Nav1.7
































































SCN9A
PDB 1byy EBI.jpg







Available structures
PDB Ortholog search: PDBe RCSB



Identifiers
Aliases
SCN9A, ETHA, FEB3B, GEFSP7, HSAN2D, NE-NA, NENA, Nav1.7, PN1, SFNP, sodium voltage-gated channel alpha subunit 9
External IDs MGI: 107636 HomoloGene: 2237 GeneCards: SCN9A


















Gene location (Human)
Chromosome 2 (human)
Chr. Chromosome 2 (human)[1]

Chromosome 2 (human)
Genomic location for SCN9A

Genomic location for SCN9A

Band 2q24.3 Start 166,195,185 bp[1]
End 166,376,001 bp[1]

































Orthologs
Species Human Mouse
Entrez


6335


20274
Ensembl


ENSG00000169432


ENSMUSG00000075316
UniProt


Q15858


Q62205
RefSeq (mRNA)


NM_002977
NM_001365536


NM_001290674
NM_001290675
NM_018852
RefSeq (protein)


NP_002968
NP_001352465


NP_001277603
NP_001277604
Location (UCSC) Chr 2: 166.2 – 166.38 Mb Chr 2: 66.48 – 66.63 Mb

PubMed search		 [3] [4]
Wikidata



View/Edit Human View/Edit Mouse

Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene.[5][6][7] It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at dorsal root ganglion (DRG) and trigeminal ganglion and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.[8][9]




Contents






  • 1 Function


  • 2 Clinical significance


    • 2.1 Animal studies


    • 2.2 Primary erythromelalgia


    • 2.3 Paroxysmal extreme pain disorder


    • 2.4 Congenital insensitivity to pain


    • 2.5 Clinical analgesics


    • 2.6 Itch


    • 2.7 Future prospects




  • 3 References


  • 4 Further reading


  • 5 External links





Function


Nav1.7 is a voltage-gated sodium channel and plays a critical role in the generation and conduction of action potentials and is thus important for electrical signaling by most excitable cells. Nav1.7 is present at the endings of pain-sensing nerves, the nociceptors, close to the region where the impulse is initiated. Stimulation of the nociceptor nerve endings produces "generator potentials", which are small changes in the voltage across the neuronal membranes. The Nav1.7 channel amplifies these membrane depolarizations, and when the membrane potential difference reaches a specific threshold, the neuron fires. In sensory neurons, multiple voltage-dependent sodium currents can be differentiated by their voltage dependence and by sensitivity to the voltage-gated sodium-channel blocker tetrodotoxin. The Nav1.7 channel produces a rapidly activating and inactivating current which is sensitive to the level of tetrodotoxin.[10] Nav1.7 is important in the early phases of neuronal electrogenesis. Nav1.7 activity consists of a slow transition of the channel into an inactive state when it is depolarized, even to a minor degree.[11] This property allows these channels to remain available for activation with even small or slowly developing depolarizations. Stimulation of the nociceptor nerve endings produces "generator potentials", small changes in the voltage across the neuronal membranes.[11] This brings neurons to a voltage that stimulate Nav1.8, which has a more depolarized activation threshold that produces most of the transmembrane current responsible for the depolarizing phase of action potentials.[12]



Clinical significance



Animal studies


The critical role of Nav1.7 in nociception and pain was originally shown using Cre-Lox recombination tissue specific knockout mice. These transgenic mice specifically lack Nav1.7 in Nav1.8 positive nociceptors and showed reduced behavioural responses, specifically to acute mechanical and inflammatory pain assays. At the same time, behavioural responses to acute thermal and neuropathic pain assays remained intact.[13] However, the expression of Nav1.7 is not restricted to Nav1.8 positive DRG neurons. Further work examining the behavioural response of two other transgenic mouse strains; one lacking Nav1.7 in all DRG neurons and the other lacking Nav1.7 in all DRG neurons as well as all sympathetic neurons, has revealed distinct sets of modality specific peripheral neurons.[14] Therefore, Nav1.7 expressed in Nav1.8 positive DRG neurons is critical for normal responses to acute mechanical and inflammatory pain assays. Whilst Nav1.7 expressed in Nav1.8 negative DRG neurons is critical for normal responses to acute thermal pain assays. Finally, Nav1.7 expressed in sympathetic neurons is critical for normal behavioural responses to neuropathic pain assays.



