%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Darren W. Gray, Michael D. Welsh, Fawad Mansoor, Simon Doherty, Olivier P. Chevallier, Christopher T. Elliott, Mark H. Mooney
DIVA metabolomics: Differentiating vaccination status following viral challenge using metabolomic profiles
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 9 0 R/Annots 10 0 R/Contents 11 0 R/TrimBox[0 0 612 792]>>
endobj
10 0 obj
[12 0 R 13 0 R 14 0 R 15 0 R 16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R 23 0 R 24 0 R 25 0 R 26 0 R]
endobj
12 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref001)>>
endobj
13 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref002)>>
endobj
14 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref003)>>
endobj
15 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref004)>>
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref005)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref006)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref007)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref008)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref006)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref009)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref010)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref011)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref012)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref013)>>
endobj
26 0 obj
<>/Border[0 0 0]/A 27 0 R>>
endobj
27 0 obj
<>
endobj
11 0 obj
[28 0 R 29 0 R 30 0 R 31 0 R 32 0 R 33 0 R 34 0 R 35 0 R 36 0 R 37 0 R 38 0 R 39 0 R 40 0 R 41 0 R 42 0 R]
endobj
28 0 obj
<>stream
q
0.83 0.64 0.02 0 k
485.0646 674.9858 m
489.7701 674.9858 l
h
f*
527.2441 649.0205 m
532.0063 649.0205 l
h
f*
536.485 649.0205 m
541.2472 649.0205 l
h
f*
292.8189 622.9984 m
297.5811 622.9984 l
h
f*
302.0598 622.9984 m
306.822 622.9984 l
h
f*
203.4142 610.0157 m
208.1764 610.0157 l
h
f*
565.0583 610.0157 m
569.8205 610.0157 l
h
f*
369.6945 544.989 m
374.4567 544.989 l
h
f*
475.7669 505.9843 m
480.5291 505.9843 l
h
f*
421.115 389.0268 m
425.8772 389.0268 l
h
f*
358.0157 194.0031 m
367.5402 194.0031 l
h
f*
371.9622 194.0031 m
381.4866 194.0031 l
h
f*
203.4142 167.9811 m
212.9386 167.9811 l
h
f*
217.3606 167.9811 m
226.885 167.9811 l
h
f*
0 g
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 706.0535 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Introduction)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 689.1023 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Bovine)Tj
2.999 0 Td
(Respiratory)Tj
4.8472 0 Td
(Disease)Tj
3.2258 0 Td
(\(BRD\))Tj
2.8403 0 Td
(is)Tj
0.8447 0 Td
(a)Tj
0.6577 0 Td
(multifactorial)Tj
5.6465 0 Td
(disease)Tj
3.0161 0 Td
(characteristic)Tj
5.5445 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(viral-bacterial)Tj
-31.2886 -1.3039 Td
(synergistic)Tj
4.4617 0 Td
(infection)Tj
3.7927 0 Td
(with)Tj
1.9956 0 Td
(predisposition)Tj
5.9584 0 Td
(from)Tj
2.2053 0 Td
(environmental)Tj
6.1114 0 Td
(stressors)Tj
3.6397 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(].)Tj
1.5987 0 Td
(The)Tj
1.7802 0 Td
(disease)Tj
3.0217 0 Td
(consti-)Tj
-34.5654 -1.2982 Td
(tutes)Tj
2.1259 0 Td
(a)Tj
0.6577 0 Td
(major)Tj
2.6078 0 Td
(source)Tj
2.8346 0 Td
(of)Tj
1.0148 0 Td
(economic)Tj
4.1386 0 Td
(loss)Tj
1.6951 0 Td
(through)Tj
3.4412 0 Td
(mortality,)Tj
4.1443 0 Td
(clinical)Tj
3.0784 0 Td
(disease)Tj
3.016 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4684 0 Td
(associated)Tj
-31.9519 -1.2983 Td
(treatments)Tj
4.4957 0 Td
(and)Tj
1.7291 0 Td
(long)Tj
1.9899 0 Td
(lasting)Tj
2.8403 0 Td
(reduced)Tj
3.4412 0 Td
(growth)Tj
3.0728 0 Td
(performance)Tj
5.3518 0 Td
(of)Tj
1.0147 0 Td
(infected)Tj
3.4186 0 Td
(young)Tj
2.7213 0 Td
(stock)Tj
2.3073 0 Td
([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2643 0 Td
(3)Tj
0 g
(].)Tj
1.2586 0 Td
(The)Tj
-34.9056 -1.3039 Td
(annual)Tj
2.9593 0 Td
(cost)Tj
1.8085 0 Td
(of)Tj
1.0148 0 Td
(BRD)Tj
2.16 0 Td
(is)Tj
0.8447 0 Td
(estimated)Tj
4.0762 0 Td
(at)Tj
0.9524 0 Td
($1billion)Tj
3.7587 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4684 0 Td
(USA,)Tj
2.3414 0 Td
(with)Tj
1.9955 0 Td
(preventative)Tj
5.1364 0 Td
(measures)Tj
3.9401 0 Td
(contribut-)Tj
-33.4939 -1.2983 Td
(ing)Tj
1.5023 0 Td
(a)Tj
0.652 0 Td
(further)Tj
3.0273 0 Td
($3billion)Tj
3.7588 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2642 0 Td
(5)Tj
0 g
(].)Tj
1.2586 0 Td
(Vaccines)Tj
3.7984 0 Td
(are)Tj
1.4456 0 Td
(commonly)Tj
4.5468 0 Td
(used)Tj
2.0579 0 Td
(for)Tj
1.389 0 Td
(controlling)Tj
4.6488 0 Td
(BRD)Tj
2.16 0 Td
(viral)Tj
1.9899 0 Td
(pathogens)Tj
-33.4996 -1.2982 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(],)Tj
1.5987 0 Td
(but)Tj
1.5534 0 Td
(despite)Tj
3.0387 0 Td
(seasonal)Tj
3.5376 0 Td
(vaccination,)Tj
5.0513 0 Td
(animals)Tj
3.3279 0 Td
(can)Tj
1.627 0 Td
(become)Tj
3.3222 0 Td
(infected)Tj
3.4242 0 Td
(with)Tj
1.9956 0 Td
(each)Tj
2.0296 0 Td
(new)Tj
1.8765 0 Td
(outbreak)Tj
3.7814 0 Td
([)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(],)Tj
-36.1641 -1.304 Td
(maintaining)Tj
5.1193 0 Td
(the)Tj
1.4683 0 Td
(infection)Tj
3.7928 0 Td
(within)Tj
2.8119 0 Td
(the)Tj
1.4683 0 Td
(population.)Tj
4.8132 0 Td
(The)Tj
1.7859 0 Td
(viral)Tj
1.9899 0 Td
(pathogens)Tj
4.3029 0 Td
(associated)Tj
4.2576 0 Td
(with)Tj
2.0013 0 Td
(BRD)Tj
-33.8114 -1.2982 Td
([Bovine)Tj
3.3391 0 Td
(Parainfluenza)Tj
5.7147 0 Td
(Virus)Tj
2.4434 0 Td
(type-3)Tj
2.7383 0 Td
(\(BPI3V\),)Tj
3.7757 0 Td
(Bovine)Tj
2.999 0 Td
(Respiratory)Tj
4.8472 0 Td
(Syncytial)Tj
3.8268 0 Td
(Virus,)Tj
2.6645 0 Td
(Bovine)Tj
2.9991 0 Td
(Viral)Tj
-35.3478 -1.2983 Td
(Diarrhoea)Tj
4.2916 0 Td
(Virus)Tj
2.4434 0 Td
(and)Tj
1.7291 0 Td
(Bovine)Tj
2.9991 0 Td
(Herpes)Tj
3.0841 0 Td
(Virus-1])Tj
3.6056 0 Td
(impair)Tj
2.897 0 Td
(immune)Tj
3.6283 0 Td
(responses)Tj
4.0932 0 Td
(in)Tj
1.0375 0 Td
(infected)Tj
3.4186 0 Td
(animals)Tj
-33.2275 -1.2983 Td
(and)Tj
1.7291 0 Td
(damage)Tj
3.3222 0 Td
(the)Tj
1.474 0 Td
(respiratory)Tj
4.5921 0 Td
(tract)Tj
2.0466 0 Td
(allowing)Tj
3.6169 0 Td
(the)Tj
1.4741 0 Td
(establishment)Tj
5.7316 0 Td
(of)Tj
1.0148 0 Td
(secondary)Tj
4.2746 0 Td
(infections,)Tj
4.3767 0 Td
(that)Tj
1.7801 0 Td
(may)Tj
-35.4328 -1.3039 Td
(develop)Tj
3.3165 0 Td
(further)Tj
3.0273 0 Td
(into)Tj
1.8426 0 Td
(bacterial)Tj
3.6283 0 Td
(pneumonia)Tj
4.8132 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(].)Tj
1.5987 0 Td
(However,)Tj
4.0762 0 Td
(vaccinated)Tj
4.456 0 Td
(animals)Tj
3.3279 0 Td
(can)Tj
1.6271 0 Td
(successfully)Tj
-31.7138 -1.2982 Td
(clear)Tj
2.1146 0 Td
(viral)Tj
1.9956 0 Td
(infections)Tj
4.1555 0 Td
(faster)Tj
