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Gene Expresion

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1. DEFINATION: Nuclear receptors are a superfamily of ligand activated transcription factors that modulate specific gene expression.
Currently there are 100 nuclear receptor are identified[1].
2. INTRODUCTION: In the field of molecular biology, nuclear receptors are a class of proteins found within other molecules. In response, these receptors work in concert with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors only happens when a ligand—a molecule which affects the receptor's behavior is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor which in turn activates the receptor resulting in up-regulation of gene expression.
A unique property of nuclear receptors which differentiate them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA. Consequently nuclear receptors play key roles in both the embryonic development and adult homeostasis of organisms [2, 3, 4].


Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases which explains why the molecular targets of approximately 13% of FDA approved drugs are nuclear receptors
A number of nuclear receptors, referred to as orphan receptors, have no known endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics[5].
[pic] [FIGURE-1]
Structural Organization ofNuclearReceptors
Top – Schematic 1D amino acid sequence of a nuclear receptor.
Bottom – 3D structures of the DBD (bound to DNA) and LBD (bound to hormone) regions of the nuclear receptor. The structures shown are of the estrogen receptor. Experimental structures of N-terminal domain (A/B), hinge region (D), and C-terminal domain (E) have not been determined therefore are represented by red, purple, and orange dashed lines respectively.
Nuclear receptors are modular in structure and contain the following domains:

• A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand. The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 (see below) to produce a more robust upregulation of gene expression. The A-B domain is highly variable in sequence between various nuclear receptors.

• C) DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers which binds to specific sequences of DNA called hormone response elements (HRE).

• D) Hinge region: Thought to be a flexible domain which connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution.

• E) Ligand binding domain (LBD): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors.

• in which three anti parallel alpha helices (the "sandwich filling") are The structure of the LBD is referred to as an alpha helical sandwich fold (SCOP flanked by two alpha helices on one side and three on the other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling". Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. Contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.

• F) C-terminal domain: Variable in sequence between various nuclear receptors [7-12].


[pic] [FIGURE-2]
Mechanism nuclear receptor action: This figure depicts the mechanism of a class II nuclear receptor (NR) which, regardless of ligand binding status is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein which in turn recruit additional proteins such as RNA polymerase that are responsible for translation of downstream DNA into RNA and eventually protein which results in a change in cell function.
Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand.
Small lipophilic substances such as natural hormones diffuse past the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. This causes a change in the conformation of the receptor which depending on the mechanistic class (type I or II), triggers a number of down stream events that eventually results in up or down regulation of gene expression.
Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes.

Type I

Ligand binding to type I nuclear receptors in the cytosol (includes members of the NR subfamily 3) results in the dissociation of heat shock proteins, homo-dimerization, translocation (i.e., active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HRE's). Type I nuclear receptors bind to HREs consisting of two half sites separated by a variable length of DNA and the second half site has a sequence inverted from the first (inverted repeat).
The nuclear receptor/DNA complex then recruits other proteins which transcribe DNA downstream from the HRE into messenger RNA and eventually protein which causes a change in cell function.

Type II

Type II receptors (principally NR subfamily 1) in contrast are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to the NR/DNA complexes which transcribe DNA into messenger RNA.

Type III

Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA as homodimers. However, type III nuclear receptors, in contrast to type I, bind to direct repeat instead of inverted repeat HREs.

Type IV

Type IV nuclear receptors bind either as monomers or dimers, but only a single DNA binding domain of the receptor binds to a single half site HRE. Examples of type IV receptors are found in most of the NR subfamilies [13-17]

5. Coregulatory proteins

Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators) which facilitate or inhibit the transcription of the associated target gene into mRNA.The function of these coregulators are varied and include chromatin remodeling (making the target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins.


Binding of agonist ligands (see section below) to nuclear receptors induces a conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic histone acetyltransferase (HAT) activity which weakens the association of histones to DNA, and therefore promotes gene transcription.


Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressor proteins. These proteins in turn recruit histone deacetylases (HDACs) which strengthens the association of histones to DNA, and therefore represses gene transcription [18-20].

6. Agonism vs Antagonism:

Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism.


The activity of endogenous ligands (such as the hormones estradiol and testosterone) when bound to their cognate nuclear receptors is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor antiiflammatory drug dexamethasone. Agonist ligands work by inducing a conformation of the receptor which favors coactivator binding (see upper half of the figure to the right).


