Intracellular receptors sex hormone binding globulin. Medical search. Frequent questions

The principal steroid binding proteins in plasma are albumin, corticosteroidbinding globulin (cbg, transcortin) sex-hormone binding globulin (shbg) which is. (jessilafree.com)
Sex hormone-binding globulin (shbg) is a circulating glycoprotein that transports testosterone and other steroids in the blood. (jessilafree.com)
Shbg binds reversibly to sex steroids. (jessilafree.com)
In recent years, a growing body of evidence has shown that circulating shbg not only is a passive carrier for steroid hormones but also actively regulates. (jessilafree.com)
Sex hormone binding globulin (shbg) is a glycoprotein composed of 373 amino acid residues and three carbohydrate side chains. (jessilafree.com)
Most of the circulating testosterone is bound to carrier proteins (SHBG = sex hormone-binding globulin). (cdc.gov)
The problem is that testosterone can be free, bound to a serum protein (albumin) or SHBG (sex hormone binding globulin). (muscleandstrength.com)
By binding to testosterone andestradiol, SHBG reduces circulating sex steroid concen-trations and thereby their cellular actions. (marysfamilymedicine.org)
SHBG mayhave independent effects via a receptor mediated mech-anism or affect sex steroid interaction with cellular re-ceptors (26 -28). (marysfamilymedicine.org)

In adult female rodents, acute HPA function following a stressor is markedly greater than it is in males, and this difference has largely been attributed to modulation by the gonadal hormones testosterone and estradiol. (nature.com)
Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. (nih.gov)
To address this, concentrations of testosterone, sex hormone binding globulin, androstanediol glucuronide (a metabolite of dihydrotestosterone) and estradiol were measured in stored serum specimens from men examined in the morning sample of the first phase of NHANES III (1988-1991). (cdc.gov)
Binding is highly specific, only estradiol and estrone displace specifically bound [3H]estradiol. (nerc.ac.uk)
Plasma from both male and female brown trout was also found to bind [3H]estradiol, but with lower affinity (kD in 10−8 M range) and higher capacity (4000 - 11,000 fmol/mg protein) and with less specificity. (nerc.ac.uk)
Estradiol, testosterone, and 11-ketotestosterone all displaced plasma-bound [3H]estradiol. (nerc.ac.uk)
It is concluded that cytosol and plasma binding of estradiol in brown trout are distinct, and indicative of the presence of an intracellular hepatic estrogen receptor and a plasma sex-steroid-binding protein. (nerc.ac.uk)
Estradiol is a sex hormone. (absoluteastronomy.com)
Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core. (absoluteastronomy.com)
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol. (absoluteastronomy.com)
Propionate is only a quickly effective testosterone that must be injected more often, and requires a much more frequent dosing schedule in order to maintain stable blood levels, Testosterone is 98% bound to a specific testosterone-estradiol binding globulin in plasma, and about 2% is free and about 90% of a dose of testosterone is excreated in the urine as glucuronic and sulphuric acid ie. (suplementibalkan.com)

There are therefore several pathways by which soy isoflavones might affect sex steroid synthesis and activity in vivo. (internetpdfarticles.com)

Basal endogenous steroid hormones, sex hormone-binding globulin, physical fitness, and health risk factors in young adult men. (jessilafree.com)
Endogenous testosterone released from the sample by ANS (8-anilino-1-naphthalene sulfonic acid) and norgestrel competes with the added testosterone derivative labeled with ruthenium complex for the binding sites on the biotinylated antibody. (cdc.gov)
Endocrine-disrupting chemicals (EDCs) comprise a diverse group of naturally occurring and synthetic compounds that mimic and interfere with the endogenous chemical hormones. (intechopen.com)
Because endogenous chemicals bind and activate FXR, it is important to examine which xenobiotic compounds would disrupt normal receptor function. (nature.com)
In vitro experiments have shown that the soy isoflavones can bind to estrogen receptors and act as competitive agonists or antagonists to endogenous estrogens depending on relative concentrations and affinities (10-12). (internetpdfarticles.com)

