Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

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ACE and weight gain

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Thanks to a yahoo group called TaubesTalk for the following news article and abstract:

SYDNEY (AFP) – Australian scientists may have discovered how to help people lose weight without cutting back on food, a breakthrough that could pave the way for fat-burning drugs.

Researchers in Melbourne found that by manipulating fat cells in mice they were able to speed up the animals’ metabolisms.

They found that when a particular enzyme, known as angiotensin converting enzyme (ACE), was removed, mice were able to eat the same amount as other mice but burn more calories and therefore gain less weight.

Animals without the enzyme were on average 20 percent lighter than normal mice and had 50 to 60 percent less body fat, senior researcher at the Howard Florey Institute Michael Mathai said.

“It is very clear that they do have less body fat,” he told AFP.

Mathai, who is also a lecturer in nutrition at Victoria University, said the slimmer mice also appeared to have less chance of developing diabetes because they processed sugar faster than normal mice.

He said the research, to be published Tuesday in the US-based Proceedings of the National Academy of Sciences, could be used to develop drugs to assist weight loss.

Drugs which impair the action of ACE already exist and are mostly used to combat high blood pressure.

“The drugs are out there because they are used for hypertension,” he said.

“So we know their safety and their tolerability. What we don’t know is whether or not they will work in humans. And we don’t know whether it will work in all obese humans.”

Mathai said it could be a question of finding the right dosage of hypertension medication, or developing a new type of drug of the same class, to be used as weight-loss pills.

“This might be one way in which you can increase metabolic rate in combination with managing nutrition to limit the intake of calories,” he said.

Mathai said the research, conducted at the Howard Florey Institute, Victoria University, La Trobe University, Deakin University, the Baker Institute and the University of Melbourne, was yet to pinpoint why the genetic manipulation led to weight loss.

“Because we deleted the gene, the gene is gone from the whole body, that means that it is gone from all tissues including the brain,” he said.

“And so we don’t know whether it’s a direct effect of the deficiency in the tissue or whether it’s something coming from the brain.” Australian scientists report weight loss breakthrough

And the abstract:

Angiotensin II (AII), acting via its G-protein linked receptor, is an important regulator of cardiac, vascular, and renal function. Following injection of AII into rats, we find that there is also a rapid tyrosine phosphorylation of the major insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in the heart. This phenomenon appears to involve JAK2 tyrosine kinase, which associates with the AT1 receptor and IRS-1/IRS-2 after AII stimulation. AII-induced phosphorylation leads to binding of phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and IRS-2; however, in contrast to other ligands, AII injection results in an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity. The latter occurs without any reduction in insulin receptor or IRS phosphorylation or in the interaction of the p85 and p110 subunits of PI 3-kinase with each other or with IRS-1/IRS-2. These effects of AII are inhibited by AT1 receptor antagonists. Thus, there is direct cross-talk between insulin and AII signaling pathways at the level of both tyrosine phosphorylation and PI 3-kinase activation. These interactions may play an important role in the association of insulin resistance, hypertension, and cardiovascular disease. Cross-talk between the insulin and angiotensin signaling systems

I think this may be why low carbohydrate diets help so many people with food chemical intolerance. Lower your insulin levels, and I bet you lower your ACE output.


Written by alienrobotgirl

1 May, 2008 at 6:24 pm

Posted in The Genetics of FCI?

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ACE and premenstrual tension

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ACE – it stands for angiotensin converting enzyme. People with a common deletion in their ACE gene secrete more angiotensin II and aldosterone than people with the common insertion variant.

Emotional upsets related to changes in ovarian hormones are highly prevalent and are responsible for psychiatric morbidity and mortality. Significant increases in acute psychiatric hospitalizations, suicidal activity, and other psychopathology occur during the premenstruum and during menstruation.

This paper reviews evidence indicating that menstrual cycle psychopathology may be mediated by the effects of estrogen, progesterone, and possibly the renin—angiotensin—aldosterone system on the brain monoamines, norepinephrine, dopamine, and serotonin.

During the menstrual cycle, psychopathology often begins with the onset of luteal estrogen—progesterone—angiotensin—aldosterone secretion and intensifies as these hormone levels later fall, prior to and during menstruation. Aldosterone is reported elevated in cases of premenstrual tension syndrome.

There are numerous reports of affective upsets occurring with the use of estrogen—progestin oral contraceptives and following their withdrawal. Contraceptives stimulate the renin—angiotensin—aldosterone system and are reported useful in alleviating premenstrual—menstrual emotional upsets and postpartum depressive episodes.

What a counter-intuitive conclusion – aldosterone increases PMT, but if you increase aldosterone even further whilst nuking the menstrual cycle, it ‘alleviates’ the problem. It certainly didn’t work that way for me. When I was on the pill my ‘premenstrual’ tension went away – I just had massive chronic tension all the time instead! My PMT always went away immediately that my period started.