Other synthetic nuclear receptor ligands have no apparent effect on gene transcription in the absence of endogenous ligand. However they block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. These ligands are referred to as antagonists. An example of antagonistic nuclear receptor drug is mifepristone which binds to the glucocorticoid and progesterone receptors and therefore blocks the activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator and promotes corepressor binding

Inverse agonists

Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists [21].
A number of drugs that work through nuclear receptors display an agonist response in some tissues and an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining the desired beneficial therapeutic effects of a drug while minimizing undesirable side effects. Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs).
Examples:nclude Selective Estrogen Receptor Modulators (SERMs) and Selective Progesterone Receptor Modulators (SPRMs). The mechanism of action of SRMs may vary depending on the chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism. In tissues where the concentration of coactivator proteins is higher than corepressors, the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate, the ligand behaves as an antagonist[22].

7. ALTERNATIVE mechanisms:


The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation. However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in a process known as transrepresson.


The classical direct effects of nuclear receptors on gene regulation normally takes hours before a functional effect is seen in cells because of the large number of intermediate steps between nuclear receptor activation and changes in protein expression levels. However it has been observed that some effects from the application of hormones such as estrogen occur within minutes which is inconsistent with the classical mechanism nuclear receptor action. While the molecular target for these non-genomic effects of nuclear receptors has not been conclusively demonstrated, it has been hypothesized that there are variants of nuclear receptors which are membrane associated instead of being localized in the cytosol or nucleus. Furthermore these membrane associated receptors function through alternative signal transduction mechanisms not involving gene regulation [23-24].

Subfamily 1: Thyroid Hormone Receptor-like

• Group A: Thyroid hormone receptor (Thyroid hormone) o 1: Thyroid hormone receptor-α (TRα) o 2: Thyroid hormone receptor-β (TRβ) • Group B: Retinoic acid receptor (Vitamin A and related compounds) o 1: Retinoic acid receptor-α (RARα) o 2: Retinoic acid receptor-β (RARβ) o 3: Retinoic acid receptor-γ (RARγ) • Group C: Peroxisome proliferator-activated receptor (fatty acids, prostaglandins) o 1: Peroxisome proliferator-activated receptor-α (PPARα ) o 2: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) o 3: Peroxisome proliferator-activated receptor-γ (PPARγ) • Group D: Rev-ErbA (heme) o 1: Rev-ErbAα o 2: Rev-ErbAβ • Group F: RAR-related orphan receptor (cholesterol) o 1: RAR-related orphan receptor-α (RORα) o 2: RAR-related orphan receptor-β (RORβ) o 3: RAR-related orphan receptor-γ (RORγ) • Group H: Liver X receptor-like (oxysterol) o 3: Liver X receptor-α (LXRα) o 2: Liver X receptor-β (LXRβ) o 4: Farnesoid X receptor (FXR) • Group I: Vitamin D receptor-like o 1: Vitamin D receptor (VDR) (vitamin D) o 2: Pregnane X receptor (PXR (xenobiotics) o 3: Constitutive androstane receptor (CAR) (androstane)

Subfamily 2: Retinoid X Receptor-like

• Group A: Hepatocyte nuclear factor-4 (HNF4) (fatty acids) o 1: Hepatocyte nuclear factor-4-α (HNF4α) o 2: Hepatocyte nuclear factor-4-γ (HNF4γ) • Group B: Retinoid X receptor (RXRα) (retinoids) o 1: Retinoid X receptor-α (RXRα) o 2: Retinoid X receptor-β (RXRβ) o 3: Retinoid X receptor-γ (RXRγ) • Group C: Testicular receptor o 1: Testicular receptor 2 (TR2) o 2: Testicular receptor 4 (TR4) • Group E: TLX/PNR o 1: Human homologue of the Drosophila tailless gene (TLX) o 2: Photoreceptor cell-specific nuclear receptor (PNR) • Group F: COUP/EAR o 1:Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) o 2:Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) o 3:V-erbA-related gene|V-erbA-related (EAR-2 )

Subfamily 3: Estrogen Receptor-like

• Group A: Estrogen receptor (Sex hormones: Estrogen) o 1: Estrogen receptor-α (ERα) o 2: Estrogen receptor-β (ERβ) • Group B: Estrogen related receptor o 1: Estrogen-related receptor-α (ERRα) o 2: Estrogen-related receptor-β (ERRβ) o 3: Estrogen-related receptor-γ (ERRγ) • Group C: 3-Ketosteroid receptors o 1: Glucocorticoid receptor (GR) (Cortisol) o 2: Mineralocorticoid receptor (MR) (Aldosterone) o 3: Progesterone receptor (PR) (Sex hormones: Progesterone) o 4: Androgen receptor (AR) (Sex hormones: Testosterone)

