1 Blood ........................................................ 1
1.1 Blood Functions ......................................... 2
1.2 Plasma .................................................. 3
1.3 Plasma Constituents ..................................... 5
1.3.1 Electrolytes ..................................... 5
1.3.2 Glucids .......................................... 6
1.3.3 Plasma Proteins .................................. 7
1.3.4 Plasma Lipids and Lipoproteins ................... 8
1.3.5 Blood Gas ....................................... 15
1.4 Blood Disorders ........................................ 15
1.4.1 Blood Cell Disorders ............................ 16
1.5 Blood Therapies ........................................ 17
1.5.1 Blood Substitutes ............................... 17
1.5.2 Plasmapheresis .................................. 18
2 Hematopoiesis ............................................... 19
2.1 Hematopoietic Stem Cells ............................... 21
2.1.1 LSK Hematopoietic Stem Cells .................... 23
2.1.2 Hemangioblast ................................... 24
2.2 Biological Models of Hematopoiesis ..................... 24
2.2.1 Arborescence Models of Hematopoiesis ............ 25
2.2.2 Lymphoid Progenitors ............................ 25
2.3 Stem Cell Niches ....................................... 27
2.3.1 Types of В one-Marrow Niches .................... 27
2.3.2 Cells of Bone Marrow Niches ..................... 28
2.3.3 Crosstalk between Niche-Resident Cells .......... 29
2.4 Regulation of Hematopoiesis ............................ 31
2.4.1 Transcription Factors of Hematopoiesis .......... 32
2.4.2 Hormones, Growth Factors, and Morphogens ........ 42
2.4.3 MicroRNAs ....................................... 49
2.4.4 Other Regulators ................................ 50
2.5 Mastocyte Formation .................................... 50
2.6 Hematopoietic Stem Cells in Angiogenesis ............... 51
3 Blood Cells ................................................. 53
3.1 Immunophenotyping of Leukocytes ........................ 53
3.2 Vasculature as an Immunity Compartment ................. 54
3.3 Proliferation and Mobilization of Blood Cells .......... 55
3.3.1 Cytokines ....................................... 55
3.3.2 Chemokines ...................................... 57
3.4 Scaffold Proteins in Immunocytes ....................... 57
3.5 Red Blood Capsules ..................................... 60
3.5.1 Formation, Maturation, and Clearance ............ 60
3.5.2 Shape ........................................... 62
3.5.3 Plasma Membrane ................................. 63
3.5.4 Influence of Oxygen Content in the Local
Environment ..................................... 66
3.5.5 Oxygen Sensor ................................... 67
3.5.6 Blood Groups of the RBC Plasma Membrane ......... 67
3.5.7 Hemoglobin Solution in Erythrocytic Capsule ..... 71
3.5.8 Iron Acquisition and Storage .................... 81
3.6 Platelets .............................................. 83
3.6.1 Platelet Cytoskeleton ........................... 84
3.6.2 Translational Machinery ......................... 84
3.6.3 Platelet Granules ............................... 84
3.6.4 Platelet Activation ............................. 86
3.6.5 Non-Genomic Function of Transcription Factors ... 87
3.6.6 Other Regulators of the PI atelet Functi on ..... 88
3.6.7 Inflammatory Platelet ........................... 89
3.7 Granulocytes ........................................... 89
3.7.1 Basophils ....................................... 89
3.7.2 Eosinophils ..................................... 92
3.7.3 Neutrophils ..................................... 93
3.8 Mastocytes ............................................. 97
3.8.1 Mastocyte Origin and Maturation ................. 98
3.8.2 Mastocyte Functions ............................. 99
3.8.3 Mastocyte Production and Types ................. 100
3.9 Lymphocytes ........................................... 106
3.9.1 Selection between CD4 and CD8 Coreceptors ...... 106
3.9.2 Sensing of Endo- and Exogenous Molecules ....... 107
3.9.3 Resistance to Oxidizing Environment ............ 108
3.9.4 PIP3 and IP4 Signals in Lymphocytes ............ 109
3.9.5 Immunological Memory ........................... 109
3.10 T Lymphocytes ......................................... 111
3.10.1 T-Lymphocyte Development ....................... 111
3.10.2 Antigen Presentation ........................... 113
