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Characterization of regulatory mechanisms affecting microRNA (miRNA) expression and activity is providing novel clues for the identification of genes and complex regulatory circuits that determine cell and tissue specificity. Here, we review the molecular events leading to miRNA biogenesis and activity, focusing above all on endogenous and epigenetic transcriptional networks involving miRNA in early development, cellular lineage specification/differentiation of nervous, skeletal and cardiac muscle tissues and in haematopoiesis, as the de-regulation of such networks may be relevant to disease pathogenesis.
During both development and adult life, transcriptional regulators, DNA and chromatin modifiers play crucial roles to ensure that proper gene expression patterns are established and maintained in any given cell type. However, the control of gene expression also occurs at the RNA level. This includes alternative splicing, messenger RNA (mRNA) stability, and translational control, all of which appear to enhance the diversity and flexibility of gene expression regulation. Very recent findings in molecular biology have shown that the participation of small regulatory non-coding RNA is required for cellular diversity in a developing organism and during adulthood. These molecules act as sequence-specific post-transcriptional regulators in the expression of other RNA transcripts.1
Small regulatory non-coding RNA molecules include microRNAs (miRNAs), small interfering RNAs (siRNAs) and repeat-associated siRNAs (rasiRNAs), which are unified by their association with the Argonaute (AGO) family of proteins and by their function. Indeed, all these RNAs direct the binding of protein complexes to specific nucleic acid sequences.1–6 SiRNAs and miRNAs repress the expression of target genes at the post-transcriptional level by interacting with the 3′ untranslated regions (UTRs) of specific mRNAs. However, siRNA also acts at the transcriptional gene level by affecting chromatin structure.7,8 RasiRNAs are produced as 29–30 nucleotide (nt) RNAs from a master gene locus composed of multiple transposons. These small RNAs differ from siRNAs and miRNAs in size and in their association with distinct protein complexes. In particular, rasiRNAs bind the Piwi (piRNAs) subfamily of AGO proteins, Aubergine, and AGO 3, and target homologous transposons scattered throughout the genome for their silencing.9–12
The specialization and evolution of the core components of the RNA-mediated silencing machinery integrate RNA silencing in various cellular physiological regulatory networks, which, in addition to the regulation of gene expression by inhibition of translation initiation and elongation, co-translational protein degradation, and premature termination of translation (ribosome drop-off), include the survey against the proliferation of transposable elements and viruses, epigenetic changes in DNA and chromatin status, and accurate chromosome segregation during cell division.13,14
Since the discovery of the first canonical miRNA genes, lin-4 and let-7, in the nematode Caenorhabditis elegans (C. elegans), the role of miRNA activities appeared as a novel common theme in cell fate determination.15,16 To date, hundreds of miRNA genes have been identified in animals; these genes display either an ubiquitous expression or a strict cell/tissue expression pattern.17 miRNA biogenesis and activity is now regarded as a key regulatory mechanism in controlling developmental timing, tissue differentiation, and maintenance of tissue identity during embryogenesis and adult life.1,3
Compelling evidence points to muscle and cardiovascular cell systems as powerful models for the understanding of the physiological regulatory networks and biological function of miRNAs during development and adult life. Moreover, recent findings indicate that miRNA expression/activity can be de-regulated in various diseases, including cardiovascular pathologies, thus offering new prospects for their therapeutic use.18
In this review, we focused on the molecular events leading to miRNA biogenesis and activity, and the endogenous and epigenetic transcriptional networks involving miRNA in early development, cellular lineage specification/differentiation of skeletal and cardiac muscle tissues, nervous tissue and haematopoiesis, as well as their potential relevance to disease pathogenesis.
Biogenesis of mature microRNAs
Genomic distribution and gene transcription
miRNAs are non-coding single-strand RNAs (ssRNAs), of ∼22 nt in length in their mature forms, that are individually encoded by their own set of genes. Genes for miRNAs are an integral component of the cell genetic program, many of them also being evolutionarily conserved.1,3 Studies on miRNA genes distribution throughout the genome, have revealed their presence in clusters transcribed as polycistronic primary transcripts, or within regions transcribed as independent units, including intergenic regions, exon sequences of non-coding transcription units or intronic sequences of either protein coding or non-coding transcription units19,20 (Figure 1A–C). Intronic miRNAs orientated in the same direction as the surrounding genes are generally transcribed coincidentally with their host genes and excised by the splicing machinery from the larger transcript in which they are embedded.21 Indeed, intronic miRNAs may represent a simple way for a protein-coding gene to regulate other protein-coding genes.
Generally, miRNAs are transcribed by the RNA polymerase II (Pol II), as a primary transcript, which may be several kilobases long, bearing hairpin-shaped structures called pri-miRNAs that transiently receive a 5′ cap and a poly(A) tail similar to that of the mRNAs.22 Recent studies, however, have shown that the RNA Pol III drives miRNA transcription from dense human clusters interspersed among repetitive Alu elements.23
Initial processing and export from the nucleus
The processing of the pri-miRNA occurs in the nucleus, in a stepwise fashion, through the activity of a double-stranded specific endonuclease RNase III (ds-RNAseIII), Drosha. Drosha and its partner, the double-stranded RNA binding domain protein DGCR8, cleave the pri-miRNA near the hairpin base and release an ∼70–90 nt pre-miRNA hairpin-shaped stem-loop precursor.22,24 An alternative pathway for pre-miRNA-like hairpin biogenesis has recently been identified in flies, nematodes, and mammalians; this pathway generates new regulatory RNAs from intronic pre-miRNA precursors called 'mirtrons', using the splicing machinery and the lariat-de-branching enzyme to bypass Drosha cleavage in initial maturation.25,26 Identification of several well-conserved mirtrons in different species indicates their relatively ancient incorporation into cellular regulatory pathways and highlights their likely contribution to animal evolution.25,26
The subsequent export of the pre-miRNA into the cytoplasm is mediated by the exportin-5, a Ran-GTP-dependent nuclear transport receptor.27 Exportin-5 interacts with the pre-miRNA 'minihelix motif' (consisting of an ∼14 nt stem and a short 3′ overhang), which also stabilizes the pre-miRNA structure.27–29
Processing into mature form, activation, and target recognition
In the cytoplasm, the pre-miRNA is processed by the cytoplasmic ds-RNaseIII Dicer into an ∼22 nt miRNA:miRNA duplex with 2 nt overhanging its 3′ end.30 The RNA strand with relatively unstable base pairs at the 5′ end is recruited as a single-stranded molecule into the RNA-induced silencing complex (RISC) and is assembled through processes that are dependent on Dicer, TAR (HIV) RNA binding protein (TRBP), and dsRNA-binding proteins of the AGO family and by other factors including helicases, nucleases and RNA binding proteins.2,6,31–33 When assembled into the RISC complex, the mature miRNA sequence targets its complementary mRNA and negatively regulates gene expression by causing either mRNA translational repression or degradation. miRNAs recognize their target mRNAs mainly through a limited base-pairing interaction between the 5′ end 'seed' region (2–8 nt from the 5′ end) and the complementary sequences present in the 3′-UTRs of phylogenetically conserved target mRNAs.3 Few animal miRNAs have enough complementarities to mRNAs to allow mRNA cleavage (slicing). The majority of animal miRNAs imprecisely match their targets, thereby causing target mRNA destabilization through 'non-slicer' mechanisms, including de-adenylation and other forms of translational repression (e.g. de-capping).34 When targeted for silencing by miRNAs, mRNAs can be concentrated, sequestered from translational machinery, degraded or stored for subsequent use in large macroscopic cytoplasmic foci, named processing bodies (P-bodies). The P-bodies contain a wide range of enzymes involved in RNA turnover, including de-capping enzymes, de-adenylases and exonucleases35 (Figure 1).
The imprecise matching between animal miRNAs and their targets implies that any given miRNA can bind different mRNAs, which bestows an enormous regulatory potential. The regulatory potential of each miRNA is rendered even more complex by recent evidence indicating that miRNAs can also bind to the 5′-UTR of mRNAs and that translation up-regulation can, in specific conditions, result from their binding to mRNA.36,37 In addition, miRNAs with a specific nuclear localization sequence can also be re-localized into the nucleus.38 In the nucleus, miRNAs can interact with, and regulate, the expression of transcribed ultraconserved regions encoding a particular set of ncRNAs, whose expression is altered in human cancer.39 These findings point to the possible involvement of miRNA in the transcriptional control of gene expression, as has already been demonstrated for gene regulation by endogenous siRNAs, piRNAs, and antisense RNAs.6–8,10,40
Regulation of microRNA expression by transcription factors and epigenetic mechanisms
During development, miRNA expression is tissue specific, which means that miRNA may play a role in establishing and maintaining cell type and tissue identity.17,41 Moreover, different expression profiling analyses have shown that most miRNAs are controlled by developmental or tissue-specific signalling. Although some miRNAs are controlled at the post-transcriptional level alone, several lines of evidence point to transcriptional regulation as the main step in the control of miRNA expression.3 However, the structure and the transcriptional regulation of miRNA genes are largely unknown. Computational approaches have yielded information on transcription and sequential processing of miRNAs in regulatory elements present in the upstream region of miRNA genes.42 These motifs are preferentially located within 1 kb upstream of the genomic region of protein-coding genes and are evolutionarily conserved.42 Recent work by Saini et al.43 has indicated regulatory binding sites for transcription factors located slightly upstream of the pre-miRNA gene regions (∼60% of these sites are clustered within 1 kb). In addition, their distribution heavily overlaps that of the predicted transcription-starting site (TSS). The predicted TSS for intronic miRNAs may lie predominantly in the −2 to −6 kb region upstream of the pre-miRNA sequence, and may correspond to the annotated TSS of the host transcript. Interestingly, miRNA genes may posses more than one predicted TSS.43 Indeed, a significant fraction of human intergenic miRNAs are characterized by two separate, prominent peaks containing the predicted TSS, with one in the vicinity of the pre-miRNA sequences (within 2 kb) and the other at a distance of about −10 kb. Putative promoters for several human miRNA genes within 0.5 kb upstream of the pre-miRNA sequences (named 'core promoter regions') are believed to contain essential components for the regulation of gene transcription.44
Indeed, a growing body of evidence indicates that transcription factors take part in specific cellular pathways of transcriptional regulation of miRNA genes. Generally, these factors activate or repress specific gene expression by interacting directly with their cis-regulatory motifs (8–15 nt long), which are often located in the genomic regions upstream of and near TSS. miRNA upstream regions usually contain a larger number of regulatory motifs if compared with the promoters of protein-coding genes.42 Moreover, miRNA activities have been found to be linked to transcription factor functions, being present in feedback loops in which they control each other's function, as described in more detail later in this review.