This region of the receptor is covered up by heat shock proteins (HSPs) which bind the receptor until the hormone is present. (wikipedia.org)
Such receptors are closely related to chaperones (namely heat shock proteins hsp90 and hsp56), which are required to maintain their inactive (but receptive) cytoplasmic conformation. (wikipedia.org)
Binding proteins of steroid hormones. (jessilafree.com)
These actions are mediated by both the actions of a number of nonsecreted proteins and hormones produced in adipocytes. (diabetesjournals.org)
Total testosterone measures testosterone that is bound to proteins in the blood using. (rosiebonds.com)
Free T4 measurements were primarily used for assessing thyroid function despite the technical difficulties in free thyroid hormone measurements owing to abnormal binding proteins, changes in binding protein concentrations, and the effects of drugs and illness on thyroid hormone binding. (pharmaceuticalintelligence.com)
Genistein can also inhibit protein tyrosine kinases, which phosphorylate intracellular proteins and are necessary for the action of insulin-like and epidermal growth factors (14,15). (internetpdfarticles.com)
The thyroid controls how quickly the body burns energy , makes proteins , and how sensitive the body should be to other hormones . (wikidoc.org)
Proteins to which calcium ions are bound. (bvsalud.org)

They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. (wikipedia.org)
The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) and 3-ketosteroids (group NR3C). (wikipedia.org)
In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones. (wikipedia.org)
Steroid receptors of the nuclear receptor family are all transcription factors. (wikipedia.org)
This uptake into the nucleus is facilitated by nuclear localization signal (NLS) found in the hinge region of the receptor. (wikipedia.org)
Hormone binding domain: The moderately conserved ligand-binding domain (LBD) can include a nuclear localization signal, amino-acid sequences capable of binding chaperones and parts of dimerization interfaces. (wikipedia.org)
Depending on their mechanism of action and subcellular distribution, nuclear receptors may be classified into at least two classes. (wikipedia.org)
Nuclear receptors that bind steroid hormones are all classified as type I receptors. (wikipedia.org)
Type II nuclear receptors have no HSP, and in contrast to the classical type I receptor are located in the cell nucleus. (wikipedia.org)
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. (nih.gov)
In a wide variety of cell types vitamin D exerts its effects by binding to the vitamin D receptor (VDR), a member of the nuclear steroid receptor superfamily and an intracellular transcription factor [2]. (vitamindwiki.com)
In the cell, T3 binds to a nuclear receptor, resulting in transcription of specific thyroid hormone response genes. (pharmaceuticalintelligence.com)

Androgens are the main physiologic anabolic steroid hormones and normal testosterone levels are necessary for a range of developmental and biological processes, including maintenance of muscle mass. (frontiersin.org)
One approach that has drawn recent attention is supplementation with androgens, hormones with anabolic properties whose levels naturally decline with age ( 9 - 12 ). (frontiersin.org)

Only type I receptors have a heat shock protein (HSP) associated with the inactive receptor that will be released when the receptor interacts with the ligand. (wikipedia.org)
In this process heat shock protein is dissociated, and the activated receptor-ligand complex is translocated into the nucleus. (wikipedia.org)
Transcortin: a corticosteroid-binding protein of plasma. (jessilafree.com)
binding) protein 2/ steroid hormones have different affinity for binding. (jessilafree.com)
Characterization of the plasma sex steroid-binding protein. (jessilafree.com)
At the same time, most guys prefer to keep the Dbol dosage low in order to prevent water retention, steroid hormone binding protein. (jessilafree.com)
However, you could increase the chances of getting amazing results if you learn how to use it, steroid hormone binding protein. (jessilafree.com)
The liver of a sexually mature female brown trout contains more than twice as many binding sites as that of the male (168 ± 15 fmol/mg protein cf. 69 ± 4 fmol/mg protein), and no difference in kD is observed between males and females (2.6 ± 0.2 nM and 2.9 ± 0.3 nM, respectively). (nerc.ac.uk)
This review will address the biology, actions, and regulation of three adipocyte hormones-leptin, acylation stimulating protein (ASP), and adiponectin-with an emphasis on the most recent literature. (diabetesjournals.org)
Work in our laboratory has primarily focused on the biology and regulation of three key adipocyte hormones: leptin, acylation-stimulating protein, and adiponectin. (diabetesjournals.org)
Bioactive testosterone is made up of free testosterone and testosterone that is freed from its binding protein. (muscleandstrength.com)
Cholecalciferol is bound to serum vitamin D-binding protein (DBP) and through a two-step enzymatic pathway involving 25-hydroxylase of the liver and 1a-hydroxylase (CYP27B1) of the kidney and extrarenal tissues, it is converted to the biologically active hormone calcitriol (1a,25(OH)2D3) [1]. (vitamindwiki.com)
Inside the follicles, colloids rich in a protein called thyroglobulin serve as a reservoir of materials for thyroid hormone production and, to a lesser extent, act as a reservoir for the hormones themselves. (wikidoc.org)

Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal. (absoluteastronomy.com)

The test is used due to associations between vitamin D, calcium and plasma parathyroid hormone (PTH) [3, 4]. (vitamindwiki.com)
Parathyroid Hormone (PTH) Intact without Calcium Blo. (walkinlab.com)
The Parathyroid Hormone (PTH) Intact without Calcium Blood Test measures the level of PTH in the blood to help screen for osteoporosis and other underlying health conditions. (walkinlab.com)

Ivermectin, an avermectin antiparasitic, has been recently identified to bind FXR-LBD and decrease serum glucose and cholesterol levels in mice 10 . (nature.com)

It was an amino acid that originally became popular for increasing the availability of androgen receptors which would thereby lead to an increase in utilization of the testosterone produced during high intensity exercise. (muscleandstrength.com)

The pleiotropic harmful effects of EDCs act through hormone-dependent downstream signaling pathways responsible for gonad development either through direct interaction with steroid hormone receptor or via epigenetic regulation. (intechopen.com)

FXR contains a DNA-binding domain for docking to target genes with an FXR response element (FXRE) and a ligand-binding domain (LBD) used by intracellular ligands. (nature.com)

Binding sites with characteristics conforming to those of a putative estrogen receptor have been identified in the liver of sexually mature male and female brown trout. (nerc.ac.uk)
Structure-activity relationships of FXR-active compounds revealed by this screening were then compared against the androgen receptor, estrogen receptor α, peroxisome proliferator-activated receptors δ and γ and the vitamin D receptor. (nature.com)

Adiponectin production is stimulated by thiazolidinedione agonists of peroxisome proliferator-activated receptor-γ and may contribute to increased insulin sensitivity. (diabetesjournals.org)

The thyroid participates in these processes by producing thyroid hormones, principally thyroxine (T 4 ) and triiodothyronine (T 3 ). (wikidoc.org)

Free (that is, unbound) steroids enter the cell cytoplasm and interact with their receptor. (wikipedia.org)
The relationship between sex steroids and fracture is poorly understood. (marysfamilymedicine.org)
Sex Steroids and Fracture in Men J Clin Endocrinol Metab, September 2009, 94(9):3337-3346 effects on bone density, structure, or biochemical indi-ces is uncertain (12). (marysfamilymedicine.org)
Most previous studies measured sex steroids using RIAtechniques, which are susceptible to artifact, particu-larly at low concentrations (30, 31). (marysfamilymedicine.org)

These gonadal hormones are produced by the hypothalamic-pituitary-gonadal (HPG) axis and have been shown to determine sex differences in adult HPA function after acute stress via their activational and organizational effects. (nature.com)
For these individuals, the preferred test is testosterone, free and total, includes sex hormone-binding globulin (adult females, children, or individuals on. (rosiebonds.com)
This rate of isoflavone intake is much greater than that shown in adult humans to alter reproductive hormones. (internetpdfarticles.com)
Prins GS, Birch L, Greene GL: Androgen receptor localization in different cell types of the adult rat prostate. (karger.com)

The hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine network that controls hormonal responses to internal and external challenges in an organism's environment, exhibits strikingly sex-biased activity. (nature.com)

