1-14. (canceled)
15. A lighting apparatus for in an adaptive vehicle, the apparatus comprising:
N radiation-emitting semiconductor chips coupled in an electrical series circuit, N being a natural number with N\u22672;
a plurality of switch elements, wherein each semiconductor chip or a group of semiconductor chips is connected in parallel with a respective one of the switch elements so that each semiconductor chip or group of semiconductor chips is electrically bypassed by the respective switch element when that semiconductor chip or group of semiconductor chips is turned off;
a controller configured to activate the switch elements independently of one another;
a constant current source coupled to energize the series circuit; and
a protection module arranged to reduce or prevent current spikes when one or more of the semiconductor chips are turned off.
16. The lighting apparatus according to claim 15, wherein:
the semiconductor chips are activated by pulse width modulation;
the activation is performed at a resolution of k bits with k\u03b5 and with k\u22673;
a modulation period has a total duration T;
the modulation period is subdivided into k or into k+1 time intervals, which apply for all semiconductor chips;
the durations of at least k of the time intervals are 2m t0 with m\u03b50; k\u22121 and with t0\u2266T2\u2212k;
the nth semiconductor chip is turned on during the modulation period with a total duration T for an turned-on duration tn and tn is composed of the total of the time intervals corresponding to the activation with the k bits with tn\u2266T;
n\u03b51;N; and
the time intervals are sorted by the protection module increasing according to the number of the semiconductor chips turned on in the respective time interval, so that during the modulation period, a number of the turned-on semiconductor chips increases monotonously at least up to the next-to-last time interval.
17. The lighting apparatus according to claim 16, wherein:
the modulation period is subdivided into k+1 time intervals,
at the end of the next-to-last time interval of the modulation period, all semiconductor chips turned on in this time interval are turned off synchronously, so that in the last time interval, all semiconductor chips are turned off; and
at least one of the semiconductor chips is turned on at least twice during the modulation period.
18. The lighting apparatus according to claim 15, wherein:
the semiconductor chips are activated by pulse width modulation;
the nth semiconductor chip is turned on during a modulation period with a total duration T for an turned-on duration tn with tn\u2266T;
n\u03b51;N; and
the nth semiconductor chip is turned on by the protection module at a point in time T\u2212tn after the beginning of the modulation period, so that all semiconductor chips turned on during the modulation period are jointly turned off synchronously at the end of the modulation period.
19. The lighting apparatus according to claim 15, wherein:
the semiconductor chips are activated by pulse width modulation;
the nth semiconductor chip is turned on during a modulation period with a total duration T for an turned-on duration tn with tn\u2266T;
n\u03b51;N;
only a part of the semiconductor chips is turned on by the protection module at the beginning of the modulation period; and
at least one of the semiconductor chips is turned off and simultaneously another of the semiconductor chips is turned on by the protection module within the modulation period.
20. The lighting apparatus according to claim 19, wherein the turned-on durations tn are adapted to one another and shifted within the modulation period by the protection module so that a number of simultaneous turning-on operations and turning-off operations of the semiconductor chips is maximized.
21. The lighting apparatus according to claim 19, wherein at least some of the target turned-on durations of the semiconductor chips output by the controller are changed by the protection module by up to 15% of the total duration T to obtain the actual turned-on durations tn.
22. The lighting apparatus according to claim 15, wherein:
the semiconductor chips are activated by pulse width modulation;
the nth semiconductor chip is turned on during a modulation period with a total duration T for a coherent turned-on duration tn with tn\u2266T;
n\u03b51;N;
a first part of the semiconductor chips is turned on by the protection module at the beginning of the modulation period; and
a second part of the semiconductor chips is turned on by the protection module at a point in time T\u2212tn after beginning the modulation period, so that the semiconductor chips of the second part are turned off simultaneously at the end of the modulation period.
23. The lighting apparatus according to claim 15, wherein:
an auxiliary switch element of the protection module is electrically connected in parallel jointly to all switch elements; and
during the turning off of the semiconductor chips, by switching of the switch elements, in each case the semiconductor chips are electrically bypassed by the auxiliary switch element.
