What is claimed is:
1. A method of fabricating a gate electrode structure for an insulated gate field effect transistor (IGFET), said method comprising the step of:
during formation of a gate electrode structure, forming a barrier region in said gate electrode material prior to introduction of a dopant into said field effect transistor, said barrier region being a diffusion retardant region for said dopant.
2. The method of claim 1 wherein said forming step includes the step of:
forming said barrier region with nitrogen-containing material.
3. The method of claim 1 wherein said forming step includes the step of:
forming said nitrogen-containing region to be generally parallel to a bottom surface of said electrode structure.
4. The method of claim 2 wherein said forming step further includes the step of forming a second nitrogen-containing barrier layer in said electrode structure.
5. A method of fabricating a gate electrode structure for an insulated gate field effect transistor (IGFET), said method comprising the steps of:
forming a polysilicon layer on an underlying gate dielectric layer, said polysilicon layer having top and bottom surfaces, said bottom surface forming an interface with said gate dielectric layer;
implanting a nitrogen-containing material to form a nitrogen-containing diffusion-retarding barrier region within said polysilicon layer;
introducing a dopant into at least a portion of said polysilicon layer disposed between said barrier region and said top surface, said dopant introduction resulting in a greater dopant concentration immediately above said barrier region than immediately below; and
removing regions of said polysilicon layer to form a gate electrode for said IGFET.
6. The method of claim 5 wherein nitrogen residing in said gate dielectric layer just below said interface has a negligible concentration.
7. The method of claim 5 wherein said removing step is performed before said dopant introducing step.
8. The method of claim 5 wherein said removing step is performed before said nitrogen-containing material implanting step.
9. The method of claim 5 wherein said implanting step comprises:
implanting a material chosen from the group consisting of elemental nitrogen (N) and molecular nitrogen (N2).
10. The method of claim 5 further comprising the step of:
annealing said implanted nitrogen-containing material after said implanting step.
11. The method of claim 5 wherein said dopant comprises boron.
12. The method of claim 5 further comprising the steps of:
implanting a nitrogen-containing material to form a second nitrogen-containing diffusion-retarding barrier region above and spaced apart from said nitrogen-containing diffusion-retarding barrier region.
13. An integrated circuit fabricated using the method of claim 1.
14. A system comprising:
a microprocessor integrated circuit fabricated using the method of claim 1, said microprocessor integrated circuit coupled to a system bus for communicating with portions of a system external to the microprocessor integrated circuit; and
an external memory sub-system coupled to said system bus.
15. A semiconductor gate electrode structure for an insulated gate field effect transistor (IGFET), said gate electrode structure comprising:
a polysilicon layer formed on an underlying gate dielectric layer, said polysilicon layer having respective top and bottom surfaces, said bottom surface forming an interface with said gate dielectric layer;
a first nitrogen-containing diffusion-retarding barrier region formed within said polysilicon layer; and
a dopant within said polysilicon layer having a greater dopant concentration immediately above said diffusion barrier region than immediately below.
16. The structure of claim 15 wherein said first barrier region is separated from both said interface and said top surface.
17. The structure of claim 15 wherein said dopant comprises boron.
18. The structure of claim 15 further comprising:
a second nitrogen-containing diffusion-retarding barrier region formed within said polysilicon layer above and separated from said barrier region.
19. A method of fabricating a gate electrode structure for an insulated gate field effect transistor (IGFET), said method comprising the steps of:
forming a polysilicon layer on an underlying gate dielectric layer, said polysilicon layer having top and bottom surfaces, said bottom surface forming an interface with said gate dielectric layer;
implanting a nitrogen-containing material to form a nitrogen-containing diffusion-retarding barrier region within said polysilicon layer, said barrier region separated from both said interface and said top surface;
implanting a boron-containing material into at least a portion of said polysilicon layer between said barrier region and said top surface, resulting in a boron doping profile exhibiting a greater doping concentration immediately above said barrier region than immediately below; and
removing regions of said polysilicon layer to form a gate electrode for said IGFET.
20. The method of claim 19 wherein said removing step is performed before said boron-containing material implanting step.
21. The method of claim 19 wherein said removing step is performed before said nitrogen-containing material implanting step.
22. The method of claim 19 further comprising the steps of:
annealing said implanted nitrogen-containing material after said implanting step.
