1. A method comprising:
at a data storage device including a resistive random access memory (ReRAM), performing:
storing data in the ReRAM by performing a first number of write operations to a storage region of the ReRAM, the storage region tracked by a counter; and
incrementing a value of the counter a second number of times responsive to storing the data in the storage region, wherein the second number is different than the first number.
2. The method of claim 1, further comprising determining a ratio between a number of cells programmed by a first write operation of the write operations and a normalization parameter.
3. The method of claim 2, wherein the normalization parameter corresponds to a data block size of the ReRAM.
4. The method of claim 3, wherein the first write operation writes first data to the ReRAM, the first data having the data block size.
5. The method of claim 4, wherein the write operations further include a second write operation, and wherein the second write operation writes second data to the ReRAM, the second data having a data size that is less than the data block size.
6. The method of claim 5, wherein the second data corresponds to a modification of one or more values of the first data.
7. The method of claim 2, further comprising, for each of the write operations, determining a number such that a probability of the number being equal to one corresponds to the ratio.
8. The method of claim 7, wherein the value of the counter is incremented by a controller of the data storage device each time the number is equal to one.
9. The method of claim 1, wherein the value of the counter approximates a number of programerase (PE) cycles associated with the storage region of the ReRAM.
10. The method of claim 1, wherein a storage capacity of the storage region is less than a total storage capacity of the ReRAM, and wherein the second number is less than the first number.
11. The method of claim 1, wherein the ReRAM has a three-dimensional (3D) memory configuration.
12. A data storage device comprising:
a resistive random access memory (ReRAM);
a counter configured to track a storage region of the ReRAM; and
a controller, wherein the controller is coupled to the ReRAM, wherein the controller is configured to perform a first number of write operations to the storage region and to increment a value of the counter a second number of times responsive to storing data in the storage region, wherein the second number is less than the first number.
13. The data storage device of claim 12, wherein the controller is further configured to determine a ratio between a number of cells programmed by a first write operation of the write operations and a normalization parameter.
14. The data storage device of claim 13, wherein the value of the counter statistically indicates a number of programerase (PE) cycles associated with the storage region.
15. The data storage device of claim 13, wherein the normalization parameter corresponds to a data block size of the ReRAM.
16. The data storage device of claim 15, wherein the first write operation writes first data to the ReRAM, and wherein the first data has the data block size.
17. The data storage device of claim 16, wherein the write operations further include a second write operation, and wherein the second write operation writes second data to the ReRAM, the second data having a data size that is less than the data block size.
18. The data storage device of claim 13, wherein the controller includes a pseudo-random number generator (PRNG) that is configured to generate a number, for each of the write operations, such that a probability of the number being equal to one corresponds to the ratio.
19. The data storage device of claim 12, wherein the controller further includes multiple counters corresponding to multiple storage regions of the ReRAM.
20. The data storage device of claim 12, further comprising a memory die, wherein the memory die includes the ReRAM, and wherein the controller includes the counter.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A polypeptide comprising an amino acid sequence of SEQ ID NO: 6, wherein the polypeptide retains a net negative charge of 1-8.
2. The polypeptide of claim 1 wherein the polypeptide retains a net negative charge of 2-8.
3. The polypeptide of claim 1 wherein the polypeptide retains a net negative charge of 3-8.
4. The polypeptide of claim 1 wherein the polypeptide retains a net negative charge of 4-8.
5. The polypeptide of claim 1 wherein the polypeptide retains a net negative charge of 5-8.
6. The polypeptide of claim 1 wherein the polypeptide retains a net negative charge of 6-8.
7. The polypeptide of claim 1 wherein the polypeptide retains a net negative charge of 7-8.
8. The polypeptide of claim 1 wherein amino acid residue sixteen is serine.
9. The polypeptide of claim 1 wherein amino acid residue twenty-one is norleucine.
10. The polypeptide of claim 1 which comprises the amino acid sequence of SEQ ID NO: 1.
11. A composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier.
12. The polypeptide of claim 1 consisting of the sequence of SEQ ID NO: 1.
13. The polypeptide of claim 1 wherein the polypeptide is fused to a membrane-penetrating peptide.
14. The polypeptide of claim 13 wherein the membrane-penetrating peptide is selected from the group consisting of: VP-22 (SEQ ID NO: 3), (SEQ ID NO: 4), and (SEQ ID NO: 5).