24. The lighting apparatus according to claim 15, wherein:
during the turning off of the semiconductor chips, by switching of the switch elements, a current supply from the constant current source is interrupted or reduced by the protection module; and
during the turning off of the semiconductor chips, the current supply is reduced in accordance with the fraction of the semiconductor chips to be turned off, in relation to the number of the turned-on semiconductor chips.
25. The lighting apparatus according to claim 15, wherein:
the protection module comprises electrical resistors and electrical capacitors, which form RC elements; and
at least a part of the switch elements are each connected to one RC element and the RC elements have different time constants.
26. The lighting apparatus according to claim 25, wherein the semiconductor chips are activated by pulse width modulation, and the time constants differ at most by a shortest time slice of the pulse width modulation.
27. The lighting apparatus according to claim 15, wherein all semiconductor chips are structurally identical and are configured to emit light of the same spectral composition.
28. A method for operating an arrangement in an adaptive vehicle headlight and an adaptation is performed by the activation of semiconductor chips, wherein:
the arrangement has N radiation-emitting semiconductor chips and N is a natural number with N\u22672,
the semiconductor chips are arranged in an electrical series circuit,
the arrangement comprises multiple switch elements and one of the switch elements is connected in parallel with each of the semiconductor chips or a group of semiconductor chips,
the arrangement comprises a controller for activating the switch elements independently of one another,
the arrangement comprises a constant current source for energizing the series circuit,
when a semiconductor chip is turned off, the respective semiconductor chip is electrically bypassed by the switch element,
the arrangement comprises a protection module, and
the protection module reduces or prevents current spikes during the turning off of one or more of the semiconductor chips.
29. A method of operating a lighting apparatus installed in an adaptive vehicle headlight that includes a plurality of radiation-emitting semiconductor chips coupled in an electrical series circuit a plurality of switch elements, each switch element beings coupled in parallel with a respective one of the semiconductor chips or a group of semiconductor chips, the method comprising:
performing activation of ones of the semiconductor chips to adapt light from the vehicle headlight;
wherein the switch elements are activated independently of one another;
wherein each respective semiconductor chip is electrically bypassed by the switch element when that semiconductor chip is turned off; and
wherein the apparatus is protected from current spikes during the turning off of one or more of the semiconductor chips.
30. The method according to claim 29, wherein the series circuit is energized by a constant current source during operation.
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 modified histone octamer for gene delivery comprising:
a modified histone core comprising an histone octamer of H2A, H2B, H3 and H4 with one or more modifications of the histone octamer;
an expression cassette complexed to the histone octamer comprising a glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-cytomegalovirus (CMV) promoter-enhancer sequence and one or more genes; and
a bi-lamellar liposome encapsulant that encapsulates the expression cassette for increased post-transfection transcription.
2. The composition of claim 1, wherein the modified histone octamer core comprises two H2AH2B dimers and one H3H4 tetramer.
3. The composition of claim 1, wherein the modified histone octamer core comprises acetylation of the histones and methylation of histone H3 lysine 4.
4. The composition of claim 1, wherein the modified histone octamer core comprises trimethylation of histone H3 lysine 4.
5. The composition of claim 1, further comprising the addition of one or more HDAC inhibitors to treat a cancer cell by increasing the expression levels of genes required to induce cell cycle arrest andor apoptosis.
6. The composition of claim 1, wherein the HDAC inhibitors comprise valproic acid, vorinostat, or a combination thereof.
7. The composition of claim 1, wherein the bi-lamellar liposome encapsulant comprises dioleoylphosphatidylethanolamine, dilauroylphosphatidylcholine or a combination thereof.
