Molecular and Cellular Signaling

Contents......Page 9
Series Preface......Page 5
Preface......Page 6
Guide to Acronyms......Page 23
1.1 Prokaryotes and Eukaryotes......Page 33
1.2 The Cytoskeleton and Extracellular Matrix......Page 34
1.3 Core Cellular Functions in Organelles......Page 35
1.4 Metabolic Processes in Mitochondria and Chloroplasts......Page 36
1.5 Cellular DNA to Chromatin......Page 37
1.6 Protein Activities in the Endoplasmic Reticulum and Golgi Apparatus......Page 38
1.7 Digestion and Recycling of Macromolecules......Page 40
1.8 Genomes of Bacteria Reveal Importance of Signaling......Page 41
1.9 Organization and Signaling of Eukaryotic Cell......Page 42
1.10 Fixed Infrastructure and the Control Layer......Page 44
1.11 Eukaryotic Gene and Protein Regulation......Page 45
1.12 Signaling Malfunction Central to Human Disease......Page 47
1.13 Organization of Text......Page 48
2. The Control Layer......Page 52
2.1 Eukaryotic Chromosomes Are Built from Nucleosomes......Page 53
2.2 The Highly Organized Interphase Nucleus......Page 54
2.3 Covalent Bonds Define the Primary Structure of a Protein......Page 57
2.4 Hydrogen Bonds Shape the Secondary Structure......Page 58
2.6 Arrangement of Protein Secondary Structure Elements and Chain Topology......Page 60
2.7 Tertiary Structure of a Protein: Motifs and Domains......Page 61
2.8 Quaternary Structure: The Arrangement of Subunits......Page 63
2.9 Many Signaling Proteins Undergo Covalent Modifications......Page 64
2.10 Anchors Enable Proteins to Attach to Membranes......Page 65
2.12 Proteolytic Processing Is Widely Used in Signaling......Page 67
2.13 Reversible Addition and Removal of Phosphoryl Groups......Page 68
2.14 Reversible Addition and Removal of Methyl and Acetyl Groups......Page 69
2.15 Reversible Addition and Removal of SUMO Groups......Page 70
2.16 Post-Translational Modifications to Histones......Page 71
3. Exploring Protein Structure and Function......Page 75
3.1 Interaction of Electromagnetic Radiation with Matter......Page 76
3.3 Protein Structure via X-Ray Crystallography......Page 79
3.5 Determining Protein Structure Through NMR......Page 83
3.6 Intrinsic Magnetic Dipole Moment of Protons and Neutrons......Page 86
3.7 Using Protein Fluorescence to Probe Control Layer......Page 87
3.8 Exploring Signaling with FRET......Page 88
3.9 Exploring Protein Structure with Circular Dichroism......Page 90
3.11 A Genetic Method for Detecting Protein Interactions......Page 91
3.12 DNA and Oligonucleotide Arrays Provide Information on Genes......Page 92
3.13 Gel Electrophoresis of Proteins......Page 93
3.14 Mass Spectroscopy of Proteins......Page 94
4.1 Amino Acids Vary in Size and Shape......Page 100
4.2 Amino Acids Behavior in Aqueous Environments......Page 101
4.4 Forces that Stabilize Proteins......Page 103
4.5 Atomic Radii of Macromolecular Forces......Page 104
4.6 Osmophobic Forces Stabilize Stressed Cells......Page 105
4.7 Protein Interfaces Aid Intra- and Intermolecular Communication......Page 106
4.8 Interfaces Utilize Shape and Electrostatic Complementarity......Page 107
4.10 Motion Models of Covalently Bonded Atoms......Page 108
4.11 Modeling van der Waals Forces......Page 110
4.12 Molecular Dynamics in the Study of System Evolution......Page 112
4.13 Importance of Water Molecules in Cellular Function......Page 113
4.14 Essential Nature of Protein Dynamics......Page 114
5. Protein Folding and Binding......Page 117
5.1 The First Law of Thermodynamics: Energy Is Conserved......Page 118
5.2 Heat Flows from a Hotter to a Cooler Body......Page 119
5.3 Direction of Heat Flow: Second Law of Thermodynamics......Page 120
5.4 Order-Creating Processes Occur Spontaneously as Gibbs Free Energy Decreases......Page 121