Affective lability, prevalent at parturition, occurs when estrogen, progesterone, and aldosterone levels are first high and later falling. Exogenous estrogen and progesterone profoundly affect mating activity in castrated rhesus monkeys, and cyclic fluctuations in sexual activity in humans may occur during the menstrual cycle. Much information links manic and depressive reactions with alterations in brain monoamines. Lithium, monoamine oxidase inhibitors, and tricylic antidepressants, specifically used to treat affective disorders, are reported useful in treating ovarian hormone—linked upsets. Similarities exist between changes in animal behavior caused by drugs altering affective states and the effects of ovarian hormones.

Like certain antidepressants, estrogen induces hyperactivity in rats. Like reserpine, progesterone exhibits sedative and soporific effects. Sexual behavior in female rats is reported linked to changes in brain monoamines. Agents increasing brain monoamine levels and availability decrease mating responses, and monoamine depletors, such as reserpine may be substituted for progesterone in activating mating behavior.

Serotonin and dopamine appear to be important in the regulation of ovulation. Brain norepinephrine varies with the phases of the rat estrus cycle. Castration increases brain norepinephrine and decreases brain dopamine. Exogenous estrogen decreases rat brain norepinephrine content. The monoamine-destroying enzymes, monoamine oxidase, and catechol O-methyl transferase are affected by ovarian steroids and show fluctuating levels during the reproductive cycle. The effects of reserpine, monoamine oxidase inhibitors, tricyclic antidepressants, and lithium on monoamines in neurophysiological preparations have been used as evidence supporting theories linking monoamine changes with human affective disorders. Estrogen, progesterone, and angiotensin also exhibit effects on in vitromonoamine systems.

Like the tricyclic antidepressants, uptake of norepinephrine and dopamine by nerve endings is inhibited in the presence of estrogen, progesterone, and angiotensin. As with reserpine, the flow of these monoamines from nerve endings is increased by progesterone. Estrogen slows the flow of norepinephrine from nerve endings and decreases the electrically induced release of serotonin and norepinephrine from brain slices. The above information provides clues that ovarian hormone—linked psychopathology, like affective disorders in general, may be related to alterations in brain monoamines. Monoamines and ovarian hormone-linked sexual and emotional changes: A review

Aldosterone is also responsible for water retention, by acting on the central nervous system to release vasopressin, the hormone which tells the kidneys to conserve water.

Written by alienrobotgirl

21 April, 2008 at 7:09 pm

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ACE interactions

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Angiotensin I-converting enzyme (ACE) is a zinc metallopeptidase whose main known functions are to convert angiotensin I into the vasoactive and aldosterone-stimulating peptide angiotensin II, and to inactivate bradykinin. ACE is believed to have other physiological roles because of its wide enzymatic specificity and wide distrubution. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.

Analysis of ACE genotypes reveal[s] that patients with the wild type ACE gene (ACE I/I) have normal angiotensin II levels, while patients with a deletion in both alleles (ACE D/D) have far higher levels, and those with a single allele deletion have intermediate levels. New Approaches to Heart Failure: From Pharmacogenomics to Drug Development

Mild quantitative changes in the expression of ACE do not affect plasma angiotensin II level or BP because of the concomitant changes in the level of angiotensin I. However, plasma [bradykinin] level changes with changes in ACE expression. Minireview: Computer Simulations of Blood Pressure Regulation by the Renin-Angiotensin System

D/D homozygotes have a 25% increase, and I/I homozygotes have a 25% decrease in plasma ACE activity relative to the I/D heterozygotes. In otherwords, feedback causes angiotensin I levels to lower to maintain correct angiotensin II levels. Examine Figure 3B in the minireview linked to above. It displays D/D types as having lower angiotensin I levels whilst maintaining relatively normal angiotensin II levels.

Now check out the interaction with monoamine oxidase:

It is concluded that diminished [angiotensin I] receptor stimulation decreases cardiac MAO activity, probably by regulating MAO expression, since ANG, ACE inhibitors, and AT(1) antagonists had no effect on MAO activity in vitro. Angiotensin I-converting enzyme inhibition increases cardiac catecholamine content and reduces monoamine oxidase activity via an angiotensin type 1 receptor-mediated mechanism.

Stressed all the time?

Angiotensin II increases thirst sensation[…] It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibers. Angiotensin Wiki

Another interaction with COMT:

Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds RATIO=10.89, 95%CI 1.14–103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics. Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics

One interesting fact I stumbled upon recently is that a low sodium diet increases monoamine oxidase activity in rats, and this operates via an angiotensin II mechanism. So does a high sodium diet decrease monoamine oxidase activity?