However, transcription factors are not the only key regulators of lineage-specific gene expression. Epigenetic mechanisms, such as DNA methylation, post-translational modifications of the histone code, and nucleosomal remodelling, all contribute to the modulation of gene expression and to the determination of cell and tissue specificity.45 DNA methylation, a normal process used by mammalian cells to maintain normal expression patterns, is achieved by the addition of methylgroups to cytosines within CpG dinucleotides (CpGs), frequently gathered in clusters (CpG islands), by DNA methyltransferases (DNMTs).46 Newly methylated CpGs act as docking sites for the recruitment of the DNA-methyl CpG-binding proteins MeCPs (methyl CpG-binding protein 2) and MBDs (methyl binding domain proteins), which stabilize the methylation process for gene silencing. DNMTs, MeCPs, and MBDs are often present in protein complexes with other chromatin remodelling activities, including histone-deacetylases (HDACs), for the transcriptional regulation of gene expression.45,46 Recent evidence suggests that miRNA expression is regulated by epigenetic mechanisms. CpG islands are present both upstream and downstream of genomic miRNAs coding sequences. A significant portion of these CpG islands (∼40%) also overlaps predicted TSS sites.43 A potential oncogenic role of altered miRNA activities has been reported as a consequence of DNA hypermethylation and histone modification of miRNA genomic regions.47–50 This opens a largely unexplored area regarding the epigenetic regulation of miRNA gene expression in normal tissues, tumour development and progression.
Transcription factors, microRNAs and lineage specification/differentiation of eukaryotic cells
Early stages of embryonic development
The essential role of miRNA activity regulation during tissue development is supported by the consequences of the targeted inactivation of Dicer, which results in loss of processed miRNAs and accumulation of miRNA precursors. In zebrafish, maternal-zygotic Dicer mutants display abnormal morphogenesis during gastrulation, brain formation, heart development, and somitogenesis. It is noteworthy that brain defects can be rescued by miRNA-430 injection.41 In mice, the elimination of Dicer activity causes embryo death before gastrulation. Dicer inactivation in mammalian limb, myogenic compartment, lung, and skin results in severe morphological defects and is associated with aberrant cell proliferation and apoptosis during tissue development.51–55
Interestingly, miRNA genes are among the components of the transcriptional regulatory circuitry believed to be regulated by Oct4, Sox2 (SRY-related HMG-box2), and Nanog in human embryonic stem (ES) cells.56 Oct4, Sox2, and Nanog are the earliest-expressed set of genes that play essential roles in early development, maintenance of ES pluripotency and lineage specification.57–59 By genome scale localization analysis (chromatin immunoprecipitation coupled with DNA microarrays), Oct4, Sox2, and Nanog were found to co-occupy the promoters of a large population of genes, mainly encoding transcription factors implicated in developmental processes of human ES cells.56 Oct4, Sox2, and Nanog were also associated with the gene loci of 14 miRNAs and co-occupied the promoters of at least two miRNA genes (miRNA-137 and miRNA-301). Moreover, increased miRNA-134 levels directed mouse ES cell differentiation towards ectodermal lineages through the post-translational attenuation of Nanog expression levels60 (Table 1). More recently, the neuronal repressor element 1 (RE1)-silencing transcription factor (REST) has been reported to play a role in the maintenance of the self-renewal and pluripotency of mouse ES cells through, among other mechanisms, transcriptional suppression of miRNA-21 expression. miRNA-21 itself can suppress ES cell self-renewal by affecting the expression of the key self-renewal regulators Oct4, Sox2, Nanog, and c-myc.61 Bioinformatic approaches have also pointed to the presence of putative miRNA-21-binding sites in Sox2 and Nanog mRNAs61 (Table 1). Taken together, these observations from ES cells lend support to the functional role of miRNAs, their modulators and targets in early physiological networks regulating normal morphogenesis, tissue and organ development.
|Biological function
|Predicted/validated targets
|Embryonic stem cells
|Self-renewal suppression
|Nanog, Sox261
|Ectodermal lineages differentiation
|Skeletal and cardiac muscle
|Cardiogenesis, myogenesis, hypertrophy
|Hand2, HDAC4, Delta64,65
|Myogenesis, inhibition of skeletal and cardiac hypertrophy
|B-ind1, Cx43, Mdm, Pola171
|Expression of β-Mhc, stress-dependent cardiac remodelling
|Nervous tissue
|Neuron maturation
|Neuronal morphogenesis
|Neuronal identity
|MeCP2, REST80
|Haematopoietic tissue
|NFI-A,90 Mef2c101
|B-cell differentiation
|B-cell lymphomas
|Cell proliferation
|Biological function
|Predicted/validated targets
|Embryonic stem cells
|Self-renewal suppression
|Nanog, Sox261
|Ectodermal lineages differentiation
|Skeletal and cardiac muscle
|Cardiogenesis, myogenesis, hypertrophy
|Hand2, HDAC4, Delta64,65
|Myogenesis, inhibition of skeletal and cardiac hypertrophy
|B-ind1, Cx43, Mdm, Pola171
|Expression of β-Mhc, stress-dependent cardiac remodelling
|Nervous tissue
|Neuron maturation
|Neuronal morphogenesis
|Neuronal identity
|MeCP2, REST80
|Haematopoietic tissue
|NFI-A,90 Mef2c101
|B-cell differentiation
|B-cell lymphomas
|Cell proliferation
Abbreviations: Sox2, SRY-related HMG-box2; Hand2, heart and neural crest derivatives expressed 2; HDAC4, histone-deacetylase 4; Delta, notch ligand delta; SRF, serum response factor; B-ind1, butyrate-induced transcript 1; Cx43, connexin 43; Mdm, monocyte-macrophage differentiation-associated protein; Pola1, DNA polymerase α largest subunit; THRAP1, thyroid-hormone-receptor-associated protein 1; Pitx3, paired-like homeodomain transcription factor; MeCP2, methyl CpG-binding protein 2; REST, RE1-silencing transcription factor; NFI-A, nuclear factor I-A; Mef2c, myocyte-specific enhancer factor 2C; kit, tyrosine kinase receptor; Tcl1, T-cell leukaemia/lymphoma; AML1, acute myeloid leukaemia-1. Reference numbers are indicated.
Skeletal and cardiac muscle
Myogenesis is characterized by the transcriptional activation of muscle-specific genes encoding contractile proteins, metabolic enzymes, ion channels, and neurotransmitter receptors. Transcription of muscle-specific genes is regulated by a set of basic helix-loop-helix muscle regulatory factors (bHLH-MRFs), which include Myf-5, MyoD, myogenin, and MRF4.62 Other more general factors, such as the myocyte enhancer factor 2 (MEF2), are essential for both skeletal muscle and cardiac development.63
Members of the miRNA-1 (miRNA-1-1, miRNA-1-2), miRNA-133 families (miRNA-133a-1, miRNA-133a-2, and miRNA-133b) and miRNA-206 have recently been described in key regulatory circuitries controlling: (i) skeletal muscle cell proliferation and differentiation; (ii) many aspects of cardiac biology, ranging from organogenesis in the embryo to hypertrophy in adulthood.64–67
miRNA-1 and miRNA-133 are specifically expressed in both skeletal muscle and heart, though their abundance differs in distinct stages of development.64–66 The vertebrate genome contains two distinct loci for the miRNA-1 and miRNA-133 bicistronic clusters that give rise to identical mature miRNA sequences. Although miRNA-133a is expressed in the same bicistronic unit as miRNA-1-1 or miRNA-1-2, miRNA-133b is expressed as a separate gene transcript. The molecular mechanisms regulating miRNA-1 and miRNA-133 processing have yet to be fully clarified. Interestingly, miRNA-1 and miRNA-133 share common cis-regulatory motifs and trans-regulation mechanisms, but have distinct biological functions. During skeletal myogenesis and in the developing heart, their tissue specific expression is largely controlled by myogenic transcriptional networks involving transcriptional regulators, such as MEF2, serum response factor (SRF), Myo-D, and myocardin.64–67 In skeletal myogenesis, miRNA-1 inhibits myoblast growth, thus favouring the differentiation pathway, whereas miRNA-133 promotes myoblast proliferation, thus suppressing differentiation.65 miRNA-1 and miRNA-133 expression levels can be regulated by cardiac and skeletal muscle-specific enhancers present upstream of their cluster gene. These enhancers are direct targets of Myo-D and MEF2 in skeletal muscle cells and of SRF in cardiac myocytes. In the developing heart, SRF binding to the pre-miRNA upstream promoter region up-regulates miRNA-1 expression.
In keeping with a cardiac requirement for SRF, mutation of the SRF site in the miRNA-1-2 regulatory region disrupts its cardiac expression.64 In cardiac myocytes, SRF induces the expression of miRNA-133, which in turn inhibits SRF itself in a feedback regulatory loop that affects differentiation and promotes progenitor proliferation. In skeletal muscle progenitors, miRNA-133 enhances myoblast proliferation by targeting SRF, whereas miRNA-1 promotes myogenesis by targeting the HDAC4. HDAC4 is a chromatin-remodelling enzyme that acts as a transcriptional repressor of MEF2, which is present in protein–protein complexes with Myo-D at muscle-specific and growth factor-inducible gene-promoter sites.64–66 Thus, miRNA-1 and miRNA-133, and their targets SRF and HDAC-4, participate in key negative feedback regulatory loops, thereby contributing to appropriate decisions regarding the proliferation and differentiation status of skeletal and cardiac muscle progenitors (Figure 2A). However, a variety of key regulators of cardiac and skeletal myogenesis, besides SRF and HDAC4, are targets of miRNA-1 and miRNA-133 activities, including Notch ligand Delta and Hand2 (a basic HLH transcription factor that promotes ventricular cardiomyocyte expansion).64,65,68
Moreover, there is evidence supporting the regulation of other miRNAs by different myogenic regulators in the control of the muscle differentiation program, including: (i) the ability of myogenin and Myo-D to bind the genomic upstream sequences of different miRNA genes (e.g. miRNA-100, miRNA-191, miRNA-138-2, and miRNA-22);69 (ii) the induction of miRNA-206, a close homolog of miRNA-1 that is specifically expressed in skeletal muscle tissue and is measurable during myoblast–myotube transition of the mesenchymal C2C12 cell line. Interestingly, miRNA-206 is transcriptionally activated by Myo-D and affects myogenesis by reducing the levels of DNA polymerase, an important component of the differentiation program, and of Id1-3 and MyoR, two inhibitors of myogenic transcription factor activities.70,71
Thus, miRNAs may be present in gradients of signalling and transcription factor networks that govern key aspects of skeletal and cardiac myogenesis and whose de-regulation may result in disease. Indeed, the knockdown of miRNA-133 expression causes cardiac hypertrophy in vivo, 72 whereas miRNA-1 cardiac-specific over-expression in the embryonic heart inhibits cardiomyocyte proliferation and prevents expansion of the ventricular myocardium.64 Thus, miRNA-1, miRNA-133 as well as other miRNAs (e.g. miRNA-195 and miRNA-208, the latter encoded by an intron of the αMHC gene), are emerging as active players in cardiac disease and, therefore, as potential targets for therapeutic intervention.18,64,72–75
Nervous tissue
Initial work in C. elegans highlighted the involvement of miRNAs in transcriptional regulatory circuits controlling nervous system patterning.1,76 Later studies revealed that neural progenitors sequentially express different miRNAs, resulting in the regulation of lineage-specific genes during mammalian neurogenesis.77 In mammalian adult brains, different miRNAs have displayed marked lineage specificity. miRNA-124 and miRNA-128 are expressed at the highest levels in neurons; miRNA-26 and miRNA-29 are more strongly expressed in astrocytes than in neurons, while miRNA-23 expression is restricted to astrocytes.77 miRNA-133b is expressed in adult mammalian midbrain dopaminergic neurons.78 miRNA-133b regulates the maturation and function of midbrain dopaminergic neurons, it being part of a negative feedback circuit that includes the paired-like homeodomain transcription factor Pitx3, a known regulator of neurons gene expression78 (Table 1). Indeed, miRNA-133b is a direct transcriptional target of Pitx3 and its induction post-transcriptionally suppresses Pitx3, which results in a functional fine-tuning circuit for dopaminergic behaviours (e.g. locomotion) (Figure 2B). Worthy of note is the fact that miRNA-133b is deficient in midbrain tissue from patients with Parkinson's disease.78
miRNA-132 expression is strongly enhanced in neurons. miRNA-132 is transcribed from a conserved genomic region that contains, upstream of the pre-miRNA sequence, a cAMP-response element recognized by the basic leucin zipper transcription factor CREB. CREB mediates the neurotrophin-dependent neuronal morphogenesis by binding to this consensus sequence, which is present on its protein coding and non-coding target gene promoters.79,80 miRNA-132 expression is specifically increased by the brain-derived neurotrophic factor (BDNF) through the activation of CREB.79 However, BDNF gene is targeted by MeCP2, while MeCP2 translation is regulated by miRNA-13281 (Table 1). Indeed, if MeCP2 levels increase, so do BDNF levels, the result being that miRNA-132 is induced and MeCP2 mRNA translation is repressed (Figure 2C). This negative feedback loop, involving the transcriptional regulation of miRNA-132, has been proposed as a regulatory mechanism for the homeostatic control of MeCP2 protein during neuronal morphogenesis.81 Interestingly, as a highly conserved CpG island is present on the entire miRNA-132 locus, both increases and decreases in MeCP2 levels can cause neurodevelopmental defects.79–81
Neuronal gene expression is transcriptionally silenced in non-neuronal cells by the REST factor.82 REST is a zinc-finger protein that mediates epigenetic silencing of target genes through its interaction with a conserved 23 nt RE1, where it recruits HDAC and MeCP2 activities.80 Among the transcriptional targets of REST, there are the upstream genomic regions of different pre-miRNAs, including that of the brain-specific miRNA-124a, which is highly expressed in the mature nervous system.83 In both neural progenitors and non-neuronal cells, REST inhibits miRNA-124a gene expression, which in turn results in the selective up-regulation of non-neuronal transcripts. During progenitor differentiation into mature neurons, REST leaves miRNA-124a gene loci, and non-neuronal transcripts are selectively degraded by the activation of this miRNA. Thus, the establishment and maintenance of neuronal identity appears to require both the transcriptional re-activation of REST-regulated genes and the post-transcriptional down-regulation of non-neuronal transcripts by miRNA-124a, whose expression levels are controlled by REST itself.80,83
Haematopoiesis is a life-long, highly regulated multistage process where a pluripotent self-renewing haematopoietic stem/progenitor cell (HSC) gives rise to all blood cell lineages. HSC self-renewal capacity as well as the growth and maturation of erythroid, granulocytic, and monocytic and megakaryocytic lineages are largely controlled by unique combinations of lineage-specific transcription factors, including AML1 (acute myeloid leukaemia-1), C/EBPα (CCAAT/enhancer-binding protein α), MAFB (v-maf musculoaponeurotic fibrosarcoma oncogene homolog B) and PU.1, which cooperatively regulate promoters or enhancers present on their specific target genes.84 In mammalian cells, specific miRNAs whose expression varies during haematopoiesis have recently been identified.85–87 The relevance in haematopoietic lineage-specification of some miRNAs has also been highlighted by the consequence of their silencing/ectopic expression in haematopoietic progenitor cells (Table 1). Down-regulation of miRNA-221 and miRNA-222 is required for erythropoietic differentiation, and that of the miRNA 17-5p-92 and 106a clusters for monocytopoiesis.88,89 Ectopic expression of miRNA-181 increases the fraction of B-lymphoid cells, whereas increased miRNA-223 levels reprogram granulocytic differentiation.85,90 During granulocytic differentiation of human myeloid progenitors, miRNA-223 levels are modulated at the transcriptional level by the competitive binding of two transcription factors, the nuclear factor I (NFI-A)91 and the C/EBPα,92 for CAAT elements present on the pre-miRNA-223 sequence.90 NFI-A transcriptional activity maintains miRNA-223 at low levels, while its replacement by C/EBPα results in miRNA-223 up-regulation and granulocytic differentiation. It is noteworthy that C/EBPα is a transcription factor involved in myeloid differentiation, whereas NFI-A has been implicated in replication and in cell growth control.84,91,92 NFI-A is also a target for miRNA-223 translational repression, which thus establishes a feedback regulatory loop circuitry that is crucial in the control of granulopoiesis (Figure 2D).90 The relevance of NFI-A for myelopoiesis is supported by recent findings indicating NFI-A as a translational target of miRNA-424, a miRNA directly induced by the master regulatory factor PU.1 during human monocyte/macrophage differentiation (Figure 2E).92,93
Another transcriptional regulatory loop that is relevant to monocytic-macrophage differentiation and maturation of human haematopoietic progenitors involves the transcriptional regulation of the miRNA 17-5p-92 and 106a-92 cluster promoters by AML1. AML1 is a transcription factor that is widely expressed in multiple haematopoietic lineages and regulates the expression of a variety of haematopoietic genes. AML1 is also a translational target of miRNA 17-5p/20a/106a activation.89 In early haematopoietic progenitors, miRNA 17-5p/20a/106a repress AML1 translation, thus maintaining their undifferentiated status. In contrast, during the monocytic-macrophage maturation of haematopoietic precursors, miRNA 17-5p/20a/106a is down-regulated, thereby unblocking AML1 translation. Increased AML1 levels induce the transcriptional silencing of the miRNA 17-5p-92 and 106a-92 clusters through the binding of AML1 to its site in promoter regions. This leads to a negative transcriptional regulatory loop, which further increases AML1 translation (Figure 2F). Thus, during lineage specification of haematopoietic multipotent progenitors, feedback transcriptional regulatory pathways may allow fine titration of the levels of both transcriptional regulatory factors and miRNA, whose key role in normal haematopoiesis is only now emerging.
Therefore, the transcriptional or epigenetic de-regulation of pathways involving miRNA genes may be relevant for the pathogenesis of haematological diseases. In keeping with this hypothesis, the myelopoiesis-regulator miRNA-223 has been reported to be a key transcription target of the AML1/ETO oncoprotein, the fusion product of the t(8;21), which is the most frequent chromosomal translocation associated with acute myeloid leukaemia.50 AML1/ETO triggers the heterochromatic silencing of the miRNA-223 gene through its interaction with an AML1 binding site present upstream of the pre-miRNA-223. Here, AML1/ETO recruits HDAC and DNMT activities that de-acetylate histone proteins and methylate sparse CpGs, all assembled in the upstream, body and downstream regions of the pre-miRNA-223 sequence. Newly methylated CpGs act as docking sites for the DNA-methyl CpG binding protein MeCP2. Through the silencing of the miRNA-223 gene, the AML1/ETO associated complex contributes to the differentiation block of myeloid progenitors, thus linking the epigenetic silencing of a miRNA locus to leukaemogenesis.
Various bodies of evidence point to a functional pathogenic role of de-regulated transcriptional pathways involving miRNA genes in haematopoietic cells. Among these, the enforced expression of the miRNA 17-5p-92 cluster in conjunction with its transcriptional regulator c-myc resulted in mouse B-cell lymphomas which were characterized by the absence of the high apoptosis levels normally associated with c-myc-induced lymphomas.94 Interestingly, both c-myc and miRNA-17-5p-92 influence cell proliferation and apoptosis and possess oncogenic functions. The activation of the oncogenic transcription factor c-myc induces the expression of miRNAs within the 17-5p-92 cluster through the direct binding to its recognition sites (E-boxes), present in conserved upstream regulatory regions.95,96 Worthy of note is the fact that two of the miRNAs included in the miRNA-17-5p-92 cluster, miRNA-17-5p, and miRNA-20a, act as negative regulators of the expression of the transcription factor E2F1. E2F1 is one of the main drivers of G1/S transition during the cell cycle. In addition, c-Myc and E2F1 can activate each other's transcription, thereby establishing a network in which c-Myc activates the transcription of E2F1, which simultaneously inhibits its translation.97,98 Thus, upon c-myc activation, miRNA-17-5p-92 may act as a brake on the c-myc/E2F1 positive feedback loop to ensure tightly controlled expression of these two proteins.98 Moreover, two consensus sequences for E2F binding present on the miRNA-17-5p-92 promoter recruit all three E2F family members for transcriptional activation,99,100 thus rendering the regulatory networks involved in the control of proliferation, apoptosis, and tumorigenesis even more complex (Figure 2G).
Concluding remarks
Evidence is emerging that transcription factors, chromatin remodelling activities and miRNAs ultimately determine the correct organization of cell-type specific gene arrays, which control developmental timing, tissue differentiation and maintenance of tissue identity. The fact that miRNAs repress the expression of multiple target genes suggests that their biogenesis, processing and activity is crucially controlled and integrated into the molecular pathways governing these physiological processes. Indeed, miRNAs participate in complex epigenetic regulatory circuitries, involving cis-acting elements for different transcription factors in their putative promoter regions. Moreover, putative binding sites for distinct miRNAs are present in the 3′-UTR of transcription factor mRNAs. The transcriptional/epigenetic regulation of miRNA genes and the factors responsible for their tissue-specific expression have only recently started emerging as a unitary mechanistic model for cell fate decision. Thus, one challenge for the future will be to unravel the contribution of individual signal cascades in the complex and highly controlled regulatory networks that are responsible for the differential expression of genes and dictate cell phenotypic changes throughout development and during adult life, as the de-regulation of such networks might explain the pathogenesis of a number of diseases.
The studies by the authors were supported in part by grants from the Italian Association for Cancer Research (AIRC), Italian Ministry for Education, University and Research (PRIN) and 'Sapienza' University of Rome.
We apologize for not directly citing many crucial references owing to space restrictions; these references can, however, be found in the cited reviews.
Conflict of interest: none declared.


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Corey Kluber vs Jake Odorizzi Tilt Ends in Cleveland 6-3 Win
Tampa Bay wasted a 11-effort from Jake Odorizzi and fell 6-3 on Friday against Cleveland at Tropicana Field.
Cleveland won as a +106 underdog, while Over-Under bettors who played OVER the total of 7.5 were rewarded at the payout window.
Cleveland got 6 2/3 innings from Corey Kluber, who gave up 2 earned runs on 9 hits, while striking out 9. He earned the victory, while the Indians got 3 RBIs from Mike Aviles in the win.
Tampa Bay got a 5-inning outing from Jake Odorizzi in the loss. He gave up 0 earned runs, 2 walks and 5 hits in his time on the mound, while David DeJesus had 4 hits in the loss for the Rays.
The battle of the bats favored Tampa Bay as they had 12 hits, while Cleveland only had 11.
Cody Allen pitched the final 1/3 innings for the save. He struck out 0 and allowed 0 hits in his outing.

subset: commoncrawl


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by Mario Fraioli, Published Jan. 16, 2011, Updated Jun. 30, 2011 at 1:57 PM UTC
He won the marathon, then went on to shatter the U.S. 50K record in 2:43:45.
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An Idea For Getting The Best Home Improvement Loan
An Idea For Getting The Best Home Improvement Loan
There are a great deal of well known home upgrades that individuals always need or need. Be that as it may, these enhancements for the most part don't come shabby, bringing on numerous individuals to swing to home change credits with a specific end goal to make their fantasies work out. Whether it's to procure another center, fine kitchen, present day restroom or possibly to have a carport assembled. With such a large number of choices accessible, it is too simple to keep running into a choice before taking a gander thinking optimistically for your home, and your accounts. There are such a variety of approaches to enhance the home, for example,
1. Space Conversions
2. Expansions
3. Twofold Glazing
4. New Driveways
It is basically essential to work out the expense of the home change, contrasted with the measure of quality it would add to your home. In the event that you investigate that the change would make you make a misfortune in your accounts, it is then up to you to work out whether the change is really required. It is likewise pretty much as essential to quantify the standard of the home enhancements you need to occur; modest upgrades at low esteem could bring about issues, as opposed to really increasing the value of your home. Keep in mind about arranging consent as well… prior to the redesigns start!
Ensure you systematically see how your home change credit is going to work with your home loan. You'll have to know contract terms, loan costs, and obviously dispossession terms also. You'll have to include the greater part of the support or home credit costs into your change advance keeping in mind the end goal to ensure that you can make the installments on the home and the majority of its supplementary advances. It may regard thoroughly redesign your kitchen, yet in the event that you can't bear the cost of the home change advance, you could really lose your home over it.
Awful lender like the default, arrear, indebtedness, CCJs, late installment and IVAs, can take advantage from the home change advance these advance are available to you without a lot of annoy it give the terrible bank a probability to enhance their financial assessment in the business sector with opportune reimbursement of the credit.
Online strategy is the immediate method for getting endorsed there are numerous moneylender which supplier online administrations to the borrower online administrations gives the borrower to sit at home and studies the business sector rates and afterward go for a credit and you simply need to fill and online application structure with few point of interest and inside 2 working days your advance application will be handled and will kept into your financial records on the off chance that it is affirmed.
Ian Foster is an authority advance specialist at online home change advance He has done MDS Management and Finance from University of Falna. Presently he is working new on angle on Home change credits, individual secured advance for home change, modest home change advance, online home change advance and online home change advances.
Banks and Housing Loans
The immense American comic, Bob Hope, said in a dull voice, "A bank is a spot that will loan you cash on the off chance that you can demonstrate that you dont need it." A late news report said that more organizations, generally little and not really little scale property engineers, would overlap up on the grounds that the financial circumstance is starting to look splendid. Banks are beginning to cut their misfortunes and the predominant state of mind is "to look and witness what will next". Since these organizations have different moneylenders other than the banks, banks are taking a gander at the awful advances figures. The enormous banks are not stressed at their home loaning offers on the grounds that, until the house is completely paid, they have their hands on the deeds of the houses. Be that as it may, for mortgage holders, particularly those with stipends from the Government, they could encounter an expansion in the loan fees of up to one percent in the following 12 months. At the point when these happens, individuals would promote fix their cut spending plans or even tackle awful credit money advances on the off chance that they have monetary crises that are outside their financial plans.
Be that as it may, for the individuals who are as of now halfway in paying for their fantasy house when the money related emergency hammered on Wall Street and the accident resounded the world over, these individuals are presently attempting to pay their home loans. One intense choice is to apply for a chapter 11 lodging advance. This advance is very hard to acquire, not at all like individual credits online that more often than not have negligible prerequisites. Be that as it may, for a chapter 11 lodging credit, the borrower must take after exceptionally strict prerequisites and high loan fees and charges. Borrowers ought to expect a littler advance sum, contrasted with different sorts of advances. Furthermore, such as applying for any sort of advance, it would be better if the borrowers have no money related commitments and they have settled with their banks. If not, the application for this kind of credit may not be endorsed. To finish everything off, the borrower may just have the capacity to get the insolvency lodging credit two years after the announcement.