8. The composition of claim 1, wherein the bi-lamellar liposome encapsulant comprises N-1-(2,3dioleyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA), cholesterol, phosphatidylcholines, or phosphatidylserines, 1,2-bis(oleoyloxy)-3-(4\u2032-trimethylammonio)propane (DOTAP), 1,2-dioleoyl-3-(4\u2032-trimethylammonio)butanoyl-sn-glycerol (DOTB), 1,2-dioleoyl-3-succinyl-sn-glycerol choline ester (DOSC), cholesteryl (4\u2032-trimethylammonio)butanoate (ChoTB), cetyltrimethylammonium bromide (CTAB), Stearylamine, 1,2-dioleoyl-3-dimethyl-hydroxyethyl ammonium bromide, (1,2-dioleyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DORIE), 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DMRIE), O,O\u2032-didodecyl-N-p-(2-trimethylammonioethyloxy)benzoyl-N,N,N-tri-methylammonium chloride, Lipospermine, DC-Chol (3a-N-(N\u2032,N\u2033-dimethylaminoethane)carbonylcholesterol), lipopoly(L-lysine), and mixtures and combinations thereof.
9. A modified reconstituted histone octamer for gene therapy composition comprising:
an isolated, modified histone octamer core comprising H2A, H2B, H3 and H4;
an expression cassette complexed to the modified histone octamer comprising an promoter-enhancer and a DNA sequence; and
a liposome that encapsulates expression cassette.
10. The composition of claim 9, wherein the modified histone octamer core comprises two H2AH2B dimers and one H3H4 tetramer.
11. The composition of claim 9, wherein the modified histone octamer core comprises acetylation of the histones and methylation of histone H3 lysine 4.
12. The composition of claim 9, wherein the modified histone octamer core comprises trimethylation of histone H3 lysine 4.
13. The composition of claim 9, wherein the expression cassette comprises a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) sequence and a cytomegalovirus (CMV) sequence.
14. The composition of claim 9, wherein the DNA sequence comprises a therapeutic gene.
15. The composition of claim 9, wherein the DNA sequence comprises plasmids for increased transcription of full-length transcripts post-transfection.
16. The composition of claim 9, wherein the liposome comprises a bi-lamellar invaginated liposome
17. The composition of claim 9, further comprising the addition of one or more HDAC inhibitors to treat a cancer cell by increasing the expression levels of genes required to induce cell cycle arrest andor apoptosis.
18. The composition of claim 9, wherein the HDAC inhibitors comprise valproic acid, vorinostat, or a combination thereof.
19. The composition of claim 9, wherein the bi-lamellar liposome encapsulant comprises dioleoylphosphatidylethanolamine, dilauroylphosphatidylcholine or a combination thereof.
20. The composition of claim 9, wherein the bi-lamellar liposome encapsulant comprises N-1-(2,3dioleyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA), cholesterol, phosphatidylcholines, or phosphatidylserines, 1,2-bis(oleoyloxy)-3-(4\u2032-trimethylammonio)propane (DOTAP), 1,2-dioleoyl-3-(4\u2032-trimethylammonio)butanoyl-sn-glycerol (DOTB), 1,2-dioleoyl-3-succinyl-sn-glycerol choline ester (DOSC), cholesteryl (4\u2032-trimethylammonio)butanoate (ChoTB), cetyltrimethylammonium bromide (CTAB), Stearylamine, 1,2-dioleoyl-3-dimethyl-hydroxyethyl ammonium bromide, (1,2-dioleyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DORIE), 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DMRIE), O,O\u2032-didodecyl-N-p-(2-trimethylammonioethyloxy)benzoyl-N,N,N-tri-methylammonium chloride, Lipospermine, DC-Chol (3a-N-(N\u2032,N\u2033-dimethylaminoethane)carbonylcholesterol), lipopoly(L-lysine), and mixtures and combinations thereof.
21. A method of treating a patient having cancer comprising the steps of:
selecting a patient having one or more cancerous cells; and
providing a therapeutic amount of a pharmaceutical composition comprising an isolated, reconstituted and modified histone octamer for gene delivery having a modified histone core comprising an histone octamer of H2A, H2B, H3 and H4 with one or more modifications of the histone octamer, an expression cassette complexed to the histone octamer comprising a glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-cytomegalovirus (CMV) promoter-enhancer sequence and one or more genes, a bi-lamellar liposome encapsulant that encapsulates the expression cassette for increased post-transfection transcription and a pharmaceutical carrier.