Primary erythromelalgia


Mutation in Nav1.7 may result in primary erythromelalgia (PE), an autosomal dominant, inherited disorder which is characterized by attacks or episodes of symmetrical burning pain of the feet, lower legs, and sometimes hands, elevated skin temperature of affected areas, and reddened extremities. The mutation causes excessive channel activity which suggests that Nav1.7 sets the gain on pain signaling in humans. It was observed that a missense mutation in the SCN9A gene affected conserved residues in the pore-forming α subunit of the Nav1.7 channel. Multiple studies have found a dozen SCN9A mutations in multiple families as causing erythromelagia.[15][16] All of the observed erythromelalgia mutations that are observed are missense mutations that change important and highly conserved amino acid residues of the Nav1.7 protein. The majority of mutations that cause PE are located in cytoplasmic linkers of the Nav1.7 channel, however some mutations are present in transmembrane domains of the channel. The PE mutations cause a hyperpolarizing shift in the voltage dependence of channel activation, which allows the channel to be activated by smaller than normal depolarizations, thus enhancing the activity of Nav1.7. Moreover, the majority of the PE mutations also slow deactivation, thus keeping the channel open longer once it is activated.[17] In addition, in response to a slow, depolarizing stimulus, most mutant channels will generate a larger than normal sodium current. Each of these alterations in activation and deactivation can contribute to the hyperexcitability of pain-signaling DRG neurons expressing these mutant channels, thus causing extreme sensitivity to pain (hyperalgesia). While the expression of PE Nav1.7 mutations produces hyperexcitability in DRG neurons, studies on cultured rat in sympathetic ganglion neurons indicate that expression of these same PE mutations results in reduction of excitability of these cells. This occurs because Nav1.8 channels, which are selectively expressed in addition to Nav1.7 in DRG neurons, are not present within sympathetic ganglion neurons. Thus lack of Nav1.7 results in inactivation of the sodium channels results in reduced excitability. Thus physiological interaction of Nav1.7 and Nav1.8 can explain the reason that PE presents with pain due to hyperexcitability of nociceptors and with sympathetic dysfunction that is most likely due to hypoexcitability of sympathetic ganglion neurons.[9]
Recent studies have associated a defect in SCN9A with congenital insensitivity to pain.[18]



Paroxysmal extreme pain disorder


Paroxysmal extreme pain disorder (PEPD) is another rare, extreme pain disorder.[19][20] Like primary erythromelalgia, PEPD is similarly the result of a gain-of-function mutation in the gene encoding the Nav1.7 channel.[19][20]



Congenital insensitivity to pain


Individuals with congenital insensitivity to pain have painless injuries beginning in infancy but otherwise normal sensory responses upon examination. Patients frequently have bruises and cuts,[21] and are often only diagnosed because of limping or lack of use of a limb. Individuals have been reported to be able to walk over burning coals and to insert knives and drive spikes through their arms. It has been observed that the insensitivity to pain does not appear to be due to axonal degeneration.


A mutation that causes loss of Nav1.7 function has been detected in three consanguineous families from northern Pakistan. All mutations observed were nonsense mutation, with the majority of affected patients having a homozygous mutation in the SCN9A gene. This discovery linked loss of Nav1.7 function with the inability to experience pain. This is in contrast with the genetic basis of primary erythromelalgia in which the disorder results from gain-of-function mutations.[18]



Clinical analgesics


Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels.[22][23] Nav1.7, as well as Nav1.3, Nav1.8, and Nav1.9, are the specific channels that have been implicated in pain signaling.[22][24] Thus, the blockade of these specific channels is likely to underlie the analgesia of local anesthetics and anticonvulsants such as phenytoin.[22] In addition, inhibition of these channels is also likely responsible for the analgesic efficacy of certain tricyclic antidepressants, and of mexiletine.[25][26]



Itch


Mutations of Nav1.7 have been linked to itching (pruritus),[27][28] and genetic knockouts of Nav1.7[29] and an antibody that inhibits Nav1.7 also appear to inhibit itching.[30][31][32]



Future prospects


As the Nav1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia,[20] there has been immense interest in developing selective Nav1.7 channel blockers as potential novel analgesics.[33] Since Nav1.7 is not present in heart tissue or the central nervous system, selective blockers of Nav1.7, unlike non-selective blockers such as local anesthetics, could be safely used systemically for pain relief. Moreover, selective Nav1.7 blockers may prove to be far more effective analgesics, and with fewer undesirable effects, relative to current pharmacotherapies.[33][34][35]


