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1.
Inter- and intrapopulation studies of ancient humans 总被引:1,自引:0,他引:1
W. W. Hauswirth C. D. Dickel D. J. Rowold M. A. Hauswirth 《Cellular and molecular life sciences : CMLS》1994,50(6):585-591
For a genetic analysis of ancient human populations to be useful, it must be demonstrated that the DNA samples under investigation represent a single human population. Toward that end, we have analyzed human DNA from the Windover site (7000–8000 BP). MHC-I analysis, using allele-specific oligonucleotide hybridization to PCR amplified Windover DNA, microsatellite analysis by PCR of the APO-A2 repeat and mtD-loop 3 region sequencing on multiple individuals spanning nearly the full range of estimated burial dates all confirm the hypothesis that there is a persistence of both nuclear and mitochondrial haplotypes at Windover throughout its entire period of use. Thus, Windover can be considered a single population. Neighbor-joining tree analysis of mtDNA sequences suggests that some mitochondrial types are clearly related to extant Amerind types, whereas others, more distantly related, may reflect genetically distinct origins. A more complete sequence analysis will be required to firmly resolve this issue. Calibrating genetic relationships deduced by tree analysis, radiocarbon dates and burial position, yields a human mtD-loop DNA rate of evolution of 3700 to 14,000 years per percent change. Both values are within the range of recent, independently calculated values using estimates of evolutionary divergence or theoretical population genetics. Thus we are beginning to relaize the promise of ancient DNA analysis to experimentally answer heretofore unapproachable questions regarding human prehistory and genetic change. 相似文献
2.
Igor P. Pogribny Frederick A. Beland 《Cellular and molecular life sciences : CMLS》2009,66(14):2249-2261
The pathogenesis of any given human disease is a complex multifactorial process characterized by many biologically significant
and interdependent alterations. One of these changes, specific to a wide range of human pathologies, is DNA hypomethylation.
DNA hypomethylation signifies one of the major DNA methylation states that refers to a relative decrease from the “normal”
methylation level. It is clear that disease by itself can induce hypomethylation of DNA; however, a decrease in DNA methylation
can also have an impact on the predisposition to pathological states and disease development. This review presents evidence
suggesting the involvement of DNA hypomethylation in the pathogenesis of several major human pathologies, including cancer,
atherosclerosis, Alzheimer’s disease, and psychiatric disorders.
The views expressed in this paper do not necessarily represent those of the US Food and Drug Administration. 相似文献
3.
Deoxyribozymes: new activities and new applications 总被引:9,自引:0,他引:9
DNA in its single-stranded form has the ability to fold into complex three-dimensional structures that serve as highly specific receptors or catalysts. Only protein enzymes and ribozymes are known to be responsible for biological catalysis, but deoxyribozymes with kinetic parameters that rival ribozymes can be created in the laboratory. Some of these engineered DNA catalysts are showing surprising potential as therapeutic agents, which makes them biologically relevant if not biologically derived. If DNA's natural role is strictly genomic, how significant is its innate catalytic prowess? New examples of engineered deoxyribozymes serve as empirical examples of the potential for catalysis by DNA. These results indicate that the true catalytic power of DNA is limited by discovery and not by chemistry. 相似文献
4.
The p53 protein was discovered 20 years ago, as a cellular protein tightly bound to the large T oncoprotein of the SV40 DNA
tumour virus. Since then, research on p53 has developed in many exciting and sometimes unexpected directions. p53 is now known
to be the product of a major tumour suppressor gene that is the most common target for genetic alterations in human cancer.
The nonmutated wild-type p53 protein (wtp53) is often found within cells in a latent state and is activated in response to
various intracellular and extracellular signals. Activation involves an increase in overall p53 protein levels, as well as
qualitative changes in the protein. Upon activation, wtp53 can induce a variety of cellular responses, most notable among
which are cell cycle arrest and apoptosis. To a great extent, these effects are mediated by the ability of p53 to activate
specific target genes. In addition, the p53 protein itself possesses biochemical functions which may facilitate DNA repair
as well as apoptosis. The role of p53 in normal development and particularly in carcinogenesis has been elucidated in depth
through the use of mouse model systems. The insights provided by p53 research over the years are now beginning to be utilized
towards better diagnosis, prognosis and treatment of cancer. 相似文献
5.
Molecular paleontology 总被引:3,自引:0,他引:3
Molecular paleontology, i.e., the recovery of DNA from ancient human, animal, and plant remains is an innovative research
field that has received progressively more attention from the scientific community since the 1980s. In the last decade, the
field was punctuated by claims which aroused great interest but eventually turned out to be fakes - the most famous being
the sequence of dinosaur DNA later shown to be of human origin. At present, the discipline is characterized by some certainties
and many doubts. We know, for example, that we have reasonable chances to recover authentic DNA from a mammoth carcass, while
our chances are negligible (or nonexistent) in the case of a dynastic mummy from Egypt. On the other hand, though we are developing
convincing models of DNA decay in bone, we are not yet able to predict whether a certain paleontological or archeological
site will yield material amenable to DNA analysis. This article reviews some of the most important and promising investigations
using molecular paleontology approaches, such as studies on the conservation of DNA in human bone, the quest for ancient DNA
in permafrost-frozen fauna, the Tyrolean iceman, and the Neandertals.
Received 5 April 2001; received after revision 5 July 2001; accepted 5 July 2001 相似文献
6.
The correct repair of double-strand breaks (DSBs) is essential for the genomic integrity of a cell, as inappropriate repair
can lead to chromosomal rearrangements such as translocations. In many hematologic cancers and sarcomas, translocations are
the etiological factor in tumorigenesis, resulting in either the deregulation of a proto-oncogene or the expression of a fusion
protein with transforming properties. Mammalian cells are able to repair DSBs by pathways involving homologous recombination
and nonhomologous end-joining. The analysis of translocation breakpoints in a number of cancers and the development of model
translocation systems are beginning to shed light on specific DSB repair pathway(s) responsible for the improper repair of
broken chromosomes.
Received 19 June 2001; received after revision 6 September 2001; accepted 11 September 2001 相似文献
7.
El-Osta A 《Cellular and molecular life sciences : CMLS》2004,61(17):2135-2136
8.
Neurodegeneration changes in primary central nervous system neurons transfected with the Alzheimer-associated neuronal thread protein gene 总被引:6,自引:0,他引:6
The AD7c-NTP gene is over-expressed in brains with Alzheimer's disease (AD), and increased levels of the corresponding protein
are detectable in cortical neurons, brain tissue extracts, cerebrospinal fluid, and urine beginning early in the course of
AD neurodegeneration. In the present study, we utilized a novel method to transfect post-mitotic primary neuronal cell cultures,
and demonstrated that over-expression of the AD7c-NTP gene causes cell death and neuritic sprouting, two prominent abnormalities
associated with AD. These results provide further evidence that aberrantly increas-ed AD7c-NTP expression may have a role
in AD-type neurodegeneration. In addition, we demonstrate that primary post-mitotic neurons can be efficiently transfected
with conventional recombinant plasmid DNA to evaluate the effects of gene over-expression in relevant in vitro models.
Received 31 January 2001; received after revision 31 March 2001; accepted 4 April 2001 相似文献
9.
Immune responses to DNA vaccines 总被引:16,自引:0,他引:16
DNA vaccines, based on plasmid vectors expressing an antigen under the control of a strong promoter, have been shown to induce
protective immune responses to a number of pathogens, including viruses, bacteria and parasites. They have also displayed
efficacy in treatment or prevention of cancer, allergic diseases and autoimmunity. Immunologically, DNA vaccines induce a
full spectrum of immune responses that include cytolytic T cells, T helper cells and antibodies. The immune response to DNA
vaccines can be enhanced by genetic engineering of the antigen to facilitate its presentation to B and T cells. Furthermore,
the immune response can be modulated by genetic adjuvants in the form of vectors expressing biologically active determinants
or by more traditional adjuvants that facilitate uptake of DNA into cells. The ease of genetic manipulation of DNA vaccines
invites their use not only as vaccines but also as research tools for immunologists and microbiologists.