Subfamily 4: Nerve Growth Factor IB-like

• Group A: NGFIB/NURR1/NOR1 o 1: Nerve Growth factor IB (NGFIB) o 2: Nuclear receptor related 1 (NURR1) o 3: Neuron-derived orphan receptor 1 (NOR1)

Subfamily 5: Steroidogenic Factor-like

• Group A: SF1/LRH1 o 1: Steroidogenic factor 1 (SF1) o 2: Liver receptor homolog-1 (LRH-1)[25-26]

Subfamily 1: Thyroid Hormone Receptor-like

The thyroid hormone receptor is a type of nuclear receptor that is activated by binding thyroid hormone. • Group A: Thyroid hormone receptor (Thyroid hormone) o 1: Thyroid hormone receptor-α (TRα) o 2: Thyroid hormone receptor-β (TRβ) • TR-α1 -widely expressed and especially high expression in cardiac and skeletal muscles • TR-α2 - widely expressed but unable to bind hormone • TR-β1 -predominately expressed in brain, liver and kidney • TR-β2 -expression primarily limited to the hypothalamus and pituitary

Disease linkage

Certain mutations in the thyroid hormone receptor are associated with thyroid hormone resistance. • Group B: Retinoic acid receptor (Vitamin A and related compounds) o 1: Retinoic acid receptor-α (RARα) o 2: Retinoic acid receptor-β (RARβ) o 3: Retinoic acid receptor-γ (RARγ)
The retinoic acid receptor (RAR) is a type of nuclear receptor which is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma encoded by the RARA, RARB, RARG genes respectively. Each receptor isoform has several splice variants: two- for alpha, four- for beta and two- for gamma.
As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein which in turn promotes transcription of the downstream target gene into mRNA and eventually protein. • Group C: Peroxisome proliferator-activated receptor (fatty acids, prostaglandins) o 1: Peroxisome proliferator-activated receptor-α (PPARα ) o 2: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) o 3: Peroxisome proliferator-activated receptor-γ (PPARγ)
In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, and protein) of higher

organisms: [pic] [FIGURE-3]
Three types of PPARs have been identified: alpha, gamma, and delta (beta). ▪ α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others ▪ β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin ▪ γ (gamma) - although transcribed by the same gene, this PPAR through alternative splicing is expressed in three forms: ▪ γ1 - expressed in virtually all tissues, including heart, muscle, colon, ▪ kidney, pancreas, and spleen ▪ γ2 - expressed mainly in adipose tissue (30 amino acids longer) ▪ γ3 - expressed in macrophages, large intestine, white adipose tissue.

PPARs were originally identified in Xenopus frogs as receptors that induce the proliferation of peroxisomes in cells. The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as peroxisome proliferators, as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity. These agents, pharmacologically related to the fibrates were discovered in the early 1980s. When it turned out that PPARs played a much more versatile role in biology, the agents were in turn termed PPAR ligands. The best-known PPAR ligands are the thiazolidinediones; see below for more details.
After PPARδ (delta) was identified in humans in 1992, it turned out to be closely-related to the PPARβ (beta) previously described during the same year in other animals (Xenopus). The name PPARδ is generally used in the US, whereas the use of the PPARβ denomination has remained in Europe where this receptor was initially discovered in Xenopus.
Physiological function:
All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. These DNA sequences are termed PPREs (peroxisome proliferator hormone response elements). The DNA consensus sequence is AGGTCAXAGGTCA, with X being a random nucleotide. In general, this sequence occurs in the promotor region of a gene, and, when the PPAR binds its ligand, transcription of target genes is increased or decreased, depending on the gene. The RXR also forms a heterodimer with a number of other receptors (e.g., vitamin D and thyroid hormone).
The function of PPARs is modified by the precise shape of their ligand-binding domain (see below) induced by ligand binding and by a number of coactivator and corepressor proteins, the presence of which can stimulate or inhibit receptor function, respectively.
Endogenous ligands for the PPARs include free fatty acids and eicosanoids. PPARγ is activated by PGJ2 (a prostaglandin). In contrast, PPARα is activated by leukotriene B4.

PPAR gamma [FIGURE-4]
Like other nuclear receptors, PPARs are modular in structure and contain the following functional domains: ▪ (A/B) N-terminal region ▪ (C) DBD (DNA-binding domain) ▪ (D) flexible hinge region ▪ (E) LBD (ligand binding domain) ▪ (F) C-terminal region
The DBD contains two zinc finger motifs, which bind to specific sequences of DNA known as hormone response elements when the receptor is activated. The LBD has an extensive secondary structure consisting of 13 alpha helices and a beta sheet Natural and synthetic ligands bind to the LBD, either activating or repressing the receptor. PPAR modulator
PPARα and PPARγ are the molecular targets of a number of marketed drugs, e.g. the fibrates. The synthetic chemical perfluorooctanoic acid activates PPARα while the synthetic perfluorononanoic acid activates both PPARα and PPARγ. ▪ Thiazolidinedione ▪ Anti-diabetic drug ▪ Diabetes mellitus ▪ Insulin resistance ▪ Metabolic syndrome[27-30]

▪ The retinoid X receptor (RXR) is a type of nuclear receptor which is activated by 9-cis retinoic acid.[2] There are three retinoic acid receptors (RXR), RXR-alpha, RXR-beta, and RXR-gamma encoded by the RXRA, RXRB, RXRG genes respectively.
▪ RXR heterodimerizes with subfamily 1 nuclear receptors including CAR, FXR, LXR, PPAR, PXR, RAR, TR, and VDR.
▪ As with other type II nuclear receptors, the RXR heterodimer in the absence of ligand is bound to hormone response elements complexed with corepressor protein. Binding of agonist ligands to RXR results in dissociation of corepressor and recruitment of coactivator protein which in turn promotes transcription of the downstream target gene into mRNA and eventually protein[28].


Estrogen receptor refers to a group of receptors which are activated by the hormone 17β-estradiol. Two types of estrogen receptor exist: ER which is a member of the nuclear hormone family of intracellular receptors and the estrogen G protein coupled receptor GPR30 (GPER), which is a G-protein coupled receptor.. The main function of the estrogen receptor is as a DNA binding transcription factor which regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding


There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2 respectively). Hormone activated estrogen receptors form dimers, and since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.[3] Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of seven domains (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER): The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand independent regulation. Due to alternative RNA splicing, several ER isoforms are known to exist. At least three ERalpha and five ERbeta isoforms have been identified. The ERbeta isoforms receptor subtypes can only transactivate transcription when a heterodimer with the functional ERß1 receptor of 59 kDa is formed. The ERß3 receptor was detected at high levels in the testis. The two other ERalpha isoforms are 36 and 46kDa.[4][5] Only in fish, but not in humans, an ERgamma receptor has been described


Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:[7]
• The ERα is found in endometrium, breast cancer cells, ovarian stroma cells and in the hypothalamus.[8]
• The expression of the ERβ protein has been documented in kidney, brain, bone, heart,[9] lungs, intestinal mucosa, prostate, and endothelial cells. The ERs are regarded to be cytoplasmic receptors in their unliganded state, but visualization research has shown that a fraction of the ERs resides in the nucleus]

Binding and functional selectivity:

Estrogen receptor bound to the estradiol hormone (top; PDB 1QKU) and to anticancer drug tamoxifen (bottom; 3ERT). These two ligands induce different conformations in the receptor (highlighted in green) which accounts for their different functional activity (agonist vs. antagonist respectively). See the estrogen molecule of the month web page for more details. The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and thereby the respective agonist or antagonist effect of the ligand.[11][12] Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:
• 17-beta-estradiol binds equally well to both receptors
• estrone and raloxifene bind preferentially to the alpha receptor • estriol and genistein to the beta receptor Subtype selective estrogen receptor modulators preferentially bind to either the α- or β-subtype of the receptor. Additionally, the different estrogen receptor combinations may respond differently to various ligands which may translate into tissue selective agonistic and antagonistic effects.[13] The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.[14] The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressors. Furthermore the ratio of coactivator to corepressor protein varies in different tissues.[15] As a consequence, the same ligand may be an agonist in some tissue (where coactivators predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in breast and is therefore used as a breast cancer treatment[16] but an ER agonist in bone (thereby preventing osteoporosis) and a partial agonist in the endometrium (increasing the risk of uterine cancer[29-32]


The Nerve Growth factor IB protein is a member of the Nur nuclear receptor family of intracellular transcription factors and is encoded by the NR4A1 gene NGFIB is involved in cell cycle mediation, inflammation and apoptosis.[4] The NGFIB protein plays a key role in mediating inflammatory responses in macrophages.[4] In addition, subcellular localization of the NGFIB protein appears to play a key role in the survival and death of cells.[5] Expression is induced by phytohemagglutinin in human lymphocytes and by serum stimulation of arrested fibroblasts. Translocation of the protein from the nucleus to mitochondria induces apoptosis. Multiple alternatively spliced variants, encoding the same protein, have been identified[33-34]


|[pic] |

The steroidogenic factor 1 (SF1) protein is a member of the nuclear receptor family of intracellular transcription factors and is encoded by the NR5A1 gene (nuclear receptor subfamily 5, group A, member 1).[1]
SF-1 is critical regulator of reproduction because its targets include genes at every level of the hypothalamic-pituitary-gonadal axis, as well as many genes involved in gonadal and adrenal steroidogenesis.[35-37]