A number of selective Nav1.7 (and/or Nav1.8) blockers are in clinical development, including funapide (TV-45070, XEN402), PF-05089771, DSP-2230, NKTR-171, GDC-0276, and RG7893 (GDC-0287).[36][37][38]Ralfinamide (formerly NW-1029, FCE-26742A, PNU-0154339E) is a multimodal, non-selective Nav channel blocker which is under development for the treatment of pain.[39]


Surprisingly, many potent Nav1.7 blockers have been found to be clinically effective but only relatively weak analgesics.[40] Recently, it has been elucidated that congenital loss of Navv1.7 results in a dramatic increase in the levels of endogenous enkephalins, and it was found that blocking these opioids with the opioid antagonist naloxone allowed for pain sensitivity both in Navv1.7 null mice and in a woman with a defective Navv1.7 gene and associated congenital insensitivity to pain.[40] Development of the venom-derived peptide, JNJ63955 allowed for selective inhibition of Nav1.7 only while it was in the closed state, which produced results, in mice, much more similar to knock-out models.[41][unreliable medical source] It is possible that channel blockade is maximal only when the channel is inhibited in its closed state. It appears that complete inactivation of Nav 1.7-mediated sodium efflux is necessary to upregulate enkephalin expression enough to achieve complete analgesia. Prior to the development of JNJ63955, the most potent [Nav 1.7] antagonists had failed in regards to achieving the same degree of analgesia as congenital Nav 1.7 inactivity.[40] The proposed mechanism also suggests that the analgesic effects of Nav1.7 blockers may be greatly potentiated by the co-administration of exogenous opioids or enkephalinase inhibitors.[40] Supporting this idea, a strong analgesic synergy between local anesthetics and topical opioids has already been observed in clinical research.[40]


An additional implication of the aforementioned findings is that congenital insensitivity to pain may be clinically treatable with opioid antagonists.[40]



References





  1. ^ abc GRCh38: Ensembl release 89: ENSG00000169432 - Ensembl, May 2017


  2. ^ abc GRCm38: Ensembl release 89: ENSMUSG00000075316 - Ensembl, May 2017


  3. ^ "Human PubMed Reference:"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output .citation q{quotes:"""""""'""'"}.mw-parser-output .citation .cs1-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .citation .cs1-lock-limited a,.mw-parser-output .citation .cs1-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .citation .cs1-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-ws-icon a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/4/4c/Wikisource-logo.svg/12px-Wikisource-logo.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{font-size:100%}.mw-parser-output .cs1-maint{display:none;color:#33aa33;margin-left:0.3em}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}


  4. ^ "Mouse PubMed Reference:".


  5. ^ Klugbauer N, Lacinova L, Flockerzi V, Hofmann F (March 1995). "Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells". The EMBO Journal. 14 (6): 1084–90. doi:10.1002/j.1460-2075.1995.tb07091.x. PMC 398185. PMID 7720699.


  6. ^ Plummer NW, Meisler MH (April 1999). "Evolution and diversity of mammalian sodium channel genes". Genomics. 57 (2): 323–31. doi:10.1006/geno.1998.5735. PMID 10198179.


  7. ^ Catterall WA, Goldin AL, Waxman SG (December 2005). "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels". Pharmacological Reviews. 57 (4): 397–409. doi:10.1124/pr.57.4.4. PMID 16382098.


  8. ^ Raymond CK, Castle J, Garrett-Engele P, Armour CD, Kan Z, Tsinoremas N, Johnson JM (October 2004). "Expression of alternatively spliced sodium channel alpha-subunit genes. Unique splicing patterns are observed in dorsal root ganglia". The Journal of Biological Chemistry. 279 (44): 46234–41. doi:10.1074/jbc.M406387200. PMID 15302875.


  9. ^ ab Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG (May 2006). "A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons". Proceedings of the National Academy of Sciences of the United States of America. 103 (21): 8245–50. doi:10.1073/pnas.0602813103. PMC 1472458. PMID 16702558.


  10. ^ Catterall WA (2000). "Structure and regulation of voltage-gated Ca2+ channels". Annual Review of Cell and Developmental Biology. 16: 521–55. doi:10.1146/annurev.cellbio.16.1.521. PMID 11031246.