2.3925 0 Td
(than)Tj
2.0295 0 Td
(non-vaccinated)Tj
6.412 0 Td
(animals)Tj
3.3278 0 Td
(through)Tj
3.4469 0 Td
(immune)Tj
3.6227 0 Td
(memory)Tj
3.617 0 Td
(response,)Tj
-33.1141 -1.2983 Td
(reducing)Tj
3.7757 0 Td
(the)Tj
1.4683 0 Td
(associated)Tj
4.2576 0 Td
(viral)Tj
1.9899 0 Td
(tissue)Tj
2.4605 0 Td
(damage)Tj
3.3222 0 Td
(or)Tj
1.0998 0 Td
(impairment)Tj
4.989 0 Td
(of)Tj
1.0147 0 Td
(immune)Tj
3.6227 0 Td
(functions)Tj
3.9912 0 Td
(preventing)Tj
-31.9916 -1.3039 Td
(the)Tj
1.4683 0 Td
(establishment)Tj
5.7373 0 Td
(of)Tj
1.0148 0 Td
(secondary)Tj
4.2689 0 Td
(bacterial)Tj
3.6283 0 Td
(and)Tj
1.7292 0 Td
(mycoplasma)Tj
5.2327 0 Td
(infections)Tj
4.1556 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(].)Tj
1.5987 0 Td
(During)Tj
3.1408 0 Td
(disease)Tj
3.016 0 Td
(out-)Tj
-34.9906 -1.2983 Td
(breaks,)Tj
3.0387 0 Td
(identification)Tj
5.5842 0 Td
(of)Tj
1.0148 0 Td
(unvaccinated)Tj
5.5332 0 Td
(animals)Tj
3.3278 0 Td
(at)Tj
0.9525 0 Td
(the)Tj
1.4683 0 Td
(early)Tj
2.1543 0 Td
(stages)Tj
2.5625 0 Td
(of)Tj
1.0148 0 Td
(infection)Tj
3.7871 0 Td
(could)Tj
2.4548 0 Td
(provide)Tj
3.2881 0 Td
(a)Tj
-36.1811 -1.2982 Td
(window)Tj
3.4355 0 Td
(for)Tj
1.389 0 Td
(effective)Tj
3.5093 0 Td
(treatment)Tj
4.1328 0 Td
(and)Tj
1.7348 0 Td
(facilitate)Tj
3.6 0 Td
(the)Tj
1.4683 0 Td
(removal)Tj
3.4753 0 Td
(of)Tj
1.0148 0 Td
(animals)Tj
3.3335 0 Td
(that)Tj
1.7745 0 Td
(pose)Tj
2.0296 0 Td
(a)Tj
0.652 0 Td
(greater)Tj
3.0103 0 Td
(risk)Tj
1.7121 0 Td
(of)Tj
-36.2718 -1.304 Td
(becoming)Tj
4.1782 0 Td
(infected)Tj
3.4242 0 Td
(and)Tj
1.7291 0 Td
(transmitting)Tj
5.1988 0 Td
(the)Tj
1.4683 0 Td
(infection)Tj
3.7927 0 Td
(to)Tj
1.0205 0 Td
(more)Tj
2.3414 0 Td
(susceptible)Tj
4.5807 0 Td
(juvenile)Tj
3.3676 0 Td
(stock.)Tj
2.5285 0 Td
(Further-)Tj
-33.63 -1.2982 Td
(more,)Tj
2.5625 0 Td
(halting)Tj
3.0047 0 Td
(viral)Tj
1.9955 0 Td
(disease)Tj
3.0161 0 Td
(progression)Tj
4.9152 0 Td
(to)Tj
1.0262 0 Td
(more)Tj
2.3357 0 Td
(severe)Tj
2.6759 0 Td
(and)Tj
1.7291 0 Td
(costly)Tj
2.5115 0 Td
(secondary)Tj
4.2689 0 Td
(bacterial)Tj
3.6227 0 Td
(infections)Tj
-33.664 -1.2983 Td
(through)Tj
3.4412 0 Td
(the)Tj
1.474 0 Td
(identification)Tj
5.5842 0 Td
(of)Tj
1.0148 0 Td
(vaccine)Tj
3.1918 0 Td
(failure)Tj
2.7779 0 Td
(animals)Tj
3.3336 0 Td
(during)Tj
2.9253 0 Td
(infection)Tj
3.7927 0 Td
(outbreaks)Tj
4.1443 0 Td
(would)Tj
2.7155 0 Td
(reduce)Tj
-34.3953 -1.2983 Td
(the)Tj
1.4683 0 Td
(level)Tj
2.0126 0 Td
(of)Tj
1.0148 0 Td
(antibiotic)Tj
4.0421 0 Td
(use)Tj
1.5307 0 Td
(in)Tj
1.0319 0 Td
(the)Tj
1.474 0 Td
(agricultural)Tj
4.8302 0 Td
(industry.)Tj
-16.2084 -1.3039 Td
(The)Tj
1.7858 0 Td
(only)Tj
1.9729 0 Td
(definitive)Tj
3.9911 0 Td
(method)Tj
3.3222 0 Td
(for)Tj
1.3833 0 Td
(successfully)Tj
4.8642 0 Td
(identifying)Tj
4.5751 0 Td
(vaccinated)Tj
4.4561 0 Td
(animals)Tj
3.3335 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(presence)Tj
-33.3862 -1.2982 Td
(of)Tj
1.0147 0 Td
(an)Tj
1.2019 0 Td
(active)Tj
2.5228 0 Td
(viral)Tj
1.99 0 Td
(infection)Tj
3.7927 0 Td
(is)Tj
0.8504 0 Td
(to)Tj
1.0204 0 Td
(determine)Tj
4.3257 0 Td
(the)Tj
1.4683 0 Td
(rate)Tj
1.7462 0 Td
(of)Tj
1.0147 0 Td
(viral)Tj
1.9956 0 Td
(shedding)Tj
3.8665 0 Td
(by)Tj
1.1848 0 Td
(virus)Tj
2.1997 0 Td
(isolation,)Tj
3.8834 0 Td
(cyto-)Tj
-34.0778 -1.2983 Td
(kine/interleukin)Tj
6.701 0 Td
(profiling)Tj
3.702 0 Td
(or)Tj
1.0942 0 Td
(virus)Tj
2.2053 0 Td
(neutralization)Tj
5.8054 0 Td
(assay)Tj
2.262 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(].)Tj
1.5987 0 Td
(These)Tj
2.5682 0 Td
(types)Tj
2.2734 0 Td
(of)Tj
1.0148 0 Td
(analysis)Tj
3.3278 0 Td
(require)Tj
-32.5528 -1.3039 Td
(repeated)Tj
3.6396 0 Td
(sampling,)Tj
4.1046 0 Td
(a)Tj
0.6519 0 Td
(period)Tj
2.8346 0 Td
(for)Tj
1.3833 0 Td
(seroconversion)Tj
6.2986 0 Td
(and)Tj
1.7291 0 Td
(are)Tj
1.4457 0 Td
(expensive)Tj
4.1045 0 Td
(compared)Tj
4.2463 0 Td
(to)Tj
1.0261 0 Td
(serology)Tj
3.5546 0 Td
(based)Tj
-35.0189 -1.2983 Td
(ELISA,)Tj
3.05 0 Td
(and)Tj
1.7291 0 Td
(are)Tj
1.4514 0 Td
(therefore)Tj
3.8551 0 Td
(not)Tj
1.5703 0 Td
(routinely)Tj
3.8665 0 Td
(employed)Tj
4.1385 0 Td
(during)Tj
2.931 0 Td
(endemic)Tj
3.651 0 Td
(viral)Tj
1.9956 0 Td
(infection)Tj
3.7927 0 Td
(outbreaks.)Tj
-32.0312 -1.2983 Td
(Differentiating)Tj
6.1454 0 Td
(infected)Tj
3.4186 0 Td
(from)Tj
2.2053 0 Td
(vaccinated)Tj
4.4561 0 Td
(animals)Tj
3.3278 0 Td
(\(DIVA\))Tj
3.3562 0 Td
(marker)Tj
3.1351 0 Td
(vaccines)Tj
3.5603 0 Td
(\(e.g.)Tj
1.8992 0 Td
(a)Tj
0.652 0 Td
(modified)Tj
-32.156 -1.3039 Td
(wild)Tj
1.9445 0 Td
(type)Tj
1.9105 0 Td
(virus)Tj
2.2054 0 Td
(with)Tj
1.9956 0 Td
(a)Tj
0.6576 0 Td
(gene)Tj
2.0806 0 Td
(deletion)Tj
3.4583 0 Td
(resulting)Tj
3.7303 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(absence)Tj
3.3392 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6577 0 Td
(particular)Tj
4.1102 0 Td
(diagnostic)Tj
4.3199 0 Td
(antigen\))Tj
-33.9304 -1.2982 Td
(can)Tj
1.6157 0 Td
(be)Tj
1.1452 0 Td
(employed)Tj
4.1329 0 Td
(to)Tj
1.0148 0 Td
(differentiate)Tj
5.0739 0 Td
(vaccine)Tj
3.1862 0 Td
(antibody)Tj
3.7587 0 Td
(responses)Tj
4.0875 0 Td
(from)Tj
2.194 0 Td
(that)Tj
1.7745 0 Td
(of)Tj
1.0091 0 Td
(wild)Tj
1.9332 0 Td
(type)Tj
1.9106 0 Td
(virus.)Tj
2.4208 0 Td
(Com-)Tj
-35.2571 -1.2983 Td
(panion)Tj
3.0387 0 Td
(serology)Tj
3.5603 0 Td
(based)Tj
2.4718 0 Td
(tests)Tj
1.9615 0 Td
(rely)Tj
1.7178 0 Td
(on)Tj
1.2756 0 Td
(seroconversion,)Tj
6.5196 0 Td
(and)Tj
1.7292 0 Td
(upon)Tj
2.3187 0 Td
(exposure)Tj
3.8154 0 Td
(to)Tj
1.0261 0 Td
(wild)Tj
1.9446 0 Td
(type)Tj
1.9162 0 Td
(virus)Tj
2.1997 0 Td
(the)Tj
-35.4952 -1.3039 Td
(antibody)Tj
3.7643 0 Td
(response)Tj
3.7304 0 Td
(to)Tj
1.0261 0 Td
(DIVA)Tj
2.6759 0 Td
(vaccines)Tj
3.5547 0 Td
(will)Tj
1.6667 0 Td
(be)Tj
1.1509 0 Td
(masked)Tj
3.2768 0 Td
(by)Tj
1.1849 0 Td
(that)Tj
1.7801 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(wild)Tj
1.9445 0 Td
(type)Tj
1.9162 0 Td
(virus.)Tj
2.4265 0 Td
(Vaccine)Tj
-32.5812 -1.2983 Td
(DIVA)Tj
2.6758 0 Td
(functionality)Tj
5.3291 0 Td
(is)Tj
0.8448 0 Td
(often)Tj
2.2847 0 Td
(limited)Tj
3.0727 0 Td
(to)Tj
1.0261 0 Td
(large)Tj
2.16 0 Td
(viruses)Tj
2.9821 0 Td
(with)Tj
2.0012 0 Td
(increased)Tj
3.9968 0 Td
(potential)Tj
3.7644 0 Td
(for)Tj
1.3833 0 Td
(gene)Tj
2.0806 0 Td
(deletion)Tj
-33.6016 -1.2982 Td
(and)Tj
1.7291 0 Td
(removal)Tj
3.4752 0 Td
(of)Tj
1.0148 0 Td
(redundant)Tj
4.4277 0 Td
(expressed)Tj
4.0932 0 Td
(antigens.)Tj
3.7927 0 Td
(Therefore,)Tj
4.3937 0 Td
(for)Tj
1.3833 0 Td
(viruses)Tj
2.9877 0 Td
(with)Tj
1.9956 0 Td
(small)Tj
2.3301 0 Td
(genomes)Tj
3.77 0 Td
(such)Tj
-35.3931 -1.2983 Td
(as)Tj
1.0147 0 Td
(paramyxoviruses)Tj
6.9902 0 Td
(\(e.g.)Tj
