Alzheimer's disease;
Epigenetics;
DNA methylation;
5-Methylcytosine (5mC);
DNA hydroxymethylation;
5-Hydroxymethylcytosine (5hmC);
Human brain;
PRECURSOR PROTEIN GENE;
NEUROFIBRILLARY TANGLES;
5-HYDROXYMETHYLCYTOSINE;
AGE;
UBIQUITIN;
5-METHYLCYTOSINE;
HYPOMETHYLATION;
QUANTIFICATION;
HIPPOCAMPUS;
PROMOTER;
D O I:
10.1016/j.neurobiolaging.2013.11.031
中图分类号:
R592 [老年病学];
C [社会科学总论];
学科分类号:
03 ;
0303 ;
100203 ;
摘要:
DNA methylation (5-methylcytosine [5mC]) is one of several epigenetic markers altered in Alzheimer's disease (AD) brain. More recently, attention has been given to DNA hydroxymethylation (5-hydroxymethylcytosine [5hmC]), the oxidized form of 5mC. Whereas 5mC is generally associated with the inhibition of gene expression, 5hmC has been associated with increased gene expression and is involved in cellular processes such as differentiation, development, and aging. Recent findings point toward a role for 5hmC in the development of diseases including AD, potentially opening new pathways for treating AD through correcting methylation and hydroxymethylation alterations. In the present study, levels of 5mC and 5hmC were investigated in the human middle frontal gyrus (MFG) and middle temporal gyrus (MTG) by immunohistochemistry. Immunoreactivity for 5mC and 5hmC were significantly increased in AD MFG (N = 13) and MTG (N = 29) compared with age-matched controls (MFG, N 13 and MTG, N = 29). Global levels of 5mC and 5hmC positively correlated with each other and with markers of AD including amyloid beta, tau, and ubiquitin loads. Our results showed a global hypermethylation in the AD brain and revealed that levels of 5hmC were also significantly increased in AD MFG and MTG with no apparent influence of gender, age, postmortem delay, or tissue storage time. Using double-fluorescent immunolabeling, we found that in control and AD brains, levels of 5mC and 5hmC were low in astrocytes and microglia but were elevated in neurons. In addition, our colocalization study showed that within the same nuclei, 5mC and 5hmC mostly do not coexist. The present study clearly demonstrates the involvement of 5mC and 5hmC in AD emphasizing the need for future studies determining the exact time frame of these epigenetic changes during the progression of AD pathology. (C) 2014 Elsevier Inc. All rights reserved.
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页码:1334 / 1344
页数:11
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[1]
[Anonymous], J ALZHEIMERS DIS, DOI DOI 10.3233/JAD-2010-100975
机构:
Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Bakulski, Kelly M.
Dolinoy, Dana C.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Dolinoy, Dana C.
Sartor, Maureen A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA
Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Sartor, Maureen A.
Paulson, Henry L.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Paulson, Henry L.
Konen, John R.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Konen, John R.
Lieberman, Andrew P.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Lieberman, Andrew P.
Albin, Roger L.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA
Vet Affairs Ann Arbor Healthcare Syst, Ann Arbor, MI USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Albin, Roger L.
Hu, Howard
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA
Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Hu, Howard
Rozek, Laura S.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Univ Michigan, Sch Med, Dept Otolaryngol, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
机构:
Univ Washington, Sch Med, Dept Med, Seattle, WA 98108 USAUniv Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA
Bekris, Lynn M.
Yu, Chang-En
论文数: 0引用数: 0
h-index: 0
机构:
Univ Washington, Sch Med, Dept Med, Seattle, WA 98108 USAUniv Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA
Yu, Chang-En
Bird, Thomas D.
论文数: 0引用数: 0
h-index: 0
机构:
Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USAUniv Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA
Bird, Thomas D.
Tsuang, Debby W.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USAUniv Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA
机构:
Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
Univ Kentucky, Alzheimers Dis Ctr, Lexington, KY 40536 USAUniv Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
Bradley-Whitman, M. A.
Lovell, M. A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
Univ Kentucky, Alzheimers Dis Ctr, Lexington, KY 40536 USA
Univ Kentucky, Dept Chem, Lexington, KY 40506 USAUniv Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
机构:
Univ Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USAUniv Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USA
Chen, Hu
Dzitoyeva, Svetlana
论文数: 0引用数: 0
h-index: 0
机构:
Univ Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USAUniv Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USA
Dzitoyeva, Svetlana
Manev, Hari
论文数: 0引用数: 0
h-index: 0
机构:
Univ Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USAUniv Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USA
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, NetherlandsMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Chouliaras, Leonidas
Mastroeni, Diego
论文数: 0引用数: 0
h-index: 0
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Banner Sun Hlth Res Inst, Sun City, AZ USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Mastroeni, Diego
Delvaux, Elaine
论文数: 0引用数: 0
h-index: 0
机构:
Banner Sun Hlth Res Inst, Sun City, AZ USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Delvaux, Elaine
Grover, Andrew
论文数: 0引用数: 0
h-index: 0
机构:
Banner Sun Hlth Res Inst, Sun City, AZ USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Grover, Andrew
Kenis, Gunter
论文数: 0引用数: 0
h-index: 0
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, NetherlandsMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Kenis, Gunter
Hof, Patrick R.
