Sorry I haven't been able to give you much this week, but you'll probably find this humdinger a nice asset to the collection. The Maryland Cookies were in fact not from The Old Line state, rather...Sweden. Specializing in wailin' garage rawk-cum-punk, the Cookies approximated later era Lime Spiders (think Cave Comes Alive) fronted by a mouthpiece (Mike Eriksson) with a thing for Stan Ridgway. From the vigorous lead off number, "You Just Fade Away," to the slammin' cowpunk surge of "Too Much Hamburgers," the quartet manages to keep the bulk of Flesh, Trash & Heat at a rolling boil with bite and sneer for miles. These gents were taut as all-get-out. The garage standard, "I Can Only Give You Everything" is given a new coat of cookie batter to sublime effect I might add. Per Discogs, it looks like three more MC albums followed. 01. You Just Fade Away02. Protection03. back on the Ground04. Too Much Hamburgers05. I Can Only Give You Everything06. Move on Baby07. New Kind of Spirit
Stan Ridgway The Big Heat Rar
Additionally, we and our advertising partners store and/or access information on your device and also process personal data, like unique identifiers, browsing activity, and other standard information sent by your device including your IP address. This information is collected over time and used for personalized ads, ad measurement, audience insights, and product development specific to our ads program.
T3binds to its receptors with approximately 10 fold higher affinity than T4. The dissociation constants for liver nuclear receptors measured in vitro are 2 x 10-9M for T4and 2 x 10-10M for T3(1,2). Nuclear receptors are approximately 75% saturated with TH in brain and pituitary and 50% saturated with TH in liver and kidney. It is notable that the extent of TH receptor occupancy varies in different tissues, providing a mechanism for alterations in circulating TH levels to alter receptor activity. In contrast to the related steroid hormone receptors, TRs are mostly nuclear both in the absence and presence of TH (1,2,30). In fact, TH receptors are tightly associated with chromatin (1-3,30), consistent with their proposed role as DNA-binding proteins that regulate gene expression.
The TRs also are expressed in specific stages during development, and are subject to regulation by hormones and other factors (78, 79). For instance, TRα-1 mRNA is expressed early whereas TRβ 1 mRNA is expressed later during embryonic brain development. In the rat pituitary gland, TH decreases TRβ 2, TRα-1, and α-2 mRNAs while slightly increasing TRβ-1 mRNA. However, in most other tissues, TH decreases TRα-1 and α-2, but not TRβ-1 mRNA. Isoform-specific knockout mice of each of the TR isoforms display distinct phenotypes (17,18). However, lack of significant TR isoform-specific gene expression was observed in cDNA microarrays of hepatic genes in TR isoform knockout mice (80). Given the apparent redundancy in TR isoform function, it is possible the different KO phenotypes may be due to absolute TR expression levels in critical tissues and developmental stages.
In the absence of TH, TR represses basal transcription in proportion to the amount of receptor and the affinity of receptor binding sites in positively-regulated target genes.This phenomenon also is referred to as transcriptional silencing (105-108). (Figure 3d-5, below). The addition of TH reverses basal repression and increases transcriptional activation above basal levels seen in the absence of receptor. Our understanding of the molecular mechanism for basal repression of transcription by unliganded receptor was advanced significantly by the discovery of a family of repressor proteins that bind selectively to unliganded TRs and RARs. This corepressor family includes silencing mediator for retinoid and TH receptors (SMRT) and nuclear receptor corepressor (NCoR) (105,109,110). These corepressors are 270 kD proteins that contain three transferable repression domains and two carboxy-terminal α -helical interaction domains. They are able to mediate basal repression by TR and RAR, as well as orphan members of the nuclear hormone receptor family such as rev-erbAα and chicken ovalbumin upstream transcription factor (COUP-TF). They have little or no interaction with steroid hormone receptors and therefore do not mediate basal repression by these receptors. Another protein, small ubiquitous nuclear co-repressor (SUN-CoR) enhances basal repression by TR and rev-erbA (31). This 16kD protein may form part of a co-repressor complex as it interacts with NCoR.