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...Universidad de Oviedo BLOQUE II. MATEMÁTICA FINANCIERA. 1 Universidad de Oviedo BLOQUE II. Matemática Financiera Tema 4. Fundamentos de la Matemática Financiera. 4.1. Capital Financiero. 4.2. Principio de proyección financiera. Equivalencia financiera y preferencia financiera. 4.3. Leyes financieras de valoración:  Leyes financieras de capitalización  Leyes financieras de descuento. 4.4. Operación financiera. Principio de equivalencia financiera. 4.5. Tipos de interés efectivos equivalentes. Tipo de interés nominal. 2 Dpto. Economía Cuantitativa Universidad de Oviedo BLOQUE II. Matemática Financiera Tema 4. Fundamentos de la Matemática Financiera. 4.6. Reserva matemática de una operación financiera. 4.7. Características comerciales de una operación financiera: unilaterales y bilaterales. 4.8. Coste y rentabilidad de una operación financiera. 4.9 Teoría de rentas:  Rentas: definición, elementos conceptuales, clasificación.  Rentas constantes: valoración 4.10. Valor actual neto (VAN). Tasa interna de retorno o rentabilidad (TIR). 3 Dpto. Economía Cuantitativa Universidad de Oviedo Dpto. Economía Cuantitativa BLOQUE II. Matemática Financiera Tema 5. Operaciones Financieras Básicas. 5.1. Depósitos bancarios a plazo 5.2. Descuento comercial. 5.3. Préstamos.  Préstamo simple (pago único)  Préstamo amortizable mediante pagos constantes (método francés) 4 Objetivo de la matemática financiera Proporcionar modelos matemáticos capaces de reflejar los intercambios......

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The Connection Between the Central Dogma of Molecular Biology/ Bioinformatics, Model Organism and Drug Designing.

...Report on the connection between the Central dogma of Molecular Biology/ Bioinformatics, Model Organism and Drug Designing. The basis of the central dogma of molecular biology is the expression of the genetic information in any call. It is a universal process that occurs in every cell. The genetic information is stored in the DNA. During gene expression DNA is transcript to RNA and these RNA are transcribed to proteins. Bioinformatics deals with the genetic information which involves collecting, analyzing, manipulating and predicting etc. For the functioning of bioinformatics it is essential to know the genetic information that is stored in DNA. Therefore sequencing of DNA, genes or genomes is the fundamental need in bioinformatics. Organisms that are used in biological experiments in laboratories are called ‘model organisms’, of which most genomes are sequenced at present (rat, yeast, Arabidopsis; plant model organism) These sequenced genomes could be analyzed using bioinformatics tools in order to identify genes of significance as in drought tolerance genes in plants etc. Information revealed from sequencing could be studied using bioinformatics tools to understand its underlying mechanisms and to generate models that could be used in further studies. This information could also be used in evolutionary studies, micro array analysis, identification of genetic disorders (Alzheimer’s disease, breast cancer, cystic fibrosis, spinal muscular atrophy......

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Model Organism

...Model Organisms Model organisms are very important to the scientific community. They are primarily used as a standard for comparison to other organisms. If a model organism is recognized then the organism can be useful for many different fields of research. Rice (Oryza sativa) is a model organism that has been introduced and has several essential attributes. When using a model organisms some qualities that should be chosen are a short life cycle, small adult size that makes it easy to grow in a small space, small genome that is well described genetically, high reproductive outcome, already have a large assembly of mutants, and be able to out cross or be self-fertile. When looking for a model organism consideration has to be taken into account for a few things too. Some of the benefits can become a hindrance. In 2010 a new model organism for studying C4 photosynthesis was suggested, a grass (Setaria viridis), by Brutnell et al. S. viridis is a C4 photosynthesis plant. Because of the C4 functions, it will be useful to aid in further research, with having its genome sequencing known, in comparison to other organisms that are not C4 plants. By having these qualities it makes it a good model organism. Some of these good attributes include its life cycle length. In short-day growth conditions it can be grown to full maturity in about six weeks. As an adult the plant is relatively short, less than 10 centimeters and takes up very little space about 50 plants can be grown in......