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 method of generating a conformation-specific antibody that specifically binds to a Xaa-Pro motif of a polypeptide, where Xaa is any amino acid residue, said method comprising administering a proline-analog-containing antigenic peptide to a human subject in an amount sufficient to generate said conformation-specific antibody, said antigenic peptide comprising a Xaa-Pro motif.
2. The method of claim 1, wherein said Xaa is serine or threonine.
3. The method of claim 1, wherein said Xaa is phosphorylated.
4. The method of claim 1, wherein said Xaa is not phosphorylated.
5. The method of claim 1, wherein the peptidyl-prolyl bond of said Xaa-Pro motif is in a cis conformation.
6. The method of claim 5, wherein said antibody binds to the cis conformation of said Xaa-Pro motif of said polypeptide with at least 10- to 100-fold greater affinity than to the trans conformation of said Xaa-Pro motif of said polypeptide.
7. The method of claim 1, wherein the peptidyl-prolyl bond of said Xaa-Pro motif is in a trans conformation.
8. The method of claim 7, wherein said antibody binds to the trans conformation of said Xaa-Pro motif of said polypeptide with at least 10- to 100-fold greater affinity than to the cis conformation of said Xaa-Pro motif of said polypeptide.
9. The method of claim 1, wherein said polypeptide is a PPIase substrate.
10. The method of claim 9, wherein said PPIase substrate is a Pin1 substrate.
11. The method of claim 10, wherein said Pin1 substrate is NIMA, RAB4, CDC25, WEE1, PLK1, MYT1, CDC27, CENP-F, Incenp, RBP1, NHERF-1, KRMP1, CK2, TopoII\u03b1, DAB2, p54nrb, Sil, EMI1, cyclin D1, Ki67, c-Myc, cyclin E, c-Jun, \u03b2-catenin, Cf-2, NF-\u03baB, RAF1, C-Fos, RAR\u03b1, AIB1SRC-3, HBx, STAT3, p53, Bcl-2, p73, BimEL, p66Shc, CHE1, tau, amyloid precursor protein (APP), APP fragment, synphilin-1, gephyrin, MCL1, NFAT, AUF1, IRF3, BTK, SIN3-RPD3, or hSpt5.
12. The method of claim 1, wherein said proline analog is homoproline, pipecolic acid (PIP), dimethyl proline (DMP), azetidine-2-carboxylic acid (Aze), tert-butyl-L-proline (TBP), trans-4-fluoro-L-proline (t-4F-Pro), 2,2-dimethyl-thiazolidine (Thz), or cis-4-fluoro-L-proline (c-4F-Pro).
13. The method of claim 12, wherein said polypeptide is tau or APP.
14. The method of claim 12, wherein said subject has, or as it risk of developing a tauopathy.
15. The method of claim 14, wherein said tauopathy is selected from the group consisting of Alzheimer’s disease, frontotemproal dementia with Parkinsonism linked to chromosome 17, Pick’s disease, and a corticobasal degeneration.
16. The method of claim 12, wherein the peptidyl-prolyl bond of said Xaa-Pro motif of said antigenic peptide is fixed in the cis conformation
17. The method of claim 12, wherein said antigenic peptide is at least 8 amino acid residues in length.
18. The method of claim 17, wherein said antigenic peptide is between 8 and 20 amino acid residues in length.
19. The method of claim 12, wherein said antigenic peptide is selected from a peptide comprising the sequence KVAVVR-(pT231)-(Dmp)-PKSPS or the sequence KKVAVVR-(pT231)-(Thz)-PKSPS.
20. The method of claim 19, wherein said antigenic peptide is selected from a peptide consisting of the sequence KVAVVR-(pT231)-(Dmp)-PKSPS or the sequence KKVAVVR-(pT231)-(Thz)-PKSPS.
21. The method of claim 1, wherein said subject has, or is at risk of developing, a cell proliferation disorder.
22. The method of claim 21, wherein said disorder is selected from the group consisting of cancer, benign prostatic hyperplasia, psoriasis, abnormal keratinization, lymphoproliferative disorders, rheumatoid arthritis, arteriosclerosis, restenosis, diabetic retinopathy, retrolental fibrioplasia, neovascular glaucoma, angiofibromas, hemangiomas, Karposi’s sarcoma, and neurodegenerative disorders.