3.10.3 T-Lymphocyte Maintenance ....................... 116
3.10.4 T-Lymphocyte Subpopulations .................... 117
3.11 Innate Lymphocytes .................................... 143
3.11.1 Lymphoid Tissue-Inducer Cells .................. 145
3.11.2 ILC17 Cells .................................... 146
3.11.3 NKR + LTi-like Cells - ILC22 Cells ............. 147
3.11.4 Nuocytes ....................................... 147
3.11.5 Natural Killer Cells ........................... 148
3.12 В Lymphocytes ......................................... 154
3.12.1 B-Lymphocyte Subpopulations .................... 155
3.12.2 B-Lymphocyte Maturation Stages ................. 155
3.12.3 Antibodies and B-Cell Receptors ................ 156
3.12.4 B-Cell Activation and Signaling ................ 159
3.12.5 Main Regulators of B-Cell Proliferation
in Germinal Centers ............................ 160
3.12.6 В Cell - T Cell Interactions ................... 160
3.12.7 Plasmocytes .................................... 160
3.13 Monocytes and Macrophages ............................. 161
3.13.1 Monocytes ...................................... 162
3.13.2 Macrophages .................................... 165
3.14 Dendritic Cells ....................................... 170
3.14.1 Myeloid and Plasmacytoid Dendritic Cells ....... 172
3.14.2 Thymic Dendritic Cells ......................... 173
3.15 Myeloid-Derived Suppressor Cells ...................... 174
4 Lymph Drainage ............................................. 177
4.1 Lymphatics ............................................ 179
4.2 Lymphoid Tissues ...................................... 179
4.2.1 Thymus ......................................... 180
4.2.2 Spleen ......................................... 180
4.2.3 Other Secondary Lymphoid Tissues ............... 181
4.2.4 Tertiary Lymphoid Tissue - Mucosa-Associated
Lymphoid Tissues ............................... 182
4.2.5 Lymph Nodes .................................... 185
4.3 Lymph ................................................. 187
5 Cardiomyocytes ............................................. 189
5.1 External Organization of Cardiomyocytes ............... 189
5.2 Internal Organization of Cardiomyocytes ............... 190
5.2.1 Sarcolemma ..................................... 190
5.2.2 Sarcoplasmic Reticulum ......................... 194
5.2.3 Mitochondria ................................... 196
5.2.4 Nuclear GPCRs .................................. 204
5.3 Sarcomere ............................................. 206
5.3.1 Myofibrils ..................................... 208
5.3.2 Myosin Thick Filaments ......................... 209
5.3.3 Actin Thin Filaments ........................... 210
5.3.4 Z Disc, a Stretch-Sensing Structure ............ 216
5.3.5 Main Sarcomeric Constituents ................... 216
5.4 Cardiac Adenylate Cyclases and the с AMP Pathway ...... 226
5.5 Calcium Signals ....................................... 227
5.5.1 Calcium-Dependent Ion Carriers ................. 227
5.5.2 Inositol Polyphosphate Messengers -
Phosphoinositide Sources ....................... 228
5.5.3 Mitochondrial Calcium Uniporter ................ 229
5.5.4 Mechanotransduction ............................ 229
5.5.5 Sodium-Calcium Exchangers and Sodium-
Potassium Pumps ................................ 230
5.5.6 Normal and Impaired Calcium Signaling .......... 230
5.6 Endocrine Function .................................... 232
5.6.1 Natriuretic Peptides ........................... 233
5.6.2 Hemojuvelin-Hepcidin Regulation ................ 240
5.7 Energy Supply and Reserve ............................. 240
5.8 Cardiomyocyte Adaptive Growth ......................... 242
5.8.1 Mechanotransduction in CMC Hypertrophy ......... 243
5.8.2 Chemical Regulators of CMC Hypertrophy ......... 244
5.9 Cardiomyocyte Orientation ............................. 252
5.10 Ion Carriers .......................................... 254
5.10.1 Voltage-Gated Sodium Channels .................. 256
5.10.2 Sodium-Calcium Exchangers ...................... 257
5.10.3 Myocardial Calcium Channels .................... 258
5.10.4 Myocardial Potassium Channels .................. 262
5.10.5 Calcium-Activated Chloride Channels ............ 268
6 Heart Wall ................................................. 271
6.1 Cardiogenesis and Cardiac Remodeling .................. 272
6.1.1 First and Second Heart Fields .................. 274
6.1.2 Heart Growth Patterns .......................... 276
6.1.3 Epithelial-Mesenchymal Transition .............. 276