5.5 Spontaneous Folding of New Proteins......Page 122
5.6 The Folding Process: An Energy Landscape Picture......Page 124
5.7 Misfolded Proteins Can Cause Disease......Page 126
5.8 Protein Problems and Alzheimer\'s Disease......Page 127
5.9 Amyloid Buildup in Neurological Disorders......Page 128
5.10 Molecular Chaperones Assist in Protein Folding in the Crowded Cell......Page 129
5.11 Role of Chaperonins in Protein Folding......Page 130
5.12 Hsp 90 Chaperones Help Maintain Signal Transduction Pathways......Page 131
5.13 Proteins: Dynamic, Flexible, and Ready to Change......Page 132
6. Stress and Pheromone Responses in Yeast......Page 138
6.1 How Signaling Begins......Page 139
6.2 Signaling Complexes Form in Response to Receptor-Ligand Binding......Page 140
6.3 Role of Protein Kinases, Phosphatases, and GTPases......Page 142
6.4 Role of Proteolytic Enzymes......Page 143
6.5 End Points Are Contact Points to Fixed Infrastructure......Page 144
6.6 Transcription Factors Combine to Alter Genes......Page 145
6.7 Protein Kinases Are Key Signal Transducers......Page 146
6.8 Kinases Often Require Second Messenger Costimulation......Page 148
6.9 Flanking Residues Direct Phosphorylation of Target Residues......Page 149
6.11 Protein Phosphatases Are Prominent Components of Signaling Pathways......Page 150
6.12 Scaffold and Anchor Protein Role in Signaling and Specificity......Page 151
6.14 Pheromone Response Pathway Is Activated by Pheromones......Page 152
6.15 Osmotic Stresses Activate Glycerol Response Pathway......Page 155
6.16 Yeasts Have a General Stress Response......Page 156
6.17 Target of Rapamycin (TOR) Adjusts Protein Synthesis......Page 158
6.18 TOR Adjusts Gene Transcription......Page 160
6.19 Signaling Proteins Move by Diffusion......Page 161
7. Two-Component Signaling Systems......Page 166
7.1 Prokaryotic Signaling Pathways......Page 167
7.2 Catalytic Action by Histidine Kinases......Page 168
7.3 The Catalytic Activity of HK Occurs at the Active Site......Page 170
7.4 The GHKL Superfamily......Page 171
7.5 Activation of Response Regulators by Phosphorylation......Page 172
7.6 Response Regulators Are Switches Thrown at Transcriptional Control Points......Page 173
7.7 Structure and Domain Organization of Bacterial Receptors......Page 174
7.8 Bacterial Receptors Form Signaling Clusters......Page 175
7.9 Bacteria with High Sensitivity and Mobility......Page 176
7.10 Feedback Loop in the Chemotactic Pathway......Page 177
7.11 How Plants Sense and Respond to Hormones......Page 179
7.13 Role of Phytochromes in Plant Cell Growth......Page 181
7.14 Cryptochromes Help Regulate Circadian Rhythms......Page 183
8. Organization of Signal Complexes by Lipids, Calcium, and Cyclic AMP......Page 187
8.1 Composition of Biological Membranes......Page 188
8.2 Microdomains and Caveolae in Membranes......Page 189
8.4 Generation of Lipid Second Messengers from PIP[sub(2)]......Page 191
8.5 Regulation of Cellular Processes by PI3K......Page 193
8.6 PIPs Regulate Lipid Signaling......Page 194
8.7 Role of Lipid-Binding Domains......Page 195
8.8 Role of Intracellular Calcium Level Elevations......Page 196
8.9 Role of Calmodulin in Signaling......Page 197
8.10 Adenylyl Cyclases and Phosphodiesterases Produce and Regulate cAMP Second Messengers......Page 198
8.11 Second Messengers Activate Certain Serine/Threonine Kinases......Page 199
8.12 Lipids and Upstream Kinases Activate PKB......Page 200
8.13 PKB Supplies a Signal Necessary for Cell Survival......Page 202
8.14 Phospholipids and Ca[sup(2+)] Activate Protein Kinase C......Page 203
8.15 Anchoring Proteins Help Localize PKA and PKC Near Substrates......Page 204
8.16 PKC Regulates Response of Cardiac Cells to Oxygen Deprivation......Page 205