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...intended. The 1980's marked the scientific discovery that specific pieces of DNA could be transferred from one organism to another (Cramer 2001). Although genetic modification dates back to prehistoric times with “natural selection”, the cross-breeding of relative species and specific characteristics and traits being exchanged. This occurred over time as nature intended with the process of evolution letting animals adapt to their surroundings. The difference is we now posses the technology that allows us to make this “natural selection” process happen at an exponential rate. Such speeds of cross-breeding can bring out deformities in the animal for not sufficient time is allowed in the development process. Every organism carries genes inside itself, a gene is a basic unit of heredity of the biological make up in an organism. Each organism has a specific genetic code but can be altered by introducing foreign DNA to give characteristics that it naturally would not have. This new direction of supposed beneficial science is supported by the scientific community and contrasted to man's selective breeding concept. Though there is an exchange of traits...

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Genetics Lectures

...letters to nature and 10 Na3HP2O7. FV solution also contained 0.2 NaF and 0.1 Na3VO4. Rarely, irreversible current rundown still occurred with FVPP. The total Na+ concentration of all cytoplasmic solutions was adjusted to 30 mM with NaOH, and pH was adjusted to 7.0 with N-methylglucamine (NMG) or HCl. PIP2 liposomes (20–200 nm) were prepared by sonicating 1 mM PIP2 (Boehringer Mannheim) in distilled water. Reconstituted monoclonal PIP2 antibody (Perspective Biosystems, Framingham, MA) was diluted 40-fold into experimental solution. Current–voltage relations of all currents reversed at EK and showed characteristic rectification, mostly owing to the presence of Na+ in FVPP and possibly also residual polyamines. Current records presented (measured at 30 C, −30 mV holding potential) are digitized strip-chart recordings. Purified bovine brain Gbg29 was diluted just before application such that the final detergent (CHAPS) concentration was 5 M. Detergent-containing solution was washed away thoroughly before application of PIP2, because application of phospholipid vesicles in the presence of detergent usually reversed the effects of Gbg; presumably, Gbg can be extracted from membranes by detergent plus phospholipids. Molecular biology. R188Q mutation was constructed by insertion of the mutant oligonucleotides between the Bsm1 and BglII sites of pSPORT– ROMK1 (ref. 11). A polymerase chain reaction (PCR) fragment (amino acids 180–391) from pSPORT–ROMK1 R188Q mutant was subcloned into......

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Utopian Society

...for human studies. Human data may present significant practical and ethical problems. Since the safety of these procedures is fairly new and is currently under investigation, there are no long-term clinical and accurate numbers of research subjects. Even with all these unanswered questions, there are still questions regarding the safety concern involving the results that the majority of genes may have multiple effects. For example, “In the late 1990s, scientists discovered a gene that is linked to memory.” (Tang et al., 1999). “Modifying this gene in mice greatly improved learning and memory, but it also caused increased sensitivity to pain.”(Wei et al., 2001) By altering genes we can’t assume that it will only affect one function, when in actuality it may turn out to disrupt other functions. Individual’s rights and liberty issues are also an issue of concern. “The long-running debate over the ethics of germline genetic alteration has focused on the technology’s broad social implications, such as potential effects on parent-child relations, social inequalities, and the human gene pool.” (Resnik, 1999). A question that has been pondered by many is, parents should be allowed to...

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Personalized Medicine

...Cahill’s article, “The genome project: more than a medical milestone” discusses the history of the human genome project. The project started in 1990. (Cahill, 2000) The goal was to map the entire human genome within 15 years, on a budget of $3 billion. The human genome project is not old by scientific standards. However, the developments from this project have been breakthrough and impressive. The benefits of personalize medicine are easily recognized. The major benefits of personalized medicine are early diagnostics and, medication and treatments are personalized to an individual for maximum results. Diagnostics use molecules to measure the levels of genes, mutation, and proteins that can be used in the provision of specified therapy that fits the patient health condition. (Science daily, 2010). Our DNA and genes can determine the likelihood of an individual developing certain diseases and how an individual can react to certain medication and treatments. With personalized medicine, medical professionals can analyze a patients genome and identify risk factors to intervene and begin a treatment plan that will best cure/treat/delay the disease of that particular patient. Personalized medicine can change the way professionals approach diseases and illnesses. It has the ability to alter healthcare to further fit their individual needs. Using the individuals genome, personalized medicine has become a future possibility. Personalized medicine is developing medicine,......