23. The method of claim 1, wherein said subject has, or is at risk of developing, a neurological disorder.
24. The method of claim 23, wherein said neurological disorder is selected from the group consisting of Alzheimer’s disease, mild cognitive impairment, Parkinson’s disease, multiple sclerosis, muscular dystrophy, corticobasal degeneration, dementia pugilistica, Down’s syndrome, frontotemporal dementias, myotonic dystrophy, Niemann-Pick disease, Pick’s disease, prion disease, progressive supranuclear palsy, subacute sclerosing panencephalistis, convulsive disorders, vascular dementia, age-related dementia, head trauma, stroke, neurofibromatosis, Lewy body disease, amyotrophic lateral sclerosis, peripheral neuropathies, and macular degeneration
25. The method of claim 1, wherein the peptidyl-prolyl bond of said Xaa-Pro motif of said antigenic peptide is fixed in the cis conformation or the trans conformation.
26. The method of claim 1, wherein said antigenic peptide is administered subcutaneously.
27. The method of claim 1, wherein said administration further comprises administering a booster dose.
28. The method of claim 1, wherein said antigenic peptide is formulated with an immunostimulating adjuvant.
29. A method of treating a human subject with a disorder, wherein said disorder is associated with a deregulation of PPIase activity, said method comprising:
(i) contacting a sample from said subject with a conformation-specific antibody or fragment thereof that specifically binds to a Xaa-Pro motif of a polypeptide present in said sample, wherein the peptidyl-prolyl bond of said Xaa-Pro motif is in a cis conformation and wherein said Xaa is any amino acid residue;
(ii) quantitating the amount of said conformation-specific antibody or fragment thereof bound to said Xaa-Pro motif in said cis conformation; and
(iii) comparing the amount of said Xaa-Pro motif in said cis conformation in said sample to the amount of said Xaa-Pro motif in said cis conformation found in subjects diagnosed with said disorder or subjects not diagnosed with said disorder,
(iv) administering a proline-analog-containing antigenic peptide to said subject if an increase in the amount of said Xaa-Pro motif in said cis conformation in said subject, in comparison the amount of said Xaa-Pro motif in said cis conformation in said subjects not diagnosed with said disorder, is determined;
wherein administering said proline-analog-containing antigenic peptide to said subject treats said disorder.
30. The method of claim 29, further comprising monitoring said Xaa-Pro motif in said cis conformation in said subject after said administration of said proline-analog-containing antigenic peptide.
31. A method of diagnosing a subject with a disorder, wherein said disorder is associated with a deregulation of PPIase activity, said method comprising:
(i) contacting a sample from said subject with a conformation-specific antibody or fragment thereof that specifically binds to a Xaa-Pro motif of a polypeptide present in said sample, wherein the peptidyl-prolyl bond of said Xaa-Pro motif is in a trans conformation and wherein said Xaa is any amino acid residue;
(ii) quantitating the amount of said conformation-specific antibody or fragment thereof bound to said Xaa-Pro motif in said trans conformation; and
(iii) comparing the amount of said Xaa-Pro motif in said trans conformation in said sample to the amount of said Xaa-Pro motif in said trans conformation found in subjects diagnosed with said disorder or subjects not diagnosed with said disorder,
(iv) administering a proline-analog-containing antigenic peptide to said subject if an increase in the amount of said Xaa-Pro motif in said trans conformation in said subject, in comparison to the amount of said Xaa-Pro motif in said trans conformation in said subjects not diagnosed with said disorder, is determined;
wherein administering said proline-analog-containing antigenic peptide to said subject treats said disorder.
32. The method of claim 31, further comprising monitoring said Xaa-Pro motif in said trans conformation in said subject after said administration of said proline-analog-containing antigenic peptide.
33. A method of generating a conformation-specific antibody that specifically binds to a Xaa-Pro motif of a polypeptide, where Xaa is any amino acid residue, said method comprising administering a proline-analog-containing antigenic peptide to a human subject in an amount sufficient to generate said conformation-specific antibody, said antigenic peptide comprising a Xaa-Pro motif, wherein the generation of said conformation specific antibody decreases the risk of said human subject developing a tauopathy.