text:
Histone-modifying enzymes: their role in the pathogenesis of acute leukemia and their therapeutic potential
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DOI: 10.1007/s12185-012-1247-y
- Cite this article as:
- Vu, L.P., Luciani, L. & Nimer, S.D. Int J Hematol (2013) 97: 198. doi:10.1007/s12185-012-1247-y
Histone-modifying enzymes have recently been shown to play a central role in the regulation of both normal and malignant hematopoiesis. Post-translational modifications of histones and non-histone proteins underlies a regulatory complexity affecting numerous processes including transcriptional regulation, RNA processing and DNA damage response. Insights into the functions of these enzymes as well as their role in the epigenetic alterations found in leukemia will guide the development of novel therapeutic approaches. This review discusses examples of the proteins that have been implicated in the pathogenesis of leukemia, that may serve as potential therapeutic targets.
KeywordsHistone-modifying enzymes Post-translational modifications Hematopoiesis Leukemia PKMTs PRMTs HATs HDACs
Histone-modifying enzymes catalyze the addition or removal of covalent, post-translational modifications (PTMs) in histone and non-histone proteins. These modifications include methylation, acetylation, phosphorylation, ubiquitination and sumoylation, and can regulate protein function by altering the protein's enzymatic activity, localization within the cell, and protein–protein interactions. Histone-modifying enzymes can be classified as "writers" which add PTMs or "erasers", proteins that can remove or alter the presence of specific PTM on histones. Another level of regulation is provided by "readers" of chromatin structure, those proteins whose domains recognize specific histone residues, generally based on the presence or absence of specific PTMs. In addition to histones, these enzymes have a broader range of substrates and as such, can regulate numerous cellular processes, including gene expression, RNA processing and the DNA damage response (DDR).
Accumulating evidence has shown that these histone-modifying enzymes play an important role in regulating virtually all aspects of hematopoiesis. Furthermore, many of these "writers, readers, or erasers" have been shown to be abnormally regulated in cancer. The epigenetic landscape is clearly altered in acute leukemia, due to a variety of acquired lesions in chromatin modifier genes, or changes in their level of expression. This provides the rationale for exploring how these abnormalities can be targeted by new therapeutic approaches. In this review, we will provide several examples of how these proteins have been implicated in the aberrant biology that characterizes malignant hematopoiesis and some suggestions as to which proteins could potentially be targeted.
Protein methylation
There are two families of histone methyltransferases, the lysine methyltransferases (PKMTs) and the protein arginine methyltransferases (PRMTs). The side chain of lysine residues can be mono-, di- or tri- methylated, while the nitrogens in arginine residues can be monomethylated or symmetrically or asymmetrically dimethylated. Unlike acetylation or phosphorylation, methylation does not change the overall charge of the molecule; however, the bulkiness of the methyl group can either promote or inhibit protein–protein interactions. These methyl marks are recognized by specific binding motifs, which include the Tudor domains, chromo domains, malignant brain tumor (MBT) domains and PHD fingers; proteins containing these motifs can distinguish the target residue (lysine vs. arginine) as well as the state of methylation. Crystal structures now exist for many of these interactions, which highlight their specificity. Recognition of combinations of PTMs dictates their output in terms of gene expression and cell behavior. Histone lysine methylation can be reversed by demethylases, which are grouped into 2 classes: (1) the amine-oxidase type lysine-specific demethylases (LSD1 and LSD2), and (2) the Jumonji C (JmJC)-domain containing histone demethylases. Not all histone lysine methyl marks appear to be susceptible to rapid reversibility, and for arginine methylation, the reversibility has not been clearly established. Rather, arginine methylation can be further chemically converted into citrulline (by the protein arginine demethylase PAD4). Such additional modifications can add further complexity to this dynamic process.
The regulation of histone methylation has been shown to be important in numerous hematopoietic processes. Alteration of a number of proteins involved in the methylation of histone and non-histone substrates has now been reported in leukemia and many other cancers [18, 81].
Protein lysine methyltransferases
The two families of protein lysine methyltransferases are characterized by the presence or absence of a SET domain: The SET domain-containing PKMTs include MLL, EZH2, NSD1 and SET7/9 (G9a) that methylate numerous substrates including histone H3 (K4, K9, K27 and K36) and H4 (K20), as well as a number of non-histone proteins, such as p53, TAF10, E2F, STAT3 and NFκB. The PKMTs that lack a SET domain include hDOT1L, a PKMT that methylates histone H3K79. