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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

EPIGENETIC MODIFICATIONS TO CYTOSINE AND ALZHEIMER’S DISEASE: A QUANTITATIVE ANALYSIS OF POST-MORTEM TISSUE

Ellison, Elizabeth M. 01 January 2017 (has links)
Alzheimer’s disease (AD) is the most common form of dementia and the sixth leading cause of death in the United States, with no therapeutic option to slow or halt disease progression. Development of two characteristic pathologic lesions, amyloid beta plaques and neurofibrillary tangles, in the brain are associated with synaptic dysfunction and neuron loss leading to memory impairment and cognitive decline. Although mutations in genes involved in amyloid beta processing are linked to increased plaque formation in the inherited familial form of AD, the more common idiopathic form, termed sporadic AD, develops in the absence of gene mutations. In contrast, alterations in gene expression and transcription occur in plaque and tangle susceptible brain regions of sporadic AD subjects, even in the earliest stages of development of pathologic burden, and may give insight into the pathogenesis of AD. Epigenetic modifications to cytosine are known to alter transcriptional states and gene expression in embryonic development as well as in cancer studies. With the discovery of enzymatically oxidized derivatives of 5-methylcytosine (5-mC), the most common epigenetic cytosine modification, a probable demethylation pathway has been suggested to alter transcriptional states of DNA. The most abundant 5-mC derivative, 5-hydroxymethylcytosine (5-hmC), while expressed at low concentrations throughout the body, is expressed at high concentrations in brain cells. To determine the role cytosine modifications play in AD, this study was directed at the quantification of epigenetic modifications to cytosine in several stages of AD progression using global, genome-wide, and gene-specific studies. To determine global levels of each cytosine derivative in brain regions relevant to AD progression, a gas chromatography/mass spectrometry quantitative analysis was utilized to analyze cytosine, 5-mC, and 5-hmC in tissue specimens from multiple brain regions of AD subjects, including early and late stages of AD progression. To determine the genome-wide impact of 5-hmC on biologically relevant pathways in AD, a single-base resolution sequencing analysis was used to map hydroxymethylation throughout the hippocampus of late stage AD subjects. Finally, to determine gene-specific levels of cytosine, 5-mC, and 5-hmC, a quantitative polymerase chain reaction (qPCR) protocol was paired with specific restriction enzyme digestion to analyze target sequences within exons of genes related to sporadic AD. Results from these studies show epigenetic modifications to cytosine are altered on the global, genome-wide, and gene-specific levels in AD subjects compared to normal aging, particularly in early stages of AD progression, suggesting alterations to the epigenetic landscape may play a role in the dysregulation of transcription and the pathogenesis of AD.
22

Epigenetická regulace genů HLA asociovaných s celiakií / Epigenetic regulation of HLA genes asociated with celiac disease

Hudec, Michael January 2017 (has links)
Introduction: HLA class II system presents one of the most important mechanism in immune system, which is able to recognise pathogens and damaged cells. Some HLA class II alleles are associated with autoimmune diseases, for example celiac disease, which is typical by chronic inflammation of small intestine and other following symptoms. The risk HLA class II variants are DQ2 and DQ8. Epigenetic mechanisms that regulates gene expression, especially methylation of cytosine in promoter region of DQ2 and/or DQ8 alleles, could have influence on development of T lymphocytes in the thymus, where T-lymphocytes develop and pass a few stages in, and only the survival clones can be part of function immune system. Aim: The aim of this study is to compare methylation level of promoter regions of HLA DQ2 and DQ8 alleles between celiac patients and healthy controls. Another goal is to compare expression level of DQ2 and DQ8 variants between these two groups. Methods: DNA and RNA were isolated from full blood of two sets of donors. DNA was converted by bisulphite conversion and then amplified by Nested PCR. The PCR product was cloned to bacteria. Than positive colonies were selected. Subsequent methylation analysis was performed. RNA was converted to cDNA by Reverse transcription. Relative expression was analyzed...
23

A Comprehensive View of the Epigenetic Landscape Part I: DNA Methylation, Passive and Active DNA Demethylation Pathways and Histone Variants

Sadakierska-Chudy, Anna, Kostrzewa, Richard M., Filip, Małgorzata 01 January 2015 (has links)
In multicellular organisms, all the cells are genetically identical but turn genes on or off at the right time to promote differentiation into specific cell types. The regulation of higher-order chromatin structure is essential for genome-wide reprogramming and for tissue-specific patterns of gene expression. The complexity of the genome is regulated by epigenetic mechanisms, which act at the level of DNA, histones, and nucleosomes. Epigenetic machinery is involved in many biological processes, including genomic imprinting, X-chromosome inactivation, heterochromatin formation, and transcriptional regulation, as well as DNA damage repair. In this review, we summarize the recent understanding of DNA methylation, cytosine derivatives, active and passive demethylation pathways as well as histone variants. DNA methylation is one of the well-characterized epigenetic signaling tools. Cytosine methylation of promoter regions usually represses transcription but methylation in the gene body may have a positive correlation with gene expression. The attachment of a methyl group to cytosine residue in the DNA sequence is catalyzed by enzymes of the DNA methyltransferase family. Recent studies have shown that the Ten-Eleven translocation family enzymes are involved in stepwise oxidation of 5-methylcytosine, creating new cytosine derivatives including 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine. Additionally, histone variants into nucleosomes create another strategy to regulate the structure and function of chromatin. The replacement of canonical histones with specialized histone variants regulates accessibility of DNA, and thus may affect multiple biological processes, such as replication, transcription, DNA repair, and play a role in various disorders such as cancer.
24

A Fluorescein-Containing, Small-Molecule, Water-Soluble Receptor for Cytosine Free Bases

Jiang, Yu L., Patel, Puneet, Klein, Suzane M. 01 October 2010 (has links)
In this study, we synthesized small-molecule, water-soluble, fluorescein-containing ureido compounds 6 and 8 as target receptors for cytosine free bases and then investigated the binding of cytosine free bases with the receptors using 15N NMR spectroscopy and partially labeled cytosine-2,4-13C-1,3,4-15N-cytosine. Binding with the receptor 6a (the disodium form of 6) caused the chemical shift of the nitrogen atom of the amino group of cytosine to move downfield; binding of the receptor 8a (the disodium form of 8), which is possessing no corresponding aryl nitrogen atom, had no effect on this signal. Fluorescence spectroscopy revealed that binding of cytosine and its derivatives led to quenching of the fluorescence of receptor 6a; in contrast, the quenching of receptor 8a was only slightly affected by cytosine. Because the fluorescence of 6a was not quenched by either deoxycytidine or uracil, it appears that this receptor is a specific for cytosine among the DNA bases. We used the fluorescence of 6a to measure the apparent binding constants for various cytosine derivatives, including the anticancer prodrug 5-fluorocytosine. Receptor 6a is the first small-molecule, water-soluble fluorescent receptor for the specific binding of cytosine free bases in aqueous solution.
25

Using Quantum Mechanics to Investigate the Photophysical Properties of the DNA and RNA Bases and their Fluorescent Analogs