论文数: 0引用数: 0
h-index: 0
机构:
Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY USA
Mt Sinai Sch Med, Friedman Brain Inst, New York, NY USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Hof, Patrick R.
Steinbusch, Harry W. M.
论文数: 0引用数: 0
h-index: 0
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, NetherlandsMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Steinbusch, Harry W. M.
Coleman, Paul D.
论文数: 0引用数: 0
h-index: 0
机构:
Banner Sun Hlth Res Inst, Sun City, AZ USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Coleman, Paul D.
Rutten, Bart P. F.
论文数: 0引用数: 0
h-index: 0
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, NetherlandsMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
机构:
Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Bakulski, Kelly M.
Dolinoy, Dana C.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Dolinoy, Dana C.
Sartor, Maureen A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA
Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Sartor, Maureen A.
Paulson, Henry L.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Paulson, Henry L.
Konen, John R.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Konen, John R.
Lieberman, Andrew P.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Lieberman, Andrew P.
Albin, Roger L.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA
Vet Affairs Ann Arbor Healthcare Syst, Ann Arbor, MI USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Albin, Roger L.
Hu, Howard
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA
Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Hu, Howard
Rozek, Laura S.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
Univ Michigan, Sch Med, Dept Otolaryngol, Ann Arbor, MI 48109 USAUniv Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
机构:
Univ Washington, Sch Med, Dept Med, Seattle, WA 98108 USAUniv Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA
Bekris, Lynn M.
Yu, Chang-En
论文数: 0引用数: 0
h-index: 0
机构:
Univ Washington, Sch Med, Dept Med, Seattle, WA 98108 USAUniv Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA
Yu, Chang-En
Bird, Thomas D.
论文数: 0引用数: 0
h-index: 0
机构:
Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USAUniv Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA
Bird, Thomas D.
Tsuang, Debby W.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USAUniv Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA
机构:
Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
Univ Kentucky, Alzheimers Dis Ctr, Lexington, KY 40536 USAUniv Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
Bradley-Whitman, M. A.
Lovell, M. A.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
Univ Kentucky, Alzheimers Dis Ctr, Lexington, KY 40536 USA
Univ Kentucky, Dept Chem, Lexington, KY 40506 USAUniv Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
机构:
Univ Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USAUniv Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USA
Chen, Hu
Dzitoyeva, Svetlana
论文数: 0引用数: 0
h-index: 0
机构:
Univ Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USAUniv Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USA
Dzitoyeva, Svetlana
Manev, Hari
论文数: 0引用数: 0
h-index: 0
机构:
Univ Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USAUniv Illinois, Dept Psychiat, Inst Psychiat, 1601 W Taylor St,M-C912, Chicago, IL 60612 USA
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, NetherlandsMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Chouliaras, Leonidas
Mastroeni, Diego
论文数: 0引用数: 0
h-index: 0
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Banner Sun Hlth Res Inst, Sun City, AZ USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Mastroeni, Diego
Delvaux, Elaine
论文数: 0引用数: 0
h-index: 0
机构:
Banner Sun Hlth Res Inst, Sun City, AZ USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Delvaux, Elaine
Grover, Andrew
论文数: 0引用数: 0
h-index: 0
机构:
Banner Sun Hlth Res Inst, Sun City, AZ USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Grover, Andrew
Kenis, Gunter
论文数: 0引用数: 0
h-index: 0
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, NetherlandsMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Kenis, Gunter
Hof, Patrick R.
论文数: 0引用数: 0
h-index: 0
机构:
Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY USA
Mt Sinai Sch Med, Friedman Brain Inst, New York, NY USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Hof, Patrick R.
Steinbusch, Harry W. M.
论文数: 0引用数: 0
h-index: 0
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, NetherlandsMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Steinbusch, Harry W. M.
Coleman, Paul D.
论文数: 0引用数: 0
h-index: 0
机构:
Banner Sun Hlth Res Inst, Sun City, AZ USAMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands
Coleman, Paul D.
Rutten, Bart P. F.
论文数: 0引用数: 0
h-index: 0
机构:
Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, NetherlandsMaastricht Univ, Sch Mental Hlth & Neurosci MHeNS, European Grad Sch Neurosci EURON,Med Ctr, Dept Psychiat & Neuropsychol,Fac Hlth Med & Life, NL-6200 MD Maastricht, Netherlands