General Information of This Target
Target ID
BTDT00157
Target Name
Potassium voltage-gated channel subfamily D member 2 (Kcnd2)
Target Bioclass
Transporter and channel
Uniprot ID
Q63881
3D Structure
Download
2D Sequence
3D Structure
Source
Predict by Alphafold2
?
Alphafold Parameters: msa_mode: mmseqs2_uniref_env model_type: auto num_recycles: auto
Gene Name
Kcnd2
Gene ID
65180
Synonym
RK5; Shal1; Voltage-gated potassium channel subunit Kv4.2
Sequence
MAAGVAAWLPFARAAAIGWMPVASGPMPAPPRQERKRTQDALIVLNVSGTRFQTWQDTLE
RYPDTLLGSSERDFFYHPETQQYFFDRDPDIFRHILNFYRTGKLHYPRHECISAYDEELA
FFGLIPEIIGDCCYEEYKDRRRENAERLQDDADTDNTGESALPTMTARQRVWRAFENPHT
STMALVFYYVTGFFIAVSVIANVVETVPCGSSPGHIKELPCGERYAVAFFCLDTACVMIF
TVEYLLRLAAAPSRYRFVRSVMSIIDVVAILPYYIGLVMTDNEDVSGAFVTLRVFRVFRI
FKFSRHSQGLRILGYTLKSCASELGFLLFSLTMAIIIFATVMFYAEKGSSASKFTSIPAA
FWYTIVTMTTLGYGDMVPKTIAGKIFGSICSLSGVLVIALPVPVIVSNFSRIYHQNQRAD
KRRAQKKARLARIRAAKSGSANAYMQSKRNGLLSNQLQSSEDEPAFVSKSGSSFETQHHH
LLHCLEKTTNHEFVDEQVFEESCMEVATVNRPSSHSPSLSSQQGVTSTCCSRRHKKSFRI
PNANVSGSHRGSVQELSTIQIRCVERTPLSNSRSSLNAKMEECVKLNCEQPYVTTAIISI
PTPPVTTPEGDDRPESPEYSGGNIVRVSAL

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Family
the potassium channel family
Function
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in rodent heart. Mediates the major part of the dendritic A-type current I(SA) in brain neurons. This current is activated at membrane potentials that are below the threshold for action potentials. It regulates neuronal excitability, prolongs the latency before the first spike in a series of action potentials, regulates the frequency of repetitive action potential firing, shortens the duration of action potentials and regulates the back-propagation of action potentials from the neuronal cell body to the dendrites. Contributes to the regulation of the circadian rhythm of action potential firing in suprachiasmatic nucleus neurons, which regulates the circadian rhythm of locomotor activity. Functions downstream of the metabotropic glutamate receptor GRM5 and plays a role in neuronal excitability and in nociception mediated by activation of GRM5. Mediates the transient outward current I(to) in rodent heart left ventricle apex cells, but not in human heart, where this current is mediated by another family member. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCND2 and KCND3; channel properties depend on the type of pore-forming alpha subunits that are part of the channel. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. Interaction with specific isoforms of the regulatory subunits KCNIP1, KCNIP2, KCNIP3 or KCNIP4 strongly increases expression at the cell surface and thereby increases channel activity; it modulates the kinetics of channel activation and inactivation, shifts the threshold for channel activation to more negative voltage values, shifts the threshold for inactivation to less negative voltages and accelerates recovery after inactivation. Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity.