Money related specialists exhort first property holders, especially those without gifts or appropriations from the Government and different organizations, to sit tight for a couple of months before purchasing the fantasy house. Likewise, individuals considering purchasing a house should first check if their FICO score is great. With the financial circumstance close by, who knows whether in the following couple of months, financing costs would go down or banks and other loaning foundations would offer a higher advance sums for lodging.
Using The Feng Shui Wood Element In Home Decor
Here are some key things of this component: the shading green, east or south-east heading, the image of a winged serpent, and more Yin than Yan vitality. The images that portray it incorporate blossoms, trees, wooden things, rectangular furniture, straw specialties, paper makes, fabric artworks, and artistic creations delineating a timberland.
Its simple to add this component to your home utilizing exceptional feng shui dolls made of wood. Here are some great case of such figures, and a clarification of their properties.
Elephant: The elephant doll will make you all the more capable and effective. Elephant turned into the image of an equitable and regarded pioneer in China. The Elephant will help you procure the important qualities to accomplish acknowledgment and high status. Place the statuette in your office or close to your work environment at home.
Frog: An amphibian with coins in its grasp is a talisman that pulls in cash. You have to put the amphibian close to the passage entryway, corner to corner. Dont set it too high or too low. A cash amphibian ought to take a gander at the front entryway, inviting riches into your home. A cash frog holds Chinese coins that symbolize success.
Winged serpent: The mythical beast will enhance the vitality of your home and help you succeed. The Dragon will enact the Yang vitality that is required for accomplishment in new attempts. The Dragon is one of the 4 defender creatures, each of which compares to one of the four cardinal focuses. A mythical beast monitors the eastern heading, so the statue is best placed in the eastern part of your home. Notwithstanding, the monster epitome of the feng shui wood component can be put anyplace.
Mythical beast on a pearl: The winged serpent is an image of the Yang vitality. In China, the monster likewise symbolizes downpour, which feeds the earth and makes it rich. The Dragon brings flourishing. The mythical serpent that sits on the divine pearl can make wishes work out as expected. This doll can be set anyplace in your home or office.
Twofold bliss: The symbolic representation Double Happiness fits connections and fortify affection. In China, it's a convention to present this symbolic representation as a wedding blessing, so that the love birds union stays solid. The symbolic representation is best hung in the south-west part of the room, to draw in and look after adoration.
The spiritualist bunch: The spiritualist bunch is one of eight characters that showed up on the soles of the Buddha (as indicated by legends). This sign is related to the unending adoration, so lovely that it has no starting or end. It's a smart thought to hang this sign in the room, to avert partitions in your relationship.
These puppets are normally cut from a solitary bit of mahogany tree, Abash tree, and numerous others. They can turn into an impeccable beautification for your home and help you adjust your life utilizing the feng shui wood component.
Architecture Of Yesteryears
Shingle style engineering is an imaginative type of Queen Anne and it was begun in America amid the most recent two many years of nineteenth century.This name was given by Vincent Scully, a student of history of building architecture.Among the different structures in America that are developed in this style, The Hotel del Coronado in San Diego is considered as the biggest.The houses that are implicit this style are even structures developed on a stone laid foundation.The lopsided plans and unpredictable development make the building procedure profoundly confused and therefore the expense of development was a long ways past the moderate reach for regular people.Thus it was considered as an extravagance homes outline. The rooftops are more mind boggling in this sort of design. A considerable lot of such houses have gabled rooftops with a tower in the front. A couple houses have rooftops that are hipped. In the gambrel type of rooftops, the third story of the building will be covered up in the rooftop so that the building will show up as a two storeyed building. The rooftop shingles and divider shingles will be in various hues. A large portion of the houses have towers and if a building is without tower, an a portion of its divider will be lump out.
This kind of engineering has the procurement for more quantities of all shapes and sizes windows. The windows are generally twofold hung with a solitary scarf underneath and numerous scarves above. For tremendous dividers, the windows will be in 2, 3 or more columns and there are different outlines for the windows. In the most complex outlines, substantial windows are kept in narrows with 1, 2 or 3 stories. The more in vogue windows will be in square, rectangular or roundabout shapes.Entrance with roomy yard is normal for this architecture.People used to unwind in the patios which are upheld by balusters, segments or stone backings.
The present day houses that are inherent Shingle style design offer a large group of unmistakable components including common surroundings, vitality productivity and sound indoor climate. These houses show how wood, stone and daylight can be used to give a sound shelter.There are numerous occasion homes that are inherent this style of design. Numerous rich individuals have built this sort of homes at celebrated resorts furthermore adrift side plots. Common hues, outside secured by wooden shingles and an unbalanced structure are the essential elements of this engineering structure. The other normal elements are huge patios, sporadic rooftops, towers, verandas, awry floors, smokestacks, gigantic staircases and chimneys and so forth.
Are you searching for Shingle style engineers and extravagance getaway homes, vanbrouck is the best decision. It is exceedingly prescribed from both a configuration and quality angle when we were hoping to home outlines and construct our fantasy home. For more data about Shingle style engineering please visit us.
Achievable Home Improvements You Can Do
Achievable Home Improvements You Can Do
Whether you need to better your home for resale, or make it a more agreeable, a la mode and energizing environment for you and your family to live in, there are a heap of home enhancements that you can effectively do yourself.
Not just would you be able to spare yourself a little fortune by removing certain tradesmen, however you'll additionally have the fulfillment of knowing you did it without anyone else's help. Even better, once you pick up the certainty to handle your own home change ventures, you'll see that DIY can be a considerable measure of fun.
So where do you begin?
Above all else you have to recognize which home change thoughts are appropriate for DIY. While there are some auxiliary remodels that are best left to the specialists, you might be amazed what number of home upgrades you can do yourself. All you have to ace are a couple of essential aptitudes, and take after demonstrated tips and strategies.
What you can would like to accomplish in Your Home
One of the most ideal approaches to change any house is with paint. With the right instruments and methods, you'll see that a do it without anyone's help paint occupation will give you moment delight.
Another fantastic approach to rapidly change the look and style of any inside is with wallpaper. You may think that its less demanding working with a partner, however once you recognize what to do, you'll be flabbergasted at how rapidly and effectively you can do it without anyone's help.
Somewhat more confounded than painting or wallpapering, laying hardwood or cover floors, and tiling dividers and floors, are assignments that truly are not that troublesome. However by supplanting old, worn floors and by tiling or retiling, you will increase the value of your home than you ever suspected conceivable
Racking is another component that fits the Home Improvements profile. Yes, you do need to know how to guarantee racks are level, and how to verify that they won't crumple when things are set on them. In any case, rest guaranteed that the systems required to hang or introduce racks are not hard to get a handle on. Besides, the main apparatuses you'll need are a drill, a screwdriver to attach screws, and a soul level – all of which are priceless for do it without anyone else's help employments around the house.
Introducing or supplanting crown embellishment or cornices between the roof and dividers, and fitting baseboards or avoiding sheets at floor level, are different potential outcomes that will lift your rooms from exhausting to delightful. You'll require a step to get to the moldings, and accepting you're working with wood, an electric bore, a reasonable saw and a screwdriver, perhaps at the same time a mallet.
There are additionally a couple plumbing overhauls you can do yourself. These reach from supplanting the washer in a spilling spigot or tap, and supplanting the tap fitting itself, to putting in new sterile product (a bowl for occurrence). Funnel work must be finished by an enrolled handyman, wherever on the planet you live.
The same idea applies to light fittings. Beyond any doubt you're working with things electrical, yet you aren't working with wiring, which implies you needn't bother with a circuit tester. So why not change the installations and fittings and enhance the look and nature of brightening in ALL your rooms?
Some Tips for Success
Presumably the most essential part of fruitful DIY Home Improvements is to know when to inspire the assistance of others. This "assistance" might be as counsel, or it might be physical help.
Before you begin actualizing your home repair and home change thoughts:
– draw up a sensible and achievable arrangement of activity for every one of the thoughts you have
– arrange completely for every individual venture; this will at last spare time and guarantee achievement
– separate between supernatural occurrence makeovers you can do yourself and auxiliary changes that require a specialist to help you
– in case you're
Amrapali Terrace Homes New Residential Property For Sale At Noida Extension
Amrapali Terrace Homes is the most recent new property available to be purchased at Noida Extension that is gone for setting new benchmarks for private properties in Noida by the Amrapali Group, a standout amongst the most trusted suppliers of land property in Noida and Delhi NCR.
offering a wode scope of seven diverse living alternatives as 2, 3 and 4 BHK condo available to be purchased in Noida Extension, the pads available to be purchased at Amrapali Terrace Homes have been set up over a roomy zone that reaches somewhere around 885 and 2070 sq. ft.
Amrapali Terrace Homes offers habitations that are well worked, as well as come completely outfitted with the most advanced solaces and accommodations that some other property in Noida Extension has offered till date. The pads available to be purchased at Terrace Homes have been valued somewhere around 17 and 41 lakhs, contingent on the sort of private property and its size.