8.17 cAMP Activates PKA, Which Regulates Ion Channel Activities......Page 206
8.18 PKs Facilitate the Transfer of Phosphoryl Groups from ATPs to Substrates......Page 208
9. Signaling by Cells of the Immune System......Page 213
9.1 Leukocytes Mediate Immune Responses......Page 214
9.2 Leukocytes Signal One Another Using Cytokines......Page 216
9.3 APC and Naïve T Cell Signals Guide Differentiation into Helper T Cells......Page 218
9.4 Five Families of Cytokines and Cytokine Receptors......Page 219
9.5 Role of NF-κB/Rel in Adaptive Immune Responses......Page 220
9.7 Role of TRAF and DD Adapters......Page 222
9.8 Toll/IL-1R Pathway Mediates Innate Immune Responses......Page 224
9.9 TNF Family Mediates Homeostasis, Death, and Survival......Page 225
9.10 Role of Hematopoietin and Related Receptors......Page 226
9.11 Role of Human Growth Hormone Cytokine......Page 228
9.12 Signal-Transducing Jaks and STATs......Page 229
9.13 Interferon System: First Line of Host Defense in Mammals Against Virus Attacks......Page 231
9.14 Chemokines Provide Navigational Cues for Leukocytes......Page 232
9.15 B and T Cell Receptors Recognize Antigens......Page 233
9.16 MHCs Present Antigens on the Cell Surface......Page 234
9.17 Antigen-Recognizing Receptors Form Signaling Complexes with Coreceptors......Page 235
9.18 Costimulatory Signals Between APCs and T Cells......Page 237
9.19 Role of Lymphocyte-Signaling Molecules......Page 238
9.20 Kinetic Proofreading and Serial Triggering of TCRs......Page 239
10.1 Cell Adhesion Receptors: Long Highly Modular Glycoproteins......Page 247
10.2 Integrins as Bidirectional Signaling Receptors......Page 249
10.3 Role of Leukocyte-Specific Integrin......Page 250
10.4 Most Integrins Bind to Proteins Belonging to the ECM......Page 251
10.5 Cadherins Are Present in Most Cells of the Body......Page 252
10.6 IgCAMs Mediate Cell–Cell and Cell–ECM Adhesion......Page 254
10.7 Selectins Are CAMs Involved in Leukocyte Motility......Page 255
10.8 Leukocytes Roll, Adhere, and Crawl to Reach the Site of an Infection......Page 256
10.9 Bonds Form and Break During Leukocyte Rolling......Page 257
10.10 Bond Dissociation of Rolling Leukocyte as Seen in Microscopy......Page 258
10.11 Slip and Catch Bonds Between Selectins and Their Carbohydrate Ligands......Page 259
10.12 Development in Central Nervous System......Page 260
10.13 Diffusible, Anchored, and Membrane-Bound Glycoproteins in Neurite Outgrowth......Page 261
10.14 Growth Cone Navigation Mechanisms......Page 262
10.15 Molecular Marking by Concentration Gradients of Netrins and Slits......Page 263
10.17 Ephrins and Their Eph Receptors Mediate Contact-Dependent Repulsion......Page 265
11. Signaling in the Endocrine System......Page 272
11.1 Five Modes of Cell-to-Cell Signaling......Page 273
11.2 Role of Growth Factors in Angiogenesis......Page 274
11.3 Role of EGF Family in Wound Healing......Page 275
11.4 Neurotrophins Control Neuron Growth, Differentiation, and Survival......Page 276
11.5 Role of Receptor Tyrosine Kinases in Signal Transduction......Page 277
11.6 Phosphoprotein Recognition Modules Utilized Widely in Signaling Pathways......Page 279
11.8 Protein–Protein Interaction Domains Utilized Widely in Signaling Pathways......Page 281
11.9 Non-RTKs Central in Metazoan Signaling Processes and Appear in Many Pathways......Page 283
11.10 Src Is a Representative NRTK......Page 284
11.11 Roles of Focal Adhesion Kinase Family of NRTKs......Page 286
11.12 GTPases Are Essential Regulators of Cellular Functions......Page 287
11.13 Signaling by Ras GTPases from Plasma Membrane and Golgi......Page 288
11.14 GTPases Cycle Between GTP- and GDP-Bound States......Page 289
11.15 Role of Rho, Rac, and Cdc42, and Their Isoforms......Page 291