1.8992 0 Td
(BPI3V)Tj
2.8687 0 Td
(and)Tj
1.7291 0 Td
(Bovine)Tj
2.999 0 Td
(Respiratory)Tj
4.8473 0 Td
(Syncytial)Tj
3.8267 0 Td
(Virus)Tj
2.4378 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(BRD)Tj
2.16 0 Td
(complex\))Tj
-33.2558 -1.3039 Td
(where)Tj
2.6475 0 Td
(gene)Tj
2.0806 0 Td
(deletion)Tj
3.4639 0 Td
(of)Tj
1.0148 0 Td
(neutralizing)Tj
5.0287 0 Td
(antigens)Tj
3.5659 0 Td
(may)Tj
1.9332 0 Td
(reduce)Tj
2.914 0 Td
(vaccine)Tj
3.1975 0 Td
(efficacy,)Tj
3.4469 0 Td
(alternative)Tj
-29.293 -1.2983 Td
(approaches)Tj
4.7338 0 Td
(are)Tj
1.4513 0 Td
(required)Tj
3.6397 0 Td
(to)Tj
1.0261 0 Td
(provide)Tj
3.2882 0 Td
(DIVA)Tj
2.6702 0 Td
(functionality.)Tj
5.5559 0 Td
(One)Tj
1.9388 0 Td
(approach)Tj
3.9515 0 Td
(is)Tj
0.8504 0 Td
(to)Tj
1.0261 0 Td
(design)Tj
2.812 0 Td
(molecular)Tj
-32.944 -1.2983 Td
(DIVA)Tj
2.6758 0 Td
(vaccines)Tj
3.5547 0 Td
(that)Tj
1.7801 0 Td
(contain)Tj
3.2428 0 Td
(a)Tj
0.6577 0 Td
(marker)Tj
3.1351 0 Td
(nucleotide)Tj
4.4106 0 Td
(sequence)Tj
3.8608 0 Td
(differing)Tj
3.668 0 Td
(from)Tj
2.2053 0 Td
(the)Tj
1.4684 0 Td
(wild)Tj
1.9445 0 Td
(type)Tj
1.9162 0 Td
(virus)Tj
-34.52 -1.3039 Td
(that)Tj
1.7744 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1509 0 Td
(employed)Tj
4.1385 0 Td
(in)Tj
1.0375 0 Td
(combination)Tj
5.3461 0 Td
(with)Tj
2.0012 0 Td
(PCR-based)Tj
4.6658 0 Td
(molecular)Tj
4.218 0 Td
(diagnostics)Tj
4.6828 0 Td
(to)Tj
1.0261 0 Td
(differentiate)Tj
-31.6684 -1.2982 Td
(between)Tj
3.5262 0 Td
(vaccine)Tj
3.1975 0 Td
(and)Tj
1.7291 0 Td
(wild)Tj
1.9446 0 Td
(virus)Tj
2.1996 0 Td
(strains)Tj
2.863 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(11)Tj
0 g
(].)Tj
1.7405 0 Td
(Successful)Tj
4.2746 0 Td
(differentiation)Tj
5.981 0 Td
(of)Tj
1.0148 0 Td
(vaccinated)Tj
4.4561 0 Td
(from)Tj
-34.6618 -1.2983 Td
(non-vaccinated)Tj
6.4062 0 Td
(animals)Tj
3.3335 0 Td
(using)Tj
2.3868 0 Td
(this)Tj
1.6781 0 Td
(technique)Tj
4.1669 0 Td
(requires)Tj
3.4696 0 Td
(concurrent)Tj
4.6658 0 Td
(vaccination)Tj
4.8245 0 Td
(and)Tj
1.7291 0 Td
(infection)Tj
-32.6605 -1.3039 Td
([)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7347 0 Td
(13)Tj
0 g
(],)Tj
1.7348 0 Td
(with)Tj
2.0013 0 Td
(a)Tj
0.6519 0 Td
(narrow)Tj
3.1351 0 Td
(diagnostic)Tj
4.32 0 Td
(window)Tj
3.4413 0 Td
(post-infection)Tj
5.8223 0 Td
(for)Tj
1.3889 0 Td
(detection)Tj
3.9345 0 Td
(of)Tj
1.0148 0 Td
(DIVA)Tj
2.6759 0 Td
(vaccine)Tj
3.1975 0 Td
(and)Tj
-35.053 -1.2983 Td
(viral)Tj
1.9899 0 Td
(genetic)Tj
3.0727 0 Td
(material.)Tj
3.736 0 Td
(Furthermore,)Tj
5.6183 0 Td
(detection)Tj
3.9344 0 Td
(of)Tj
1.0148 0 Td
(vaccine)Tj
3.1975 0 Td
(genetic)Tj
3.0671 0 Td
(material)Tj
3.5149 0 Td
(only)Tj
1.9786 0 Td
(demonstrates)Tj
-31.1242 -1.2983 Td
(exposure)Tj
3.8154 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4683 0 Td
(vaccine)Tj
3.1975 0 Td
(and)Tj
1.7291 0 Td
(not)Tj
1.5704 0 Td
(the)Tj
1.474 0 Td
(successful)Tj
4.1612 0 Td
(generation)Tj
4.5071 0 Td
(of)Tj
1.0148 0 Td
(immune)Tj
3.6283 0 Td
(protection,)Tj
4.6035 0 Td
(limiting)Tj
-32.1957 -1.3039 Td
(functionality)Tj
5.3291 0 Td
(in)Tj
1.0318 0 Td
(assessment)Tj
4.6147 0 Td
(of)Tj
1.0148 0 Td
(herd)Tj
2.0693 0 Td
(level)Tj
2.0126 0 Td
(immunity.)Tj
4.4504 0 Td
(Consequently,)Tj
5.9527 0 Td
(there)Tj
2.2677 0 Td
(is)Tj
0.8447 0 Td
(a)Tj
0.6576 0 Td
(clear)Tj
2.1147 0 Td
(need)Tj
2.1429 0 Td
(for)Tj
-34.503 -1.2982 Td
(alternative)Tj
4.4163 0 Td
(diagnostic)Tj
4.32 0 Td
(methods)Tj
3.685 0 Td
(that)Tj
1.7801 0 Td
(can)Tj
1.6271 0 Td
(assess)Tj
2.5172 0 Td
(efficacy)Tj
3.2258 0 Td
(of)Tj
1.0148 0 Td
(vaccines)Tj
3.5546 0 Td
(and)Tj
1.7291 0 Td
(vaccination)Tj
4.8245 0 Td
(status)Tj
2.5059 0 Td
(of)Tj
-35.2004 -1.2983 Td
(animals)Tj
3.3278 0 Td
(exposed)Tj
3.4469 0 Td
(to)Tj
1.0261 0 Td
(BRD)Tj
2.1544 0 Td
(viral)Tj
1.9955 0 Td
(pathogens)Tj
4.303 0 Td
(at)Tj
0.9524 0 Td
(the)Tj
1.4684 0 Td
(early)Tj
2.1486 0 Td
(stages)Tj
2.5625 0 Td
(of)Tj
1.0148 0 Td
(infection)Tj
3.7928 0 Td
(prior)Tj
2.2563 0 Td
(to)Tj
1.0262 0 Td
(seroconversion)Tj
-31.4757 -1.2983 Td
(and)Tj
1.7291 0 Td
(which)Tj
2.6475 0 Td
(do)Tj
1.2586 0 Td
(not)Tj
1.5704 0 Td
(require)Tj
3.1124 0 Td
(repeated)Tj
3.6397 0 Td
(sampling.)Tj
4.1045 0 Td
(Additionally,)Tj
5.4538 0 Td
(the)Tj
1.4684 0 Td
(lower)Tj
2.4547 0 Td
(initial)Tj
2.5455 0 Td
(exposure)Tj
3.8211 0 Td
(rates)Tj
2.1033 0 Td
(to)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 507.2314 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(DIVA)Tj
2.5228 0 Td
(metabolo)Tj
4.0394 0 Td
(mics)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.01944)Tj
4.089 0 Td
(88)Tj
0 g
2.0906 0 Td
(April)Tj
2.1827 0 Td
(5,)Tj
1.0417 0 Td
(2018)Tj
35.6814 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
29 0 obj
<>stream
endstream
endobj
30 0 obj
<>stream
endstream
endobj
31 0 obj
<>stream
endstream
endobj
32 0 obj
<>stream
endstream
endobj
33 0 obj
<>stream
endstream
endobj
34 0 obj
<>stream
endstream
endobj
35 0 obj
<>stream
endstream
endobj
36 0 obj
<>stream
endstream
endobj
37 0 obj
<>stream
endstream
endobj
38 0 obj
<>stream
endstream
endobj
39 0 obj
<>stream
endstream
endobj
40 0 obj
<>stream
endstream
endobj
41 0 obj
<>stream
endstream
endobj
42 0 obj
<>stream
BT
66.402 0 Td
(20)Tj
ET
Q
endstream
endobj
43 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 9 0 R/Annots 46 0 R/Contents 47 0 R/TrimBox[0 0 612 792]>>
endobj
46 0 obj
[48 0 R 49 0 R 50 0 R 51 0 R 52 0 R 53 0 R 54 0 R 55 0 R 56 0 R 57 0 R 58 0 R]
endobj
48 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref014)>>
endobj
49 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref015)>>
endobj
50 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref016)>>
endobj
51 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref019)>>
endobj
52 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref020)>>
endobj
53 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref021)>>
endobj
54 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref022)>>
endobj
55 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref023)>>
endobj
56 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref022)>>
endobj
57 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref024)>>
endobj
58 0 obj
<>/Border[0 0 0]/A 59 0 R>>
endobj
59 0 obj
<>
endobj
47 0 obj
[60 0 R 61 0 R 62 0 R 63 0 R 64 0 R 65 0 R 66 0 R 67 0 R 68 0 R 69 0 R 70 0 R 71 0 R]
endobj
60 0 obj
<>stream
q
0.83 0.64 0.02 0 k
380.4661 615.3449 m
389.9906 615.3449 l
h
f*
394.4126 615.3449 m
403.937 615.3449 l
h
f*
404.1638 589.3228 m
413.6882 589.3228 l
h
f*
418.8472 589.3228 m
428.3717 589.3228 l
h
f*
477.5244 563.3008 m
486.9921 563.3008 l
h
f*
348.2079 550.3181 m
357.7323 550.3181 l