Amrapali Terrace Homes additionally appreciates all the advantages of an immaculate area, as it is arranged in a tranquil and quiet area at Noida Extension, and the private complex itself is spread out over a sprawling region of 70 sections of land, which incorporates 75% of open territory with colossal extends of lavish greens.
All flats in this rich private property will be 3-side open, which implies that all living arrangements might be greatly very much lit and ventilated.
Aside from this, the individuals who book a level at Amrapali Terrace Homes might likewise be spoiled with enhancements, for example, 2-Tier Security System, a Gated Community, Modular Kitchens, a to a great degree all around prepared Gymnasium, a Sports Academy, twofold stature porch, Vaastu-accommodating designs and stop and play regions.
Amrapali Terrace Homes additionally appreciates simple network to all significant business and recreational centers and in addition general purposes of premiums like healing facilities, banks and neighborhood markets.
This joined with the solid sponsorship of a developer like Amrapali Group makes Terrace Homes effortlessly qualify as a standout amongst the most alluring spots to book a level at Noida Extension.
Trendy Bath Vanities, Sinks And Faucets Offer Feng Shui Asian Fusion Flair
There are a large group of alternatives available to you. Twofold sink vanities, custom stockpiling boxes and divider mounted cupboards all blending shape and capacity. You should simply decide your style statementcontemporary, customary, vintage, Asian propelled or Old World.
With respect to your configuration style, lets say its Asian propelled. You wouldnt be separated from everyone else with enthusiasm for that theme. The American shower society has to be sure changed. Focused on mortgage holders look for shelter and comfort and thats why so a large portion of us are making situations in our homes helpful for the Eastern idea of focusing. You dont must be a confirmed Feng Shui expert to remember this expanding pattern. Which means basic, clean lines and moderate components that are a mark of the Asian-impacted configuration inclining. So hot in home furniture, its not in any manner astounding that this topical has advanced into the kitchen and shower. Its a measure of good outline.
Its about worldwide style. From profound drenching tubs, intriguing shower waterfalls
what's more, sinks that smoothly embody the specialty of Zen.
As mortgage holders incorporate Japanese koi lakes into home doors and lanai water highlights (as in a serene Asian-style lavishly finished yards), the Asian-themes effortlessness and magnificence keeps on being utilized for frill, flooring and
furniture. In hardgoods, there are a lot of Asian-roused looks, including:
spigots with a bamboo-like etched completions, alongside drawer pulls reminiscent of bamboo, wood cabinetry enlivened by Asian feel and a sink arrangement with its square wooden bowls displayed after a customary Japanese
drenching tub.
Clean lines and straightforward structures particularly describe vanity cupboards characterized by Pacific/eastern societies. Asian outline can be more hilter kilter. It is inconspicuous, yet emotional, and makes a quiet feel. Whats essential about Asian combination nuts and bolts is that a portion of the items arent even fundamentally characterized thusly. However, what makes them work so well is that they offer a toning it down would be ideal perspective with straight, smooth and contemporary sensibilities that consolidate one of a kind and separating components.
Architecture meets Industrial Design
Title: Architecture meets Industrial Design
Content and Photography: Foster + Partners
Obscuring the lines between engineering, inside outline and modern configuration, F+P at the end of the day demonstrate that plan is consistent and widespread
Foster+Partners has demonstrated its configuration ability past the building business and conveys it forward to planning the insides and furniture for a business flying machine, drawing on its past payments for yachts and private planes.
Taking after the effective renovation of The Wing, Cathay Pacific's leader lounge at Hong Kong International Airport, the practice has conveyed the parlor's refined outline into the top of the line lodge of the Boeing 777-300ER armada reviving the recompense winning lodge.
The Wing, which opened prior this year,is the second in a progression of parlors by Foster + Partners for Cathay Pacific at HongKong International Airport. Everything about the interiors,from the Champagne Bar to the washroom fittings in the lavish top of the line – cabanas', has been hand crafted by the practice to make an extraordinary affair for visitors.
Other than the extravagant insides, the parlors are outfitted with various remarkable pieces outlined by Foster + Partners, including a marble gathering desk,food counter and a detached champagne bar with incorporated plate – down to the subtle element of porcelain plates. Nearby the bespoke items and erratic furniture pieces, The Wing likewise includes the Ilium round and hollow table light, created with Nemo and the Foster 503 rocker by Walter Knoll.The highlight is the Cathay Solus Chair, the aircraft's mark created with Poltrona Frau that reacts to the yearning for security amidst a bustling open space with its hourglass structure and multi-utility constitution: the roundabout structure consolidates a wide,comfortable seat, a coordinated a force supply and a table, which can be utilized as a casual work area. The ribs of pad at the back of the seat reach out in spots to shape edges, which can be utilized as armrests.
Making a consistent affair for travelers, the lodge's outline shares the parlor's palette of warm white leather,reflective dim dark surfaces and walnut completions to make a quiet, downplayed inside. Each component is considered and refined, including the line of the bespoke spreads for Cathay Pacific's praised five star situate, the high quality woolen cover, the restored bathrooms and the new perusing light, which has been specially crafted to cast less shadows when working or eating.
to view pictures click on globalhop.indiaartndesign.com
5 Surprising Health Dangers Lurking In Your Home
5 Surprising Health Dangers Lurking In Your Home
There are numerous perils in your own particular home, which are obvious and not noticeable to the eyes. Certain ordinary things can fall apart decently fast and represent some concealed wellbeing dangers. In this manner, it is imperative to keep your home, from the room to the kitchen, sheltered and clean. To do this, you can have an expert visit your home or handle the occupation without anyone else's input.
Taking after are 5 shrouded wellbeing risks in your home that you may not think about.
1. Mold and organism
Mold and organism can bring about wellbeing issues, from hypersensitivities to more serious contaminations. They can create behind your flawless mortar or in old rug and floor coverings. So you ought to have your home analyzed in the event that you think mold. You can likewise utilize dehumidifiers and fans in spots where dampness is normally happening. In addition, you have to keep your floor coverings parasite free by steam-cleaning with a vinegar, liquor, and cleaning arrangement blended with warm water routinely. Also, you have to hold all regions under carpets as dry as could reasonably be expected dispose of any mold spores.
2. Flawed wires
Flawed wires can be another peril in your home. Notwithstanding when you're wiring is totally redesigned, you may at present have electrical issues that could posture potential issues. Consequently, it ought to be better on the off chance that you look at the wires and do other repair work to maintain a strategic distance from these perils.
3. Home stacks
There is amassing of dust in the smokestacks since they are utilized all as the year progressed. This can bring about a blockage in the stack framework, which makes the smoke of the fire push back in the home. So it is important to have your fireplaces reviewed every year by a confirmed smokestack authority. You ought to likewise keep them clean and tidy free.
4. Furniture shine
Furniture shine can harm your wellbeing since it contains noxious mixes. When you utilize this family unit cleaning thing, you may encounter indications of harming, for example, eye disturbance. Additionally, furniture shine harming can happen on the off chance that you breathe in an over the top measure of this shine. So be extremely watchful when utilizing this and other family unit items.
5. Dangerous channels
Water funnels may contain Legionella, pneumonia-impelling microbes that flourish in water and causes Legionnaires' sickness. So consistent cleaning of channels assumes a vital part to forestall wellbeing issues.
Affordable Indoor And Outdoor Residential Stair Lifts
Limited versatility is liable to negatively affect the physically tested and the elderly, making them discouraged and detached. Also, such people think that its hard to climb steep staircases, and are liable to fall and harm themselves. With colossal advancement in innovation, availability issues can be effectively settled through the establishment of reasonable indoor and open air private stair lifts.
Guarantees Safe Access in and around Your Home
The security measures fused in private indoor and outside stair lifts are exceptional. The imperative elements incorporate collapsing arms, collapsing tracks, safety belts, block sensors, swivel seats, shrouded gear jack and some more. It is additionally given customizable seats, with the goal that it can hold the clients in a standing or situated position. Greater part of the models are outlined with handheld controls keeping in mind the end goal to encourage easy operation. Stair lifts are accessible in AC and DC models. The upside of having a DC model stair lift is that, it can be worked notwithstanding amid force breakdowns, as it is bolstered with battery reinforcements. Looking at costs, DC models are significantly more costly than AC models.
These stair lifts can be altered as needs be, in order to suit both bended and winding staircases. They are additionally given exceptional components to spare your living space. Besides, these furnish the client with tranquil and smooth operation. To run well with testing climate conditions, open air stair lift models are joined with abundant climate safe systems.
Make the Right Product Selection
While buying indoor and open air stair lifts, it is imperative to pick the right model, from the assortment of accessible decisions. Consideration ought to be taken to pick a quality item that is to a great degree dependable and sturdy based upon your remarkable prerequisites. It is additionally prudent to make the buy from understood producers. Marked makers offering indoor and outside private stair lifts incorporate ThyssenKrupp Access, Bruno and Savaria Concord.
In spite of the fact that an extravagance thing previously, private stair lifts are currently a need for the greater part of the living arrangements, as these give simple and hazard free access between the floors for matured and impaired individuals from the family.
Paper Lanterns An Integral Part Of Feng Shui
Every one of us have known the magnificence that can be made by the utilization of paper lamps. Nonetheless, not very many of us have any thought regarding the various use and impacts of utilizing paper lamps. Chinese have been utilizing paper lamps from a great many years and as indicated by them it assumes a huge part in feng shui.