Kistler, Kurt Andrew January 2010 (has links)
The ability of the nucleic acids to absorb ultraviolet light and remain relatively photostable is a property upon which life depends. The nucleobases, which are the primary chromophores, when irradiated display rapid radiationless decay back to the ground state, in general faster than is needed for photoreaction. Fluorescent analogs of these bases have structures similar to the nucleic acid bases, but display much longer excited state lifetimes. Theoretical investigations using quantum mechanical methods can provide insight into the precise mechanisms of these decay processes, and to the molecular specifics that contribute to them. The results of multi-reference configuration interaction (MRCI) ab initio investigations into these mechanisms are presented, with emphasis on cytosine and its fluorescent analog 5-methyl-2-pyrimidinone (5M2P). A comprehensive picture of the potential energy surfaces of these two bases is given, including stationary points and conical intersections, where radiationless transitions are promoted, between up to three state surfaces, as well as pathways connecting these points for each base. Cytosine is shown to have two different energetically accessible radiationless decay channels. The fluorescence of 5M2P is also demonstrated theoretically, with mechanism proposed. The potential energy surfaces of the two bases have many close similarities, with the different photophysical properties being attributed to subtle energetic differences between the two bases. Nonadiabatic coupling and the geometric phase effect are analyzed in detail near conical intersections in cytosine, including in a region close to a three-state conical intersection. A substituent effect study on the 2-pyrimidinone ring system shows that the presence, position and orientation of the amino group in cytosine is central to its photophysical properties, particularly its high absorption energy, and can be explained with a simple Frontier Molecular Orbital model. The effects of water solvent on the excitation energies of cytosine and uracil are theoretically investigated using two multi-reference ab initio methods, a quantum mechanical molecular mechanics method using MRCI (MRCI-QM/MM), and the fragment molecular orbital multiconfiguration self-consistent field method (FMO-MCSCF). The solvatochromic shifts calculated from both methods agree well with other more expensive methods and experimental data. The effects of water on the photophysical pathways of cytosine is also investigated using MRCI-QM/MM, including considerations of solvent reorganization. Results show that the overall effect of water on the decay mechanisms is small, with neither decay channel being significantly blocked or favored. / Chemistry
26

Evaluation of Computational and Experimental Parameters in RNA Bisulfite Sequencing Analysis and Applications in Brain Development Studies

Johnson, Zachary Austin 13 September 2023 (has links)
Epitranscriptomics, the study of RNA modifications, has become a hotspot of research over the last decade. Over 170 unique modifications have been discovered with a widespread occurrence in a diverse range of RNAs. 5-methylcytosine, m5C, is an evolutionarily conserved and reversable modification that regulates the stability and export of tRNAs, rRNAs, and mRNAs. m5C has recently been implicated in many biological phenomena including tumorigenesis, embryonic cell expansion and differentiation, brain development, and neuronal functions. While we are just beginning to understand the functions of m5C, a gold standard of m5C detection has yet to be established due to the low signal-to-noise presence of m5C. In this work, we utilize RNA bisulfite sequencing as a transcriptome-wide approach to understand the computational and chemical parameters needed to optimize m5C discovery in the mitochondria and the developing brain. In Chapter 1, we systematically evaluate four preparation conditions of bisulfite sequencing to identify potential presence of m5C-mRNAs localized to the mitochondria in neuronal stem cells. In tandem, we utilize unique molecular identifiers and a consortium of control template transcripts to evaluate sources of false positive m5C sites that may emerge from sequencing errors, PCR amplification, and the inadequate bisulfite conversion of transcripts. While improvements to mitochondrial transcript bisulfite conversion and false positive filtering were observed, no mitochondrial mRNAs were identified to be methylated, indicating no or very few methylated cytosines in mitochondrial mRNAs and the need for improved