6.1.4 Vasculo-and Angiogenesis ....................... 277
6.1.5 Neurogenesis ................................... 278
6.1.6 Valvulogenesis ................................. 279
6.1.7 Postnatal Growth ............................... 281
6.1.8 Regulators ..................................... 282
6.1.9 Cardiac Progenitor Cells and Precursors ........ 294
6.2 Wall Structure ........................................ 299
6.2.1 Cardiofibroblasts .............................. 300
6.2.2 Telocytes ...................................... 303
6.2.3 Epicardial Adipose Tissue and Adipokines ....... 303
6.2.4 Heart Valves ................................... 306
6.2.5 Conduction Paths of the Depolarization Wave .... 308
6.3 Cardiac Regulation of Energy Homeostasis .............. 313
6.4 Main Ion Currents ..................................... 314
6.4.1 Pacemaker Cells ................................ 315
6.4.2 Ventriculomyocytes ............................. 322
6.5 Action Potential ...................................... 324
6.5.1 Sinoatrial Node Action Potential ............... 325
6.5.2 Ventricular Action Potential ................... 328
6.5.3 Electrophysiological Myocyte Types ............. 329
6.5.4 Repolarization ................................. 331
6.5.5 Electrophysiology and Contraction Kinetics ..... 331
6.6 Excitation-Contraction Coupling ....................... 332
6.6.1 Intercellular and Cell-Matrix Adhesions ........ 334
6.6.2 Troponins and Tropomyosin ...................... 334
6.6.3 Calcium Ion and Its Partners ................... 334
6.6.4 Zinc Ion and Its Partners ...................... 337
6.6.5 Cyclic Adenosine Monophosphate ................. 338
6.6.6 S100 Protein ................................... 339
6.6.7 Nervous Influences ............................. 339
6.6.8 Cell Excitability Adjustment ................... 342
6.6.9 Electromechanical Modeling ..................... 343
6.7 Nervous Inputs ........................................ 344
7 Vessel Wall ................................................ 349
7.1 Physical Environment .................................. 349
7.2 Vasculature Development ............................... 350
7.3 Wall Structure ........................................ 351
7.3.1 Large Vessels .................................. 353
7.3.2 Small Vessels .................................. 359
7.4 Blood-Brain Barrier ................................... 361
7.4.1 BBB Restricted Permeability .................... 362
7.4.2 Neurovascular Units ............................ 364
7.4.3 Functional Hyperemia ........................... 366
7.4.4 Drug Delivery .................................. 367
7.4.5 BBB Formation .................................. 368
7.5 Other Cerebral Epithelial Barriers - Choroid Plexi .... 368
7.6 Perivascular Nerves ................................... 369
7.7 Pericytes ............................................. 369
7.8 Nervous Inputs ........................................ 371
7.9 ATP Signaling in Blood Vessel Walls ................... 373
7.9.1 Extracellular ATP Processing ................... 374
7.9.2 Nucleotide Receptors ........................... 375
7.9.3 ATP Release .................................... 375
7.10 Vascular Oxygen Sensing ............................... 378
7.11 Wall Adaptability ..................................... 379
8 Smooth Myocytes ............................................ 381
8.1 Markers of Smooth Myocytes ............................ 382
8.1.1 Actin .......................................... 383
8.1.2 Tropomyosin .................................... 383
8.1.3 Myosin ......................................... 383
8.1.4 Calmodulin ..................................... 384
8.1.5 Caldesmon ...................................... 386
8.1.6 Calponin ....................................... 386
8.2 Glycocalyx ............................................ 386
8.3 Intrinsic Regulators of Smooth Myocyte Tone ........... 387
8.3.1 Caldesmon and Calmodulin ....................... 387
8.3.2 Arachidonic Acid ............................... 388
8.3.3 G-Protein-Coupled Receptors .................... 388
8.3.4 Guanylate Cyclases, Nitric Oxide, and
Natriuretic Peptides ........................... 388
8.3.5 Inositol Trisphosphate Receptors and Calcium
Release ........................................ 389
8.4 Airway Smooth Myocytes ................................ 393
8.4.1 Mechanical Loading-Induced Cytoskeleton
Remodeling ..................................... 393