The farnesoid X receptor (FXR) regulates the homeostasis of bile acids, lipids and glucose. (nature.com)
Pituitary TSH regulates the secretion of the thyroid hormones T4 (thyroxine) and T3 (triiodothyronine). (pharmaceuticalintelligence.com)

Stressors increase corticoreleasing hormone, adrenocorticoreleasing hormone, cortisol and prolactin and decrease prostaglandin E2 release and vasoconstriction induced/potentiated by angiotensin II, nitric oxide, acetylcholine and serotonin. (gremjournal.com)

Thyrotropin, or thyroid-stimulating hormone (TSH), is one of a family of glycoprotein hormones including luteinizing hormone (LH), follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) that share a common α-subunit and a unique β-subunit. (pharmaceuticalintelligence.com)

It is responsible for development of secondary sex characters in males at the time of puberty and subsequent maintenance of spermatogenesis during reproductive life of males. (suplementibalkan.com)
1999. Adverse reproductive outcomes in the transgenic Ah receptor-deficient mouse. (cdc.gov)

Although these actions of gonadal hormones are well supported, the possibility that sex chromosomes similarly influence HPA activity is unexplored. (nature.com)
Moreover, questions remain regarding sex differences in the activity of the HPA axis following chronic stress and the underlying contributions of gonadal hormones and sex chromosomes. (nature.com)
We primarily outline what is known about how gonadal hormones and sex chromosomes modulate HPA axis activity following acute stress, and then focus on sex-biased HPA axis activity post-chronic stress, which is far less well understood. (nature.com)
It binds to intracellular receptors in target cells where as the hormone receptor complex translocates to nucleus where it attaches to specific binding sites on the chromosomes. (suplementibalkan.com)

The cell membrane aldosterone receptor has shown to increase the activity of the basolateral Na/K ATPase, ENaC sodium channels and ROMK potassium channels of the principal cell in the distal tubule and cortical collecting duct of nephrons (as well as in the large bowel and possibly in sweat glands). (wikipedia.org)

This can't be, testosterone is the most anabolic hormone in the body. (muscleandstrength.com)

At other times, this anxious touch may be exerted through ros, cytokines (interleukins [il], tumor necrosis factor-alpha, sex hormone-binding globulin, and luteinizing discovery of a 6. (ben.edu)

The molecular mechanism(s) and intracellular mediators of both spontaneous-and treatment-induced apoptosis are not fully elucidated. (biomedcentral.com)

Thus, their ligands pass through the cell membrane and cytoplasm and enter the nucleus where they activate the receptor without release of HSP. (wikipedia.org)
this is an exogenous agent that interferes in the production, liberation, transport, metabolism, the union to a receptor or a modifier of the action or elimination of natural ligands responsible for maintaining homeostasis and the regulation and development of the organism. (ivis.org)

In short, central overproduction of androgen, increased peripheral conversion of androgen, decreased metabolism, and enhanced receptor binding are each potential causes of hirsutism. (medscape.com)
Hormones produced by adipose tissue play a critical role in the regulation of energy intake, energy expenditure, and lipid and carbohydrate metabolism. (diabetesjournals.org)
Adipocytes produce a number of hormones that have wide-ranging effects on energy intake, energy expenditure, and carbohydrate and lipid metabolism, including nutrient partitioning and fuel selection. (diabetesjournals.org)
These hormones regulate the rate of metabolism and affect the growth and rate of function of many other systems in the body. (wikidoc.org)

The primary function of the thyroid is production of the hormones thyroxine (T4), triiodothyronine (T3), and calcitonin . (wikidoc.org)

Upon binding by the hormone the receptor undergoes a conformational change releasing the HSP, and the receptor together with the bound hormone enter the nucleus to act upon transcription. (wikipedia.org)
The activated receptor interacts with the hormone response element and the transcription process is initiated as with type I receptors. (wikipedia.org)

The amino acid series in hygetropin is identical to the body's naturally produced human growth hormone (hgh). (youthparlor.com)
The Iron and Total Iron-Binding Capacity (TIBC) Blood Test assesses the body's ability to bind and transport iron in the blood, which can help identify an iron deficiency, anemia, or overload. (walkinlab.com)