h
f*
251.6598 537.3354 m
261.1843 537.3354 l
h
f*
281.1969 511.3134 m
290.6646 511.3134 l
h
f*
318.0472 276.9449 m
327.5717 276.9449 l
h
f*
389.9339 211.9181 m
399.4016 211.9181 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(viral)Tj
1.9899 0 Td
(infections)Tj
4.1555 0 Td
(in)Tj
1.0375 0 Td
(field)Tj
1.9672 0 Td
(settings)Tj
3.2428 0 Td
(combined)Tj
4.2463 0 Td
(with)Tj
1.9956 0 Td
(variation)Tj
3.8041 0 Td
(in)Tj
1.0374 0 Td
(strain)Tj
2.5002 0 Td
(nucleotide)Tj
4.4107 0 Td
(sequences)Tj
4.2179 0 Td
(and)Tj
-34.6051 -1.3039 Td
(short)Tj
2.2847 0 Td
(periods)Tj
3.1918 0 Td
(of)Tj
1.0147 0 Td
(virus)Tj
2.2054 0 Td
(secretion)Tj
3.8437 0 Td
(highlights)Tj
4.1726 0 Td
(the)Tj
1.4684 0 Td
(requirement)Tj
5.2043 0 Td
(for)Tj
1.3833 0 Td
(a)Tj
0.6577 0 Td
(DIVA)Tj
2.6702 0 Td
(approach)Tj
3.9515 0 Td
(with)Tj
2.0012 0 Td
(a)Tj
0.652 0 Td
(long)Tj
-34.7015 -1.2982 Td
(diagnostic)Tj
4.3199 0 Td
(window)Tj
3.4356 0 Td
(which)Tj
2.6532 0 Td
(is)Tj
0.8447 0 Td
(not)Tj
1.5761 0 Td
(strain)Tj
2.5001 0 Td
(specific.)Tj
-14.1334 -1.2983 Td
(A)Tj
0.907 0 Td
(potential)Tj
3.7588 0 Td
(approach)Tj
3.9514 0 Td
(that)Tj
1.7802 0 Td
(can)Tj
1.6271 0 Td
(meet)Tj
2.1826 0 Td
(these)Tj
2.2564 0 Td
(needs)Tj
2.5058 0 Td
(is)Tj
0.8447 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.474 0 Td
(application)Tj
4.6771 0 Td
(of)Tj
1.0148 0 Td
(metabolomics)Tj
-31.9235 -1.2983 Td
(to)Tj
1.0261 0 Td
(identify)Tj
3.2938 0 Td
(metabolites)Tj
4.8019 0 Td
(or)Tj
1.0998 0 Td
(`small)Tj
2.5512 0 Td
(molecules')Tj
4.4163 0 Td
(in)Tj
1.0375 0 Td
(biological)Tj
4.0875 0 Td
(samples)Tj
3.3846 0 Td
(that)Tj
1.7745 0 Td
(are)Tj
1.4513 0 Td
(signatures)Tj
4.2746 0 Td
(that)Tj
1.7802 0 Td
(corre-)Tj
-34.9793 -1.3039 Td
(late)Tj
1.6214 0 Td
(or)Tj
1.0998 0 Td
(provide)Tj
3.2882 0 Td
(some)Tj
2.33 0 Td
(evidence)Tj
3.7134 0 Td
(of)Tj
1.0148 0 Td
(immune)Tj
3.6226 0 Td
(protection.)Tj
4.6091 0 Td
(These)Tj
2.5682 0 Td
(metabolites)Tj
4.8019 0 Td
(are)Tj
1.4513 0 Td
(often)Tj
2.2847 0 Td
(the)Tj
1.4684 0 Td
(end)Tj
1.7234 0 Td
(stage)Tj
-35.5972 -1.2982 Td
(products)Tj
3.753 0 Td
(of)Tj
1.0148 0 Td
(biological)Tj
4.0875 0 Td
(processes)Tj
3.9685 0 Td
(and)Tj
1.7348 0 Td
(therefore)Tj
3.8494 0 Td
(provide)Tj
3.2939 0 Td
(an)Tj
1.2018 0 Td
(accurate)Tj
3.5547 0 Td
(representation)Tj
6.015 0 Td
(of)Tj
1.0148 0 Td
(an)Tj
1.2019 0 Td
(organ-)Tj
-34.6901 -1.2983 Td
(ism's)Tj
2.245 0 Td
(homeostatic)Tj
5.0853 0 Td
(status)Tj
2.5001 0 Td
(at)Tj
0.9525 0 Td
(time)Tj
2.0296 0 Td
(of)Tj
1.0148 0 Td
(sampling)Tj
3.8777 0 Td
([)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(15)Tj
0 g
(].)Tj
1.7405 0 Td
(Metabolomic)Tj
5.5445 0 Td
(analysis)Tj
3.3222 0 Td
(of)Tj
1.0148 0 Td
(bio-fluids)Tj
4.0705 0 Td
(has)Tj
-35.1323 -1.3039 Td
(provided)Tj
3.8154 0 Td
(new)Tj
1.8765 0 Td
(insights)Tj
3.3165 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(understanding)Tj
6.0661 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(patho-physiological)Tj
8.0787 0 Td
(processes)Tj
3.9684 0 Td
(involved)Tj
3.6454 0 Td
(in)Tj
-35.7503 -1.2983 Td
(disease)Tj
3.016 0 Td
(establishment,)Tj
5.9641 0 Td
(development)Tj
5.4084 0 Td
(and)Tj
1.7291 0 Td
(diagnosis)Tj
3.9572 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(].)Tj
3.5489 0 Td
(Whilst)Tj
2.8857 0 Td
(metabolomics)Tj
5.8337 0 Td
(has)Tj
1.542 0 Td
(had)Tj
1.7064 0 Td
(lim-)Tj
-35.5915 -1.2983 Td
(ited)Tj
1.7347 0 Td
(application)Tj
4.6828 0 Td
(in)Tj
1.0319 0 Td
(the)Tj
1.474 0 Td
(field)Tj
1.9729 0 Td
(of)Tj
1.0148 0 Td
(veterinary)Tj
4.2632 0 Td
(research,)Tj
3.7814 0 Td
(several)Tj
2.9367 0 Td
(studies)Tj
2.982 0 Td
(have)Tj
2.0636 0 Td
(demonstrated)Tj
5.76 0 Td
(the)Tj
-33.698 -1.3039 Td
(potential)Tj
3.7587 0 Td
(of)Tj
1.0148 0 Td
(this)Tj
1.6724 0 Td
(technique)Tj
4.1669 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(prediction)Tj
4.371 0 Td
(of)Tj
1.0148 0 Td
(BRD)Tj
2.16 0 Td
(disease)Tj
3.016 0 Td
(outcome)Tj
3.7304 0 Td
([)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(],)Tj
2.0749 0 Td
(differentiation)Tj
5.9754 0 Td
(of)Tj
-35.4611 -1.2982 Td
(stress)Tj
2.3924 0 Td
(from)Tj
2.211 0 Td
(viral)Tj
1.9899 0 Td
(infection)Tj
3.7927 0 Td
(responses)Tj
4.0932 0 Td
([)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
(],)Tj
2.075 0 Td
(and)Tj
1.7348 0 Td
(characteristic)Tj
5.5445 0 Td
(of)Tj
1.0148 0 Td
(immune)Tj
3.6227 0 Td
(responses)Tj
4.0932 0 Td
(following)Tj
-32.5642 -1.2983 Td
(vaccination)Tj
4.8245 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(].)Tj
2.0749 0 Td
(This)Tj
1.9899 0 Td
(study)Tj
2.3868 0 Td
(focuses)Tj
3.1124 0 Td
(specifically)Tj
4.5751 0 Td
(on)Tj
1.2756 0 Td
(BPI3V)Tj
2.8686 0 Td
(due)Tj
1.6951 0 Td
(to)Tj
1.0262 0 Td
(its)Tj
1.1452 0 Td
(endemnicity)Tj
5.227 0 Td
(within)Tj
2.812 0 Td
(cattle)Tj
-35.0133 -1.3039 Td
(populations)Tj
4.9492 0 Td
(and)Tj
1.7291 0 Td
(absence)Tj
3.3449 0 Td
(of)Tj
1.0148 0 Td
(clinical)Tj
3.0727 0 Td
(symptoms)Tj
4.3597 0 Td
(which)Tj
2.6532 0 Td
(still)Tj
1.6384 0 Td
(predispose)Tj
4.4957 0 Td
(animals)Tj
3.3279 0 Td
(to)Tj
1.0261 0 Td
(more)Tj
2.3414 0 Td
(severe)Tj
-33.9531 -1.2983 Td
(bacterial)Tj
3.6226 0 Td
(infections)Tj
4.1556 0 Td
([)Tj
0.83 0.64 0.02 0 k
(23)Tj
0 g
(].)Tj
2.0749 0 Td
(Due)Tj
1.9049 0 Td
(to)Tj
1.0261 0 Td
(its)Tj
1.1452 0 Td
(small)Tj
2.3301 0 Td
(genome)Tj
3.4072 0 Td
(and)Tj
1.7291 0 Td
(absence)Tj
3.3392 0 Td
(of)Tj
1.0148 0 Td
(non-redundant)Tj
6.3836 0 Td
(proteins)Tj
3.5149 0 Td
(suit-)Tj
-35.6482 -1.2982 Td
(able)Tj
1.8311 0 Td
(for)Tj
1.3833 0 Td
(removal)Tj
3.4753 0 Td
(in)Tj
1.0374 0 Td
(DIVA)Tj
2.6759 0 Td
(vaccines,)Tj
3.7814 0 Td
(BPI3V)Tj
2.8687 0 Td
(is)Tj
0.8504 0 Td
(an)Tj
1.2018 0 Td
(excellent)Tj
3.7191 0 Td
(model)Tj
2.7439 0 Td
(for)Tj
1.3833 0 Td
(assessing)Tj
3.8041 0 Td
(the)Tj
1.4683 0 Td
(potential)Tj
3.7587 0 Td
(of)Tj
-35.9827 -1.2983 Td
(metabolomics)Tj
5.8336 0 Td
(to)Tj
1.0261 0 Td
(establish)Tj
3.6454 0 Td
(vaccination)Tj
4.8245 0 Td
(status)Tj
2.5002 0 Td
(in)Tj
1.0374 0 Td
(infected)Tj
3.4186 0 Td
(animals.)Tj
3.5546 0 Td
(The)Tj
1.7858 0 Td
(aims)Tj
2.0977 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(current)Tj
3.1804 0 Td
(study)Tj
-35.3931 -1.3039 Td
(were)Tj
2.1203 0 Td
(therefore)Tj
3.855 0 Td
(to)Tj
1.0262 0 Td
(assess)Tj
2.5228 0 Td
(the)Tj
1.4683 0 Td
(performance)Tj
5.3461 0 Td
(of)Tj
1.0148 0 Td
(Reverse)Tj
3.2995 0 Td
(Phase)Tj
2.5229 0 Td
(\(RP\))Tj
2.0806 0 Td
(and)Tj
1.7348 0 Td
(Hydrophobic)Tj
5.5955 0 Td
(Interaction)Tj
-32.5868 -1.2983 Td
(Liquid)Tj
2.8516 0 Td
(Chromatography)Tj
7.1206 0 Td
(\(HILIC\))Tj
3.5489 0 Td
(separation)Tj
4.3824 0 Td
(methods)Tj
3.685 0 Td
(for)Tj
1.3833 0 Td
(Ultra)Tj
2.3074 0 Td
(Performance)Tj