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Nature Verses Nurture

...Nature Verses Nurture The discussion on the importance of heredity and environment in human development is not new. The nature verses nurture question has been debated for years (Psychology). Nurture side of the debate considers all the environmental influences on an individual after conception. While the nature side of the debate focus on nature that which is inherited, or know as genetics. The nature verse nurture discussion has been a part of the history of psychology that goes back to Francis Galton. Galton was influenced by the book, The Origin of Species written by his cousin, Charles Darwin. The Origin of Species has been criticized for over simplifying two theories of why a lifestyle of wealth, education and privilege seems to be passed on to biological children. Galton takes credit for the phrase in his English Men of Science: Their Nature and Nurture, first published in 1874. In this book he states that nature and nurture are, "a convenient jingle of words, for it separates under two distinct heads the innumerable elements of which personality is composed. Nature is all that a man brings with himself into the world and nurture is every influence that affects him after his birth” (p.12). It is thought that how one is nurtured is what controls the psychological aspects of child development and the concept of growth applies to the biological facets of human life.  When infants bonds to the individual(s) bestowing love and affection, she/he has received,......

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Human Cloneing

...cloning research is just science fiction. That cloning can only be found in movies and book, but the truth is that cloning is real, and it could be happening now. In fact, there are many benefits to human cloning such as diminished disease, new possibilities in science, and better wellness. First, what if I said that doctors and scientist have found a way cure or terminate the suffering cause by diseases and cancers? Well the true is it could be done. Through the studies of cloning and techniques that are learn, and we may be able to diminish diseases and eliminate cancers from society. Which can be accomplished is by learning the human genome and later using the cloning techniques to change the genetic code. This type of science is could gene therapy or genetic modification. By just adding or removing parts off genic cade are, immune system could fright off the worst diseases and cancers. Next, numerous of remarkable benefits come from cloning knowledge, and that would open new possibilities in science. One of these possibilities is the treatment for damaged nerves. By injuring cloned nerve cells where damage was due. A second possibility is clone individual organs. This could be a solution to ever growing demand for organ donors. “The regeneration of diseased or damaged tissues and body parts made is made possible by cloning” Finally, with the help of cloning life would be better. It will give an overall better wellness throughout the world. From cloning, a person......

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Genetic Influence on Behaviour

..."Do Our Genes Influence Behavior?" "Do Our Genes Influence Behavior? Why We Want to Think They Do" Chronicle of Higher Education, November 26, 2004 A few weeks ago I was hurrying past a newsstand in Grand Central Station when the cover of the latest issue of Time stopped me short. Superimposed on a painting of a blue-skinned, red-lipped woman, her hands clasped in prayer, were the words "The God Gene." The article within reported that in a new book with that title, the geneticist Dean Hamer had traced belief in God to a specific gene. "Does our DNA compel us to seek a higher power?" Time asked. The article left me pondering a different question: Given the track record of behavioral geneticists in general, and Dean Hamer in particular, why does anyone still take their claims seriously? Behavioral genetics, which attempts to explain what we are and do in genetic terms, began with the English polymath Francis Galton, who in 1883 coined the term "eugenics" to refer to his proposal that humanity improve itself through judicious breeding. Galton's measurements of the physical and mental characteristics of various groups had convinced him that upper-class gentlemen like himself were innately smarter than poor white men, let alone "inferior races" like Africans. On a trip to Africa, however, Galton was mightily impressed with the physical endowments of Hottentot women, whose bodies he measured from afar with a sextant because he was too timorous to approach......

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Gattaca Film Analysis

...Joshua Barott Professor Peterson Writing 121 30 July 2012 Four Little Nucleotides In an age of rapidly advancing technology, there are those who argue for slowing it down, so it can be critically and ethically examined. However, there are many who believe the opposite, and that there should be as few restrictions as possible. The movie GATTACA is an example of a dystopian future where the advancement and role of technology in our society has been allowed to run unchecked. Ironically, GATTACA, through its obsession with perfection, has created a world less perfect than the one that came before. The value of human life, individuality, relationships, and morals are corrupted. In GATTACA, we are presented with a society where genetic engineering and perfection are worshipped, and anything less is unacceptable and is discriminated against. As Vincent says in the movie, “We have discrimination down to a science.” Every aspect of a person’s life is determined by their genetic code: their job, their personal relationships, and even their basic civil rights. Yet even the genetically advanced suffer from “the burden of perfection.” The world of GATTACA is so totalitarian in nature that human rights are trampled upon and individuality is suppressed. Surely, this is not a perfect world. Vincent would certainly agree. He laments the ways in which society has changed in the ongoing pursuit to create perfection. Old values can no longer contain the same message and relevance. The......