11.16 Ran Family Coordinates Traffic In and Out of the Nucleus......Page 292
11.17 Rab and ARF Families Mediate the Transport of Cargo......Page 293
12. Signaling in the Endocrine and Nervous Systems Through GPCRs......Page 299
12.1 GPCRs Classification Criteria......Page 300
12.2 Study of Rhodopsin GPCR with Cryoelectron Microscopy and X-Ray Crystallography......Page 302
12.3 Subunits of Heterotrimeric G Proteins......Page 303
12.4 The Four Families of G[sub(α)] Subunits......Page 304
12.5 Adenylyl Cyclases and Phosphodiesterases Key to Second Messenger Signaling......Page 305
12.6 Desensitization Strategy of G Proteins to Maintain Responsiveness to Environment......Page 306
12.7 GPCRs Are Internalized, and Then Recycled or Degraded......Page 308
12.8 Hormone-Sending and Receiving Glands......Page 309
12.9 Functions of Signaling Molecules......Page 312
12.10 Neuromodulators Influence Emotions, Cognition, Pain, and Feeling Well......Page 313
12.11 Ill Effects of Improper Dopamine Levels......Page 315
12.13 GPCRs\' Role in the Somatosensory System Responsible for Sense of Touch and Nociception......Page 316
12.14 Substances that Regulate Pain and Fever Responses......Page 317
12.15 Composition of Rhodopsin Photoreceptor......Page 319
12.17 GPCRs Transduce Signals Conveyed by Odorants......Page 321
12.18 GPCRs and Ion Channels Respond to Tastants......Page 323
13. Cell Fate and Polarity......Page 328
13.1 Notch Signaling Mediates Cell Fate Decision......Page 329
13.2 How Cell Fate Decisions Are Mediated......Page 330
13.3 Proteolytic Processing of Key Signaling Elements......Page 331
13.4 Three Components of TGF-β Signaling......Page 334
13.5 Smad Proteins Convey TGF-β Signals into the Nucleus......Page 336
13.6 Multiple Wnt Signaling Pathways Guide Embryonic Development......Page 337
13.8 Hedgehog Signaling Role During Development......Page 340
13.9 Gli Receives Hh Signals......Page 341
13.10 Stages of Embryonic Development Use Morphogens......Page 343
13.11 Gene Family Hierarchy of Cell Fate Determinants in Drosophila......Page 344
13.12 Egg Development in D. Melanogaster......Page 345
13.13 Gap Genes Help Partition the Body into Bands......Page 346
13.14 Pair-Rule Genes Partition the Body into Segments......Page 347
13.15 Segment Polarity Genes Guide Parasegment Development......Page 348
13.16 Hox Genes Guide Patterning in Axially Symmetric Animals......Page 349
14. Cancer......Page 353
14.1 Several Critical Mutations Generate a Transformed Cell......Page 354
14.2 Ras Switch Sticks to \"On\" Under Certain Mutations......Page 356
14.4 Overexpressed GFRs Spontaneously Dimerize in Many Cancers......Page 358
14.5 GFRs and Adhesion Molecules Cooperate to Promote Tumor Growth......Page 359
14.6 Role of Mutated Forms of Proteins in Cancer Development......Page 360
14.7 Translocated and Fused Genes Are Present in Leukemias......Page 361
14.8 Repair of DNA Damage......Page 362
14.9 Double-Strand-Break Repair Machinery......Page 364
14.10 How Breast Cancer (BRCA) Proteins Interact with DNA......Page 366
14.11 PI3K Superfamily Members that Recognize Double-Strand Breaks......Page 367
14.12 Checkpoints Regulate Transition Events in a Network......Page 368
14.14 pRb Regulates Cell Cycle in Response to Mitogenic Signals......Page 369
14.15 p53 Halts Cell Cycle While DNA Repairs Are Made......Page 371
14.16 p53 and pRb Controllers Central to Metazoan Cancer Prevention Program......Page 372
14.17 p53 Structure Supports Its Role as a Central Controller......Page 374
14.18 Telomerase Production in Cancer Cells......Page 376
15. Apoptosis......Page 380
15.1 Caspases and Bcl-2 Proteins Are Key Mediators of Apoptosis......Page 381
15.2 Caspases Are Proteolytic Enzymes Synthesized as Inactive Zymogens......Page 382