5.3914 0 Td
(Liquid)Tj
2.8517 0 Td
(Chroma-)Tj
-33.5223 -1.2983 Td
(tography-Mass)Tj
6.1908 0 Td
(Spectrometry)Tj
5.6069 0 Td
(\(UPLC-MS\))Tj
5.1136 0 Td
(metabolomic)Tj
5.4765 0 Td
(profiling)Tj
3.6964 0 Td
(of)Tj
1.0148 0 Td
(bovine)Tj
2.9253 0 Td
(plasma)Tj
3.0331 0 Td
(and)Tj
1.7291 0 Td
(iden-)Tj
-34.7865 -1.3039 Td
(tify)Tj
1.525 0 Td
(plasma)Tj
3.033 0 Td
(metabolomic)Tj
5.4709 0 Td
(markers)Tj
3.4979 0 Td
(capable)Tj
3.2088 0 Td
(of)Tj
1.0148 0 Td
(differentiating)Tj
5.9357 0 Td
(between)Tj
3.5263 0 Td
(vaccinated)Tj
4.456 0 Td
(and)Tj
1.7291 0 Td
(non-)Tj
-33.3975 -1.2982 Td
(vaccinated)Tj
4.456 0 Td
(calves)Tj
2.5625 0 Td
(following)Tj
3.9798 0 Td
(intranasal)Tj
4.1612 0 Td
(challenge)Tj
3.9572 0 Td
(with)Tj
1.9956 0 Td
(BPI3V.)Tj
3.0954 0 Td
(This)Tj
1.9899 0 Td
(work)Tj
2.279 0 Td
(for)Tj
1.3833 0 Td
(the)Tj
1.4684 0 Td
(first)Tj
1.8084 0 Td
(time)Tj
-33.1367 -1.2983 Td
(reports)Tj
3.067 0 Td
(the)Tj
1.4684 0 Td
(metabolomic)Tj
5.4765 0 Td
(responses)Tj
4.0932 0 Td
(following)Tj
3.9798 0 Td
(challenge)Tj
3.9571 0 Td
(with)Tj
1.9956 0 Td
(BPI3V)Tj
2.8686 0 Td
(and)Tj
1.7348 0 Td
(demonstrates)Tj
5.5899 0 Td
(how)Tj
-34.2309 -1.3039 Td
(the)Tj
1.4683 0 Td
(application)Tj
4.6828 0 Td
(of)Tj
1.0148 0 Td
(metabolomic)Tj
5.4708 0 Td
(profiling)Tj
3.6964 0 Td
(may)Tj
1.9275 0 Td
(help)Tj
1.9389 0 Td
(overcome)Tj
4.1499 0 Td
(current)Tj
3.1805 0 Td
(limitations)Tj
4.5354 0 Td
(in)Tj
1.0374 0 Td
(DIVA)Tj
-33.1027 -1.2983 Td
(diagnostics)Tj
4.6771 0 Td
(by)Tj
1.1849 0 Td
(identifying)Tj
4.575 0 Td
(markers)Tj
3.498 0 Td
(capable)Tj
3.2031 0 Td
(of)Tj
1.0148 0 Td
(differentiating)Tj
5.9357 0 Td
(between)Tj
3.532 0 Td
(vaccinated)Tj
4.4503 0 Td
(and)Tj
1.7348 0 Td
(non-vac-)Tj
-33.8057 -1.2983 Td
(cinated)Tj
3.1407 0 Td
(animals,)Tj
3.5546 0 Td
(and)Tj
1.7348 0 Td
(importantly)Tj
4.9776 0 Td
(allow)Tj
2.3414 0 Td
(the)Tj
1.4684 0 Td
(development)Tj
5.4084 0 Td
(of)Tj
1.0148 0 Td
(better)Tj
2.5455 0 Td
(tools)Tj
2.1374 0 Td
(to)Tj
1.0261 0 Td
(assess)Tj
2.5228 0 Td
(the)Tj
1.4683 0 Td
(perfor-)Tj
-33.3408 -1.2982 Td
(mance)Tj
2.8686 0 Td
(of)Tj
1.0148 0 Td
(vaccines.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 325.9842 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Results)Tj
/F10 1 Tf
0 -1.4976 Td
(Clinical)Tj
3.4724 0 Td
(health)Tj
2.83 0 Td
(assessment)Tj
4.8189 0 Td
(of)Tj
1.0677 0 Td
(experimental)Tj
5.7166 0 Td
(animals)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 291.0047 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Assessment)Tj
4.8585 0 Td
(of)Tj
1.0148 0 Td
(clinical)Tj
3.0784 0 Td
(findings)Tj
3.4923 0 Td
(of)Tj
1.0148 0 Td
(animals)Tj
3.3335 0 Td
(post)Tj
1.8992 0 Td
(BPI3V)Tj
2.8686 0 Td
(vaccination)Tj
4.8302 0 Td
(and)Tj
1.7292 0 Td
(challenge)Tj
3.9571 0 Td
(have)Tj
2.0579 0 Td
(been)Tj
-34.1345 -1.2982 Td
(reported)Tj
3.6566 0 Td
(in)Tj
1.0375 0 Td
(detail)Tj
2.4151 0 Td
(previously)Tj
4.354 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(].)Tj
2.0749 0 Td
(Briefly,)Tj
3.0784 0 Td
(animals)Tj
3.3279 0 Td
(were)Tj
2.126 0 Td
(healthy)Tj
3.1294 0 Td
(throughout)Tj
4.7792 0 Td
(the)Tj
1.4683 0 Td
(duration)Tj
3.702 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
-36.1641 -1.3039 Td
(study)Tj
2.3867 0 Td
(with)Tj
2.0013 0 Td
(no)Tj
1.2755 0 Td
(clinical)Tj
3.0728 0 Td
(signs)Tj
2.2223 0 Td
(of)Tj
1.0148 0 Td
(disease)Tj
3.0217 0 Td
(in)Tj
1.0318 0 Td
(vaccinated)Tj
4.4561 0 Td
(or)Tj
1.0998 0 Td
(non-vaccinated)Tj
6.4063 0 Td
(study)Tj
2.3924 0 Td
(groups.)Tj
3.1918 0 Td
(Calves)Tj
-33.5733 -1.2983 Td
(were)Tj
2.1203 0 Td
(sourced)Tj
3.3618 0 Td
(from)Tj
2.2054 0 Td
(respiratory)Tj
4.5977 0 Td
(disease)Tj
3.0161 0 Td
(free)Tj
1.7291 0 Td
(farms)Tj
2.4945 0 Td
(with)Tj
1.9955 0 Td
(no)Tj
1.2756 0 Td
(history)Tj
3.0047 0 Td
(of)Tj
1.0148 0 Td
(vaccination)Tj
4.8302 0 Td
(against)Tj
3.0274 0 Td
(BRD.)Tj
-34.6731 -1.2983 Td
(Prior)Tj
2.296 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(commencement)Tj
6.6954 0 Td
(of)Tj
1.0148 0 Td
(vaccination)Tj
4.8302 0 Td
(all)Tj
1.1452 0 Td
(calves)Tj
2.5625 0 Td
(tested)Tj
2.5511 0 Td
(seropositive)Tj
4.9776 0 Td
(for)Tj
1.389 0 Td
(anti-BPI3V)Tj
4.7678 0 Td
(IgG.)Tj
-34.7241 -1.3039 Td
(These)Tj
2.5681 0 Td
(residual)Tj
3.3732 0 Td
(levels)Tj
2.3754 0 Td
(of)Tj
1.0148 0 Td
(maternally)Tj
4.5014 0 Td
(derived)Tj
3.2145 0 Td
(anti-BPI3V)Tj
4.7678 0 Td
(immunoglobulin)Tj
7.0243 0 Td
(are)Tj
1.4456 0 Td
(in)Tj
1.0375 0 Td
(keeping)Tj
3.3619 0 Td
(with)Tj
-34.6845 -1.2982 Td
(other)Tj
2.347 0 Td
(studies)Tj
2.9877 0 Td
(employing)Tj
4.4674 0 Td
(calves)Tj
2.5625 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(same)Tj
2.2621 0 Td
(age)Tj
1.542 0 Td
([)Tj
0.83 0.64 0.02 0 k
(24)Tj
0 g
(].)Tj
2.0749 0 Td
(At)Tj
1.2019 0 Td
(the)Tj
1.4684 0 Td
(commencement)Tj
6.701 0 Td
(of)Tj
1.0148 0 Td
(vaccination)Tj
-31.1128 -1.2983 Td
(there)Tj
2.262 0 Td
(was)Tj
1.7008 0 Td
(no)Tj
1.2755 0 Td
(significant)Tj
4.388 0 Td
(difference)Tj
4.2066 0 Td
(in)Tj
1.0318 0 Td
(anti-BPI3V)Tj
4.7679 0 Td
(IgG)Tj
1.7404 0 Td
(observed)Tj
3.7984 0 Td
(between)Tj
3.5263 0 Td
(treatment)Tj
4.1386 0 Td
(groups.)Tj
-32.8363 -1.3039 Td
(Vaccination)Tj
5.0626 0 Td
(with)Tj
2.0012 0 Td
(RISPOVAL)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 317.2535 191.4519 cm
BT
/F11 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 324.6803 186.9732 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(PI3+RSV)Tj
3.9684 0 Td
(resulted)Tj
3.4016 0 Td
(in)Tj
1.0318 0 Td
(a)Tj
0.6576 0 Td
(significant)Tj
4.388 0 Td
(increase)Tj
3.4696 0 Td
(in)Tj
1.0375 0 Td
(anti-BPI3V)Tj
4.7678 0 Td
(IgG)Tj
-35.1889 -1.2982 Td
(with)Tj
1.9955 0 Td
(no)Tj
1.2756 0 Td
(significant)Tj
4.388 0 Td
(increase)Tj
3.4753 0 Td
(in)Tj
1.0318 0 Td
(non-vaccinated)Tj
6.4118 0 Td
(controls.)Tj
3.7077 0 Td
(Following)Tj
4.2179 0 Td
(BPI3V)Tj
2.8687 0 Td
(challenge)Tj
3.9571 0 Td
(vaccinated)Tj
-33.3294 -1.2983 Td
(calves)Tj
2.5625 0 Td
(had)Tj
1.7064 0 Td
(significantly)Tj
5.091 0 Td
(higher)Tj
2.8006 0 Td
(plasma)Tj
3.033 0 Td
(anti-BPI3V)Tj
4.7678 0 Td
(IgG)Tj
1.7405 0 Td
(relative)Tj
3.1407 0 Td
(to)Tj
1.0262 0 Td
(non-vaccinated)Tj
6.4062 0 Td
(animals.)Tj
-32.2749 -1.2982 Td
(Post-BPI3V)Tj
4.9435 0 Td
(challenge,)Tj
4.184 0 Td
(anti-BPI3V)Tj
4.7677 0 Td
(IgG)Tj
1.7405 0 Td
(remained)Tj
4.0365 0 Td
(elevated)Tj
3.4526 0 Td
(in)Tj
1.0318 0 Td
(vaccinated)Tj
4.456 0 Td
(animals.)Tj
3.5546 0 Td
(Although)Tj
4.0082 0 Td
(no)Tj
-36.1754 -1.304 Td
(significant)Tj
4.388 0 Td
(differences)Tj
4.5637 0 Td
(in)Tj
1.0375 0 Td
(anti-BPI3V)Tj
4.7677 0 Td
(IgG)Tj
1.7405 0 Td
(levels)Tj
2.3754 0 Td
(were)Tj
2.1203 0 Td
(observed)Tj
3.7984 0 Td
(in)Tj
1.0318 0 Td
(non-vaccinated)Tj