Paper lamps help in expanding fruitfulness:
A large number of ladies all through the world face trouble in getting pregnant. This can be an overwhelming background if the hold up is truly long. Numerous individuals don't accept exclusively on specialists to help them battle the issue with their fruitfulness. Feng shui is accepted to help in enhancing fruitfulness by utilizing red paper lights. As indicated by the hypothesis of feng shui, red paper lights if held tight both side of bed can help in getting pregnancy. Numerous feng shui specialists even propose utilizing a red paper light straightforwardly over the bed.
Paper lamps help in getting positive vitality house
Feng shui is surely understood as a workmanship that acquires constructive vitality people groups life. Paper lights are accepted to assume a critical part in bringing a positive vitality and harmonica impact in your room and house. Keeping paper lamps on both or either side of bed is useful in bringing positive Yang vitality into the room and enhances the effectively exhibit chi vitality. Brilliant hued paper lights are more successful for tackling Yang vitality.
Paper lamps help in conveying concordance to marriage
Feng shui utilizes the vitality of extremity and as per it utilizing a couple of same article is extremely compelling. Utilizing a couple of red paper lamps on sides of bed, both lit at the same time imply a long and cheerful marriage. Notwithstanding, for the impact to be more it is critical to lit and switch off both the lights in the meantime with the goal that they work in congruity. This amicability is image of marriage and implies the concordance amongst a couple.
Paper lamps are vital piece of feng shui process. The individuals who have confidence in feng shui will realize that paper lamps are beautifying as well as a wellspring of positive vitality.
Architecture Animation
In this day and age of moment delight, Architecture Animation is giving a virtual voyage through the property in a future-finished state can be an exceptionally extraordinary and enthusiastic experience in spite of the fact that it is in the idea stage in all actuality. Movement as a rule starts with the all encompassing representation of the outer elements that incorporate arranging, supports, wall, streets and outside surroundings when all is said in done. The outside perspective of the building demonstrates the faade where engineering, materials and outline can be caught on. Structural Animation is a little compositional motion picture made on a PC. A structural activity is a progression of hundreds or even a large number of still pictures. At the point when these pictures are gathered and played back they create a film impact much like a genuine motion picture. The Architectural Animation venture comprised of outside and inside Visuals to help with configuration endorsement. The Architectural Development was precisely appeared inside the Architectural Visualizations and the Architectural Animation. It is conceivable to include a PC made environment around the working to upgrade reality and to better pass on its relationship to the encompassing region; this should all be possible before the venture is assembled giving creators and partners a reasonable perspective of the finished task. Structural Animation is presently a key part in Architectural Project Development. Lately the quickening significance of movement in conveying engineering, it can come to fruition in an assortment of ways – smooth vivified renderings breathing life into an imminent task, a completed venture layered with music and a story bringing the emotive measurements of a working to the surface, and even the simply applied articulation of design as a masterful investigation. They speak to an activity object of engineering by contemplating different geometrical elements and standards. Design Animation are made with concentrating intensely on various elements like width, tallness, expansiveness, lines, surface with bends of building segments. Considering in the parkway of film or in current occasions how time and cost expending it could be to reproduce an occasion. The design movement permits craftsmen to make these occasions utilizing models, than rendering the models, which gives life into the structure to make an arrangement of occasions. Envision that you need to improve your working than others in a viable way. At that point you will require something to make you clear about how to assemble your proposed constructing structure. On the off chance that you have some kind activity of your building admirably before it gets built, then it turns into a considerable measure less demanding for you to accomplish your objective. Vivified structures and energized insides outline for structures are the best reasonable choice for you.
A Small History of Housing in Williamsburg Brooklyn
Williamsburg is an area in the New York City body electorate of Brooklyn, flanking Greenpoint down toward the North, Bedford, from Stuyvesant toward the South, Bushwick and Ridgewood, Queens down toward the East and the East River down toward the West. The area is a piece of Brooklyn Community Board 1. The area is served through the New York Police Department (NYPD's) 90th Precinct. In the City Council, the southern and western part of the area is spoken to with the 33rd District; and the eastern part of the area is spoken to by the 34th District.
Williamsburg is a powerful center point implied for non mainstream rock, fashionable person society, furthermore the neighborhood workmanship group. A few ethnic gatherings likewise have enclaves in Williamsburg, including Italians, Puerto Ricans, Jews, and Dominicans. The area is reclassified by a developing populace and the quick improvement of lodging and retail space principally obliged an affluent populace that has truly been generally outside to the area.
Williamsburg, the area expanding fanwise from the Williamsburg Bridge to Flushing and Bushwick Avenues, has a tremendous bilingual populace. Here, with the erection in 1936-1937 of Williamsburg Houses, a PWA development venture began Brooklyn's first examination in vast scale low-lease lodging.
Williamsburg Houses, Scholes Street to Maujer Street, Leonard Street down to Bushwick Avenue, is the greatest ghetto freedom and low-lease lodging task was refined under the Federal Housing program (1939). Worked at an expense around $12,800,000, the improvement joins twenty flats, of four stories high, pleasing 1,622 low-pay families, around six (6) thousand persons.
The structures, involving around 30 for each penny of the gross zone, are gathered into four (4) superblocks, framed by shutting two (2) through roads to movement. Three (3) squares have six (6) flats each; the other join two houses, the new William J. Gaynor Junior High School, a play area, and a recreation center. The structures, separately fulfilling in outline, are of flame resistant development with standard solid floors. Shading gives quite a bit of their appeal yellow ochre block, blue-dim earthenware between windows, dim bond, brilliant blue entryways, and dim blue store front parapets. All flats, two to five rooms, are furnished with fridges, electric stoves, and cutting edge plumbing, and supplied with steam warmth, icy and high temp water. The family room of a great loft has a story range of 150 square feet; the room, 120 and the kitchen, 75.
Williamsburg Houses are under the control and administration of the New York City Housing Authority. Occupants are singled out the premise of salary and the need for better lodging. The social exercises are seen in the social and specialty rooms of the venture and the group focus of the secondary school. The Authority gives enough space to classes for moms in brain science and youngster care, men's and ladies' clubs, an inhabitants' committee, a joy club, and youth bunches, however these exercises are started furthermore directed by the occupants themselves. It was then pronounced that the Williamsburg improvement offers a greater amount of the administrations of good lodging than numerous costly Park Avenue flats.
Tips for Home Improvement Contractors to Convert More Leads
Lead era can be an extraordinary way to deal with build up your association and develop. Leads are intense as they can be changed over into contracts that make salary for your business. One ought to utilize various methodologies to guarantee that the home change temporary worker leads are fruitful. Various leads, for example, kitchen contractual worker promoting drives, free jack of all trades leads and also plumbing web showcasing can help the home change temporary worker in growing the extent of his or her business.
There are a couple tips that one ought to remember for fruitful home change contractual worker leads.
Be Clear About Your Objective
As a home change contractual worker, you should organize the sort of leads you need for your business. These could be either kitchen temporary worker promoting drives, free jack of all trades leads or notwithstanding plumbing web showcasing, contingent on the sort of administrations you give. It is imperative to be constant about the lead on the off chance that you need that to change over into a long haul customer. Here and there, you may need to call the potential customers quite often for couple of weeks to at long last get some outcomes.
Understanding Your Customer
In the event that a client has consented to meet you, that is only the start of the whole procedure. Keeping in mind the end goal to guarantee that the client would need to work with you, you should comprehend his or her needs. Keeping in mind the end goal to have fruitful home change contractual worker drives, it is basic that your business capacities are solid. On the off chance that you can't inspire the client, then they may not clutch your business for long.
Do Your Research
Simply knowing your client is insufficient on the off chance that you need information about anything identified with your industry. On the off chance that your organization puts resources into pipes web advertising, kitchen contractual worker showcasing leads or free jack of all trades drives, then the workplace representatives need information about the business with the goal that they can clear up any questions of the potential clients. This will showcase the experience and additionally information you have in your field that will help in changing over the leads.
After the client has met with you, it is presently basic to catch up with him or her about when he or she may require your administrations. Clients tend to get together various home change contractual workers and pick the best amongst them. In the event that you can awe the client with your tirelessness, aptitudes, learning and experience, then you have a higher shot of changing over the lead. A standout amongst the most crucial strides in doing as such is taking a criticism from the clients and creating upon them to enhance and improve your business capacities.
Bedroom Feng Shui Today
We spend the vast majority of our lives in the room, so it is vital to have a right mix of divider works of art, feng shui images, furniture, hues and living nature, for example, plants, blooms, fish tank. Subsequently, Bedroom feng shui can give us the key apparatuses to make a spot where you can unwind, great night rest, no anxiety from work, enhanced family connections et cetera. Each room is distinctive, so as to completely value the significance of symphonious courses of action, essentially consider how hopeless and hostile, untidy, mess, dull room resembles. Great skimming chi can bring you luckiness, particularly in riches, wellbeing and sentiment yet awful chi can makes your life hopeless.
With a specific end goal to anticipate awful chi in our room, there are some room feng shui rules you should take after. Firstly, don't put anything, for example, furniture, plant behind the entryway since you needs chi going to your room, not blocking chi. At the point when the entryway opens, ensure dependably make it at 90 degree-edge at any rate. Anything underneath 90 degree-point can forestall chi going to your room, which is you don't need that to happen. Some feng shui books additionally propose that you make them live things to lay eyes pretty much as you enter the room. These living things can be plant, fish tank, bloom, painting or whatever else that can causes a constructive reaction from individuals.
