0 Td
(factor)Tj
2.5398 0 Td
(\(bFGF;)Tj
-32.5528 -1.2982 Td
(Sigma-Aldrich\))Tj
6.4175 0 Td
(and)Tj
1.7292 0 Td
(20)Tj
/F10 1 Tf
1.1735 0 Td
[()]TJ
/F5 1 Tf
(l/ml)Tj
2.3698 0 Td
(B27)Tj
1.7518 0 Td
(supplement)Tj
4.9039 0 Td
(\(GIBCO,)Tj
3.8267 0 Td
(Life)Tj
1.7405 0 Td
(Technologies\).)Tj
6.0944 0 Td
(Cells)Tj
2.16 0 Td
(were)Tj
2.1203 0 Td
(plated)Tj
-34.2876 -1.304 Td
(at)Tj
0.9524 0 Td
(a)Tj
0.6519 0 Td
(density)Tj
3.1011 0 Td
(of)Tj
1.0148 0 Td
(1,000)Tj
2.3471 0 Td
(cells/well)Tj
3.8494 0 Td
(on)Tj
1.2756 0 Td
(ultra-low)Tj
3.8891 0 Td
(attachment)Tj
4.7225 0 Td
(surface)Tj
3.0501 0 Td
(24-well)Tj
3.1237 0 Td
(plates)Tj
2.5002 0 Td
(\(Corning)Tj
3.9288 0 Td
(Inc.,)Tj
-34.4067 -1.2982 Td
(Lowell,)Tj
3.0897 0 Td
(MA,)Tj
2.0239 0 Td
(USA\).)Tj
2.6816 0 Td
(DCA)Tj
2.3017 0 Td
(was)Tj
1.7008 0 Td
(added)Tj
2.6589 0 Td
(to)Tj
1.0261 0 Td
(treatment)Tj
4.1329 0 Td
(groups)Tj
2.9707 0 Td
(to)Tj
1.0261 0 Td
(a)Tj
0.652 0 Td
(final)Tj
2.0069 0 Td
(concentration)Tj
5.8166 0 Td
(of)Tj
1.0148 0 Td
(50)Tj
1.1736 0 Td
(mM.)Tj
-34.2763 -1.2983 Td
(The)Tj
1.7801 0 Td
(number)Tj
3.4186 0 Td
(of)Tj
1.0148 0 Td
(spheres)Tj
3.2031 0 Td
(was)Tj
1.7008 0 Td
(counted)Tj
3.4752 0 Td
(at)Tj
0.9524 0 Td
(day)Tj
1.6385 0 Td
(10.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 217.0204 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Clonogenic)Tj
5.1496 0 Td
(assay)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 200.0125 cm
BT
/F5 1 Tf
1 TL
-0.009 Tc
0 0 Td
(Cells)Tj
2.1316 0 Td
(in)Tj
1.0261 0 Td
(flasks)Tj
2.3754 0 Td
(were)Tj
2.1033 0 Td
(exposed)Tj
3.4129 0 Td
(to)Tj
1.0148 0 Td
(X-irradiation)Tj
5.4482 0 Td
(\(130)Tj
1.9672 0 Td
(kVp,)Tj
2.1373 0 Td
(5)Tj
0.6917 0 Td
(mA,)Tj
1.9332 0 Td
(approximately)Tj
5.9074 0 Td
(0.9)Tj
1.3832 0 Td
(Gy/min\))Tj
3.6624 0 Td
(at)Tj
-35.1947 -1.3039 Td
(doses)Tj
2.3754 0 Td
(of)Tj
1.0034 0 Td
(2,)Tj
0.9128 0 Td
(4,)Tj
0.9071 0 Td
(6,)Tj
0.9127 0 Td
(and)Tj
1.7178 0 Td
(8)Tj
0.686 0 Td
(Gy.)Tj
1.6044 0 Td
(After)Tj
2.2563 0 Td
(irradiation,)Tj
4.6828 0 Td
(the)Tj
1.4514 0 Td
(cells)Tj
1.8935 0 Td
(were)Tj
2.1033 0 Td
(trypsinized)Tj
4.6148 0 Td
(and)Tj
1.7178 0 Td
(counted,)Tj
3.6623 0 Td
(and)Tj
1.7121 0 Td
(the)Tj
1.457 0 Td
(pre-)Tj
-35.6709 -1.2982 Td
(determined)Tj
4.8018 0 Td
(number)Tj
3.3846 0 Td
(of)Tj
1.0034 0 Td
(cells)Tj
1.8992 0 Td
(was)Tj
1.6838 0 Td
(plated)Tj
2.6362 0 Td
(onto)Tj
2.0579 0 Td
(three)Tj
2.2394 0 Td
(60-mm)Tj
3.1408 0 Td
(dishes)Tj
2.6532 0 Td
(\(Falcon,)Tj
3.4355 0 Td
(Becton)Tj
2.9707 0 Td
(Dickinson\))Tj
-31.9065 -1.2983 Td
(for)Tj
1.3719 0 Td
(each)Tj
2.0069 0 Td
(dose)Tj
2.0183 0 Td
(point.)Tj
2.5511 0 Td
(After)Tj
2.2621 0 Td
(incubation)Tj
4.5014 0 Td
(for)Tj
1.3719 0 Td
(14)Tj
1.1566 0 Td
(days,)Tj
2.1996 0 Td
(the)Tj
1.457 0 Td