chemical methods to detect mitochondrial m5C-mRNAs if any. In Chapter 2, we employ the computational approaches established in Chapter 1 to survey the m5C landscape of the developing mammalian brain. We discover a general increase in unique m5C sites in mouse whole brain tissue when compared to neuronal cell cultures. Of these sites, we found the post-natal day 0 and 17 brain time points to undergo significant methylation level changes in comparison to the 6-week-old brain. These differentially methylated sites were significantly enriched for brain development, synaptic development, and transcriptional control gene network pathways. In Chapter 3, we expand on our findings in Chapter 2 to understand the impact of m5C reader FMRP and m5C eraser TET1 loss in the mouse post-natal day 17 brain. Among a set of m5C sites identified in wildtype or knockout samples, few were differentially methylated after protein ablation, suggesting m5C may rely on compensatory enzymes. Using FMRP-RNA pulldown assays to validate FMRP binding positions, we identified Ralbp1 to be hypermethylated and overexpressed in Fmr1-KO brain tissues. RalBP1 is a binding protein responsible for the endocytosis of AMPA receptors, a process critical for neuronal long term depression and brain development. / Doctor of Philosophy / Ribonucleic acid (RNA) is the product of deoxyribonucleic acid (DNA) transcription and the precursor to protein translation. Chemical modifications can be made to the bases of DNA, known as epigenetic modifications, to elicit new functions and responses to the environment. Epitranscriptomics refers to the study of RNA modifications that also serve unique roles and functions depending on the type of modification made. Here, we study the presence of 5-methylcytosine, a methyl group added to the cytosine (C) base of RNA. This modification is found throughout all branches of life and is known to promote the stability and export of many RNA types. Recently, studies have utilized many techniques including RNA bisulfite sequencing to find links between the presence of m5C-RNAs and cancer progression, stem cell development, and brain development. RNA bisulfite sequencing uses chemical applications to convert non-methylated "C"s to the RNA base "U", while retaining a "C" signature on methylated "C"s. However, due to the extremely low presence of RNA-m5C in comparison to DNA-m5C, sources of noise make it difficult to identify a true m5C signal. Because of this discrepancy, established analytical methods based on DNA biology may not be suitable for RNA analysis. To address shortcomings in current detection methods of RNA-m5C, we performed systematic analysis of 1) different preparation methods for improved m5C detection methods and 2) computational approaches for the filtering of false positive m5C sites, as described in Chapter 1. To achieve these goals, we expanded the breadth of analytical methods by including unique molecular identifiers and expanding the set of control RNA sequences to better grasp how false positive sites might be introduced into non-methylated sequences. While noticeable improvements were made to control RNA sequence false positive detection, we found that most mitochondrial RNAs did not carry the same m5C signatures as RNAs from other sources. Because of this difference, we could not conclude that mitochondrial mRNAs were methylated. Therefore, we suggest that future studies may need to develop better or alternative methods for the detection of mitochondrial RNA-m5Cs. In Chapters 2 and 3, we utilize the computational methods developed in Chapter 1 to understand how m5C levels change throughout the development of a mouse's brain. By investigating the m5C profiles of mouse newborn, young child, and juvenile brains, we found significant changes in m5C levels specific to certain RNAs. These RNAs are associated with neuronal growth, development, and maturation, which may have implications for m5C's role in cognitive development, intellectual disabilities, and neurodegenerative disorders. To discover if these RNAs could be affected by the absence of m5C-specific proteins, we created mice deficient in a protein m5C reader, FMRP, and an m5C eraser protein, TET1. Interestingly, we did not find a significant difference in mice deficient in the proteins, indicating m5C may rely on multiple proteins to serve redundant functions. However, one RNA, Ralbp1, was found to be significantly methylated in FMRP deficient models. This RNA is essential for developmental changes in the brain as well as neuronal growth and could be an interesting target for future research.
27