6.4119 0 Td
(animals)Tj
3.3279 0 Td
(at)Tj
-35.5631 -1.2982 Td
(days)Tj
1.9955 0 Td
(1220)Tj
2.6419 0 Td
(post-infection)Tj
5.8223 0 Td
(\(p.i.\),)Tj
2.364 0 Td
(IgG)Tj
1.7405 0 Td
(was)Tj
1.6951 0 Td
(elevated)Tj
3.4526 0 Td
(in)Tj
1.0374 0 Td
(2/3)Tj
1.5024 0 Td
(animals)Tj
3.3278 0 Td
(relative)Tj
3.1408 0 Td
(to)Tj
1.0261 0 Td
(day)Tj
1.6328 0 Td
(0)Tj
0.6973 0 Td
(levels,)Tj
2.6022 0 Td
(with)Tj
-34.6787 -1.2983 Td
(the)Tj
1.457 0 Td
(remaining)Tj
4.3539 0 Td
(animal)Tj
2.9594 0 Td
(demonstrating)Tj
6.083 0 Td
(elevated)Tj
3.4412 0 Td
(levels)Tj
2.3641 0 Td
(from)Tj
2.194 0 Td
(days)Tj
1.9899 0 Td
(14)Tj
1.1622 0 Td
(to)Tj
1.0148 0 Td
(day)Tj
1.6271 0 Td
(20)Tj
1.1622 0 Td
(p.i.)Tj
1.44 0 Td
(There)Tj
2.5682 0 Td
(was)Tj
1.6894 0 Td
(a)Tj
0.6463 0 Td
(sig-)Tj
-36.1527 -1.3039 Td
(nificant)Tj
3.2938 0 Td
(increase)Tj
3.4696 0 Td
(in)Tj
1.0375 0 Td
(lymphocyte)Tj
4.8924 0 Td
(counts)Tj
2.8857 0 Td
(in)Tj
1.0374 0 Td
(non-vaccinated)Tj
6.412 0 Td
(animals)Tj
3.3278 0 Td
(from)Tj
2.2054 0 Td
(day)Tj
1.6384 0 Td
(0)Tj
0.6916 0 Td
(to)Tj
1.0262 0 Td
(5)Tj
0.6973 0 Td
(p.i.,)Tj
1.6781 0 Td
(and)Tj
1.7348 0 Td
(a)Tj
-36.028 -1.2983 Td
(significant)Tj
4.388 0 Td
(decrease)Tj
3.6056 0 Td
(from)Tj
2.2053 0 Td
(days)Tj
2.0013 0 Td
(5)Tj
0.6915 0 Td
(to)Tj
1.0262 0 Td
(12,)Tj
1.4003 0 Td
(with)Tj
1.9956 0 Td
(no)Tj
1.2755 0 Td
(significant)Tj
4.388 0 Td
(variations)Tj
4.1613 0 Td
(observed)Tj
3.7984 0 Td
(in)Tj
1.0318 0 Td
(vaccinated)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 507.2314 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(DIVA)Tj
2.5228 0 Td
(metabolo)Tj
4.0394 0 Td
(mics)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.01944)Tj
4.089 0 Td
(88)Tj
0 g
2.0906 0 Td
(April)Tj
2.1827 0 Td
(5,)Tj
1.0417 0 Td
(2018)Tj
35.6814 0 Td
(3)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
61 0 obj
<>stream
endstream
endobj
62 0 obj
<>stream
endstream
endobj
63 0 obj
<>stream
endstream
endobj
64 0 obj
<>stream
endstream
endobj
65 0 obj
<>stream
endstream
endobj
66 0 obj
<>stream
endstream
endobj
67 0 obj
<>stream
endstream
endobj
68 0 obj
<>stream
endstream
endobj
69 0 obj
<>stream
endstream
endobj
70 0 obj
<>stream
endstream
endobj
71 0 obj
<>stream
BT
66.402 0 Td
(20)Tj
ET
Q
endstream
endobj
72 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 9 0 R/Annots 74 0 R/Contents 75 0 R/TrimBox[0 0 612 792]>>
endobj
74 0 obj
[76 0 R 77 0 R 78 0 R 79 0 R 80 0 R 81 0 R 82 0 R 83 0 R 84 0 R 85 0 R 86 0 R 87 0 R]
endobj
76 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.ref025)>>
endobj
77 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.g001)>>
endobj
78 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.g001)>>
endobj
79 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.g001)>>
endobj
80 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.s005)>>
endobj
81 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.g002)>>
endobj
82 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.g002)>>
endobj
83 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.g002)>>
endobj
84 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.s001)>>
endobj
85 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.g003)>>
endobj
86 0 obj
<>/Border[0 0 0]/Dest(Rpone.0194488.g003)>>
endobj
87 0 obj
<>/Border[0 0 0]/A 88 0 R>>
endobj
88 0 obj
<>
endobj
75 0 obj
[89 0 R 90 0 R 91 0 R 92 0 R 93 0 R 94 0 R 95 0 R 96 0 R 97 0 R]
endobj
89 0 obj
<>stream
q
0.83 0.64 0.02 0 k
558.3118 530.1354 m
567.7795 530.1354 l
h
f*
519.7606 491.1307 m
563.4709 491.1307 l
h
f*
200.0126 478.148 m
210.5575 478.148 l
h
f*
321.9024 478.148 m
379.7291 478.148 l
h
f*
272.9197 452.126 m
297.2409 452.126 l
h
f*
479.5654 387.0992 m
505.9843 387.0992 l
h
f*
553.0961 361.1339 m
565.7386 361.1339 l
h
f*
200.0126 348.0945 m
210.5575 348.0945 l
h
f*
396 237.9402 m
429.9591 237.9402 l
h
f*
380.6362 172.9134 m
406.9984 172.9134 l
h
f*
347.0173 81.9213 m
372.4157 81.9213 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(animals.)Tj
3.5546 0 Td
(There)Tj
2.5795 0 Td
(were)Tj
2.1203 0 Td
(no)Tj
1.2756 0 Td
(significant)Tj
4.388 0 Td
(differences)Tj
4.5637 0 Td
(in)Tj
1.0375 0 Td
(neutrophil)Tj
4.456 0 Td
(counts)Tj
2.8857 0 Td
(between)Tj
3.5263 0 Td
(study)Tj
2.3924 0 Td
(groups)Tj
2.9707 0 Td
(at)Tj
-35.7503 -1.3039 Td
(sampling)Tj
3.8777 0 Td
(points)Tj
2.7213 0 Td
(post-infection,)Tj
6.0491 0 Td
(however)Tj
3.6113 0 Td
(significant)Tj
4.388 0 Td
(\(p)Tj
/F12 1 Tf
0 Tc
1.0771 0 Td
(<)Tj
/F6 1 Tf
-0.004 Tc
0.9922 0 Td
(0.05\))Tj
2.211 0 Td
(temporal)Tj
3.8381 0 Td
(variations)Tj
4.1612 0 Td
(were)Tj
-32.927 -1.2982 Td
(observed)Tj
3.7927 0 Td
(with)Tj
2.0012 0 Td
(a)Tj
0.652 0 Td
(decrease)Tj
3.6056 0 Td
(from)Tj
2.2054 0 Td
(day)Tj
1.6384 0 Td
(0)Tj
0.6973 0 Td
(to)Tj
1.0261 0 Td
(5)Tj
0.6917 0 Td
(in)Tj
1.0375 0 Td
(non-vaccinated)Tj
6.4119 0 Td
(animals,)Tj
3.5546 0 Td
(and)Tj
1.7291 0 Td
(an)Tj
1.2019 0 Td
(increase)Tj
3.4753 0 Td
(from)Tj
2.2053 0 Td
(day)Tj
-35.926 -1.2983 Td
(5)Tj
0.6916 0 Td
(to)Tj
1.0261 0 Td
(12)Tj
1.1736 0 Td
(in)Tj
1.0374 0 Td
(both)Tj
2.058 0 Td
(study)Tj
2.3867 0 Td
(groups.)Tj
3.1975 0 Td
(At)Tj
1.2019 0 Td
(day)Tj
1.6384 0 Td
(6)Tj
0.6916 0 Td
(p.i.,)Tj
1.6838 0 Td
(3)Tj
0.6973 0 Td
(animals)Tj
3.3279 0 Td
(per)Tj
1.5307 0 Td
(group)Tj
2.6078 0 Td
(were)Tj
2.126 0 Td
(prepared)Tj
3.8041 0 Td
(for)Tj
1.389 0 Td
(gross)Tj
2.2847 0 Td
(post-)Tj
-34.5541 -1.2983 Td
(mortem)Tj
3.4582 0 Td
(analysis.)Tj
3.5489 0 Td
(Two)Tj
2.024 0 Td
(of)Tj
1.0148 0 Td
(3)Tj
0.6973 0 Td
(animals)Tj
3.3278 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4684 0 Td
(non-vaccinated)Tj
6.4119 0 Td
(group)Tj
2.6078 0 Td
(showed)Tj
3.2485 0 Td
(gross)Tj
2.2847 0 Td
(inflammatory)Tj
-31.1298 -1.3039 Td
(lesions,)Tj
3.1577 0 Td
(with)Tj
1.9956 0 Td
(some)Tj
2.3357 0 Td
(peri-vascular)Tj
5.3972 0 Td
(cuffing)Tj
3.033 0 Td
(consistent)Tj
4.252 0 Td
(with)Tj
2.0012 0 Td
(pneumonia.)Tj
5.04 0 Td
(No)Tj
1.4626 0 Td
(significant)Tj
4.388 0 Td
(gross)Tj
2.2848 0 Td
(/)Tj
0.5499 0 Td
(his-)Tj
-35.8977 -1.2982 Td
(tological)Tj
3.6113 0 Td
(abnormalities)Tj
5.7089 0 Td
(were)Tj
2.1203 0 Td
(detected)Tj
3.566 0 Td
(in)Tj
1.0374 0 Td
(3/3)Tj
1.4967 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(vaccinated)Tj
4.4504 0 Td
(calves)Tj
2.5625 0 Td
(at)Tj
0.9524 0 Td
(6)Tj
0.6974 0 Td
(day)Tj
1.6384 0 Td
(p.i.)Tj
1.4513 0 Td
(at)Tj
0.9524 0 Td
(post-)Tj
-32.7342 -1.2983 Td
(mortem.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 588.1889 cm
BT
/F10 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Evaluation)Tj
4.7244 0 Td
(of)Tj
1.0677 0 Td
(metabolomic)Tj
5.6883 0 Td
(methods)Tj
3.8268 0 Td
(for)Tj
1.4693 0 Td
