3c67c8f71a83bc77b99880466da6f58d pmc_32050516.pdf 6f82292ddf8d8ee1215bbb4045ff883d805a3cb7 pmc_32050516.pdf fd6ecf702eec25365c03cbf1ac86a6acf3fb944cf4de86e0ab87f4aa9f3da7e1 pmc_32050516.pdf Title: Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice Subject: Cognitive and behavioural disturbances are a growing public healthcare issue for the modern society, as stressful lifestyle is becoming more and more common. Besides, several pieces of evidence state that environment is crucial in the development of several diseases as well as compromising healthy aging. Therefore, it is important to study the effects of stress on cognition and its relationship with aging. To address these queries, Chronic Mild Stress (CMS) paradigm was used in the senescence-accelerated mouse prone 8 (SAMP8) and resistant 1 (SAMR1). On one hand, we determined the changes produced in the three main epigenetic marks after 4 weeks of CMS treatment, such as a reduction in histone posttranslational modifications and DNA methylation, and up-regulation or down-regulation of several miRNA involved in different cellular processes in mice. In addition, CMS treatment induced reactive oxygen species (ROS) damage accumulation and loss of antioxidant defence mechanisms, as well as inflammatory signalling activation through NF-B pathway and astrogliosis markers, like Gfap. Remarkably, CMS altered mTORC1 signalling in both strains, decreasing autophagy only in SAMR1 mice. We found a decrease in glycogen synthase kinase 3 (GSK-3) inactivation, hyperphosphorylation of Tau and an increase in sAPP protein levels in mice under CMS. Moreover, reduction in the non-amyloidogenic secretase ADAM10 protein levels was found in SAMR1 CMS group. Consequently, detrimental effects on behaviour and cognitive performance were detected in CMS treated mice, affecting mainly SAMR1 mice, promoting a turning to SAMP8 phenotype. In conclusion, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence. Keywords: stress; epigenetics; senescence; cognition; age-related cognitive decline; Alzheimer’s disease; SAMP8; SAMR1; oxidative stress; inflammation; autophagy Author: Dolors Puigoriol-Illamola, Mirna Martínez-Damas, Christian Griñán-Ferré and Mercè Pallàs Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Mon Feb 10 07:37:42 2020 CET ModDate: Mon Feb 10 07:37:42 2020 CET Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 23 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3878948 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- EHBBJK+URWPalladioL-Ital Type 1 Custom yes yes no 130 0 TLXLGJ+URWPalladioL-Bold Type 1 Custom yes yes no 131 0 JFLFCJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 132 0 QTLELQ+Pxbsy Type 1 Builtin yes yes no 133 0 VHIAUC+URWPalladioL-Roma Type 1 Custom yes yes no 134 0 AMQPYL+VnURWPalladioL Type 1 Custom yes yes no 135 0 EZRNSZ+Pxsy Type 1 Builtin yes yes no 136 0 DCZNHD+Rpxr Type 1 Builtin yes yes no 137 0 QPZFHW+EURM10 Type 1 Builtin yes yes no 138 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 143 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 144 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 163 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 164 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 165 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 260 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 261 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 262 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 263 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 288 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 289 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 290 