Improving room is an essential thing a portion of room feng shui. Use unwinding hues when painting the dividers, abstain from utilizing reds or blacks. With your bed, you have to feel good and must be in an order position. What do I mean in order position? Essentially, simply need to put the bed where you can see the entryway. Abstain from putting your bed in a corner or any sharp corners confronting you in the room, feng shui called "poison bolts". No mirrors in the room particularly for couple, feng shui think having mirrors is much the same as having a third individual in the room.
Keep your room clean at untouched is another piece of room feng shui summon. On the off chance that you can, please abstain from bring books, sustenances, water, and PC to your room. On the off chance that there are excessively numerous things in the room, then you are making terrible chi in your room. On the off chance that you ever feel discouraged, wiped out or migraine in the morning, observe around in your room and see what you can do to enhance great chi going to your room. Jumble can bring about a negative impact on the comparing part of your life. So by clearing mess in your room you can relinquish a wide range of negative feelings.


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Top Definition
A racist whore who writes for the Globe and Mail. Hates Newfoundlanders, and probably other races/groupes of people. She should die a horrible, painful death.
"I'm gonna fuck her and all of her fish-eatin lesbian friends in front of their mothers. Then I'll kill her."
by The Godfather January 08, 2005
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The What is your REAL age Test
Their result for The What is your REAL age Test ...
You are 46 years old!!
Their Analysis (Vertical line = Average)
They scored 46% on Age, higher than 88% of your peers.
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Terrorists 'fill policing vacuum in poor areas'
Published 08/02/2011
The lack of effective, community-based police services in loyalist and republican areas has created a vacuum which is being filled by paramilitary activity, leading experts have warned.
A major study into relationships between the PSNI, communities and paramilitary groups claimed police "inertia" had created a space for paramilitarism to flourish.
The study has been compiled by Dr John Topping, a lecturer in criminology at the University of Ulster, and Jonny Byrne from its institute for research in social sciences.
It claims the policing experience promised by the PSNI in the post-Patten era failed to meet community expectations or address fears about ongoing crime and anti-social behaviour.
"This has resulted in a growing acceptance of paramilitary 'policing' where there is a clear policing vacuum, with paramilitaries as 'entrepreneurs' seeking to exploit the gaps," Dr Topping said.
The authors conducted interviews with community groups, politicians and PSNI officers in loyalist and republican areas of Belfast.
Some 95 interviews were carried out between 2007 and 2009 — 60 from loyalist and republican communities and the other 35 with PSNI officers in those areas.
A loyalist community activist is quoted as saying: "I would say every area is the same. Every area has got a paramilitary influence... and the politicians, the bosses in the PSNI are burying their heads.
"I live in a loyalist working-class area and it (policing) hasn't changed one bit and, if anything, it has got worse.
"So if anyone asks has the peace process done anything, we say no.
"This paramilitary influence has been brushed under the carpet by the politicians and the police don't deal with it and it's business as usual."
One republican interviewee told the researchers: "There's a palate out there for that (paramilitary justice) because people are getting so frustrated (at the lack of state policing).
"They're saying: 'I don't care who hits them (criminals) as long as somebody's hitting them, stopping it (crime)."
Dr Topping said the study indicated that changing the hearts and minds of communities regarding the paramilitary option had been underestimated by both the PSNI and politicians, in terms of the need for more effective frontline policing.
"In this regard, the evidence pointed to paramilitary organisations cashing in on the lack of confidence in policing, as delivered by the PSNI," he added.
The PSNI was unable to comment when contacted last night.
Belfast Telegraph


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National Rottweiler Council (Australia)
Guardian of the Rottweiler
Welcome to the website for the National Rottweiler Council (Australia).
Latest News
The following links provide useful information to rottweiler owners:
1. Click here to download a report on Juvenile-onset Laryngeal Paralysis and Polyneuropathy
2. FCI Docked dog statement - http://www.fci.be/en/CROPPED-DOCKED-DOGS-OF-BREEDS-CUSTOMARILY-CROPPED-DOCKED-246.html
Other news:
We've been advised by the IFR that they still have stocks of the book "The Rottweiler" – the Rottweiler bible by A Pienkoss.
Details of the book's content can be read on the IFR website www.ifrottweilerfriends.org
The IFR is offering the book for purchase for the reduced price of 35,00 Euro instead of 44,50 Euro (plus postage and packaging costs).
Latest Site Updates
March 2016: New schedules added to the Club Events page. Click here to view them
January 2016: 2016 AGM and SGM documents uploaded to the members only file download area.
January 2016: An Information Booklet for the 26th National, hosted by the NDRC is now available. Click here to download the booklet.
The NRC(A) is affiliated with the following organisations:
International Federation of Australian National Kennel
Rottweilerfriends (IFR) Council (ANKC)
Rottweiler Clubs
The following Australian Rottweiler clubs are members of the National Rottweiler Council (Australia):
Contact details for these clubs can be accessed on our Club Contact Details page.


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Data storage compliance and archiving
Data storage compliance and archiving
Data storage compliance and archiving News
February 20, 2017
Cloudian, Panzura expand cloud data archiving options
Cloudian and Panzura have come up with new cloud data archiving products to help organizations move on-premises data to the cloud. Cloudian's new HyperStore 4000 is a 7U scale-out object storage ...
January 27, 2017
Quantum video storage customers range from police to pot growers
Quantum's scale-out storage business is growing like a weed, with the help of a large weed grower. While Quantum's DXi disk backup library increased the most of all its product lines last quarter, ...
January 17, 2017
Qumulo Core data-aware arrays help researchers manage sequencer data
Carnegie Institution for Science's embryology department manages research data with Qumulo Core data-aware NAS storage, taking advantage of advanced analytics.
December 21, 2016
Panzura wants to provide archiving freedom, for a price
Cloud NAS vendor Panzura is expanding into archiving. The vendor today made available Freedom Archive software that moves infrequently accessed data to public clouds or low-cost on-premises ...
Data storage compliance and archiving Get Started
Bring yourself up to speed with our introductory content
In enterprise data storage, an archive is a collection of infrequently accessed data that needs to be stored for long periods of time to meet backup and compliance requirements. Continue Reading
secondary storage
Secondary storage is non-volatile storage that is not under the direct control of a computer's CPU. It can also refer to offline or remote storage. Continue Reading
Cloud archiving for cold and not-so-cold storage
Cloud archiving is shaping up as one of the "killer apps" for cloud storage, but don't be tempted by capacity alone. Continue Reading
Server-attached storage threatens SAN/NAS status quo
Storage magazine's May issue looks at products under the umbrella of server-attached storage, examines data archivers and presents our Storage Purchasing Intentions survey.
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Evaluate Data storage compliance and archiving Vendors & Products
Weigh the pros and cons of technologies, products and projects you are considering.
Focus attention on a cognitive data management system
Jon Toigo advises paying less attention to storage component stories and more to system-focused narratives such as a cognitive data management process. Continue Reading
A defense of tape storage systems and how they're improving
Tape gets less respect than Rodney Dangerfield among the IT crowd. But tape still has its staunch defenders who say the medium remains technologically sound and continues to improve. A major ... Continue Reading
In a tape archive system, how can LTFS and LTO products help?
Linear Tape File System and Linear Tape-Open technology can improve user access and durability in your tape archive system. Explore specific products that do the job. Continue Reading
Manage Data storage compliance and archiving
Learn to apply best practices and optimize your operations.
Drowning in data storage capacity? Set it free!
We're all guilty of data hoarding, and managing it is costing companies billions of dollars. The answer? Do a better job of managing all that useless data. Continue Reading
Align data protection requirements and compliance
While many compliance mandates discuss the importance of data protection guidelines, not all are as prescriptive as you'd think or like them to be. Continue Reading
Converged backup and archive strategy requires careful planning
While converging backup and archiving may seem enticing, it's not always the right move. Explore important questions to ask before implementing this approach. Continue Reading
Problem Solve Data storage compliance and archiving Issues
We've gathered up expert advice and tips from professionals like you so that the answers you need are always available.
What's best for archiving?
What's the best choice: tape-based, disk-based or cloud-based archiving? Continue Reading
Misconceptions about using a single platform for backup and archive
Brien Posey discusses how backup and archive can be accomplished using a single software platform today and common misconceptions about this approach. Continue Reading
Data archiving system selection dependent on features, capabilities
Once you've determined the specific data archiving needs of your organization, you'll have to sift through existing products to find the best fit. Continue Reading


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Mug Shots
December 4th, 2011
AFPP would like to bail these three out.
(submitted by Eric)
"AFPP would like to bail these three out."
NO! No! Anything but that!!!
cute, but I think the intent (w/photoshop) disqualifies this from being truly awkward
This reminds me, quite well, that I'm very much looking forward to see what you come up with this year.
Is this Big Al?
I hope there's a back-story because I'm not gettin' it.
It's important to note that this photo was used for our Christmas card in 2010.
Looks so much like my dog, I showed him the picture and told him "This is going to happen to you if you keep acting up". Love it.
this one is hilarious! It made my day to have a good (much needed) laugh!!!
The one in the middle look like the innocent one. I love this photo.
I LOVE this picture! I have to look at it every morning.
So rad, not awkward! ha ha ha I love it!
This is the stuff of nightmares
How did they get the ring in the dog's nose?