8.4.2 Contractile and Proliferative Phenotype ........ 393
8.4.3 Calcium Influx ................................. 393
8.4.4 Airway Smooth Myocyte Products ................. 394
8.4.5 Hyperresponsiveness and Hypersensitivity ....... 402
8.4.6 Deep Inspiration as Bronchodilation Inducer .... 402
8.5 Vascular Smooth Myocytes .............................. 405
8.5.1 Vascular Smooth Myocyte Subtypes ............... 407
8.5.2 Mesangial and Juxtaglomerular Cells ............ 407
8.5.3 Vascular Smooth Myocyte Phenotypes ............. 408
8.5.4 Vascular Smooth Myocyte Uptake ................. 417
8.5.5 Vascular Smooth Myocyte Activity ............... 417
8.5.6 Vascular Smooth Myocyte Production ............. 423
8.5.7 Vascular Smooth Myocyte Migration .............. 425
8.5.8 Vasomotor Tone ................................. 429
9 Vascular Endothelium ....................................... 453
9.1 Endothelial Cell ...................................... 454
9.1.1 Glycocalyx ..................................... 456
9.1.2 Endothelial Cell Adhesions ..................... 457
9.1.3 Vascular Permeability .......................... 467
9.2 Endothelium Types ..................................... 468
9.2.1 High Endothelial Venules ....................... 468
9.2.2 Lymphatic Endothelium .......................... 469
9.2.3 Endothelial Fenestrae .......................... 469
9.3 Endothelial Progenitor Cells .......................... 469
9.3.1 Hemangioblast .................................. 470
9.3.2 Endothelial Progenitor Cell - Circulating
Angiogenic Cell ................................ 472
9.4 Endothelial Cell Migration ............................ 474
9.5 Molecular Expression in the Vascular Endothelium ...... 474
9.5.1 Caveolae ....................................... 477
9.5.2 Nuclear Receptors .............................. 479
9.5.3 Examples of Endothelial Receptors .............. 479
9.5.4 Ion Carriers of Endothelial Cell ............... 485
9.5.5 Hormones and Vasoactive Substances ............. 492
9.5.6 Adhesion Molecules ............................. 498
9.5.7 Miscellaneous .................................. 499
9.5.8 Vessel Wall Homeostasis ........................ 499
9.5.9 Growth Factors and Regulators of Growth
Factor Signaling ............................... 504
9.5.10 MicroRNAs ...................................... 507
9.5.11 Angiogenesis Guidance Molecules ................ 510
9.5.12 Blood Group Antigens ........................... 512
9.6 Transendothelial Mass Transfer ........................ 512
9.6.1 Flow-Dependent Transendothelial Transport ...... 513
9.6.2 Transport Mechanisms ........................... 514
9.6.3 Endothelial Permeability and Vascular
Compartments ................................... 522
9.6.4 Endothelial Permeability Regulation ............ 522
9.7 Extravasation ......................................... 535
9.7.1 Flowing Cell Adhesion to Endothelium ........... 536
9.7.2 Cell Movement over the Wetted Endothelial
Surface ........................................ 537
9.7.3 Integrin-Based Cell Adhesion ................... 538
9.7.4 Intracellular Signaling in Endothelial Cells ... 538
9.7.5 Intracellular Signaling in Leukocytes .......... 539
9.7.6 Extravasation Steps ............................ 540
9.7.7 Extravasation Modes ............................ 543
9.7.8 Migration across Pericyte Sheath and Basement
Membrane ....................................... 544
9.7.9 Migration through Subendothelial Layer
and Interstitium ............................... 545
9.7.10 Regulation of Inflammation ..................... 546
9.8 Hemostasis ............................................ 548
9.8.1 Blood Coagulation .............................. 553
9.8.2 Fibrinolysis ................................... 561
9.8.3 Embolus Extravasation .......................... 562
9.8.4 Thrombosis ..................................... 562
9.8.5 Mathematical Modeling and Numerical
Simulations .................................... 564
9.9 Effects of High-Density Lipoproteins on Endothelium ... 565
9.10 Chemical and Mechanical Regulation of the Vasomotor
Tone .................................................. 566
9.10.1 Transducers of Mechanical Stresses ............. 570
9.10.2 Flow Chambers .................................. 575
9.10.3 Nitric Oxide ................................... 578
9.10.4 Endothelin ..................................... 582
9.10.5 Calcium Signaling in Vasomotor Tone
Regulation ..................................... 583