1991. Effects of polychlorinated biphenyls with Ah receptor affinity on lymphoid development in the thymus and the bursa of Fabricius on chick embryos in ovo and in mouse thymus anlagen in vitro . (cdc.gov)

Results from RNA sequencing revealed that AEG‑1 modulated neuronal morphology and development by regulating the expression of numerous genes, such as ubiquitin C, C‑X‑C motif chemokine ligand 1, MMP9, Notch1, neuropilin 1 and ephrin type‑A receptor 4. (spandidos-publications.com)
ABSTRACT Teleost eggs contain an abundant store of maternal thyroid hormones (THs) and early in zebrafish embryonic development all the genes necessary for TH signalling are expressed. (pharmaceuticalintelligence.com)

However, it remains unclear whether in the US population circulating concentrations of sex steroid hormones vary by race/ethnicity. (cdc.gov)

Although it primarily focuses on the rodent literature, a brief discussion of sex differences in the human HPA axis is also included. (nature.com)
We conclude with a brief discussion of sex differences in the human HPA axis with the caveat that they are less pronounced than in rodents and are largely dependent on the stress modality. (nature.com)
If you re ready to bypass your genetics and stack on pounds of lean muscle mass, HyperGH 14X is the best human growth hormone supplement on the market, seance bras musculation. (kfs09.com)
Human growth hormone (hgh) receptor linked to the transmembrane and intracellular. (youthparlor.com)
This is a detailed article about human growth hormone (hgh). (youthparlor.com)
To investigate the relationship amongst human growth hormone (hgh), sex, and age groups. (youthparlor.com)
Among the many different therapeutic approaches, including exercise, hormone, nutritional therapy, and/or a combination thereof, no one approach has emerged as superior in animal or human studies, and the great variability in the clinical outcomes of patients treated with these approaches has prevented identification of the most effective therapy ( 7 , 8 ). (frontiersin.org)
Unfortunately, at the time of clinical diagnosis, human prostate cancers mostly present themselves as heterogeneous entities - hormone-dependent and hormone-independent, and proliferating and non-proliferating. (biomedcentral.com)
1999. Transactivation activity of human, zebrafish, and rainbow trout aryl hydrocarbon receptors expressed in COS-7 cells: Greater insight into species differences in toxic potency of polychlorinated dibenzo- p -dioxin, dibenzofuran, and biphenyl congeners. (cdc.gov)
Since the available evidence suggests that infants can digest and absorb dietary phytoestrogens in active forms and since neonates are generally more susceptible than adults to perturbations of the sex steroid milieu, we suggest that it would be highly desirable to study the effects of soy isoflavones on steroid-dependent developmental processes in human babies. (internetpdfarticles.com)

A review examining the role of these three hormones in regulating energy homeostasis and insulin action was published in early 2002. (diabetesjournals.org)
The thyroid also produces the hormone calcitonin , which plays a role in calcium homeostasis . (wikidoc.org)

The secretion of testosterone is regulated by luteinizing hormone (LH), and is subject to negative feedback via the pituitary and hypothalamus. (cdc.gov)
TSH secretion, in turn, is controlled through negative feedback by thyroid hormone on the pituitary thyrotrope. (pharmaceuticalintelligence.com)

1994. Ah receptor in embryonic mouse palate and effects of TCDD on receptor expression. (cdc.gov)

Estrogen-binding sites in the liver of sexually mature male and female brown trout, Salmo trutta L. (nerc.ac.uk)

In this system, hormones are responsible for transmitting information between the organs, in addition to being essential in functions such as reproduction, being involved in the normal development of organisms, and in brain function and differentiation. (ivis.org)
In sebaceous glands, both immature and mature sebocytes express muscarinic acetylcholine receptors that are important for sebocyte differentiation and sebum production. (capsulehealth.one)

Naturopathic physicians are very well-suited to hormone test interpretation because of our training in physiologic ranges, with regard to optimal and suboptimal ranges. (ndnr.com)