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Taxonomy ID
10116
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Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Rodentia
Family: Muridae
Genus: Rattus
Species: Rattus norvegicus
Toxin Information Related to This Target
                           Toxin Name Activity Data Type Activity Data Reference
 Toxin Info    Defensin-like protein 1 Inhibition rate . [1]
 Toxin Info    Crotamine Inhibition rate . [2]
 Toxin Info    Kappa-actitoxin-Bcs3a Inhibition rate . [3]
 Toxin Info    Kappa-actitoxin-Bcs3b Inhibition rate . [3]
 Toxin Info    Kunitz-type serine protease inhibitor homolog alpha-dendrotoxin Inhibition rate . [4]
 Toxin Info    Potassium channel toxin alpha-KTx 1.17 Inhibition rate . [5]
 Toxin Info    Toxin PhcrTx2 Inhibition rate . [6]
 Toxin Info    Kunitz-type serine protease inhibitor homolog dendrotoxin I Inhibition rate . [4]
 Toxin Info    Potassium channel toxin alpha-KTx 1.15 Inhibition rate . [7]
 Toxin Info    Potassium channel toxin alpha-KTx 1.16 Inhibition rate . [5]
 Toxin Info    Potassium channel toxin alpha-KTx 8.8 Inhibition rate . [8]
 Toxin Info    Potassium channel toxin epsilon-KTx 1.2 Inhibition rate . [9]
 Toxin Info    Potassium channel toxin kappa-KTx 2.5 Inhibition rate . [10]
 Toxin Info    Kappa-actitoxin-Bcs4a Inhibition rate . [11]
 Toxin Info    Potassium channel toxin AbeTx1 Inhibition rate . [12]
 Toxin Info    Potassium channel toxin AbeTx1 Inhibition rate . [12]
 Toxin Info    U-actitoxin-Oulsp1 Inhibition rate . [13]
 Toxin Info    U-actitoxin-Oulsp1 Inhibition rate . [14]
 Toxin Info    Mu-theraphotoxin-Pspp1 Inhibition rate . [15]
 Toxin Info    Kappa-actitoxin-Ate1a Inhibition rate . [16]
 Toxin Info    APETx2 Inhibition rate . [17- 26]
 Toxin Info    Potassium channel toxin alpha-KTx 21.1 Inhibition rate . [27]
 Toxin Info    Potassium channel toxin alpha-KTx 21.1 Inhibition rate . [27- 31]
 Toxin Info    KappaPI-actitoxin-Ael3a Inhibition rate . [32], [33]
 Toxin Info    Pi-stichotoxin-Hcr5b Inhibition rate
5 %
[34]
 Toxin Info    BmK86-P1 Inhibition rate
11 %
[35]
 Toxin Info    Potassium channel toxin epsilon-KTx 1.2 Inhibition rate
20 %
[9- 37]
 Toxin Info    Potassium channel toxin epsilon-KTx 1.1 Inhibition rate
25 %
[9]
 Toxin Info    Potassium channel toxin epsilon-KTx 1.1 Inhibition rate
25 %
[9- 37]
 Toxin Info    Kappa-theraphotoxin-Ps1a IC50
5 nM
[38], [39], [40]
 Toxin Info    JZTX-V (Y1A) IC50
7 nM
[41]
 Toxin Info    JZTX-V (K12A) IC50
10 nM
[41]
 Toxin Info    JZTX-V (S11A) IC50
10 nM
[41]
 Toxin Info    Beta/kappa-theraphotoxin-Cg2a IC50
13.2 nM
[42- 47]
 Toxin Info    JZTX-V (K4A) IC50
14 nM
[41]
 Toxin Info    JZTX-V (I28A) IC50
15 nM
[41]
 Toxin Info    JZTX-V (L23A) IC50
15 nM
[41]
 Toxin Info    JZTX-V (Q3A) IC50
18 nM
[41]
 Toxin Info    JZTX-V (R13A) IC50
18 nM
[41]
 Toxin Info    JZTX-V (I29A) IC50
20 nM
[41]
 Toxin Info    JZTX-V (K27A) IC50
33 nM
[41]
 Toxin Info    Kappa-theraphotoxin-Ps1b IC50
34 nM
[38]
 Toxin Info    JZTX-V (E17A) IC50
55 nM
[41]
 Toxin Info    Kappa-sparatoxin-Hv1c IC50
67 nM
[48]
 Toxin Info    Jingzhaotoxin F7-15.33 IC50
68 nM
[43]
 Toxin Info    Kappa-theraphotoxin-Gr1a IC50
100 nM
[49- 55]
 Toxin Info    Kappa-sparatoxin-Hv1a IC50
100 nM
[48]
 Toxin Info    Kappa-sparatoxin-Hv1b IC50
100 nM
[56]
 Toxin Info    JZTX-V (K22A) IC50
125 nM
[41]
 Toxin Info    Kappa-LhTx-1 IC50
140 nM
[57]
 Toxin Info    JZTX-V (W7A) IC50
172 nM
[41]
 Toxin Info    JZTX-V (W5A) IC50
180 nM
[41]
 Toxin Info    JZTX-V (R20A) IC50
194 nM
[41]
 Toxin Info    JZTX-V (M6A) IC50
312 nM
[41]
 Toxin Info    Potassium channel toxin TsTXK-beta IC50
652 nM
[29- 62]
References
Ref 1 The antifungal plant defensin AtPDF2.3 from Arabidopsis thaliana blocks potassium channels. Sci Rep. 2016 Aug 30;6:32121. doi: 10.1038/srep32121.
Ref 2 Crotamine pharmacology revisited: novel insights based on the inhibition of KV channels. Mol Pharmacol. 2012 Jul;82(1):90-6. doi: 10.1124/mol.112.078188. Epub 2012 Apr 12.
Ref 3 Biochemical and electrophysiological characterization of two sea anemone type 1 potassium toxins from a geographically distant population of Bunodosoma caissarum. Mar Drugs. 2013 Mar 6;11(3):655-79. doi: 10.3390/md11030655.
Ref 4 Functional characterization of RK5, a voltage-gated K+ channel cloned from the rat cardiovascular system. FEBS Lett. 1991 Dec 16;295(1-3):211-3. doi: 10.1016/0014-5793(91)81420-d.
Ref 5 K(V)1.2 channel-specific blocker from Mesobuthus eupeus scorpion venom: Structural basis of selectivity. Neuropharmacology. 2018 Dec;143:228-238. doi: 10.1016/j.neuropharm.2018.09.030. Epub 2018 Sep 22.
Ref 6 PhcrTx2, a New Crab-Paralyzing Peptide Toxin from the Sea Anemone Phymanthus crucifer. Toxins (Basel). 2018 Feb 7;10(2):72. doi: 10.3390/toxins10020072.
Ref 7 Different pharmacological properties between scorpion toxin BmKcug2 and its degraded analogs highlight the diversity of K(+) channel blockers from thermally processed scorpions. Int J Biol Macromol. 2021 May 1;178:143-153. doi: 10.1016/j.ijbiomac.2021.02.155. Epub 2021 Feb 23.
Ref 8 C-Terminal residues in small potassium channel blockers OdK1 and OSK3 from scorpion venom fine-tune the selectivity. Biochim Biophys Acta Proteins Proteom. 2017 May;1865(5):465-472. doi: 10.1016/j.bbapap.2017.02.001. Epub 2017 Feb 4.
Ref 9 Structural and Functional Elucidation of Peptide Ts11 Shows Evidence of a Novel Subfamily of Scorpion Venom Toxins. Toxins (Basel). 2016 Sep 30;8(10):288. doi: 10.3390/toxins8100288.
Ref 10 The new kappa-KTx 2.5 from the scorpion Opisthacanthus cayaporum. Peptides. 2011 Jul;32(7):1509-17. doi: 10.1016/j.peptides.2011.05.017. Epub 2011 May 23.
Ref 11 BcsTx3 is a founder of a novel sea anemone toxin family of potassium channel blocker. FEBS J. 2013 Oct;280(19):4839-52. doi: 10.1111/febs.12456. Epub 2013 Aug 23.
Ref 12 AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K? Channels Activation. Mar Drugs. 2018 Oct 1;16(10):360. doi: 10.3390/md16100360.
Ref 13 Sunanda, Punnepalli, et al. "Identification, chemical synthesis, structure, and function of a new KV1 channel blocking peptide from Oulactis sp." Peptide Science 110.4 (2018): e24073.
Ref 14 Structure, folding and stability of a minimal homologue from Anemonia sulcata of the sea anemone potassium channel blocker ShK. Peptides. 2018 Jan;99:169-178. doi: 10.1016/j.peptides.2017.10.001. Epub 2017 Oct 6.
Ref 15 Chemical Synthesis, Proper Folding, Na(v) Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1. Toxins (Basel). 2019 Jun 21;11(6):367. doi: 10.3390/toxins11060367.
Ref 16 PHAB toxins: a unique family of predatory sea anemone toxins evolving via intra-gene concerted evolution defines a new peptide fold. Cell Mol Life Sci. 2018 Dec;75(24):4511-4524. doi: 10.1007/s00018-018-2897-6. Epub 2018 Aug 14.
Ref 17 A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J. 2004 Apr 7;23(7):1516-25. doi: 10.1038/sj.emboj.7600177. Epub 2004 Mar 25.
Ref 18 ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J. 2008 Nov 19;27(22):3047-55. doi: 10.1038/emboj.2008.213. Epub 2008 Oct 16.
Ref 19 Chemical synthesis and folding of APETx2, a potent and selective inhibitor of acid sensing ion channel 3. Toxicon. 2009 Jul;54(1):56-61. doi: 10.1016/j.toxicon.2009.03.014. Epub 2009 Mar 21.
Ref 20 Expression in Pichia pastoris and characterization of APETx2, a specific inhibitor of acid sensing ion channel 3. Toxicon. 2010 Dec;56(8):1388-97. doi: 10.1016/j.toxicon.2010.08.004. Epub 2010 Sep 9.
Ref 21 Inhibition of voltage-gated Na(+) currents in sensory neurones by the sea anemone toxin APETx2. Br J Pharmacol. 2012 Apr;165(7):2167-77. doi: 10.1111/j.1476-5381.2011.01674.x.
Ref 22 A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins. FASEB J. 2012 Dec;26(12):5141-51. doi: 10.1096/fj.12-218479. Epub 2012 Sep 12.
Ref 23 Cyclisation increases the stability of the sea anemone peptide APETx2 but decreases its activity at acid-sensing ion channel 3. Mar Drugs. 2012 Jul;10(7):1511-1527. doi: 10.3390/md10071511. Epub 2012 Jul 16.
Ref 24 Functional expression in Escherichia coli of the disulfide-rich sea anemone peptide APETx2, a potent blocker of acid-sensing ion channel 3. Mar Drugs. 2012 Jul;10(7):1605-1618. doi: 10.3390/md10071605. Epub 2012 Jul 23.
Ref 25 Solution structure of APETx2, a specific peptide inhibitor of ASIC3 proton-gated channels. Protein Sci. 2005 Aug;14(8):2003-10. doi: 10.1110/ps.051378905. Epub 2005 Jun 29.
Ref 26 Understanding the molecular basis of toxin promiscuity: the analgesic sea anemone peptide APETx2 interacts with acid-sensing ion channel 3 and hERG channels via overlapping pharmacophores. J Med Chem. 2014 Nov 13;57(21):9195-203. doi: 10.1021/jm501400p. Epub 2014 Nov 4.
Ref 27 Purification and characterization of Ts15, the first member of a new -KTX subfamily from the venom of the Brazilian scorpion Tityus serrulatus. Toxicon. 2011 Jul;58(1):54-61. doi: 10.1016/j.toxicon.2011.05.001. Epub 2011 May 13.
Ref 28 Proteomic endorsed transcriptomic profiles of venom glands from Tityus obscurus and T. serrulatus scorpions. PLoS One. 2018 Mar 21;13(3):e0193739. doi: 10.1371/journal.pone.0193739. eCollection 2018.
Ref 29 Novel components of Tityus serrulatus venom: A transcriptomic approach. Toxicon. 2021 Jan 15;189:91-104. doi: 10.1016/j.toxicon.2020.11.001. Epub 2020 Nov 10.