Received 26 October 1998; received after revision 3 December 1998; accepted 3 December 1998 相似文献
10.
B. S. Shastry 《Cellular and molecular life sciences : CMLS》1994,50(11-12):1099-1105
In the past 3 years, seven human neurological disorders have been found to be associated with an abnormal number of unstable trinucleotide repeats within exons or non-expressed regions of a gene. These forms of mutations are called dynamic mutations. The expansion in copy number of trinucleotide repeats may represent a large number of hereditary disorders. The correlation between the length of the repeated size and the disease severity and variable onset has provided some genetic explanation for a phenomenon called anticipation. However, there are numerous questions which cannot be explained by anticipation. Many other factors such as genomic imprinting and variable DNA methylation may also contribute to the puzzling features of these phenotypes. 相似文献
11.
The RecQ helicases belong to the Superfamily II group of DNA helicases, and are defined by amino acid motifs that show sequence
similarity to the catalytic domain of Escherichia coli RecQ. RecQ helicases have crucial roles in the maintenance of genome stability. In humans, there are five RecQ helicases
and deficiencies in three of them cause genetic disorders characterised by cancer predisposition, premature aging and/or developmental
abnormalities. RecQ helicase-deficient cells exhibit aberrant genetic recombination and/or DNA replication, which result in
chromosomal instability and a decreased potential for proliferation. Here, we review the current knowledge of the molecular
genetics of RecQ helicases, focusing on the human RecQ helicase disorders and mouse models of these conditions.
Received 9 March 2007; received after revision 26 April 2007; accepted 2 May 2007 相似文献
12.
Exposure to estrogens is a risk factor for breast and other human cancers. Initiation of breast, prostate and other cancers
has been hypothesized to result from reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA to
form depurinating adducts at the N-7 of guanine and N-3 of adenine by 1,4-Michael addition. The catechol of the carcinogenic
synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts
with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine. The catecholamine dopamine and the metabolite
catechol (1,2-dihydroxybenzene) of the leukemogen benzene can also be oxidized to their quinones, which react with DNA to
form predominantly analogous depurinating adducts. Apurinic sites formed by depurinating adducts are converted into tumor-initiating
mutations by error-prone repair. These mutations could initiate cancer by estrogens and benzene, and Parkinson's disease by
the neurotransmitter dopamine. These data suggest a unifying molecular mechanism of initiation for many cancers and neurodegenerative
diseases and lay the groundwork for designing strategies to assess risk and prevent these diseases.
Received 4 September 2001; received after revision 28 November 2001; accepted 2 December 2001 相似文献
13.
Comparison of the growing number of disorders known to be associated with triplet repeat expansions reveals both common features
and a diversity of molecular pathways. Despite significant progress towards the characterization of proteins coded by the
mutant genes, the complex nature of these disorders requires identification of all molecular components of the triplet repeat
pathways. In this brief review we will discuss recent progress in determining the molecular mechanisms of disorders with unstable
trinucleotide mutations.
Received 13 January 1999; received after revision 8 March 1999; accepted 9 March 1999 相似文献
14.
15.
The leucine-rich repeat structure 总被引:2,自引:0,他引:2
Bella J Hindle KL McEwan PA Lovell SC 《Cellular and molecular life sciences : CMLS》2008,65(15):2307-2333
The leucine-rich repeat is a widespread structural motif of 20-30 amino acids with a characteristic repetitive sequence pattern rich in leucines. Leucine-rich repeat domains are built from tandems of two or more repeats and form curved solenoid structures that are particularly suitable for protein-protein interactions. Thousands of protein sequences containing leucine-rich repeats have been identified by automatic annotation methods. Three-dimensional structures of leucine-rich repeat domains determined to date reveal a degree of structural variability that translates into the considerable functional versatility of this protein superfamily. As the essential structural principles become well established, the leucine-rich repeat architecture is emerging as an attractive framework for structural prediction and protein engineering. This review presents an update of the current understanding of leucine-rich repeat structure at the primary, secondary, tertiary and quaternary levels and discusses specific examples from recently determined three-dimensional structures. 相似文献
16.