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Genetics Essay

...Genetics Essay Genetics is the science of heredity. Genetics are important to all living things because it is their genes and shows what they look like and how they act. Biological traits are stored in DNA and can be passed on to successive generations through meiosis, which increases genetic variability. DNA stores and transmits genetic information to the next generation. The structure of DNA is double stacked and double helix. Genetic information is stored is stored in DNA chromosomes in 23 pairs. DNA transmits information to the next generation through cellular division. Meiosis increases reproductive variability through crossing-over. Meiosis is the reproduction of gametes (sex cells). Crossing-over is the exchange of chromosomal segments between a pair of homologous chromosomes during prophase I of meiosis. Crossing-over helps variability in cells because it makes the cell different and more adaptable to new or different environments. DNA alternations such as insertions, deletions, and substitutions can cause the appearance of new traits. Insertions are pieces or a piece of DNA copied too many times. Deletions are pieces or a piece of DNA code for one gene is lost. Substitutions change one base for another. These 3 alternations cause new traits to appear by making too many or not enough DNA. Sexual reproduction and asexual reproduction both have advantages and disadvantages. 2 advantages of sexual reproduction are that the offspring is not identical in......

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Biology Osmosis

...Temperature has a great effect on osmosis. Based on our data, the bags that contained water at 55 degrees Celsius had a much greater rate of osmosis than the bags at 15 degrees Celsius. When the environment is heated up, reactions occur at a much faster rate. This is because the extra heat provides more energy. Increasing the concentration also increases the rate of osmosis. This is because there is a lesser concentration of water inside the bag in the 40% rather than the 15%. The water will rush into the bag at a greater rate because of this. Our data shows that at both temperatures the bag that had 40% NaCl concentration added more water faster than the 15% concentration. Every experimental bag increased in weight, but they did not increase at the same rate. According to our data graph, the concentration of NaCl that would be isotonic to the contents of the potato cells would be around 0.30%. The only concentration that was hypotonic to the potato cells was the 0% concentration of NaCl, in which water rushed into the cell. The 0.50%, 1.0%, 2.0%, and the 3.0% were all hypertonic, because water left the potato cells due to the concentrations of NaCl. The turgor pressure was greatest in the 0% solution due to the outward push the extra water molecules put on the cell wall. The 3.0% solution had the least amount of turgor pressure, because more of the water already in the cells rushed out, leaving the cell wall not as rigid. In the 0.6% NaCl solution, the cells were more......

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...clear picture of the basic biology of organisms. There are several fields that have been revolutionized by the technology used in bioinformatics (Ouzounis & Christos, 2012). These fields include human health, the environment, agriculture, energy and biotechnology. This science of bioinformatics is also called computational biology and has found a lot of use in increasing the quality of life. Bioinformatics developed due to the great need to internalize the DNA which is the code of life. Growth in the field of bioinformatics has been facilitated by development of many DNA sequencing projects. The basic biology of life is controlled by the basic molecule of life called DNA. The DNA acts as the blue print for genes which code for proteins. The proteins coded for by these genes determine the biological composition of all the living organisms. The variation and errors that occur in the replication, transcription and translation of genomic DNA determines whether one develops a certain disease or resistance to the same disease (Vivian, Lópe, Luis, María ,Moreno, & Corchado, 2012). Bioinformatics is currently in use and more uses are expected in future...

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Mendelian Inheritance of Ptc Tasting in Humans

...expected monohybrid rations of 3 taster: 1 non-taster phenotypes respectively. This supported the hypothesis that the traits were controlled by one gene with two alleles, where T is dominant to t. INTRODUCTION Mendel’s Law of Segregation – that two copies of a character (gene) segregate from each other during the formation of gametes, is apparent in the inheritance of PTC tasting in humans (Begg, 1959). The PTC sensory variation was first discovered in the early 1930s by A.L. Fox, which subsequently led to much research. It was reported not long after that PTC tasting is controlled by one gene with two alleles, and that inheritance of these traits is that of Mendel’s monohybrid ration of 3:1. However, there is evidence to suggest transmission of PTC tasting is more complex than this (Kim & Drayna, 2005). The presence of the dominant allele T determines wether or not an individual can taste PTC. A monohybrid cross of two heterozygotes results in three possible genotypes – TT, Tt, and tt, the only non-taster phenotype being tt (Schull, 1948). This study investigated inheritance of PTC tasting in humans to determine wether or not taster and non-taster phenotypes fell into the expected Mendelian ration. It was hypothesised that there would be a ratio of 3 taster: 1 non-taster phenotypes, and that the traits are controlled by one gene with two alleles, where T is dominant to t. MATERIALS AND METHODS Data was collected by 3rd year Genetics students. Blank paper and......

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