15.3 Caspases Are Initiators and Executioners of Apoptosis Programs......Page 383
15.4 There Are Three Kinds of Bcl-2 Proteins......Page 384
15.5 How Caspases Are Activated......Page 386
15.6 Cell-to-Cell Signals Stimulate Formation of the DISC......Page 387
15.7 Death Signals Are Conveyed by the Caspase 8 Pathway......Page 388
15.8 How Pro- and Antiapoptotic Signals Are Relayed......Page 389
15.9 Bcl-2 Proteins Regulate Mitochondrial Membrane Permeability......Page 390
15.10 Mitochondria Release Cytochrome c in Response to Oxidative Stresses......Page 392
15.11 Mitochondria Release Apoptosis-Promoting Agents......Page 393
15.12 Role of Apoptosome in (Mitochondrial Pathway to) Apoptosis......Page 394
15.13 Inhibitors of Apoptosis Proteins Regulate Caspase Activity......Page 395
15.15 Feedback Loops Coordinate Actions at Various Control Points......Page 396
15.16 Cells Can Produce Several Different Kinds of Calcium Signals......Page 397
15.17 Excessive [Ca[sup(2+)]] in Mitochondria Can Trigger Apoptosis......Page 398
15.18 p53 Promotes Cell Death in Response to Irreparable DNA Damage......Page 399
15.19 Anti-Cancer Drugs Target the Cell\'s Apoptosis Machinery......Page 400
16. Gene Regulation in Eukaryotes......Page 405
16.1 Organization of the Gene Regulatory Region......Page 406
16.2 How Promoters Regulate Genes......Page 407
16.3 TFs Bind DNA Through Their DNA-Binding Domains......Page 409
16.4 Transcriptional Activation Domains Initiate Transcription......Page 412
16.6 Composition and Structure of the Basal Transcription Machinery......Page 413
16.7 RNAP II Is Core Module of the Transcription Machinery......Page 414
16.8 Regulation by Chromatin-Modifying Enzymes......Page 415
16.9 Multiprotein Complex Use of Energy of ATP Hydrolysis......Page 417
16.10 Protein Complexes Act as Interfaces Between TFs and RNAP II......Page 418
16.11 Alternative Splicing to Generate Multiple Proteins......Page 419
16.12 Pre-Messenger RNA Molecules Contain Splice Sites......Page 420
16.13 Small Nuclear RNAs (snRNAs)......Page 421
16.14 How Exon Splices Are Determined......Page 423
16.15 Translation Initiation Factors Regulate Start of Translation......Page 424
16.16 eIF2 Interfaces Upstream Regulatory Signals and the Ribosomal Machinery......Page 426
16.17 Critical Control Points for Protein Synthesis......Page 427
17. Cell Regulation in Bacteria......Page 431
17.2 Transcription Is Initiated by RNAP Holoenzymes......Page 432
17.4 Bacteria Utilize Sigma Factors to Make Major Changes in Gene Expression......Page 434
17.5 Mechanism of Bacterial Transcription Factors......Page 436
17.6 Many TFs Function as Response Regulators......Page 437
17.7 Organization of Protein-Encoding Regions and Their Regulatory Sequences......Page 438
17.8 The Lac Operon Helps Control Metabolism in E. coli......Page 439
17.9 Flagellar Motors Are Erected in Several Stages......Page 441
17.10 Under Starvation Conditions, B. subtilis Undergoes Sporulation......Page 442
17.11 Cell-Cycle Progression and Differentiation in C. crescentus......Page 444
17.13 Bacteria Organize into Communities When Nutrient Conditions Are Favorable......Page 446
17.14 Quorum Sensing Plays a Key Role in Establishing a Colony......Page 448
17.16 Horizontal Gene Transfer (HGT)......Page 450
17.17 Pathogenic Species Possess Virulence Cassettes......Page 451
17.18 Bacterial Death Modules......Page 453
17.19 Myxobacteria Exhibit Two Distinct Forms of Social Behavior......Page 454
17.20 Structure Formation by Heterocystous Cyanobacteria......Page 455
17.21 Rhizobia Communicate and Form Symbiotic Associations with Legumes......Page 456
18. Regulation by Viruses......Page 461
18.2 Viruses Enter and Exit the Nucleus in Several Ways......Page 462