15. A method of activating a CFTR protein comprising:
administering an effective amount of a polypeptide to a cell comprising a CFTR protein which forms a cAMP-regulated chloride channel, said polypeptide comprising the sequence of SEQ ID NO: 6, whereby the CFTR protein is activated.
16. The method of claim 15 wherein the polypeptide comprises the sequence of SEQ ID NO: 1.
17. The method of claim 15 wherein the effective amount of the polypeptide increases open probability of the channel formed by the CFTR by at least 25%.
18. The method of claim 15 wherein open probability of the channel formed by the CFTR increases by at least 50%.
19. The method of claim 15 wherein open probability of the channel formed by the CFTR increases by at least 75%.
20. The method of claim 15 wherein open probability of the channel formed by the CFTR increases by at least 100%.
21. The method of claim 15 wherein open probability of the channel formed by the CFTR increases by at least 125%.
22. The method of claim 15 wherein open probability of the channel formed by the CFTR increases by at least 150%.
23. The method of claim 15 wherein open probability of the channel formed by the CFTR increases by at least 175%.
24. The method of claim 15 wherein open probability of the channel formed by the CFTR increases by at least 200%.
25. The method of claim 15 wherein open probability of the channel formed by the CFTR increases by at least 300%.
26. The method of claim 15 wherein said polypeptide is administered to achieve a concentration of 0.5 to 14 M.
27. The method of claim 15 wherein said polypeptide is administered to achieve a concentration of 4-6 M.
28. The method of claim 15 wherein the CFTR protein is a mutant which reaches the cell’s plasma membrane but fails to undergo full activation in the absence of said polypeptide.
29. The method of claim 28 wherein the mutant CFTR protein is selected from the group consisting of 816CT, 741TG, 471delAGG, 363CT, 102TA, 94GT, 33GA 132CG, P5L, S10R, S13F, 1851GT, 1854AT, 18613CG, W19C, G27E, R31C, R31L, 232del18, S42F, D44G, A46D, 279AG, I50T, S50P, S50Y, 2963insT, 2961GT, 2961GC, 2962TC, 2969AT, 29612TC, 29728insA, 2973CA, 2973CT, 2972AG, 29710TG, 29712insA, E56K, W57G, W57R, D58N, D58G, E60K, E60L, N66S, P67L, K68E, K68N, A72T, A72D, R74W, R74Q, R75L, W79R, G85E, G85V, F87L, L88S, Y89C, L90S, G91R, 4051GA, 4053AC, 4054AG, 40610CG, 4066TC, 4063TC, 4062AG, 4062AC, 4061GC, 4061GA, 4061GT, E92K, A96E, Q98R, P99L, I105N, S108F, Y109N, Y109C, D110H, D110Y, D110E, P111A, P111L, delta E115, E116Q, E116K, R117C, R117H, R117P, R117L, A120T, I125T, G126D, L137R, L137H, L138ins, H139R, P140S, P140L, A141D, H146R, I148T, I148N, G149R, M152V, M152R, 591del18, A155P, S158R, Y161N, Y161D, Y161S, K162E, 621GA, 6211GT, 621TC, 6212TG, 6213AG, 6222AC, 6221GA, L165S, K166Q, R170C, R170G, R170H, I175V, I177T, G178R, Q179K, N186K, N187K, D192N, delta D192, D192G, E193K, 7111GT, 7113AC, 7113AG, 7113AT, 7115GA, 71134AG, 7121GT, G194V, A198P, H199Y, H199Q, V201M, P205S, L206W, L206F, A209S, E217G, Q220R, C225R, L227R, V232D, Q237E, G239R, G241R, M243L, M244K, R248T, 