This is because the isoflavones may cause perturbations of the sex steroid milieu, which are poorly tolerated by neonates (7). (internetpdfarticles.com)

Testosterone promotes the development of the secondary sex characteristics in men and serves to maintain the function of the prostate and seminal vesicles. (cdc.gov)

Strikingly, women are at twice the risk of men for developing many of these diseases, likely due to sex differences in the function and regulation of the HPA axis [ 5 ]. (nature.com)
The purpose of the present review is to summarize the most important aspects of the biology, actions, and regulation of these hormones and to serve as an update of new information published during the past ∼18 months. (diabetesjournals.org)
The regulation of VDR expression is one of the main mechanisms through which target cells respond to calcitriol so that polymorphisms of this receptor can change the usual mode of functioning. (vitamindwiki.com)

In North America and Western Europe only small amounts of vitamin D, a fat-soluble secosteroid hormone, enter the metabolic circle via dietary uptake (e.g. from fish), although dietary supplement intake has increased in recent years (Figure 1). (vitamindwiki.com)

These hormones, the pathways controlling their production, and their receptors are promising targets for managing obesity, hyperlipidemia, and insulin resistance. (diabetesjournals.org)

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. (wikipedia.org)
Depending upon the type of receptor, they are either located in the cytosol and move to the cell nucleus upon activation, or remain in the nucleus waiting for the steroid hormone to enter and activate them. (wikipedia.org)
Hinge region: This area controls the movement of the receptor to the nucleus. (wikipedia.org)
Type II receptors are located in the nucleus. (wikipedia.org)
Recently we showed that 24 h after copulation to satiety, there is a reduction in androgen receptor density (ARd) in the medial preoptic area (MPOA) and in the ventromedial hypothalamic nucleus (VMH), but not in the bed nucleus of the stria terminalis (BST). (karger.com)

It has been proposed that racial/ethnic variation in prostate cancer incidence may be, in part, due to racial/ethnic variation in sex steroid hormone levels. (cdc.gov)
This assumption is very likely false.6 While TSH may provide some useful information, it tells you nothing about the actual levels of the thyroid hormones, T3 and T4. (ndnr.com)
We would never assess testosterone levels by only measuring the signal from the brain to the testicles, ie, luteinizing hormone (LH). (ndnr.com)
Deficiency of purine nucleoside phosphorylase (PNP) and adenosine deaminase (ADA) elevates intracellular levels of deoxyguanosine and deoxyadenosine, respectively. (medscape.com)
All of the major organs in the body are affected by altered levels of thyroid hormone. (pharmaceuticalintelligence.com)
Sex steroid levels white men and all 446 minority men. (marysfamilymedicine.org)

Distortion of the aimed directly at both ends of a premature decline in female afferents on intracellular molecular processes. (ben.edu)

Synthesis:Androstenedione is the common precursor of male and female sex. (absoluteastronomy.com)
Analysis of receptor synthesis and degradation by the density-shift technique. (karger.com)

It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. (absoluteastronomy.com)

Anatomy3

Diseases4

Chemicals and Drugs46

Analytical, Diagnostic and Therapeutic Techniques and Equipment8

Phenomena and Processes13

Information Science3

Health Care7

SHBG9

Estradiol11

Affect sex steroid1

Endogenous5

Proteins9

Nuclear12

Androgens2

Protein13

Estrogens1

Parathyroid Hormone3

Serum1

Androgen receptors1

Steroid hormone1

Ligand-bindin1

Estrogen receptor2

Agonists1

Principally1

Steroids4

Adult4

Adrenal1

Regulates2

Cortisol1

Glycoprotein1

Reproductive2

Chromosomes4

Aldosterone1

Anabolic1

Tumor1

Mechanism1

Ligands2

Metabolism4

Thyroxine1

Transcription2

Body's2

Affinity1

Genes2

Concentrations1

Human10

Homeostasis2

Pituitary2

Embryonic1

Liver1

Differentiation2

Physiologic1

Poorly1

Secondary1

Regulation3

Metabolic1

Obesity1

Nucleus5

Levels6

Decline1

Synthesis2

Plasma1