18.3 Ways that Viruses Exit a Cell......Page 463
18.4 Viruses Produce a Variety of Disorders in Humans......Page 464
18.5 Virus–Host Interactions Underlie Virus Survival and Proliferation......Page 465
18.6 Multilayered Defenses Are Balanced by Multilayered Attacks......Page 466
18.8 Hepatitis C Virus Disables Host Cell\'s Interferon System......Page 467
18.9 Human T Lymphotropic Virus Type 1 Can Cause Cancer......Page 469
18.10 DNA and RNA Viruses that Can Cause Cancer......Page 470
18.11 HIV Is a Retrovirus......Page 472
18.12 Role of gp120 Envelope Protein in HIV......Page 473
18.13 Early-Acting tat, rev, and nef Regulatory Genes......Page 474
18.14 Late-Acting vpr, vif, vpu, and vpx Regulatory Genes......Page 476
18.15 Bacteriophages\' Two Lifestyles: Lytic and Lysogenic......Page 477
18.16 Deciding Between Lytic and Lysogenic Lifestyles......Page 478
18.17 Encoding of Shiga Toxin in E. coli......Page 479
19. Ion Channels......Page 484
19.1 How Membrane Potentials Arise......Page 485
19.2 Membrane and Action Potentials Have Regenerative Properties......Page 487
19.3 Hodgkin–Huxley Equations Describe How Action Potentials Arise......Page 489
19.4 Ion Channels Have Gates that Open and Close......Page 491
19.5 Families of Ion Channels Expressed in Plasma Membrane of Neurons......Page 493
19.6 Assembly of Ion Channels......Page 495
19.8 Gates and Filters in Potassium Channels......Page 497
19.9 Voltage-Gated Chloride Channels Form a Double-Barreled Pore......Page 498
19.10 Nicotinic Acetylcholine Receptors Are Ligand-Gated Ion Channels......Page 499
19.11 Operation of Glutamate Receptor Ion Channels......Page 502
20.1 Heartbeat Is Generated by Pacemaker Cells......Page 506
20.2 HCN Channels\' Role in Pacemaker Activities......Page 508
20.4 Role of Low Voltage-Activated Calcium Channels......Page 511
20.5 Neuromodulators Modify the Activities of Voltage-Gated Ion Channels......Page 513
20.6 Gap Junctions Formed by Connexins Mediate Rapid Signaling Between Cells......Page 514
20.7 Synchronization of Neural Firing......Page 516
20.9 Epileptic Seizures and Abnormal Brain Rhythms......Page 517
20.10 Swimming and Digestive Rhythms in Lower Vertebrates......Page 518
20.11 CPGs Have a Number of Common Features......Page 521
20.12 Neural Circuits Are Connected to Other Circuits and Form Systems......Page 523
20.13 A Variety of Neuromodulators Regulate Operation of the Crustacean STG......Page 524
20.14 Motor Systems Adapt to Their Environment and Learn......Page 525
21. Learning and Memory......Page 530
21.1 Architecture of Brain Neurons by Function......Page 531
21.2 Protein Complexes\' Structural and Signaling Bridges Across Synaptic Cleft......Page 533
21.3 The Presynaptic Terminal and the Secretion of Signaling Molecules......Page 534
21.4 PSD Region Is Highly Enriched in Signaling Molecules......Page 537
21.5 The Several Different Forms of Learning and Memory......Page 539
21.6 Signal Integration in Learning and Memory Formation......Page 540
21.7 Hippocampal LTP Is an Experimental Model of Learning and Memory......Page 542
21.8 Initiation and Consolidation Phases of LTP......Page 543
21.9 CREB Is the Control Point at the Terminus of the Learning Pathway......Page 544
21.10 Synapses Respond to Use by Strengthening and Weakening......Page 545
21.11 Neurons Must Maintain Synaptic Homeostasis......Page 547
21.13 Areas of the Brain Relating to Drug Addiction......Page 548
21.14 Drug-Reward Circuits Mediate Addictive Responses......Page 550
21.15 Drug Addiction May Be an Aberrant Form of Synaptic Plasticity......Page 551
21.16 In Reward-Seeking Behavior, the Organism Predicts Future Events......Page 552
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