(profiling)Tj
3.9165 0 Td
(of)Tj
1.0678 0 Td
(bovine)Tj
3.0094 0 Td
(plasma)Tj
3.1985 0 Td
(by)Tj
1.2094 0 Td
(RP)Tj
-29.1781 -1.1669 Td
(and)Tj
1.7905 0 Td
(HILIC-UPLC-MS)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 557.1779 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Preliminary)Tj
4.9832 0 Td
(metabolomic)Tj
5.4709 0 Td
(analysis)Tj
3.3278 0 Td
(was)Tj
1.6951 0 Td
(performed)Tj
4.4731 0 Td
(to)Tj
1.0261 0 Td
(select)Tj
2.3924 0 Td
(a)Tj
0.6577 0 Td
(suitable)Tj
3.2825 0 Td
(method)Tj
3.3221 0 Td
(for)Tj
1.389 0 Td
(the)Tj
1.4683 0 Td
(compre-)Tj
-33.4882 -1.2982 Td
(hensive)Tj
3.2258 0 Td
(profiling)Tj
3.6963 0 Td
(of)Tj
1.0148 0 Td
(metabolites)Tj
4.8075 0 Td
(within)Tj
2.812 0 Td
(bovine)Tj
2.9253 0 Td
(plasma.)Tj
3.2598 0 Td
(RP)Tj
1.4004 0 Td
(and)Tj
1.7291 0 Td
(HILIC)Tj
2.8686 0 Td
(chromatographic)Tj
7.1149 0 Td
(meth-)Tj
-34.8545 -1.2983 Td
(ods)Tj
1.6157 0 Td
(were)Tj
2.1203 0 Td
(compared)Tj
4.2463 0 Td
(using)Tj
2.3867 0 Td
(day)Tj
1.6384 0 Td
(6)Tj
0.6974 0 Td
(p.i.)Tj
1.4513 0 Td
(samples)Tj
3.3845 0 Td
(\(n)Tj
1.1055 0 Td
(=)Tj
0.8051 0 Td
(6\),)Tj
1.2585 0 Td
(which)Tj
2.6476 0 Td
(corresponds)Tj
5.142 0 Td
(to)Tj
1.0261 0 Td
(peak)Tj
2.092 0 Td
(viral)Tj
1.9899 0 Td
(titre)Tj
1.8822 0 Td
([)Tj
0.83 0.64 0.02 0 k
(25)Tj
0 g
(].)Tj
-35.4895 -1.3039 Td
(Despite)Tj
3.2484 0 Td
(improved)Tj
4.1046 0 Td
(resolution)Tj
4.2803 0 Td
(of)Tj
1.0148 0 Td
(poorly)Tj
2.8232 0 Td
(retained)Tj
3.515 0 Td
(hydrophobic)Tj
5.3574 0 Td
(compounds)Tj
4.955 0 Td
(eluting)Tj
2.999 0 Td
(between)Tj
3.5263 0 Td
(1-)Tj
-35.824 -1.2983 Td
(2min)Tj
2.3243 0 Td
(by)Tj
1.1736 0 Td
(HILIC)Tj
2.863 0 Td
(separation,)Tj
4.5977 0 Td
(increased)Tj
3.9912 0 Td
(chromatographic)Tj
7.1092 0 Td
(peaks)Tj
2.4435 0 Td
(corresponding)Tj
6.0547 0 Td
(to)Tj
1.0148 0 Td
(plasma)Tj
3.0274 0 Td
(derived)Tj
-34.5994 -1.2982 Td
(compounds)Tj
4.9605 0 Td
(\(relative)Tj
3.4753 0 Td
(to)Tj
1.0261 0 Td
(blank)Tj
2.4548 0 Td
(injections\))Tj
4.4561 0 Td
(were)Tj
2.1259 0 Td
(observed)Tj
3.7928 0 Td
(in)Tj
1.0374 0 Td
(RP)Tj
1.4003 0 Td
(acquired)Tj
3.7021 0 Td
(profiles)Tj
3.2031 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(1A)Tj
1.3777 0 Td
(and)Tj
-34.8319 -1.2983 Td
(1B)Tj
0 g
(\))Tj
1.6157 0 Td
(relative)Tj
3.1351 0 Td
(to)Tj
1.0261 0 Td
(HILIC)Tj
2.8687 0 Td
(profiles)Tj
3.2031 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(1C)Tj
1.3606 0 Td
(and)Tj
1.7292 0 Td
(1D)Tj
0 g
(\).)Tj
1.9955 0 Td
(Observable)Tj
4.6942 0 Td
(differences)Tj
4.5694 0 Td
(between)Tj
3.5263 0 Td
(plasma)Tj
3.033 0 Td
(sam-)Tj
-34.5767 -1.3039 Td
(ples)Tj
1.7688 0 Td
(from)Tj
2.2053 0 Td
(vaccinated)Tj
4.456 0 Td
(and)Tj
1.7292 0 Td
(non-vaccinated)Tj
6.4062 0 Td
(animals)Tj
3.3335 0 Td
(within)Tj
2.812 0 Td
(chromatogram)Tj
6.1965 0 Td
(profiles)Tj
3.2031 0 Td
(were)Tj
2.1203 0 Td
(only)Tj
-34.2309 -1.2983 Td
(present)Tj
3.1634 0 Td
(using)Tj
2.3868 0 Td
(RP)Tj
1.4003 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1)Tj
1.5136 0 Td
(Fig)Tj
0 g
(\).)Tj
2.0466 0 Td
(Furthermore,)Tj
5.6126 0 Td
(upon)Tj
2.3187 0 Td
(data)Tj
1.9162 0 Td
(extraction)Tj
4.2577 0 Td
(and)Tj
1.7291 0 Td
(processing)Tj
4.4674 0 Td
(\(metabolites)Tj
-30.8124 -1.2982 Td
(with)Tj
1.9955 0 Td
(CV)Tj
/F12 1 Tf
0 Tc
1.5761 0 Td
(>)Tj
/F6 1 Tf
-0.004 Tc
0.9921 0 Td
(50%)Tj
1.9275 0 Td
(in)Tj
1.0375 0 Td
(QC)Tj
1.6328 0 Td
(pools\),)Tj
2.9196 0 Td
(increased)Tj
4.0025 0 Td
(numbers)Tj
3.7758 0 Td
(of)Tj
1.0147 0 Td
(accurate)Tj
3.5603 0 Td
(mass)Tj
2.194 0 Td
(retention)Tj
3.9062 0 Td
(time)Tj
2.0296 0 Td
(pairs)Tj
-32.5642 -1.304 Td
(\(AMRTPs\))Tj
4.6261 0 Td
(were)Tj
2.1259 0 Td
(observed)Tj
3.7928 0 Td
(following)Tj
3.9798 0 Td
(RP)Tj
1.4003 0 Td
(\(n)Tj
1.1112 0 Td
(=)Tj
0.7993 0 Td
(1165\))Tj
2.4605 0 Td
(relative)Tj
3.1408 0 Td
(to)Tj
1.0261 0 Td
(HILIC)Tj
2.8686 0 Td
(\(n)Tj
1.1055 0 Td
(=)Tj
0.7994 0 Td
(538\))Tj
1.9899 0 Td
(separation)Tj
4.3823 0 Td
(of)Tj
-35.6085 -1.2982 Td
(plasma.)Tj
3.2541 0 Td
(Unsupervised)Tj
5.743 0 Td
(PCA)Tj
2.1259 0 Td
(analysis)Tj
3.3279 0 Td
(of)Tj
1.0148 0 Td
(plasma)Tj
3.0274 0 Td
(profiles)Tj
3.2031 0 Td
(acquired)Tj
3.702 0 Td
(by)Tj
1.1792 0 Td
(RP-UPLC-MS)Tj
5.9697 0 Td
(resulted)Tj
3.4016 0 Td
(in)Tj
-35.9487 -1.2983 Td
(clear)Tj
2.1146 0 Td
(separation)Tj
4.3823 0 Td
(between)Tj
3.532 0 Td
(study)Tj
2.3867 0 Td
(groups)Tj
2.9707 0 Td
(when)Tj
2.4038 0 Td
(assessing)Tj
3.804 0 Td
(principle)Tj
3.7984 0 Td
(components)Tj
5.1761 0 Td
(\(PC\))Tj
2.1203 0 Td
(1)Tj
0.6973 0 Td
(and)Tj
1.7291 0 Td
(2)Tj
-35.1153 -1.3039 Td
(\(57.4%)Tj
2.9706 0 Td
(of)Tj
1.0148 0 Td
(systemic)Tj
3.6284 0 Td
(\(R2X\))Tj
2.6475 0 Td
(variation)Tj
3.8041 0 Td
(within)Tj
2.8119 0 Td
(the)Tj
1.4684 0 Td
(dataset\))Tj
3.3392 0 Td
(as)Tj
1.0147 0 Td
(illustrated)Tj
4.218 0 Td
(in)Tj
0.83 0.64 0.02 0 k
1.0374 0 Td
(Fig)Tj
1.4797 0 Td
(2A)Tj
0 g
(.)Tj
1.6044 0 Td
(In)Tj
1.1112 0 Td
(contrast,)Tj
-32.1503 -1.2983 Td
(HILIC-UPLC-MS)Tj
7.4323 0 Td
(metabolomic)Tj
5.4765 0 Td
(profiles)Tj
3.1975 0 Td
(facilitated)Tj
4.1272 0 Td
(only)Tj
1.9786 0 Td
(partial)Tj
2.7893 0 Td
(separation)Tj
4.3823 0 Td
(between)Tj
3.5263 0 Td
(study)Tj
-32.91 -1.2982 Td
(groups)Tj
2.9706 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4684 0 Td
(PCA)Tj
2.1259 0 Td
(scores)Tj
2.6702 0 Td
(plot)Tj
1.7859 0 Td
(\(PC1)Tj
2.2563 0 Td
(and)Tj
1.7348 0 Td
(PC2,)Tj
2.143 0 Td
(35.6%)Tj
2.6249 0 Td
(of)Tj
1.0148 0 Td
(systemic)Tj
3.6283 0 Td
(\(R2X\))Tj
2.6532 0 Td
(variation\))Tj
4.1442 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
-34.9679 -1.3039 Td
(2B)Tj
0 g
(\).)Tj
1.8425 0 Td
(Due)Tj
1.9048 0 Td
(to)Tj
1.0262 0 Td
(the)Tj
1.4683 0 Td
(small)Tj
2.3301 0 Td
(number)Tj
3.4129 0 Td
(of)Tj
1.0148 0 Td
(chromatographic)Tj
7.1149 0 Td
(peaks,)Tj
2.6815 0 Td
(fewer)Tj
2.4095 0 Td
(AMRTPs)Tj
3.9458 0 Td
(and)Tj
1.7348 0 Td
(poor)Tj
2.1203 0 Td
(unsuper-)Tj
-33.0064 -1.2983 Td
(vised)Tj
2.2506 0 Td
(PCA)Tj
2.126 0 Td
(separation)Tj
4.3823 0 Td
(of)Tj
1.0148 0 Td
(plasma)Tj
3.0331 0 Td
(profiles)Tj
3.2031 0 Td
(acquired)Tj
3.7021 0 Td
(following)Tj
3.9798 0 Td
(HILIC-UPLC-MS)Tj
7.4324 0 Td
(chromatogra-)Tj
-31.1242 -1.2983 Td
(phy,)Tj
1.9445 0 Td
(RP-UPLC-MS)Tj
5.9641 0 Td
(was)Tj
1.7007 0 Td
(selected)Tj
3.3449 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(method)Tj
3.3222 0 Td
(of)Tj
1.0148 0 Td
(choice)Tj
2.7949 0 Td
(for)Tj
1.3833 0 Td
(metabolomic)Tj
5.4709 0 Td
(profiling)Tj
3.702 0 Td
(of)Tj
-33.1311 -1.2982 Td
(remaining)Tj
4.3653 0 Td
(study)Tj
2.3867 0 Td
(plasma)Tj
3.0331 0 Td
(samples.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 281.9905 cm
BT
/F10 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(RP-UPLC-MS)Tj