Ref 30 Moving pieces in a venomic puzzle: unveiling post-translationally modified toxins from Tityus serrulatus. J Proteome Res. 2013 Jul 5;12(7):3460-70. doi: 10.1021/pr4003068. Epub 2013 Jun 13.
Ref 31 Influence of post-starvation extraction time and prey-specific diet in Tityus serrulatus scorpion venom composition and hyaluronidase activity. Toxicon. 2014 Nov;90:326-36. doi: 10.1016/j.toxicon.2014.08.064. Epub 2014 Sep 6.
Ref 32 A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties. Biochem Pharmacol. 2011 Jul 1;82(1):81-90. doi: 10.1016/j.bcp.2011.03.023. Epub 2011 Apr 6.
Ref 33 Development of a rational nomenclature for naming peptide and protein toxins from sea anemones. Toxicon. 2012 Sep 15;60(4):539-50. doi: 10.1016/j.toxicon.2012.05.020. Epub 2012 Jun 5.
Ref 34 A Tale of Toxin Promiscuity: The Versatile Pharmacological Effects of Hcr 1b-2 Sea Anemone Peptide on Voltage-Gated Ion Channels. Mar Drugs. 2022 Feb 17;20(2):147. doi: 10.3390/md20020147.
Ref 35 BmK86-P1, a New Degradation Peptide with Desirable Thermostability and Kv1.2 Channel-Specific Activity from Traditional Chinese Scorpion Medicinal Material. Toxins (Basel). 2021 Aug 30;13(9):610. doi: 10.3390/toxins13090610.
Ref 36 Novel structural class of four disulfide-bridged peptides from Tityus serrulatus venom. Biochem Biophys Res Commun. 2003 Feb 21;301(4):1086-92. doi: 10.1016/s0006-291x(03)00082-2.
Ref 37 Tityus serrulatus scorpion venom and toxins: an overview. Protein Pept Lett. 2009;16(8):920-32. doi: 10.2174/092986609788923329.
Ref 38 Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis. Br J Pharmacol. 1999 Jan;126(1):251-63. doi: 10.1038/sj.bjp.0702283.
Ref 39 Studies examining the relationship between the chemical structure of protoxin II and its activity on voltage gated sodium channels. J Med Chem. 2014 Aug 14;57(15):6623-31. doi: 10.1021/jm500687u. Epub 2014 Jul 24.
Ref 40 Solution structure of Phrixotoxin 1, a specific peptide inhibitor of Kv4 potassium channels from the venom of the theraphosid spider Phrixotrichus auratus. Protein Sci. 2004 May;13(5):1197-208. doi: 10.1110/ps.03584304.
Ref 41 JZTX-V Targets the Voltage Sensor in Kv4.2 to Inhibit I(to) Potassium Channels in Cardiomyocytes. Front Pharmacol. 2019 Apr 16;10:357. doi: 10.3389/fphar.2019.00357. eCollection 2019.
Ref 42 Isolation and characterization of Jingzhaotoxin-V, a novel neurotoxin from the venom of the spider Chilobrachys jingzhao. Toxicon. 2007 Mar 1;49(3):388-99. doi: 10.1016/j.toxicon.2006.10.012. Epub 2006 Nov 6.
Ref 43 Proteomic and peptidomic analysis of the venom from Chinese tarantula Chilobrachys jingzhao. Proteomics. 2007 Jun;7(11):1892-907. doi: 10.1002/pmic.200600785.
Ref 44 Effects and mechanism of Chinese tarantula toxins on the Kv2.1 potassium channels. Biochem Biophys Res Commun. 2007 Jan 19;352(3):799-804. doi: 10.1016/j.bbrc.2006.11.086. Epub 2006 Nov 27.
Ref 45 Molecular diversity and evolution of cystine knot toxins of the tarantula Chilobrachys jingzhao. Cell Mol Life Sci. 2008 Aug;65(15):2431-44. doi: 10.1007/s00018-008-8135-x.