8751GC, 8751GA, 87614del12, 87610del8, 8763CT, R258G, V920L, M265R, E278del, N287Y, 994del9, 10023TG, E292K, R297W, R297Q, A299T, Y301C, S307N, A309D, A309G, delta F311, F311L, G314R, G314V, G314E, F316L, V317A, L320V, L320F, V322A, L327R, R334W, R334L, R334Q, I336K, T338I, E474K, L346P, R347C, R347H, R347P, R347L, M348K, A349V, R352W, R352Q, Q353H, Q359KT360K, Q359R, W361R(TC), W361R(TA), S364P, L365P, 1243ins6, 12481GA, 124929delAT, 124927delTA, 12495AG, L375F, E379X, L383S, T360R, V392A, V392G, M394R, A399V, E403D, 1341GA, 1341GA, 13411GA, 134118AC, 134211TTTG, 13422AC, 13421GC, E407V, N418S, G424S, D443Y, I444S, Q452P, delta L453, A455E, V456F, G458V, 15246insC, 15251GA, S466L, G480S, G480C, G480D, H484Y, H484R, S485C, C491R, S492F, Q493R, P499A, T501A, I502T, E504Q, I506L, delta I507, I506S, I506T, delta F508, F508S, D513G, Y517C, V520F, V520I, 1706del16, 1706del17, E527Q, E527G, 17161GA, E528D, 17162TC, 17178GA, 17173TG, 17172AG, 17171GA, 17179TA, D529H, A534E, I539T, G544S, G544V, S549R(AC), S549N, S549I, S549R(TG), G550R, G551S, G551D, Q552K, R553G, R553Q, R555G, I556V, L558S, A559T, A559E, R560K, R560T, 18111GC, 18111.6kbAG, 181118GA, 18121GA, R560S, A561E, V562L, V562I, Y563D, Y563N, Y563C, L568F, Y569D, Y569H, Y569C, L571S, D572N, P574H, G576A, Y577F, D579Y, D579G, D579A, T582I, T582R, S589N, S589I, 18981GT, 18981GC, 18981GA, 18983AC, 18983AG, 18985GT, 18985GA, 189873TG, R600G, I601F, V603F, T604I, 1949del84, H609R, L610S, A613T, D614Y, D614G, I618T, L619S, H620P, H620Q, G622D, G628R(GA), G628R(GC), L633P, L636P, D648V, D651N, T665S, E672del, K683R, F693L(CTT), F693L(TTG), K698R, E725K, P750L, V754M, T760M, R766M, N782K, R792G, A800G, E822K, E826K, 26221GT, 26221GA, 26222del6, D836Y, R851L, C866Y, L867X, 2751GA, 27512TA, 27513AG, 275226AG, 27521GT, 27521GC, T908N, 27892insA, 27893delG, 27895GA, 27902AG, 27901GC, 27901GT, Q890R, D891G, S895T, T896I, N900T, 2851AG, S912L, Y913C, Y917D, Y917C, I918M, Y919C, V920M, D924N, L927P, F932S, R933S, V938G, H939D, H939R, S945L, S945L, K946X, H949Y, H949R, M952T, M952I, M961I, L967S, G970R, 30402TC, 30411GA, G970D, L973F, L973P, S977P, S977F, D979V, D979A, I980K, D985H, D985Y, I991V, D993Y, F994C, 3120GA, 31201GA, 31212AT, 31212AG, 31211GA, L997F, 3131del15, I1005R, A1006E, V1008D, A1009T, P1013L, Y1014C, P1021S, 3195del6, 3196del54, 3199del6, I1027T, M1028R, M1028I, Y1032C, I1366T, 3271delGG, 32711GA, 32711delGG, 327226AG, 32729AT, 32724AG, 32721GA, G1047D, F1052V, T1053I, T1053I, H1054D, T1057A, K1060T, G1061R, L1065F, L1065R, L1065P, R1066S, R1066C, R1066H, R1066L, A1067T, A1067D, G1069R, R1070W, R1070Q, R1070P, Q1071P, Q1071H, P1072L, F1074L, L1077P, H1085R, T1086I, N1088D, Y1082H, L1093P, L1096R, W1098R, Q1100P, M1101R, M1101K, S1118F, S1118C, G1123R, 34992TC, 34993AG, 34996AG, 35002AG, E1123del, G1127E, 3523AG, A1136T, M1137V, M1137R, I1139V, delta M1140, M1140K, T1142I, V1147I, N1148K, D1152H, V1153E, D1154G, 3600GA, 36002insT, 36005GA, 360120TC, 360117TC, 36012AG, S1159P, S1159F, D1168G, K1177R, 3696GA, V1190P, 3750delAG, 3755delG, M1210I, V1212I, L1227S, E1228G, I1230T, I1234V, S1235R, G1237S, Q1238R, 