6.0756 0 Td
(metabolomic)Tj
5.6882 0 Td
(profiling)Tj
3.9166 0 Td
(of)Tj
1.0677 0 Td
(bovine)Tj
3.0095 0 Td
(plasma)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 264.9826 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Plasma)Tj
3.0727 0 Td
(samples)Tj
3.3845 0 Td
(from)Tj
2.2054 0 Td
(days)Tj
1.9956 0 Td
(0,)Tj
0.9184 0 Td
(2,)Tj
0.9241 0 Td
(14)Tj
1.1735 0 Td
(and)Tj
1.7291 0 Td
(20)Tj
1.1679 0 Td
(p.i.)Tj
1.457 0 Td
(were)Tj
2.1203 0 Td
(extracted,)Tj
4.1102 0 Td
(analysed)Tj
3.651 0 Td
(and)Tj
1.7291 0 Td
(combined)Tj
4.2463 0 Td
(with)Tj
1.9956 0 Td
(day)Tj
-35.8807 -1.2982 Td
(6)Tj
0.6916 0 Td
(p.i.)Tj
1.457 0 Td
(data)Tj
1.9162 0 Td
(for)Tj
1.3833 0 Td
(multivariate)Tj
5.0626 0 Td
(analysis.)Tj
3.5547 0 Td
(Mass)Tj
2.2677 0 Td
(accuracy)Tj
3.7133 0 Td
(and)Tj
1.7292 0 Td
(retention)Tj
3.9061 0 Td
(time)Tj
2.0296 0 Td
(deviation)Tj
3.9458 0 Td
(of)Tj
1.0148 0 Td
(reference)Tj
-32.6719 -1.2983 Td
(compounds)Tj
4.9605 0 Td
(between)Tj
3.5263 0 Td
(analysis)Tj
3.3279 0 Td
(runs)Tj
2.0296 0 Td
(was)Tj
1.6951 0 Td
(excellent)Tj
3.719 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1)Tj
1.5137 0 Td
(Table)Tj
0 g
(\))Tj
2.7779 0 Td
(and)Tj
1.7348 0 Td
(within)Tj
2.812 0 Td
(Marker)Tj
3.2088 0 Td
(Lynx)Tj
2.228 0 Td
(extraction)Tj
-33.5336 -1.3039 Td
(parameters)Tj
4.6714 0 Td
(\(0.02Da)Tj
3.3846 0 Td
(and)Tj
1.7291 0 Td
(0.2min)Tj
3.033 0 Td
(respectively\))Tj
5.2214 0 Td
(ensuring)Tj
3.7361 0 Td
(accurate)Tj
3.5546 0 Td
(peak)Tj
2.0919 0 Td
(matching.)Tj
4.2293 0 Td
(AMRTPs)Tj
-31.6514 -1.2983 Td
(\(n)Tj
1.0998 0 Td
(=)Tj
0.788 0 Td
(1593\))Tj
2.4548 0 Td
(with)Tj
1.9899 0 Td
(%CV)Tj
2.3301 0 Td
(less)Tj
1.5987 0 Td
(than)Tj
2.0239 0 Td
(50%)Tj
1.9162 0 Td
(in)Tj
1.0318 0 Td
(inter-run)Tj
3.9175 0 Td
(quality)Tj
2.948 0 Td
(control)Tj
3.1124 0 Td
(plasma)Tj
3.0217 0 Td
(pools)Tj
2.3528 0 Td
(were)Tj
2.1089 0 Td
(used)Tj
2.0523 0 Td
(to)Tj
1.0205 0 Td
(con-)Tj
-35.7673 -1.2982 Td
(struct)Tj
2.5001 0 Td
(of)Tj
1.0148 0 Td
(PCA)Tj
2.126 0 Td
(models)Tj
3.1067 0 Td
(\(pre-filtered)Tj
5.0683 0 Td
(from)Tj
2.2054 0 Td
(7690)Tj
2.1203 0 Td
(AMRTPs)Tj
3.9514 0 Td
(extracted)Tj
3.8835 0 Td
(from)Tj
2.2053 0 Td
(raw)Tj
1.7121 0 Td
(data\).)Tj
2.4775 0 Td
(The)Tj
1.7801 0 Td
(effect)Tj
2.3698 0 Td
(of)Tj
-36.5213 -1.3039 Td
(BPI3V)Tj
2.8686 0 Td
(challenge)Tj
3.9571 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4684 0 Td
(metabolite)Tj
4.4446 0 Td
(profile)Tj
2.8403 0 Td
(of)Tj
1.0148 0 Td
(all)Tj
1.1452 0 Td
(animals)Tj
3.3336 0 Td
(irrespective)Tj
4.8245 0 Td
(of)Tj
1.0148 0 Td
(vaccination)Tj
4.8245 0 Td
(status,)Tj
2.7269 0 Td
(was)Tj
-35.7389 -1.2983 Td
(illustrated)Tj
4.2179 0 Td
(in)Tj
1.0374 0 Td
(un-supervised)Tj
5.8847 0 Td
(PCA)Tj
2.126 0 Td
(scores)Tj
2.6646 0 Td
(plot)Tj
1.7914 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8199 0 Td
(3A)Tj
0 g
(\))Tj
1.7178 0 Td
(by)Tj
1.1792 0 Td
(separation)Tj
4.3823 0 Td
(in)Tj
1.0375 0 Td
(pre-)Tj
1.8822 0 Td
(\(day)Tj
1.9785 0 Td
(0)Tj
0.6974 0 Td
(p.i.\))Tj
1.7914 0 Td
(and)Tj
-34.2082 -1.2983 Td
(post-BPI3V)Tj
4.9039 0 Td
(challenge)Tj
3.9571 0 Td
(samples)Tj
3.3845 0 Td
(\(days)Tj
2.3358 0 Td
(220)Tj
2.1656 0 Td
(p.i.\))Tj
1.7915 0 Td
(when)Tj
2.4038 0 Td
(observing)Tj
4.1272 0 Td
(PC2)Tj
1.9162 0 Td
(and)Tj
1.7291 0 Td
(PC3)Tj
1.9219 0 Td
(\(14.1%)Tj
2.9707 0 Td
(R2X\).)Tj
-33.6073 -1.2982 Td
(The)Tj
1.7801 0 Td
(greatest)Tj
3.2938 0 Td
(separation)Tj
4.3824 0 Td
(was)Tj
1.7007 0 Td
(observed)Tj
3.7984 0 Td
(between)Tj
3.5263 0 Td
(day)Tj
1.6384 0 Td
(0)Tj
0.6917 0 Td
(pre-)Tj
1.8822 0 Td
(and)Tj
1.7348 0 Td
(day)Tj
1.6327 0 Td
(2)Tj
0.6973 0 Td
(p.i.)Tj
1.457 0 Td
(post-challenge)Tj
5.9924 0 Td
(stages)Tj
2.5625 0 Td
(in)Tj
-36.7707 -1.304 Td
(vaccinated)Tj
4.456 0 Td
(and)Tj
1.7291 0 Td
(non-vaccinated)Tj
6.4063 0 Td
(animals.)Tj
3.5603 0 Td
(Differentiation)Tj
6.1851 0 Td
(of)Tj
1.0148 0 Td
(vaccinated)Tj
4.456 0 Td
(from)Tj
2.2054 0 Td
(non-vaccinated)Tj
-30.013 -1.2982 Td
(animals)Tj
3.3278 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(metabolite)Tj
4.4447 0 Td
(profiles)Tj
3.2031 0 Td
(following)Tj
3.9798 0 Td
(challenge)Tj
3.9572 0 Td
(with)Tj
1.9955 0 Td
(BPI3V)Tj
2.8744 0 Td
(was)Tj
1.6951 0 Td
(investigated)Tj
4.9889 0 Td
(using)Tj
-34.2139 -1.2983 Td
(un-supervised)Tj
5.879 0 Td
(\(PCA\))Tj
2.8062 0 Td
(and)Tj
1.7348 0 Td
(supervised)Tj
4.4504 0 Td
(\(OPLS-DA\))Tj
4.9946 0 Td
(multivariate)Tj
5.057 0 Td
(analysis.)Tj
3.5546 0 Td
(Prior)Tj
2.2961 0 Td
(to)Tj
1.0261 0 Td
(BPI3V)Tj
2.8686 0 Td
(chal-)Tj
-34.6674 -1.3039 Td
(lenge)Tj
2.3243 0 Td
(metabolite)Tj
4.4447 0 Td
(profile)Tj
2.8403 0 Td
(variation)Tj
3.8041 0 Td
(between)Tj
3.5263 0 Td
(vaccinated)Tj
4.456 0 Td
(and)Tj
1.7291 0 Td
(non-vaccinated)Tj
6.412 0 Td
(animals)Tj
3.3278 0 Td
(was)Tj
1.7008 0 Td
(low,)Tj
-34.5654 -1.2983 Td
(evidenced)Tj
4.2406 0 Td
(by)Tj
1.1792 0 Td
(no)Tj
1.2755 0 Td
(separation)Tj
4.3824 0 Td
(at)Tj
0.9524 0 Td
(day)Tj
1.6384 0 Td
(0)Tj
0.6917 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(3B)Tj
0 g
(\))Tj
1.6157 0 Td
(when)Tj
2.4038 0 Td
(observing)Tj
4.1272 0 Td
(all)Tj
1.1452 0 Td
(PCs.)Tj
2.0296 0 Td
(With)Tj
2.279 0 Td
(study)Tj
2.3925 0 Td
(progression)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 507.2314 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(DIVA)Tj
2.5228 0 Td
(metabolo)Tj
4.0394 0 Td
(mics)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
81.5811 34.9228 m
237.8835 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https://doi.or)Tj
5.4142 0 Td
(g/10.137)Tj
3.8198 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.01944)Tj
4.089 0 Td
(88)Tj
0 g
2.0906 0 Td
(April)Tj
2.1827 0 Td
(5,)Tj
1.0417 0 Td
(2018)Tj
35.6814 0 Td
(4)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
90 0 obj
<>stream
endstream
endobj
91 0 obj
<>stream
endstream
endobj
92 0 obj
<>stream
endstream
endobj
93 0 obj
<>stream
endstream
endobj
94 0 obj
<>stream
endstream
endobj
95 0 obj
<>stream
endstream
endobj
96 0 obj
<>stream
endstream
endobj
97 0 obj
<>stream
BT
66.402 0 Td
(20)Tj
ET
Q
endstream
endobj
98 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 9 0 R/Annots 101 0 R/Contents 102 0 R/TrimBox[0 0 612 792]>>
endobj
100 0 obj
<>stream
xUxgݷ`Jds9'$sp@QI
ڿ7~$AECQ]j8Vc! H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$ H@$+%$˗/ψKqL.aqApٳgL̙3($81 ;l[fϝ;_|g6;A_qq84ud^} H@$ H@$ H@$ H@$ H@$ H@'Sӟ7yW_}őwsiX~ĉSI;vuqС#G`Dܬ3m,p,[Zh8h4~7hϕ$ H@$ H@$ H@$ H@$ H@$p[P?@J'~;Dh;Woǃ% H@$ H@$ H@$ H@$ H@$ CcK~Bz_~幜"wۿ뷇Q[.'Dx
#q< Kw;|tC%S|LϜ9C'O"-'Jw"[n@ wX=e$ H@$ H@$ H@$ H@$ H@$ "7N;MUVIb{ǖ+o;UO֭[.]2ΉYI̘1߸qݻw$;Ͱܑ*[
6,[l+V?>Dlg.\h^x17Kh ܲH@$ H@$ H@$ H@$ H@$ H@@ PÜ@b>}zW^ZZjoȑCe}q)Nim\s0^uQ]۶mRJURjժ̓>?/_Fu֭C