22. The method of claim 21, wherein the modified histone octamer core comprises two H2AH2B dimers and one H3H4 tetramer.
23. The method of claim 21, wherein the modified histone octamer core comprises acetylation of the histones and methylation of histone H3 lysine 4.
24. The method of claim 21, wherein the modified histone octamer core comprises trimethylation of histone H3 lysine 4.
25. The method of claim 21, further comprising the addition of one or more HDAC inhibitors to treat a cancer cell by increasing the expression levels of genes required to induce cell cycle arrest andor apoptosis.
26. The method of claim 21, wherein the HDAC inhibitors comprise valproic acid, vorinostat, or a combination thereof.
27. The method of claim 21, wherein the bi-lamellar liposome encapsulant comprises dioleoylphosphatidylethanolamine, dilauroylphosphatidylcholine or a combination thereof.
28. The method of claim 21, wherein the bi-lamellar liposome encapsulant comprises N-1-(2,3dioleyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA), cholesterol, phosphatidylcholines, or phosphatidylserines, 1,2-bis(oleoyloxy)-3-(4\u2032-trimethylammonio)propane (DOTAP), 1,2-dioleoyl-3-(4\u2032-trimethylammonio)butanoyl-sn-glycerol (DOTB), 1,2-dioleoyl-3-succinyl-sn-glycerol choline ester (DOSC), cholesteryl (4\u2032-trimethylammonio)butanoate (ChoTB), cetyltrimethylammonium bromide (CTAB), Stearylamine, 1,2-dioleoyl-3-dimethyl-hydroxyethyl ammonium bromide, (1,2-dioleyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DORIE), 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DMRIE), O,O\u2032-didodecyl-N-p-(2-trimethylammonioethyloxy)benzoyl-N,N,N-tri-methylammonium chloride, Lipospermine, DC-Chol (3a-N-(N\u2032,N\u2033-dimethylaminoethane)carbonylcholesterol), lipopoly(L-lysine), and mixtures and combinations thereof.
29. A process for delivering a nucleic acid to a mammalian cell comprising the steps of:
delivering a therapeutic amount of a pharmaceutical composition to a mammalian cell, wherein the pharmaceutical composition comprises a reconstituted, modified histone octamer for gene delivery having a modified histone core comprising an histone octamer of H2A, H2B, H3 and H4 with one or more modifications of the histone octamer, an expression cassette complexed to the histone octamer comprising a glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-cytomegalovirus (CMV) promoter-enhancer sequence and one or more genes, a bi-lamellar liposome encapsulant that encapsulates the expression cassette for increased post-transfection transcription and a pharmaceutical carrier.
30. The method of claim 29, wherein the modified histone octamer core comprises two H2AH2B dimers and one H3H4 tetramer.
31. The method of claim 29, wherein the modified histone octamer core comprises acetylation of the histones and methylation of histone H3 lysine 4.
32. The method of claim 29, further comprising the modified histone octamer core comprises trimethylation of histone H3 lysine 4.
33. The method of claim 29, wherein the addition of one or more HDAC inhibitors to treat a cancer cell by increasing the expression levels of genes required to induce cell cycle arrest andor apoptosis.
34. The method of claim 29, wherein the HDAC inhibitors comprise valproic acid, vorinostat, or a combination thereof.
35. The method of claim 29, wherein the bi-lamellar liposome encapsulant comprises dioleoylphosphatidylethanolamine, dilauroylphosphatidylcholine or a combination thereof.