And check out the interaction with vitamin D receptors:

Mice lacking the Vitamin D receptor (VDR) have elevated production of renin and angiotensin (Ang) II, leading to hypertension, cardiac hypertrophy and increased water intake. These abnormalities can be prevented by treatment with an ACE inhibitor or AT(1) receptor antagonist. Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure

In fact the lower your vitamin D levels the higher your whole renin-angiotensin sytem. Vitamin D is an extremely effective way to lower your blood pressure.

Written by alienrobotgirl

19 April, 2008 at 3:48 pm

Posted in The Genetics of FCI?

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What are the odds of new mutations causing autism?

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This is to follow on from previous posts I’ve made about the Autism Genome Project and the two genetic theories of autism.

The “new mutations” genetic theory of autism is one pioneered by scientists such as Professors Michael Wigler and Jonathan Sebat at the Cold Spring Harbor Laboratory on Long Island, New York. This short piece from the New Scientist explains their theory:

Duplications or deletions of portions of the genome may cause many – if not most – cases of autism.

Such errors can alter the number of copies of particular genes in the regions affected. These copy-number variations are 10 times as common in autistic children as in other children.

A team led by Jonathan Sebat of Cold Spring Harbor Laboratory on Long Island, New York, examined 118 families that have one autistic child and 99 families with children who are not autistic. Ten per cent of the autistic children, but only 1 per cent of the other children, had copy-number variants in their genomes that didn’t appear in their parents (Science, DOI: 10.1126/science.1138659).

The copy-number variants tend to affect different genes in each autistic child. This suggests that autism is not caused by a single genetic defect. Clues to autism revealed in copied genes

I’ve spent most of my time recently talking about single nucleotide polymorphisms – where one letter of a gene is substituted for another letter. Here, the scientists studied deletions and duplications of genes. Deletions and duplications and variants of genes are normal, very common, and widely found in the genetic code of all human beings. What the scientists have found here is that new deletions and duplications are present in a small but significant minority of autistic children – ten percent of autistic children to be exact, whereas they are normally present in about one percent of births. This is not at all surprising, considering the correlation of low-functioning DNA methylation genes with autism.

What we have to be cautious about is concluding causation from this – deletions/duplications rarely cause any observable changes in people, and they can occur anywhere in our genome – which consists of tens of thousands of different genes. For deletions/duplications to actually have some effect on the likelihood of being born with autism, they need to occur in genes that affect personality or the brain and nervous system.

What does the rest of the scientific community think?

Much of the autism research community believes there may be roughly six major genes involved in autism, and maybe 30 others that may confer some risk. A combination of mutations in any of these genes could contribute to the likelihood of being born with autism. Largest Ever Autism Study Identifies Two Genetic Culprits

Even if we included all of the personality and nervous system genes, that’s still a pretty narrow selection of genes that would have to be deleted or duplicated in order to produce changes in the child’s personality, let alone changes that cause autism.

One of the regular genes identified in autism by the Autism Genome Project is CNTNAP2. CNTNAP2 encodes neurexins – synaptic cell surface proteins – which are involved in glutamate functioning in the nervous system and brain. According to Entrez Gene, “This gene encompasses almost 1.5% of chromosome 7 and is one of the largest genes in the human genome.” That’s a lot of room for variation isn’t it?

Written by alienrobotgirl

7 February, 2008 at 9:08 pm

Posted in Autism Genetics

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The genetics of chronic fatigue syndrome

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To begin with, here is an overview of the frequency of CFS and the factors thought to be involved:

The US case definition of CFS (the CDC-definition) is most widespread in research and clinical practice. Estimates of prevalence vary from 0.2% to above 2%. The female-male ratio is approximately 3:1. […] Present knowledge suggests that certain genetic polymorphisms and personality traits might be regarded as predisposing factors, some infections and severe psychosocial stress constitute precipitating factors, whereas disturbances of immunity, skeletal muscle, cognitive abilities, endocrine control and cardiovascular homeostasis are possible perpetuating factors. The chronic fatigue syndrome–an update

Angiotension converting enzyme (ACE) deletions are associated with Gulf War Syndrome:

Increased risk for CFS/ICF was associated with alterations of the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene within the Gulf War veteran sample only. […] Veterans with the DD genotype were eight times more likely to develop CFS/ICF than were those with the II genotype. Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in Gulf War veterans

Corticosteroid-binding globulin (CBG) polymorphisms are associated with CFS:

A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. […] Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G–>T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls […] Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients […] Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions. Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism

Serotonin (5-hydroxy-tryptamine) transport protein (5-HTT, also known as SERT) polymorphisms are associated with CFS:

Interaction between the hypothalamo-pituitary-adrenal axis and the serotonergic system is thought to be disrupted in chronic fatigue syndrome (CFS) patients. We examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT […] A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls […] Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome

We have recently reported the association of serotonin transporter gene polymorphism in CFS. A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls. Compared to S allele, the L allele is believed to retain higher transcriptional activity, which causes decreased concentration of serotonin in the extracellular space, namely, active serotonin in CFS. These results thus support the serotonin hypothesis in the pathogenesis of CFS. Genetic background of chronic fatigue syndrome

Having serotonin levels that are too low can be caused by genetics, or by a viral infection:

Attenuation of serotonin neurotransmission can be caused by increased expression of serotonin transporter, which results either from viral infection and subsequent production of interferon–alpha or from abnormal promoter for serotonin transporter gene. Chronic fatigue syndrome and neurotransmitters

Yes, you read that right. The production of interferon-alpha due to a viral infection actually interferes with the genetic transcription of SERT, causing it to overproduce. This downregulates serotonin neurotransmission. Salicylate stimulates serotonin synthesis (the cause of the flavour chemical intolerant’s familiar ‘happy high’), so I suspect it works on CFS in a similar manner, by causing short term rebound deficiencies in substrates due to overproduction, and long-term downregulation of production. I know of several people who have complained of SSRI-like withdrawal symptoms when they begin the failsafe diet.

Serotonin receptor (HTR) polymorphisms are also involved in CFS:

The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality. A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined […] Of the polymorphisms examined, three markers (-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of -1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. Further, in silico analysis revealed that the -1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 to the A allele but not the G allele at this locus. These data indicate that sequence variation in HTR2A, potentially resulting in its enhanced activity, may be involved in the pathophysiology of CFS. Genetic evaluation of the serotonergic system in chronic fatigue syndrome

Proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2) polymorphisms are all associated with CFS:

This study examined whether genetic differences underlie the individual subgroups of the latent class solution. Polymorphisms in 11 candidate genes related to both hypothalamic-pituitary-adrenal (HPA) axis function and mood-related neurotransmitter systems were evaluated. […] Of the five classes of subjects with unexplained fatigue, three classes were distinguished by gene polymorphsims involved in either HPA axis function or neurotransmitter systems, including proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2). These data support the hypothesis that medically unexplained chronic fatigue is heterogeneous and presents preliminary evidence of the genetic mechanisms underlying some of the putative conditions. Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue

Catechol-O-methyltransferase (COMT) polymorphisms, along with some genes already listed above, are associated with CFS:

This paper asks whether the presence of chronic fatigue syndrome (CFS) can be more accurately predicted from single nucleotide polymorphism (SNP) profiles than would occur by chance. […] The top three genes containing the SNPs accounting for the highest accumulated importances were neuronal tryptophan hydroxylase (TPH2), catechol-O-methyltransferase (COMT) and nuclear receptor subfamily 3, group C, member 1 glucocorticoid receptor (NR3C1). CONCLUSION: The fact that only 28 out of several million possible SNPs predict whether a person has CFS with 76% accuracy indicates that CFS has a genetic component that may help to explain some aspects of the illness. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome

Wait. Let’s read that again: only twenty eight out of several million genetic polymorphisms predict whether a person has CFS with a 76% accuracy.

Yasko tests for some of the common polymorphisms listed above: ACE, MAO-A, and COMT. She doesn’t test for CBG, 5-HTT/SERT, POMC, NR3C1, MAO-B or TPH2.

You know you’re on to something when you can predict the genes that are involved in particular illnesses. Though Yasko doesn’t test for POMC variants, we’ve actually been discussing POMC on FailsafeNT recently. It is probably one of the primary genetic components of opioid sensitivity and pain perception. Also, I’ve also been puzzled for a while as to why Yasko doesn’t test for SERT polymorphisms, particularly as serotonin promotes sociability and for this reason is thought to be lacking in some autistics.

Of course, fibromyalgia is very closely related to CFS:

The exposure of a genetically predisposed individual to a host of environmental stressors is presumed to lead to the development of FMS. Fibromyalgia overlaps with several related syndromes, collectively compromising the spectrum of the functional somatic disorder. FMS is characterized by a strong familial aggregation. Recent evidence suggests a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the etiopathogenesis of FMS. These polymorphisms are not specific for FMS and are similarly associated with additional comorbid conditions. The mode of inheritance in FMS is unknown, but it is most probably polygenic. Recognition of these gene polymorphisms may help to better subgroup FMS patients and to guide a more rational pharmacological approach. The genetics of fibromyalgia syndrome

Written by alienrobotgirl

31 January, 2008 at 6:46 pm

Posted in The Genetics of FCI?

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