  11. ^ ab Cummins TR, Howe JR, Waxman SG (December 1998). "Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel". The Journal of Neuroscience. 18 (23): 9607–19. doi:10.1523/JNEUROSCI.18-23-09607.1998. PMID 9822722.


  12. ^ Renganathan M, Cummins TR, Waxman SG (August 2001). "Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons". Journal of Neurophysiology. 86 (2): 629–40. doi:10.1152/jn.2001.86.2.629. PMID 11495938.


  13. ^ Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA, Dickenson AH, Wood JN (August 2004). "Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain". Proceedings of the National Academy of Sciences of the United States of America. 101 (34): 12706–11. doi:10.1073/pnas.0404915101. PMC 515119. PMID 15314237.


  14. ^ Minett MS, Nassar MA, Clark AK, Passmore G, Dickenson AH, Wang F, Malcangio M, Wood JN (April 2012). "Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons". Nature Communications. 3 (4): 791–799. doi:10.1038/ncomms1795. PMC 3337979. PMID 22531176.


  15. ^ Dib-Hajj SD, Yang Y, Black JA, Waxman SG (January 2013). "The Na(V)1.7 sodium channel: from molecule to man". Nature Reviews. Neuroscience. 14 (1): 49–62. doi:10.1038/nrn3404. PMID 23232607.


  16. ^ Tang Z, Chen Z, Tang B, Jiang H (September 2015). "Primary erythromelalgia: a review". Orphanet Journal of Rare Diseases. 10: 127. doi:10.1186/s13023-015-0347-1. PMC 4589109. PMID 26419464.


  17. ^ Drenth JP, Michiels JJ (June 1994). "Erythromelalgia and erythermalgia: diagnostic differentiation". International Journal of Dermatology. 33 (6): 393–7. doi:10.1111/j.1365-4362.1994.tb04037.x. PMID 8056469.


  18. ^ ab Golshani AE, Kamdar AA, Spence SC, Beckmann NM (August 2014). "Congenital indifference to pain: an illustrated case report and literature review". Journal of Radiology Case Reports. 8 (8): 16–23. doi:10.3941/jrcr.v8i8.2194. PMC 4242143. PMID 25426241.


  19. ^ ab Allerton C, Fox D (2013). Pain Therapeutics: Current and Future Treatment Paradigms. Royal Society of Chemistry. pp. 146–148. ISBN 978-1-84973-645-9.


  20. ^ abc Kew JN, Davies CH (2010). Ion Channels: From Structure to Function. Oxford University Press. pp. 153–154. ISBN 978-0-19-929675-0.


  21. ^ Peddareddygari LR, Oberoi K, Grewal RP (2014-09-18). "Congenital insensitivity to pain: a case report and review of the literature". Case Reports in Neurological Medicine. 2014: 141953. doi:10.1155/2014/141953. PMC 4182687. PMID 25309764.


  22. ^ abc Mashour GA, Lydic R (7 September 2011). Neuroscientific Foundations of Anesthesiology. Oxford University Press. p. 154. ISBN 978-0-19-987546-7.


  23. ^ Mohamed Chahine. Recent advances in voltage-gated sodium channels, their pharmacology and related diseases. Frontiers E-books. p. 90. ISBN 978-2-88919-128-4.


  24. ^ Lamberth C, Dinges J (9 August 2012). Bioactive Heterocyclic Compound Classes: Pharmaceuticals. John Wiley & Sons. p. 127. ISBN 978-3-527-66448-1.


  25. ^ Cairns BE (1 September 2009). Peripheral Receptor Targets for Analgesia: Novel Approaches to Pain Management. John Wiley & Sons. pp. 66–68. ISBN 978-0-470-52221-9.


  26. ^ James WD, Berger T, Elston D (12 April 2015). Andrews' Diseases of the Skin: Clinical Dermatology. Elsevier Health Sciences. pp. 810–. ISBN 978-0-323-31969-0.


  27. ^ Grazia Devigilia, Roberto Eleopraa, Tiziana Pierrob, Raffaella Lombardib, Sara Rinaldoa, Christian Lettieria, Catharina G. Faberc, Ingemar S.J. Merkiesc, d, Stephen G. Waxmane, Giuseppe Lauriab (September 2014). "Paroxysmal itch caused by gain-of-function Nav1.7 mutation". Pain.CS1 maint: Multiple names: authors list (link)


  28. ^ "An SCN9A variant, known to cause pain, is now found to cause itch" (PDF). Pain.