Bandholtz L Guo Y Palmberg C Mattsson K Ohlsson B High A Shabanowitz J Hunt DF Jörnvall H Wigzell H Agerberth B Gudmundsson GH 《Cellular and molecular life sciences : CMLS》2003,60(2):422-429
CpG motifs originating from bacterial DNA (CpG DNA) can act as danger signals for the mammalian immune system. These CpG
DNA motifs like many other pathogen-associated molecular patterns are believed to be recognized by a member of the toll-like
receptor family, TLR-9. Here we show results suggesting that heat shock protein 90 (hsp90) is also implicated in the recognition
of CpG DNA. Hsp90 was characterized as a binder to oligodeoxynucleotides (ODNs) containing CpG motifs (CpG ODNs) after several
purification steps from crude protein extracts of peripheral blood mononuclear cells. This finding was further supported by
direct binding of CpG ODNs to commercially available human hsp90. Additionally, immunohistochemistry studies showed redistribution
of hsp90 upon CpG ODN uptake. Thus, we propose that hsp90 can act as a ligand transfer molecule and/or play a central role
in the signaling cascade induced by CpG DNA.
Received 18 December 2002; accepted 6 January 2002
RID="*"
ID="*"Corresponding author. B. Agerberth and G. H. Gudmundsson contributed equally to this work. 相似文献
17.
Transmission of the genetic information from the parental DNA strand to the offspring is crucial for the survival of any living species. In nature, all DNA synthesis in DNA replication, recombination and repair is catalyzed by DNA polymerases and depends on their ability to select the canonical nucleobase pair from a pool of structurally similar building blocks. Recently, a wealth of valuable new insights into DNA polymerase mechanisms have been gained through application of carefully designed synthetic nucleotides and oligonucleotides in functional enzyme studies. The applied analogues exhibit features that differ in certain aspects from their natural counterparts and, thus, allow investigation of the involvement and efficacy of a chosen particular aspect on the entire complex enzyme mechanism. This review will focus on a depiction of the efforts that have been undertaken towards the development of nucleotide analogues with carefully altered properties. The different approaches will be discussed in the context of the motivation and the problem under investigation.Received 16 March 2005; received after revision 5 May 2005; accepted 8 June 2005 相似文献
18.
Saha BK Bishayee A Kanjilal NB Chatterjee M 《Cellular and molecular life sciences : CMLS》2001,58(8):1141-1149
The possible promoting effect of streptozotocin (STZ; 65 mg/kg body weight, intraperitoneal)-induced diabetes during 2-acetylaminofluorene
(2-AAF; 0.04% in basal diet)-initiated hepatocarcinogenesis and modulatory effect of 1α,25-dihydroxyvitamin D3 (VD3; 0.3 μg/0.1 ml in propylene glycol, per os) were investigated by monitoring chromosomal aberrations (CAs), DNA strand breaks
and specific DNA adducts in rat liver. VD3 treatment (twice a week) was started 4 weeks before the 2-AAF regimen and continued throughout the study. Aberrant metaphase
chromosomes were counted from the regenerating hepatocytes 15, 30 or 45 weeks after STZ injection, while DNA strand break
and adduct assays were performed 45 days post-STZ treatment. Dietary exposure to 2-AAF elicited a substantial increase in
CAs and elevated the extent of DNA strand breaks and formation of N-(deoxyguanosin-8-yl)-2-aminofluorene. A promoting effect of STZ was evident from CAs coupled with DNA strand break analysis.
VD3 treatment substantially reducted 2-AAF+STZ-induced CAs as well as DNA strand breaks and adducts. Thus, VD3 appears to be effective in suppressing liver-specific early chromosomal as well as DNA damage during the process of rat hepatocarcinogenesis
initiated with 2-AAF and promoted by STZ contributing to its promise as a cancer chemotherapeutic agent.
Received 27 April 2001; accepted 22 May 2001 相似文献
19.
20.
K. Sandman S. L. Pereira J. N. Reeve 《Cellular and molecular life sciences : CMLS》1998,54(12):1350-1364