9.10.6 Other Mechanotransduction Effects .............. 585
9.10.7 Other Aspects of the Regulation of the
Vasomotor Tone ................................. 588
9.10.8 Hypoxic Vasoconstriction of Pulmonary
Arteries ....................................... 594
9.10.9 Hypoxic Vasodilation of Cerebral Arterioles .... 594
9.10.10 Vasomotor Tone during Pregnancy ............... 596
9.10.11 Modeling of Mechanotransduction in Arteries ... 596
10 Vasculature Growth ......................................... 605
10.1 Vasculogenesis ........................................ 606
10.2 Angiogenesis .......................................... 606
10.2.1 Stem, Progenitor, and Precursor Cells
in Angiogenesis and Neovascularization ......... 607
10.2.2 Involved Factors in Angiogenesis ............... 609
10.2.3 Endothelial Sprouting: Tip and Stalk Cells ..... 609
10.2.4 Other Modes of Vessel Formation and
Remodeling ..................................... 613
10.2.5 Lumenogenesis .................................. 614
10.3 Arteriogenesis ........................................ 615
10.4 Vasculature Compartments .............................. 616
10.4.1 Lumen Size and Vessel Architecture ............. 616
10.4.2 Cost Functions ................................. 616
10.4.3 Arteriovenous Differentiation .................. 616
10.5 Extracellular Matrix in Vessel Formation .............. 618
10.5.1 Growth Factors ................................. 618
10.5.2 Protein Fragments and Peptidases of the
Extracellular Matrix ........................... 620
10.5.3 Cell Adhesion Molecules ........................ 622
10.5.4 Fibulins ....................................... 624
10.5.5 Thrombospondins ................................ 625
10.5.6 Matrix Metallopeptidases ....................... 625
10.5.7 Transglutaminase and Carboxypeptidases ......... 625
10.5.8 Collagen Prolyl 4-Hydroxylase .................. 626
10.6 Mediators of Vascular Formation ....................... 626
10.6.1 Navigation Signals ............................. 626
10.6.2 Transcriptional Regulators ..................... 630
10.6.3 MicroRNAs ...................................... 634
10.6.4 Morphogens ..................................... 636
10.6.5 Growth Factors ................................. 639
10.6.6 Hormones and Cytokines ......................... 647
10.6.7 G-Protein-Coupled Receptors .................... 653
10.6.8 Regulators of Small GTPases .................... 654
10.6.9 Phosphoinositide 3-Kinase and Phospholipase-C .. 654
10.6.10 Protein Kinase-B .............................. 655
10.6.11 Cyclooxygenases and Prostaglandins ............ 656
10.6.12 Tissue Factor ................................. 657
10.6.13 Tissue Kallikrein and Kininogen ............... 657
10.6.14 Gasotransmitters Hydrogen Sulfide and Nitric
Oxide ......................................... 658
10.6.15 Oxidative Stress and Inflammation ............. 660
10.6.16 Mechanical Signals ............................ 661
10.7 Angiogenesis-Targeted Therapies ....................... 662
10.7.1 Angiogenesis Promotion ......................... 662
10.7.2 Angiogenesis Inhibition ........................ 664
10.8 Lymphangiogenesis ..................................... 668
10.8.1 Transcription Factors in Lymphangiogenesis ..... 669
10.8.2 Growth Factors and Guidance Molecules .......... 670
10.8.3 Other Mediators ................................ 671
10.9 Modeling of Angiogenesis .............................. 671
11 Tissue Development, Repair, and Remodeling ................. 675
11.1 Organogenesis ......................................... 676
11.1.1 Ecto-, Endo-, and Mesoderm ..................... 676
11.1.2 Precursor Cells ................................ 678
11.1.3 Organogenesis, Vascularization, and
Innervation .................................... 679
11.1.4 Regulation of Organogenesis .................... 680
11.2 Cell Differentiation .................................. 682
11.3 Branching Morphogenesis ............................... 682
11.3.1 Airway Morphogenesis ........................... 683
11.3.2 Airway Morphogenesis Mediators ................. 684
11.3.3 Mechanical Basis of Branching .................. 688
11.3.4 Molecular Basis of Branching ................... 688
11.4 Therapeutic Repair .................................... 692
11.4.1 Stem Cells and Regenerative Therapy ............ 692
11.4.2 Gene Therapy ................................... 697
11.4.3 Tissue Engineering ............................. 699