  29. ^ Gingras J, Smith S, Matson DJ, Johnson D, Nye K, Couture L, Feric E, Yin R, Moyer BD, Peterson ML, Rottman JB, Beiler RJ, Malmberg AB, McDonough SI (2014). "Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain". PLOS One. 9 (9): e105895. doi:10.1371/journal.pone.0105895. PMC 4154897. PMID 25188265.


  30. ^ Lee JH, Park CK, Chen G, Han Q, Xie RG, Liu T, Ji RR, Lee SY (June 2014). "A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief". Cell. 157 (6): 1393–404. doi:10.1016/j.cell.2014.03.064. PMC 4098795. PMID 24856969.


  31. ^ Martz L. "Nav-i-gating antibodies for pain". SciBX.


  32. ^ Sheila Yong (May 22, 2014). "One Molecule To Block Both Pain And Itch".


  33. ^ ab Altman RB, Flockhart D, Goldstein DB (23 January 2012). Principles of Pharmacogenetics and Pharmacogenomics. Cambridge University Press. p. 224. ISBN 978-1-107-37747-9.


  34. ^ Waxman SG (December 2006). "Neurobiology: a channel sets the gain on pain". Nature. 444 (7121): 831–2. doi:10.1038/444831a. PMID 17167466.


  35. ^ Dib-Hajj SD, Cummins TR, Black JA, Waxman SG (November 2007). "From genes to pain: Na v 1.7 and human pain disorders". Trends in Neurosciences. 30 (11): 555–63. doi:10.1016/j.tins.2007.08.004. PMID 17950472.


  36. ^ Bagal SK, Chapman ML, Marron BE, Prime R, Storer RI, Swain NA (August 2014). "Recent progress in sodium channel modulators for pain". Bioorganic & Medicinal Chemistry Letters. 24 (16): 3690–9. doi:10.1016/j.bmcl.2014.06.038. PMID 25060923.


  37. ^ Martz L (2014). "Nav-i-gating antibodies for pain". Science-Business EXchange. 7 (23): 662. doi:10.1038/scibx.2014.662. ISSN 1945-3477.


  38. ^ McMahon S, Koltzenburg M, Tracey I, Turk DC (1 March 2013). Wall & Melzack's Textbook of Pain: Expert Consult - Online. Elsevier Health Sciences. p. 508. ISBN 978-0-7020-5374-0.


  39. ^ Simpson DM, McArthur JC, Dworkin RH (21 June 2012). Neuropathic Pain: Mechanisms, Diagnosis and Treatment. Oxford University Press. pp. 40–. ISBN 978-0-19-539470-2.


  40. ^ abcdef Minett MS, Pereira V, Sikandar S, Matsuyama A, Lolignier S, Kanellopoulos AH, Mancini F, Iannetti GD, Bogdanov YD, Santana-Varela S, Millet Q, Baskozos G, MacAllister R, Cox JJ, Zhao J, Wood JN (December 2015). "Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7". Nature Communications. 6: 8967. doi:10.1038/ncomms9967. PMC 4686868. PMID 26634308.


  41. ^ Flinspach M, Xu Q, Piekarz AD, Fellows R, Hagan R, Gibbs A, Liu Y, Neff RA, Freedman J, Eckert WA, Zhou M, Bonesteel R, Pennington MW, Eddinger KA, Yaksh TL, Hunter M, Swanson RV, Wickenden AD (January 2017). "Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor". Scientific Reports. 7: 39662. doi:10.1038/srep39662. PMC 5206724. PMID 28045073.




Further reading


.mw-parser-output .refbegin{font-size:90%;margin-bottom:0.5em}.mw-parser-output .refbegin-hanging-indents>ul{list-style-type:none;margin-left:0}.mw-parser-output .refbegin-hanging-indents>ul>li,.mw-parser-output .refbegin-hanging-indents>dl>dd{margin-left:0;padding-left:3.2em;text-indent:-3.2em;list-style:none}.mw-parser-output .refbegin-100{font-size:100%}


  • Emery EC, Luiz AP, Wood JN (August 2016). "Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief". Expert Opinion on Therapeutic Targets. 20 (8): 975–83. doi:10.1517/14728222.2016.1162295. PMC 4950419. PMID 26941184.