3849GA, 38491GA, 38494AG, 384910kbCT, 38495GA, 38503TG, 38501GA, V1240G, G1244V, G1244E, T1246I, G1247R, G1249R, G1249E, S1251N, T1252P, S1255P, S1255L, F1257L, delta L1260, 3922del10C, I1269N, D1270N, W1282G, W1282R, W1282C, R1283M, R1283K, F1286S, Q1291R, Q1291H, 40051GA, 40052TC, 400661del14, 400619del3, 400614CG, 40068TA, 40064AG, V1293I, T12991, F1300L, N1303H, N1303I, N1303K, D1305E, Q1313K, V1318A, E1321Q, 409628GA, 40963CG, L1335P, F1337V, L1339F, G1349S, G1349D, K1351E, Q1352H*, R1358S, A1364V, D1377H, L1388Q, V1397E, E1409V, Q1412X, 437410TC, 43741GA, 43741GT, 43751GC, R1422W, S1426P, D1445N, R1453W, CFTRdele14a, CFTRdele19, 2104insA21092118del10, and CF25kbdel as listed in Table 1.
30. The method of claim 15 wherein the polypeptide is administered in an aerosol to a patient with a mutant CFTR protein.
31. The method of claim 15 wherein the polypeptide is administered in an aerosol to a patient with insufficient amounts of wild-type CFTR to maintain chloride transport.
32. The method of claim 30 wherein the aerosolized polypeptide is co-administered with an expression vector wherein said expression vector encodes wild-type CFTR protein.
33. The method of claim 31 wherein the aerosolized polypeptide is co-administered with an expression vector wherein said expression vector encodes wild-type CFTR protein.
34. A method of activating a CFTR protein comprising:
applying an effective amount of a polypeptide to a CFTR protein in a lipid bilayer wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 6, whereby the CFTR protein is activated.
35. The method of claim 34 wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 1.
36. The method of claim 34 further comprising measuring a change in conductance upon applying the polypeptide.
37. A method of synthesizing a CFTR activating polypeptide comprising:
sequentially linking units of one or more amino acid residues to form a polypeptide comprising the amino acid sequence of SEQ ID NO: 6.
38. The method of claim 37 wherein F-moc synthesis is used.
39. The method of claim 37 wherein the polypeptide has the sequence of SEQ ID NO: 1.
40. A polypeptide comprising the amino acid sequence as shown in SEQ ID NO: 2.
41. The polypeptide of claim 40 wherein the polypeptide is fused to a membrane-penetrating peptide.
42. The polypeptide of claim 41 wherein the membrane-penetrating peptide is selected from the group consisting of: VP-22 (SEQ ID NO: 3), (SEQ ID NO: 4) and (SEQ ID NO: 5).
43. A nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide according to SEQ ID NO: 2.
44. A method of activating a CFTR protein, comprising:
administering a nucleic acid comprising a sequence encoding a polypeptide according to SEQ ID NO: 2 to a cell comprising the CFTR protein, whereby the polypeptide is expressed and the CFTR protein is activated.
45. The method of claim 44 wherein the cell is in a patient and the nucleic acid is administered as an aerosol to the patient’s airways.
46. The method of claim 45 wherein the nucleic acid molecule is co-administered with an expression vector encoding a wild-type CFTR protein.