36. The method of claim 29, wherein the bi-lamellar liposome encapsulant comprises N-1-(2,3dioleyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA), cholesterol, phosphatidylcholines, or phosphatidylserines, 1,2-bis(oleoyloxy)-3-(4\u2032-trimethylammonio)propane (DOTAP), 1,2-dioleoyl-3-(4\u2032-trimethylammonio)butanoyl-sn-glycerol (DOTB), 1,2-dioleoyl-3-succinyl-sn-glycerol choline ester (DOSC), cholesteryl (4\u2032-trimethylammonio)butanoate (ChoTB), cetyltrimethylammonium bromide (CTAB), Stearylamine, 1,2-dioleoyl-3-dimethyl-hydroxyethyl ammonium bromide, (1,2-dioleyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DORIE), 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DMRIE), O,O\u2032-didodecyl-N-p-(2-trimethylammonioethyloxy)benzoyl-N,N,N-tri-methylammonium chloride, Lipospermine, DC-Chol (3a-N-(N\u2032,N\u2033-dimethylaminoethane)carbonylcholesterol), lipopoly(L-lysine), and mixtures and combinations thereof.
37. A method to regulate expression of a nucleic acid sequence of interest comprising the steps of:
providing a therapeutic amount of a pharmaceutical composition comprising an isolated, reconstituted and modified histone octamer for gene delivery having a modified histone core comprising an histone octamer of H2A, H2B, H3 and H4 with one or more modifications of the histone octamer, an expression cassette complexed to the histone octamer comprising a glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-cytomegalovirus (CMV) promoter-enhancer sequence and one or more genes, a bi-lamellar liposome encapsulant that encapsulates the expression cassette for increased post-transfection transcription and a pharmaceutical carrier.
38. The method of claim 37, wherein the modified histone octamer core comprises two H2AH2B dimers and one H3H4 tetramer.
39. The method of claim 37, wherein the modified histone octamer core comprises acetylation of the histones and methylation of histone H3 lysine 4.
40. The method of claim 37, wherein the modified histone octamer core comprises trimethylation of histone H3 lysine 4.
41. The method of claim 37, further comprising the addition of one or more HDAC inhibitors to treat a cancer cell by increasing the expression levels of genes required to induce cell cycle arrest andor apoptosis.
42. The method of claim 37, wherein the HDAC inhibitors comprise valproic acid, vorinostat, or a combination thereof.
43. The method of claim 37, wherein the bi-lamellar liposome encapsulant comprises dioleoylphosphatidylethanolamine, dilauroylphosphatidylcholine or a combination thereof.
44. The method of claim 37, wherein the bi-lamellar liposome encapsulant comprises N-1-(2,3dioleyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA), cholesterol, phosphatidylcholines, or phosphatidylserines, 1,2-bis(oleoyloxy)-3-(4\u2032-trimethylammonio)propane (DOTAP), 1,2-dioleoyl-3-(4\u2032-trimethylammonio)butanoyl-sn-glycerol (DOTB), 1,2-dioleoyl-3-succinyl-sn-glycerol choline ester (DOSC), cholesteryl (4\u2032-trimethylammonio)butanoate (ChoTB), cetyltrimethylammonium bromide (CTAB), Stearylamine, 1,2-dioleoyl-3-dimethyl-hydroxyethyl ammonium bromide, (1,2-dioleyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DORIE), 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DMRIE), O,O\u2032-didodecyl-N-p-(2-trimethylammonioethyloxy)benzoyl-N,N,N-tri-methylammonium chloride, Lipospermine, DC-Chol (3a-N-(N\u2032,N\u2033-dimethylaminoethane)carbonylcholesterol), lipopoly(L-lysine), and mixtures and combinations thereof.
45. A method of forming a reconstituted modified histone octamer for gene delivery comprising the steps of:
reconstituting a modified histone core comprising an histone octamer of H2A, H2B, H3 and H4 with one or more modifications of the histone octamer;
complexing an expression cassette with the histone octamer, wherein the expression cassette comprises a glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-cytomegalovirus (CMV) promoter-enhancer sequence and one or more genes; and
encapsulating the expression cassette in a bi-lamellar liposome encapsulant to increase post-transfection transcription.