Ref 46 Molecular surface of JZTX-V (-Theraphotoxin-Cj2a) interacting with voltage-gated sodium channel subtype NaV1.4. Toxins (Basel). 2014 Jul 23;6(7):2177-93. doi: 10.3390/toxins6072177.
Ref 47 Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V. PLoS One. 2018 May 3;13(5):e0196791. doi: 10.1371/journal.pone.0196791. eCollection 2018.
Ref 48 Heteropodatoxins: peptides isolated from spider venom that block Kv4.2 potassium channels. Mol Pharmacol. 1997 Mar;51(3):491-8.
Ref 49 An inhibitor of the Kv2.1 potassium channel isolated from the venom of a Chilean tarantula. Neuron. 1995 Oct;15(4):941-9. doi: 10.1016/0896-6273(95)90184-1.
Ref 50 Hanatoxin modifies the gating of a voltage-dependent K+ channel through multiple binding sites. Neuron. 1997 Apr;18(4):665-73. doi: 10.1016/s0896-6273(00)80306-2.
Ref 51 Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels. Neuron. 1997 Apr;18(4):675-82. doi: 10.1016/s0896-6273(00)80307-4.
Ref 52 Gating modifier toxins reveal a conserved structural motif in voltage-gated Ca2+ and K+ channels. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8585-9. doi: 10.1073/pnas.95.15.8585.
Ref 53 Voltage-sensor activation with a tarantula toxin as cargo. Nature. 2005 Aug 11;436(7052):857-60. doi: 10.1038/nature03873.
Ref 54 Gating modifier peptides as probes of pancreatic beta-cell physiology. Toxicon. 2007 Feb;49(2):231-8. doi: 10.1016/j.toxicon.2006.09.012. Epub 2006 Sep 23.
Ref 55 Solution structure of hanatoxin1, a gating modifier of voltage-dependent K(+) channels: common surface features of gating modifier toxins. J Mol Biol. 2000 Mar 31;297(3):771-80. doi: 10.1006/jmbi.2000.3609.
Ref 56 Heteropoda toxin 2 is a gating modifier toxin specific for voltage-gated K+ channels of the Kv4 family. Toxicon. 2005 Mar 15;45(4):431-42. doi: 10.1016/j.toxicon.2004.11.015.
Ref 57 Variation of Two S3b Residues in K(V)4.1-4.3 Channels Underlies Their Different Modulations by Spider Toxin -LhTx-1. Front Pharmacol. 2021 Jun 10;12:692076. doi: 10.3389/fphar.2021.692076. eCollection 2021.
Ref 58 Screening of expression libraries using ELISA: identification of immunogenic proteins from Tityus bahiensis and Tityus serrulatus venom. Toxicon. 2001 May;39(5):679-85. doi: 10.1016/s0041-0101(00)00194-x.
Ref 59 Evidence for a new class of scorpion toxins active against K+ channels. FEBS Lett. 1998 Jul 24;431(3):375-80. doi: 10.1016/s0014-5793(98)00780-7.
Ref 60 Tityus serrulatus venom peptidomics: assessing venom peptide diversity. Toxicon. 2008 Oct;52(5):611-8. doi: 10.1016/j.toxicon.2008.07.010. Epub 2008 Jul 31.
Ref 61 Tityustoxin K alpha blocks voltage-gated noninactivating K+ channels and unblocks inactivating K+ channels blocked by alpha-dendrotoxin in synaptosomes. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1475-9. doi: 10.1073/pnas.91.4.1475.
Ref 62 Ts8 scorpion toxin inhibits the Kv4.2 channel and produces nociception in?vivo. Toxicon. 2016 Sep 1;119:244-52. doi: 10.1016/j.toxicon.2016.06.014. Epub 2016 Jun 23.
Ref 63 Experimental conversion of a defensin into a neurotoxin: implications for origin of toxic function. Mol Biol Evol. 2014 Mar;31(3):546-59. doi: 10.1093/molbev/msu038. Epub 2014 Jan 14.
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