There are several different potential mechanisms for negative regulation by TH. Negative regulation may involve receptor interference with the actions of other transcription factors or with the basal transcription apparatus (135,136). For instance, TR can inhibit the activity of AP-1, a heterodimeric transcription factor composed of Jun and Fos. T3-mediated repression of the prolactin promoter has been proposed to occur by preventing AP-1 binding (137). The TR also interacts with other classes of transcription factors, including NF-1, Oct-1, Sp-1, p53, Pit-1, CTCF, and GATA (138-144). By binding to these, or other positive transcription factors, the TH receptor may be able to inhibit gene expression by protein-protein interactions. Negative regulation may also occur by TR directly binding to DNA. A negative TRE from the TSHβ gene resides in an exon downstream of the start site of transcription (134) raising the possibility that it occludes the formation of a transcription complex. (Figure 3d-6, above) Additionally, liganded TRs may potentially recruit positive cofactors off DNA (squelching), which in turn, could lead to decreased transcription of target genes.
Transcriptional regulation by TRs is a multistep process involving: (1) association of TRs with regulatory sites in the genome (usually within the targe gene promoters) in the context of chromatin, (2) ligand-dependent recruitment and function of coregulators to modify chromatin and thereby regulating RNA Pol II recruitment to the target genes, and (3)co-valent modifications of histones to alter chromatin structure, recruit RNA pol II complex, and to mediate transcription. In particular, the site-specific acetylation of histone tails induces local relaxation of chromatin, which enhances the binding of some transcriptional regulators and facilitates the recruitment and functioning of the general transcriptional machinery. Recent studies have demonstarted that thyroid hormone-positively regulated target genes may have distinct patterns of coactivator recruitment and histone acetylation that may enable highly specific regulation (129). However the epigenetic changes associated with negetively regulated gene seems to be much more complex. For instance, histone acetylation of H3K9 and H3K18 sites, two modifications usually associated with transcriptional activation, occur in negative regulation of TSHapromoter. T3also caused the release of a corepressor complex composed of histone deacetylase 3 (HDAC3), transducin b-like protein 1, and nuclear receptor coprepressor (NCoR)/ silencing mediator for retinoic and thyroid hormone receptor from TSHapromoter in chromatin immunoprecipitation assays. These findings demonstrate the critical role of NCoR/HDAC3 complex in negative regulation of TSHagene expression and show that similar complexes and overlapping epigenetic modifications can participate in both negative and positive transcriptional regulation (150). Of note, histone deacetylation has been observed in T3-mediated negative regulation of several target genes (150-152). Moreover, abberant histone modification at the TRH and TSHagenes has been implicated in the inappropriate TSH secretion observed in resistance to thyroid hormone (RTH) syndrome (150,151)). Other coregulators may be involved in T3-mediated regulation as RIP140, a coregulator that can decrease transcription by some nuclear hormone receptors, mediated T3repression of Crabp1 gene via chromatin remodeling during adipocyte differentiation (153). Interestingly, the use of HDAC inhibitors to counteract the effects of basal repression of target genes have restored some transcriptional activity in hypothyroidism associated with RTH syndrome and hypothyroidism (154,155). Although nuclear CoRs play a prominent role in T3 nuclear action (156,157), NCoR-independent signaling may account for basal repression by unliganded TRs for a significant number of target genes (158).
There are many reports providing evidence that reduced TR expression and/or alterations in TH levels are common events in human cancer (173, 174). These alterations include loss of heterozygosity, gene rearrangements, promoter methylation, aberrant splicing and point mutations (173,175). Tumors, including lung, breast, head and neck, melanoma, renal, uterine, ovarian and testicular tumors, present high frequencies of somatic deletions and mutations in both TR alpha/beta loci (176-178). Aberrant TRs have also been found in more than 70% of human hepatocellular carcinomas The tendency for TR expression to disappear as malignancies progress suggests that TR can act as a tumor suppressor in human cancers; therefore, loss of expression and/or function of this receptor could result in cell transformation and tumor development (179). In fact, TR overexpression in hepatoma cell lines shows repression of various tumor promoting genes such as PTTG1 (180), and activation of anti-tumorogenic TGF-beta. However certain mutant TRs like TRbPV/PVmey even enhance tumor growth by non-genomicaly activating beta-catenin and PI3K pathways (181,182). Last, it recently has been reported that miRNAs can downregulate the expression of dio 1 in renal cell carcinoma, and TRbin papillary thyroid, carcinoma. Clarifying the molecular mechanisms by which TRs influence tumor progression and elucidating the epigenetic modifications ofT3target genes in cancers would perhaps lead to a better understanding of the treatment regime in humans. 2ff7e9595c
コメント