Modulation of RNA Cytosine-5 Methylation by Neuronal Activity and Methyl-donor Folate

Xu, Xiguang 09 June 2020 (has links)
RNA epigenetics or Epitranscriptomics has emerged as a new field for understanding the post-transcriptional regulation of gene expression by RNA modifications. Among numerous types of RNA modifications, RNA cytosine-5 methylation (5-mrC) is recognized as an important epitranscriptomic mark that modulates mRNA transportation, stability and translation. In chapter 1, we summarize the currently available approaches to detect 5-mrC modification at global, transcriptome-wide and locus-specific levels, and compare the corresponding advantages and disadvantages of the techniques. We further focus on the bioinformatics data analysis of RNA bisulfite sequencing datasets by comparing existing packages with respect to key parameters for alignment and methylation calling and filtering of potentially false positive 5-mrC sites. To investigate the dynamic regulation of 5-mrC modification, as described in chapter 2, we adopt a widely used neuronal activity model, and perform RNA sequencing (RNA-seq) and RNA bisulfite sequencing (RNA BS-seq) to profile gene expression as well as transcriptome-wide 5-mrC modification. We have identified distinct gene expression profiles and differentially methylated 5-mrC sites (DMS) in neurons upon activation, and the genes with DMS sites are enriched with mitochondrial and synaptic functions. Moreover, it reveals a negative correlation between RNA methylation and mRNA expression in mouse cortical neurons during neuronal activity. Thus, these findings identify the dynamic regulation of 5-mrC modification during neuronal activity and reveal a potential link between RNA methylation and mRNA expression. In chapter 3, we investigate the effect of folate, a methyl-donor, on RNA cytosine-5 methylation (5-mrC) modification in adult mouse neural stem cells (NSCs). Compared to the control, NSCs cultured in folate deficiency or supplementation condition have shown no changes in mRNA expression, but significant changes in mRNA translation efficiency. RNA bisulfite sequencing of both total and polysome poly(A) RNA samples shows distinct 5-mrC profiles in NSCs treated with different concentrations of folic acid. It also shows consistent hypermethylation in polysome mRNAs than that in total mRNAs. This study presents the comprehensive influence of folate deficiency and supplementation on RNA cytosine-5 methylation and mRNA translation. / Doctor of Philosophy / RNA epigenetics, a collection of RNA modifications, has recently emerged as an exciting, new field for understanding post-transcriptional regulation of gene expression. RNA cytosine-5 methylation (5-mrC) is one of the most well-known RNA modifications that modulates mRNA export, stability and translation. In the first chapter, we summarize the currently available methods for the measurement of 5-mrC modification. We highlight one of the techniques, RNA bisulfite sequencing (RNA BS-seq) and focus on the bioinformatics data analysis of RNA BS-seq datasets. We have compared several existing tools in regard of the key parameters in data analysis. In the second chapter, we adopt a widely used neuronal activity model to study the dynamic regulation of RNA cytosine-5 methylation (5-mrC). We perform RNA-seq and RNA BS-seq in neurons in response to stimulation. We have identified numerous differentially expressed genes and differentially methylated 5-mrC sites in activated neurons and find that these DMS-related genes are associated with mitochondrial and synaptic functions. Furthermore, we identify a negative correlation between RNA methylation and mRNA expression, indicating a potential role of 5-mrC modification in the regulation of mRNA expression. In the third chapter, we investigate the influence of a nutrient supplement, folic acid, on 5-mrC modification in adult mouse neural stem cells. Compared to the control, NSCs cultured in folate deficiency or supplementation condition have shown no changes in mRNA expression, but significant changes in mRNA translation efficiency. We perform RNA bisulfite sequencing of both total poly(A) RNA samples and polysome poly(A) RNA samples. We identify distinct 5-mrC profiles in NSCs treated with different concentrations of folic acid. It shows consistent hypermethylation in polysome mRNAs than that in total mRNAs. This study presents the comprehensive influence of folate deficiency and supplementation on RNA cytosine-5 methylation and mRNA translation.
28

Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome.

Pedersen, J.S., Valen, E., Velazquez, A.M.V., Parker, B.J., Lindgreen, S., Lilje, B., Tobin, Desmond J., Kelly, T.K., Vang, S., Andersson, R., Jones, P.A., Hoover, C.A., Prokhortchouk, E., Rubin, E.M., Sandelin, A., Gilbert, M.T.P., Krogh, A., Willerslev, E. January 2014 (has links)
Yes / Epigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of DNA isolated from ancient remains. Using the genome sequence data generated from hair shafts of a 4000-yr-old Paleo- Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues. Using ancient methylation information, we estimated the age at death of the Saqqaq individual and illustrate how epigenetic information can be used to infer ancient gene expression. Similar epigenetic signatures were found in other fossil material, such as 110,000- to 130,000-yr-old bones, supporting the contention that ancient epigenomic information can be reconstructed from a deep past. Our findings lay the foundation for extracting epigenomic information from ancient samples, allowing shifts in epialleles to be tracked through evolutionary time, as well as providing an original window into modern epigenomics.
29