External links




  • SCN9A+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)

  • GeneReviews/NCBI/NIH/UW entry on SCN9A-Related Inherited Erythromelalgia









Comments

Post a Comment

Popular posts from this blog

Information security

Image
This article is part of a series on Information security Related security categories Internet security Cyberwarfare Computer security Mobile security Network security Threats Computer crime Vulnerability Eavesdropping Malware Spyware Ransomware Trojans Viruses Worms Rootkits Bootkits Keyloggers Screen scrapers Exploits Backdoors Logic bombs Payloads Denial of service Defenses Computer access control Application security Antivirus software Secure coding Secure by default Secure by design Secure operating systems Authentication Multi-factor authentication Authorization Data-centric security Encryption Firewall Intrusion detection system Mobile secure gateway Runtime application self-protection (RASP) v t e Information security , sometimes shortened to InfoSec , is the practice of preventing unauthorized access, use, disclosure, disruption, modification, inspection, recording or destruction of information. Th...
Read more

Lambak Kiri

Image
For Lambak Kiri public housing area, see Lambak Kiri Landless Indigenous Citizens' Housing Scheme. Village in Brunei-Muara, Brunei Lambak Kiri Village Location in Brunei Coordinates: 4°59′26″N 114°57′04″E  /  4.990472°N 114.951114°E  / 4.990472; 114.951114 Coordinates: 4°59′26″N 114°57′04″E  /  4.990472°N 114.951114°E  / 4.990472; 114.951114 Country Brunei District Brunei-Muara Mukim Berakas A Government  • Village head Hamdani Omar Postcode BB1214 Lambak Kiri is a populated place in Brunei-Muara District, Brunei. It is officially a village subdivision under Berakas A, a mukim in the district. Lambak Kiri may also refer to the greater area which includes the Lambak Kiri public housing area of the Landless Indigenous Citizens' Housing Scheme (Malay: Skim Tanah Kurnia Rakyat Jati ), although the latter is a separate subdivision. Contents 1 Name 2 Administration 3 See also 4 References Name ...
Read more

章鱼与海女图

Image
本条目 可参照英語維基百科相應條目来扩充 。 （2014/5/25） 若您熟悉来源语言和主题，请协助参考外语维基扩充条目。请勿直接提交机械翻译，也不要翻译不可靠、低品质内容。依版权协议，译文需在编辑摘要注明来源，或于讨论页顶部标记 {{Translated page}} 标签。 本条目 需要擴充。 （2013年8月15日） 请協助改善这篇條目，更進一步的信息可能會在討論頁或扩充请求中找到。请在擴充條目後將此模板移除。 《 章鱼与海女 》（日语： 蛸と海女 ／ たことあま   Tako to ama ）是一幅由日本畫家葛饰北斋创作的浮世绘，出自1814年（文化4年）出版的艳本《喜能会之故真通》（日语： 喜能会之故真通 ／ きのえのこまつ   Kinoe no Komatsu ）。畫中有兩隻章鱼以觸手攻擊一名採珠的海女，並進行擬似戀獸癖的交媾行為。作品尺寸为6½" × 8¾" （16.51 cm × 22.23 cm）。 [1] 在此之前的类似作品还有北尾重政的艳本《謡曲色番組》及勝川春潮的艳本《艳本千夜多女志》等，有被北斋作为参考的可能性。 《章鱼与海女图》有不同英文翻译，一般称The Dream of the Fisherman's Wife，又作Girl Diver and Octopi、Diver and Two Octopi，Richard Douglas Lane称其为 Girl Diver and Octopi [2] ，Mathi Forrer 称其为 Pearl Diver and Two Octopi [3] ，Danielle Talerico 称其为 Diver and Two Octopi 。 [4] 目录 1 作品介绍 1.1 画中对话 1.2 解释 2 评价 3 影响 3.1 模仿作品 4 另见 5 参考来源 6 外部連結 作品介绍 画中对话 原文 译文 大蛸： いつぞハいつぞハとねらいすましてゐたかいがあつて、けふといふけふ、とうとうとらまへたア。てもむつくりとしたいいぼぼだ。いもよりハなをこうぶつだ。サアサア、すつてすつてすいつくして...
Read more