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 291 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 317 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 318 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 319 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 320 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 344 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 345 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 346 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 347 0 ODDJLG+PalatinoLinotype CID TrueType Identity-H yes yes yes 376 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 377 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 378 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 379 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 380 0 YWGLGW+Rpxi Type 1 Builtin yes yes no 409 0 VZPSRL+Rpxmi Type 1 Builtin yes yes no 410 0 ODDJLG+PalatinoLinotype CID TrueType Identity-H yes yes yes 416 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 417 0 ODDKBG+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 418 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 419 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 420 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 421 0 ODDJLG+PalatinoLinotype CID TrueType Identity-H yes yes yes 462 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 463 0 ODDKBG+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 464 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 465 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 466 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 467 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 505 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 506 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 507 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 508 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 541 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 542 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 543 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 544 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 586 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 587 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 588 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 589 0 YICMPF+Rpcxr Type 1 Builtin yes yes no 675 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 688 0 ODDJLH+PalatinoLinotype TrueType WinAnsi yes yes no 705 0 ODDKBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 706 0 ODDKBJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 707 0 ODDKLH+TimesNewRoman CID TrueType Identity-H yes yes yes 708 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 04:15:03 CEST RepresentationInformation: pmc_32050516.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 11:44:07 CEST Size: 3878948 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはの〠 Item: Title: げづびふぬぴび〠 Children: Item: Title: ぅばどでづのづぴどっ〠きはつふぬちぴどはの〠ごひどででづひび〠ぃはねばちっぴづつ〠ぃとひはねちぴどの〠ちてぴづひ〠ぃとひはのどっ〠きどぬつ〠こぴひづびび〠 Item: Title: ぃとひはのどっ〠きどぬつ〠こぴひづびび〠ぁぴぴづのふちぴづび〠ぁのぴどはへどつちのぴ〠いづてづのっづ〠きづっとちのどびねび〠 Item: Title: ぉのてぬちねねちぴはひべ〠ぁっぴどぶちぴどはの〠どび〠ぉのつふっづつ〠ちてぴづひ〠ぁばばぬどっちぴどはの〠はて〠ぃとひはのどっ〠きどぬつ〠こぴひづびび〠 Item: Title: ぃとひはのどっ〠きどぬつ〠こぴひづびび〠きはつふぬちぴづび〠ぁぐぐ〠ぐひはっづびびどので〠ちび〠しづぬぬ〠ちび〠ぁぬぴづひび〠きどっひはぴふぢふぬづ〠こぴちぢどぬどぺちぴどはの〠ごとひはふでと〠えべばづひばとはびばとはひべぬちぴどはの〠はて〠ごちふ〠ぐひはぴづどの〠 Item: Title: ぃとひはのどっ〠きどぬつ〠こぴひづびび〠ぐひはねはぴづび〠ぁふぴはばとちでべ〠ぁっぴどぶちぴどはの〠 Item: Title: ぁのへどづぴべ〭がどにづ〠あづとちぶどはふひ〬〠きづねはひべ〠いづっぬどのづ〠ちのつ〠ぐははひづひ〠ぃはでのどぴどぶづ〠ぁぢどぬどぴどづび〠ぁてぴづひ〠ぃとひはのどっ〠きどぬつ〠こぴひづびび〠 Item: Title: いどびっふびびどはの〠 Item: Title: きちぴづひどちぬび〠ちのつ〠きづぴとはつび〠 Children: Item: Title: ぁのどねちぬび〠ちのつ〠ぃとひはのどっ〠きどぬつ〠こぴひづびび〠ぐひはっづつふひづ〠 Item: Title: ぇぬふっはびづ〠ごはぬづひちのっづ〠ごづびぴ〠 Item: Title: あづとちぶどはふひちぬ〠ちのつ〠ぃはでのどぴどぶづ〠ごづびぴ〠 Children: Item: Title: くばづの〠うどづぬつ〠ごづびぴ〠〨くうご〩〠 Item: Title: ぎはぶづぬ〠くぢなづっぴ〠げづっはでのどぴどはの〠ごづびぴ〠〨ぎくげご〩〠 Item: Title: きはひひどび〠しちぴづひ〠きちぺづ〠〨きしき〩〠 Item: Title: ぉねねふのはつづぴづっぴどはの〠ぅへばづひどねづのぴび〠 Children: Item: Title: あひちどの〠ぐひはっづびびどので〠 Item: Title: しづびぴづひの〠あぬはぴぴどので〠 Item: Title: げぎぁ〠ぅへぴひちっぴどはの〠ちのつ〠ぇづのづ〠ぅへばひづびびどはの〠いづぴづひねどのちぴどはの〠ぢべ〠ぱ〭ぐぃげ〠 Item: Title: ぇぬはぢちぬ〠いぎぁ〠きづぴとべぬちぴどはの〠ちのつ〠えべつひはへべねづぴとべぬちぴどはの〠いづぴづひねどのちぴどはの〠 Item: Title: ねどげぎぁ〠ぅへばひづびびどはの〠ぁひひちべ〠ちのつ〠ざちぬどつちぴどはの〠ぢべ〠こどのでぬづ〠げづちぬ〭ごどねづ〠ぐぃげ〠 Item: Title: くへどつちぴどぶづ〠こぴひづびび〠いづぴづひねどのちぴどはの〠 Item: Title: いちぴち〠ぁのちぬべびどび〠 Item: Title: ぃはのっぬふびどはのび〠 Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: EHBBJK+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 122 FontDescriptor: FontName: EHBBJK+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: TLXLGJ+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 241 FontDescriptor: FontName: TLXLGJ+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YICMPF+Rpcxr FontSubset: true FirstChar: 151 LastChar: 174 FontDescriptor: FontName: YICMPF+Rpcxr Flags: Symbolic FontBBox: -212, -286, 1344, 973 FontFile: true Font: BaseFont: JFLFCJ+VnURWPalladioL-Bold FontSubset: true FirstChar: 160 LastChar: 189 FontDescriptor: FontName: JFLFCJ+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QTLELQ+Pxbsy FontSubset: true FirstChar: 121 LastChar: 121 FontDescriptor: FontName: QTLELQ+Pxbsy Flags: Symbolic FontBBox: 5, -978, 1382, 913 FontFile: true Font: BaseFont: VHIAUC+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 241 FontDescriptor: FontName: VHIAUC+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: AMQPYL+VnURWPalladioL FontSubset: true FirstChar: 129 LastChar: 243 FontDescriptor: FontName: AMQPYL+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: EZRNSZ+Pxsy FontSubset: true FirstChar: 0 LastChar: 121 FontDescriptor: FontName: EZRNSZ+Pxsy Flags: Symbolic FontBBox: -21, -994, 1292, 912 FontFile: true Font: BaseFont: DCZNHD+Rpxr FontSubset: true FirstChar: 11 LastChar: 61 FontDescriptor: FontName: DCZNHD+Rpxr Flags: Symbolic FontBBox: -40, -283, 904, 728 FontFile: true Font: BaseFont: QPZFHW+EURM10 FontSubset: true FirstChar: 12 LastChar: 22 FontDescriptor: FontName: QPZFHW+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: MPUDFL+PazoMath FontSubset: true FirstChar: 68 LastChar: 68 FontDescriptor: FontName: MPUDFL+PazoMath Flags: Symbolic FontBBox: -40, -283, 878, 946 FontFile: true Font: BaseFont: YWGLGW+Rpxi FontSubset: true FirstChar: 47 LastChar: 47 FontDescriptor: FontName: YWGLGW+Rpxi Flags: Symbolic FontBBox: -162, -280, 856, 733 FontFile: true Font: BaseFont: VZPSRL+Rpxmi FontSubset: true FirstChar: 11 LastChar: 12 FontDescriptor: FontName: VZPSRL+Rpxmi Flags: Symbolic FontBBox: -70, -289, 949, 802 FontFile: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 75, 757, 221, 793 Annotation: Subtype: Link Rect: 474, 757, 519, 793 Annotation: Subtype: Link Rect: 206, 640, 217, 654 Annotation: Subtype: Link Rect: 160, 629, 171, 640 Annotation: Subtype: Link Rect: 466, 475, 518, 494 Annotation: Subtype: Link Rect: 193, 38, 270, 50 Annotation: Subtype: Link Rect: 416, 38, 519, 50 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 221, 743, 228, 752 ActionDest: 698 Annotation: Subtype: Link Rect: 425, 688, 432, 698 ActionDest: 752 Annotation: Subtype: Link Rect: 137, 661, 144, 671 ActionDest: 752 Annotation: Subtype: Link Rect: 231, 648, 238, 657 ActionDest: 752 Annotation: Subtype: Link Rect: 291, 594, 298, 603 ActionDest: 752 Annotation: Subtype: Link Rect: 317, 580, 324, 590 ActionDest: 752 Annotation: Subtype: Link Rect: 324, 580, 331, 590 ActionDest: 752 Annotation: Subtype: Link Rect: 167, 526, 174, 535 ActionDest: 752 Annotation: Subtype: Link Rect: 355, 513, 362, 522 ActionDest: 752 Annotation: Subtype: Link Rect: 496, 513, 503, 522 ActionDest: 752 Annotation: Subtype: Link Rect: 504, 513, 516, 522 ActionDest: 752 Annotation: Subtype: Link Rect: 181, 499, 193, 508 ActionDest: 752 Annotation: Subtype: Link Rect: 296, 499, 308, 508 ActionDest: 752 Annotation: Subtype: Link Rect: 315, 486, 327, 495 ActionDest: 752 Annotation: Subtype: Link Rect: 337, 405, 349, 414 ActionDest: 752 Annotation: Subtype: Link Rect: 101, 378, 112, 387 ActionDest: 752 Annotation: Subtype: Link Rect: 441, 364, 453, 373 ActionDest: 752 Annotation: Subtype: Link Rect: 453, 364, 465, 373 ActionDest: 752 Annotation: Subtype: Link Rect: 157, 324, 169, 333 ActionDest: 752 Annotation: Subtype: Link Rect: 415, 283, 427, 292 ActionDest: 752 Annotation: Subtype: Link Rect: 430, 283, 442, 292 ActionDest: 752 Annotation: Subtype: Link Rect: 295, 243, 307, 252 ActionDest: 752 Annotation: Subtype: Link Rect: 419, 202, 426, 211 ActionDest: 698 Annotation: Subtype: Link Rect: 427, 202, 439, 211 ActionDest: 752 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 267, 602, 274, 614 ActionDest: 281 Annotation: Subtype: Link Rect: 440, 589, 447, 601 ActionDest: 281 Annotation: Subtype: Link Rect: 468, 562, 475, 574 ActionDest: 281 Annotation: Subtype: Link Rect: 227, 521, 234, 533 ActionDest: 281 Annotation: Subtype: Link Rect: 109, 494, 116, 506 ActionDest: 281 Annotation: Subtype: Link Rect: 461, 454, 468, 466 ActionDest: 281 Annotation: Subtype: Link Rect: 449, 427, 456, 439 ActionDest: 281 Annotation: Subtype: Link Rect: 473, 400, 480, 412 ActionDest: 281 Annotation: Subtype: Link Rect: 382, 359, 389, 371 ActionDest: 336 Annotation: Subtype: Link Rect: 110, 319, 117, 331 ActionDest: 281 Annotation: Subtype: Link Rect: 451, 305, 458, 317 ActionDest: 281 Annotation: Subtype: Link Rect: 167, 197, 174, 209 ActionDest: 336 Annotation: Subtype: Link Rect: 154, 170, 161, 182 ActionDest: 336 Annotation: Subtype: Link Rect: 392, 130, 399, 142 ActionDest: 336 Annotation: Subtype: Link Rect: 155, 103, 163, 115 ActionDest: 336 Annotation: Subtype: Link Rect: 501, 103, 508, 115 ActionDest: 336 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 258, 740, 265, 752 ActionDest: 336 Annotation: Subtype: Link Rect: 501, 726, 508, 738 ActionDest: 336 Annotation: Subtype: Link Rect: 232, 699, 239, 711 ActionDest: 336 Annotation: Subtype: Link Rect: 255, 672, 262, 684 ActionDest: 336 Annotation: Subtype: Link Rect: 500, 672, 507, 684 ActionDest: 336 Page: Sequence: 5 Page: Sequence: 6 Page: Sequence: 7 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 490, 543, 496, 555 ActionDest: 368 Annotation: Subtype: Link Rect: 214, 489, 221, 501 ActionDest: 368 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 381, 595, 388, 607 ActionDest: 406 Annotation: Subtype: Link Rect: 194, 555, 201, 567 ActionDest: 406 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 249, 668, 256, 680 ActionDest: 336 Annotation: Subtype: Link Rect: 328, 668, 335, 680 ActionDest: 454 Annotation: Subtype: Link Rect: 328, 655, 335, 667 ActionDest: 454 Annotation: Subtype: Link Rect: 474, 641, 481, 653 ActionDest: 454 Annotation: Subtype: Link Rect: 381, 614, 388, 626 ActionDest: 454 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 109, 626, 116, 638 ActionDest: 497 Annotation: Subtype: Link Rect: 170, 626, 177, 638 ActionDest: 336 Annotation: Subtype: Link Rect: 230, 112, 237, 124 ActionDest: 578 Annotation: Subtype: Link Rect: 240, 72, 247, 84 ActionDest: 578 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 239, 726, 246, 738 ActionDest: 578 Annotation: Subtype: Link Rect: 473, 659, 480, 671 ActionDest: 578 Annotation: Subtype: Link Rect: 490, 645, 497, 657 ActionDest: 578 Annotation: Subtype: Link Rect: 109, 605, 116, 617 ActionDest: 578 Annotation: Subtype: Link Rect: 265, 510, 271, 522 ActionDest: 578 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 479, 91, 486, 100 ActionDest: 752 Annotation: Subtype: Link Rect: 486, 91, 498, 100 ActionDest: 752 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 491, 688, 503, 698 ActionDest: 787 Annotation: Subtype: Link Rect: 503, 688, 515, 698 ActionDest: 787 Annotation: Subtype: Link Rect: 114, 634, 121, 644 ActionDest: 752 Annotation: Subtype: Link Rect: 121, 634, 133, 644 ActionDest: 787 Annotation: Subtype: Link Rect: 134, 634, 146, 644 ActionDest: 787 Annotation: Subtype: Link Rect: 217, 607, 229, 617 ActionDest: 787 Annotation: Subtype: Link Rect: 371, 607, 383, 617 ActionDest: 787 Annotation: Subtype: Link Rect: 218, 513, 230, 522 ActionDest: 787 Annotation: Subtype: Link Rect: 256, 472, 268, 481 ActionDest: 787 Annotation: Subtype: Link Rect: 105, 432, 117, 441 ActionDest: 787 Annotation: Subtype: Link Rect: 202, 418, 214, 427 ActionDest: 787 Annotation: Subtype: Link Rect: 214, 418, 226, 427 ActionDest: 787 Annotation: Subtype: Link Rect: 436, 418, 448, 427 ActionDest: 787 Annotation: Subtype: Link Rect: 334, 364, 341, 373 ActionDest: 752 Annotation: Subtype: Link Rect: 341, 364, 353, 373 ActionDest: 787 Annotation: Subtype: Link Rect: 354, 364, 365, 373 ActionDest: 787 Annotation: Subtype: Link Rect: 159, 283, 166, 292 ActionDest: 752 Annotation: Subtype: Link Rect: 115, 256, 127, 265 ActionDest: 787 Annotation: Subtype: Link Rect: 427, 215, 439, 225 ActionDest: 787 Annotation: Subtype: Link Rect: 412, 161, 424, 171 ActionDest: 787 Annotation: Subtype: Link Rect: 324, 121, 336, 130 ActionDest: 787 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 409, 702, 420, 711 ActionDest: 787 Annotation: Subtype: Link Rect: 153, 580, 165, 590 ActionDest: 787 Annotation: Subtype: Link Rect: 165, 580, 177, 590 ActionDest: 787 Annotation: Subtype: Link Rect: 357, 472, 369, 481 ActionDest: 787 Annotation: Subtype: Link Rect: 233, 445, 245, 454 ActionDest: 787 Annotation: Subtype: Link Rect: 325, 418, 337, 427 ActionDest: 787 Annotation: Subtype: Link Rect: 308, 391, 320, 400 ActionDest: 787 Annotation: Subtype: Link Rect: 393, 80, 405, 90 ActionDest: 752 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 124, 567, 131, 576 ActionDest: 752 Annotation: Subtype: Link Rect: 445, 526, 457, 535 ActionDest: 752 Annotation: Subtype: Link Rect: 255, 459, 267, 468 ActionDest: 752 Annotation: Subtype: Link Rect: 274, 418, 286, 427 ActionDest: 787 Annotation: Subtype: Link Rect: 267, 364, 279, 373 ActionDest: 752 Annotation: Subtype: Link Rect: 280, 364, 292, 373 ActionDest: 787 Annotation: Subtype: Link Rect: 213, 351, 220, 360 ActionDest: 752 Annotation: Subtype: Link Rect: 220, 351, 232, 360 ActionDest: 787 Annotation: Subtype: Link Rect: 233, 351, 245, 360 ActionDest: 798 Annotation: Subtype: Link Rect: 127, 162, 138, 171 ActionDest: 798 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 503, 619, 515, 628 ActionDest: 752 Annotation: Subtype: Link Rect: 397, 334, 409, 344 ActionDest: 798 Annotation: Subtype: Link Rect: 187, 224, 199, 233 ActionDest: 798 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 345, 723, 357, 732 ActionDest: 798 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 503, 634, 515, 644 ActionDest: 787 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 193, 657, 200, 668 ActionDest: 698 Annotation: Subtype: Link Rect: 343, 264, 519, 275 Annotation: Subtype: Link Rect: 331, 74, 369, 85 Annotation: Subtype: Link Rect: 375, 74, 411, 85 Page: Sequence: 21 Annotations: Annotation: Subtype: Link Rect: 172, 728, 210, 738 Annotation: Subtype: Link Rect: 216, 728, 252, 738 Annotation: Subtype: Link Rect: 438, 714, 475, 725 Annotation: Subtype: Link Rect: 481, 714, 516, 725 Annotation: Subtype: Link Rect: 319, 663, 356, 673 Annotation: Subtype: Link Rect: 362, 663, 398, 673 Annotation: Subtype: Link Rect: 313, 637, 351, 648 Annotation: Subtype: Link Rect: 357, 637, 393, 648 Annotation: Subtype: Link Rect: 367, 611, 404, 622 Annotation: Subtype: Link Rect: 363, 598, 401, 609 Annotation: Subtype: Link Rect: 407, 598, 443, 609 Annotation: Subtype: Link Rect: 172, 560, 210, 570 Annotation: Subtype: Link Rect: 275, 508, 313, 519 Annotation: Subtype: Link Rect: 435, 482, 473, 493 Annotation: Subtype: Link Rect: 298, 443, 336, 454 Annotation: Subtype: Link Rect: 100, 418, 137, 428 Annotation: Subtype: Link Rect: 143, 418, 179, 428 Annotation: Subtype: Link Rect: 100, 379, 137, 389 Annotation: Subtype: Link Rect: 143, 379, 179, 389 Annotation: Subtype: Link Rect: 241, 340, 279, 351 Annotation: Subtype: Link Rect: 285, 340, 321, 351 Annotation: Subtype: Link Rect: 329, 301, 367, 312 Annotation: Subtype: Link Rect: 373, 301, 409, 312 Annotation: Subtype: Link Rect: 334, 275, 371, 286 Annotation: Subtype: Link Rect: 377, 249, 415, 260 Annotation: Subtype: Link Rect: 154, 224, 192, 234 Annotation: Subtype: Link Rect: 479, 185, 516, 196 Annotation: Subtype: Link Rect: 346, 134, 383, 144 Annotation: Subtype: Link Rect: 472, 107, 509, 118 Page: Sequence: 22 Annotations: Annotation: Subtype: Link Rect: 437, 714, 475, 725 Annotation: Subtype: Link Rect: 290, 675, 328, 686 Annotation: Subtype: Link Rect: 334, 675, 370, 686 Annotation: Subtype: Link Rect: 329, 624, 367, 635 Annotation: Subtype: Link Rect: 408, 585, 446, 596 Annotation: Subtype: Link Rect: 100, 560, 137, 570 Annotation: Subtype: Link Rect: 256, 534, 293, 544 Annotation: Subtype: Link Rect: 100, 508, 137, 519 Annotation: Subtype: Link Rect: 143, 508, 179, 519 Annotation: Subtype: Link Rect: 114, 470, 151, 480 Annotation: Subtype: Link Rect: 158, 470, 194, 480 Annotation: Subtype: Link Rect: 361, 443, 398, 454 Annotation: Subtype: Link Rect: 404, 443, 440, 454 Annotation: Subtype: Link Rect: 132, 405, 169, 415 Annotation: Subtype: Link Rect: 176, 405, 212, 415 Annotation: Subtype: Link Rect: 384, 378, 422, 389 Annotation: Subtype: Link Rect: 428, 378, 464, 389 Annotation: Subtype: Link Rect: 314, 353, 352, 364 Annotation: Subtype: Link Rect: 370, 327, 407, 338 Annotation: Subtype: Link Rect: 100, 302, 137, 312 Annotation: Subtype: Link Rect: 203, 275, 241, 286 Annotation: Subtype: Link Rect: 418, 249, 455, 260 Annotation: Subtype: Link Rect: 350, 211, 387, 222 Annotation: Subtype: Link Rect: 214, 186, 252, 196 Annotation: Subtype: Link Rect: 177, 147, 214, 157 Annotation: Subtype: Link Rect: 220, 147, 256, 157 Annotation: Subtype: Link Rect: 136, 108, 174, 118 Annotation: Subtype: Link Rect: 180, 108, 216, 118 Annotation: Subtype: Link Rect: 372, 82, 410, 92 Page: Sequence: 23 Annotations: Annotation: Subtype: Link Rect: 340, 728, 378, 738 Annotation: Subtype: Link Rect: 431, 701, 468, 712 Annotation: Subtype: Link Rect: 159, 651, 196, 661 Annotation: Subtype: Link Rect: 136, 612, 174, 622 Annotation: Subtype: Link Rect: 306, 585, 344, 596 Annotation: Subtype: Link Rect: 76, 543, 166, 574 Annotation: Subtype: Link Rect: 234, 537, 407, 548 Checksum: fa0c3872 Type: CRC32 Checksum: 3c67c8f71a83bc77b99880466da6f58d Type: MD5 Checksum: 6f82292ddf8d8ee1215bbb4045ff883d805a3cb7 Type: SHA-1 Checksum: fd6ecf702eec25365c03cbf1ac86a6acf3fb944cf4de86e0ab87f4aa9f3da7e1 Type: SHA-256