11.5 Inflammation .......................................... 703
11.5.1 Extravasation .................................. 703
11.5.2 Molecular Basis of Extravasation ............... 704
11.5.3 Crossing of the Vascular Basement Membrane ..... 713
11.5.4 Interstitial Migration of Leukocytes ........... 713
11.5.5 Molecular Mechanisms of Leukocyte Chemotaxis ... 713
11.5.6 Inflammatory Mediators ......................... 715
11.5.7 Angiogenesis and Inflammation .................. 728
11.5.8 Inflammatory Diseases .......................... 730
11.6 Healing ............................................... 731
11.6.1 Plasma Enzymatic Systems ....................... 732
11.6.2 Involved Cells ................................. 732
11.6.3 Myofibroblasts ................................. 733
11.6.4 Healing Phases ................................. 735
11.6.5 Modeling of Healing ............................ 737
11.7 Respiratory Epithelium Repair ......................... 739
11.8 Vascular Tissue Remodeling ............................ 740
11.8.1 Myocardium Remodeling .......................... 741
11.8.2 Vessel Wall Remodeling ......................... 742
11.9 Growth Modeling ....................................... 745
12 Airway Surface Liquid and Respiratory Mucus ................ 749
12.1 Double-Layered Airway Surface Fluid ................... 751
12.1.1 Control of the Quantity and Composition
of the Airway Surface Fluid ................... 752
12.2 Mucociliary Clearance ................................. 754
12.2.1 Factors of the Mucociliary Clearance ........... 755
12.2.2 Cough Clearance ................................ 755
12.2.3 Mucociliary Clearance and Infection ............ 756
12.2.4 Alterations in Mucociliary Clearance ........... 756
12.3 Mucus Delivery ........................................ 758
12.3.1 Secretory Cells ................................ 758
12.3.2 Mucus Release .................................. 766
12.3.3 Regulation of Mucus Secretion .................. 767
12.4 Mucus Composition ..................................... 769
12.4.1 Mucin .......................................... 770
12.4.2 Other Proteic Constituents of Mucus ............ 772
12.4.3 Lipids ......................................... 773
12.4.4 Surfactant ..................................... 773
12.4.5 Minerals ....................................... 773
12.5 Mucus Properties ...................................... 774
12.5.1 Mucus Permeability ............................. 774
12.5.2 Mucus Contact Properties ....................... 775
12.5.3 Mucus Rheology ................................. 775
12.6 Mucus Motility ........................................ 778
12.6.1 Respiratory Cilium ............................. 778
12.6.2 Cilium Beats ................................... 780
12.6.3 Ciliogenesis ................................... 785
12.7 Mucus Transport Modeling .............................. 786
12.7.1 Governing Equations ................................. 787
13 Surfactant ................................................. 789
13.1 Surface Tension ....................................... 789
13.2 Alveolar Surfactant ................................... 794
13.2.1 Formation of the Alveolar Surface Film ......... 794
13.2.2 Alveolar Liquid Film Homeostasis ............... 795
13.2.3 Secretion and Role of Alveolar Surfactant ...... 796
13.3 Surfactant Composition ................................ 797
13.3.1 Surfactant Proteins ............................ 797
13.3.2 Surfactant Lipids .............................. 799
13.3.3 Calcium ........................................ 800
13.4 Immune Function of Surfactant ......................... 800
13.5 Governing Equations and Surfactant Transport
Modeling .............................................. 800
13.5.1 Interfacial Tension and Marangoni Stress ....... 801
13.5.2 Dimensionless Governing Parameters ............. 801
13.5.3 Surfactant and Marangoni Flows ................. 802
14 Conclusion ................................................. 805
References .................................................... 813
Notation Rules: Aliases and Symbols ........................... 903
List of Currently Used Prefixes and Suffixes .................. 909
List of Aliases ............................................... 913
Complementary Lists of Notations .............................. 943
Index ......................................................... 949
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