(colonies)Tj
3.4583 0 Td
(were)Tj
2.1033 0 Td
(fixed)Tj
2.1656 0 Td
(and)Tj
1.7178 0 Td
(stained)Tj
3.0444 0 Td
(with)Tj
-33.3862 -1.2983 Td
(0.25%)Tj
2.6021 0 Td
(methylene)Tj
4.3427 0 Td
(blue)Tj
1.9049 0 Td
(solution)Tj
3.4412 0 Td
(\(Wako\))Tj
3.2712 0 Td
(in)Tj
1.0261 0 Td
(90%)Tj
1.9162 0 Td
(ethanol)Tj
3.1691 0 Td
(solution.)Tj
3.6624 0 Td
(The)Tj
1.7688 0 Td
(number)Tj
3.3845 0 Td
(of)Tj
1.0091 0 Td
(surviving)Tj
3.8891 0 Td
(colo-)Tj
-35.3874 -1.3039 Td
(nies)Tj
1.7971 0 Td
(that)Tj
1.7575 0 Td
(included)Tj
3.6737 0 Td
(50)Tj
1.1621 0 Td
(cells)Tj
1.8936 0 Td
(or)Tj
1.0885 0 Td
(more)Tj
2.3244 0 Td
(was)Tj
1.6837 0 Td
(counted)Tj
3.4413 0 Td
(and)Tj
1.7121 0 Td
(averaged)Tj
3.7134 0 Td
([)Tj
0.83 0.64 0.02 0 k
(39)Tj
0 g
(].)Tj
2.0522 0 Td
(Survival)Tj
3.4129 0 Td
(curves)Tj
2.7496 0 Td
(were)Tj
2.1033 0 Td
(fitted)Tj
-34.5654 -1.2982 Td
(to)Tj
1.0147 0 Td
(the)Tj
1.4514 0 Td
(linear-quadratic)Tj
6.5763 0 Td
(model)Tj
2.7156 0 Td
(using)Tj
2.3641 0 Td
(DeltaGraph)Tj
4.8755 0 Td
(v.5.4)Tj
2.0523 0 Td
(software)Tj
3.5433 0 Td
(\(RedRock)Tj
4.1442 0 Td
(Software,)Tj
3.8834 0 Td
(Inc.,)Tj
1.9559 0 Td
(Salt)Tj
-34.5767 -1.2983 Td
(Lake)Tj
2.0919 0 Td
(City,)Tj
2.1033 0 Td
(UT,)Tj
1.7745 0 Td
(USA\))Tj
2.4378 0 Td
(as)Tj
1.0034 0 Td
(previously)Tj
4.303 0 Td
(described)Tj
4.0081 0 Td
([)Tj
0.83 0.64 0.02 0 k
(40)Tj
0 g
(].)Tj
2.0523 0 Td
(Sensitivity)Tj
4.2803 0 Td
(enhancement)Tj
5.5842 0 Td
(ratio)Tj
2.0693 0 Td
(at)Tj
0.9468 0 Td
(4)Tj
0.6859 0 Td
(Gy)Tj
1.3833 0 Td
(\(SER)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 200.0125 94.337 cm
BT
/F5 1 Tf
1 TL
-0.012 Tc
0 0 Td
(\(4.0\))Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 213.6188 95.9811 cm
BT
/F5 1 Tf
1 TL
-0.009 Tc
0 0 Td
(\))Tj
0.5555 0 Td
(was)Tj
1.6838 0 Td
(calculated)Tj
4.1556 0 Td
(from)Tj
2.1826 0 Td
(the)Tj
1.457 0 Td
(equation)Tj
3.6907 0 Td
(SER)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 369.6377 94.337 cm
BT
/F5 1 Tf
1 TL
-0.012 Tc
0 0 Td
(\(4.0\))Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 385.4551 95.9811 cm
BT
/F5 1 Tf
1 TL
-0.009 Tc
0 0 Td
(=)Tj
0.7936 0 Td
(log)Tj
1.423 0 Td
(Sf)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 417.3732 94.337 cm
BT
/F5 1 Tf
1 TL
-0.012 Tc
0 0 Td
(\(DCA,)Tj
2.9027 0 Td
(4.0\))Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 452.4661 95.9811 cm
BT
/F5 1 Tf
1 TL
-0.009 Tc
0 0 Td
(/)Tj
0.5442 0 Td
(log)Tj
1.423 0 Td
(Sf)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 481.8897 94.337 cm
BT
/F5 1 Tf
1 TL
-0.012 Tc
0 0 Td
(\(4.0\))Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 495.496 95.9811 cm
BT
/F5 1 Tf
1 TL
-0.009 Tc
0 0 Td
(,)Tj
0.4422 0 Td
(where)Tj
2.6248 0 Td
(Sf)Tj
ET
Q
q
1 j
1 J
0 w
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