Mechanistic Studies and Function Discovery of Mononuclear Amidohydrolase Enzymes

Hall, Richard Stuart 2009 December 1900 (has links)
The amidohydrolase superfamily is a functionally diverse group of evolutionarily related proteins which utilize metal cofactors in the activation of a hydrolytic water molecule and in the stabilization of the resulting tetrahedral intermediate. Members of this superfamily have been described which use one or two divalent transition metals. These metal cofactors are located in either or both of two active-site metal binding centers which are labeled as the Ma and MB sites. The goal of this research was to elucidate the nature of the reactions catalyzed by Ma and MB mononuclear members of the amidohydrolase superfamily. This was approached through comprehensive mechanistic evaluations of two enzymes which utilized the different metal sites. Nacetyl- D-glucosamine-6-phosphate deacetylase from E. coli (NagA) and cytosine deaminase from E. coli (CDA) served as models for mononuclear amidohydrolase superfamily enzymes which have evolved to utilize a single B-metal and a single a-metal for hydrolysis, respectively. This research elucidated the different properties imparted by the distinct a and B active sites and the specific interactions utilized by the enzymes for substrate binding and catalysis. These studies led to the eventual proposal of detailed chemical mechanisms and the identification of rate determining steps. Knowledge of sequence-function relationships was applied toward the discovery of function for enzymes related to cytosine deaminase and guanine deaminase. The first group of enzymes investigated was proposed to catalyze the fourth step in riboflavin and coenzyme F420 biosynthesis in Achaea. Three putative deaminases; Mm0823 from Methanosarcina mazei, MmarC7_0625 from Methanococcus maripaludis C7 and Sso0398 from Sulfolobus solfataricus were cloned and expressed. These proteins proved to be intractably insoluble. A second set of enzymes, Pa0142 from Pseudomonas aeruginosa PA01 and SGX-9236e (with crystal structure PDB: 3HPA) were found to catalyze the novel deamination of 8-oxoguanine, a mutagenic product of DNA oxidation. 9236e was cloned from an unidentified environmental sample of the Sargasso Sea. The closest homolog (98% identical) is Bcep18194_A5267 from Burkholderia sp. 383. Additionally, it was discovered that the proteins SGX-9339a (with crystal structure PDB: 2PAJ) and SGX-9236b catalyzed the deamination of isoxanthopterin and pterin-6- carboxylate in a poorly characterized folate degradation pathway. These enzymes were also from unknown environmental samples of the Sargasso Sea. The closest homolog of 9339a (88% identical) is Bxe_A2016 from Burkholderia xenovorans LB400. The closest homolog of 9236b (95% identical) is Bphyt_7136 from Burkholderia phytofirmans PsJN.
30

Effect of DNA methyltransferase 1 on transmission ratio distortion and epigenetic inheritance

Yang, Lanjian, 1976- January 2008 (has links)
Epigenetic modification of DNA plays an important role in gene regulation. During gametogenesis and early embryogenesis epigenetic states are reset to ensure embryonic-specific gene expression patterns after fertilization. However, certain genomic regions may resist epigenetic reprogramming. This may result in transgenerational epigenetic inheritance. Earlier, a grandparental origin dependent (GPO) transmission ratio distortion (TRD) of alleles in the distal region of mouse chromosome 12 had been found (Croteau et al ., 2002). The distorted region overlaps with the imprinted region of chromosome 12. The mechanism underlying this TRD is unknown, and we hypothesized that it was due to failure to reset imprints in the imprinted region in a proportion of germ cells. Such an imprint resetting failure would represent a particular case of transgenerational epigenetic inheritance. DNA (Cytosine-5) methyltransferase 1 (DNMT1) plays a key role in the maintenance of epigenetic states in mammalian genomes. To test the role of DNA methylation and DNMT1 in the genesis of TRD and its relationship to epigenetic inheritance we investigated the effect of Dnmt1 loss-of-function mutations using two mouse models: GPO (grandparental origin dependent)-TRD (transmission ratio distortion) and epigenetic inheritance at the agouti locus. Here, we report that Dnmt1 mutations have a modifying parental effect on the transmission of grandparental chromosome 12 alleles. However, the same Dnmt1 mutation did not affect the agouti coat color inheritance patterns in mice that inherited the Avy (agouti viable yellow) mutant allele from the father. Our results suggest that Dnmt1 is a trans-acting modifier of allelic transmission and support the role of epigenetic states in the genesis of TRD.

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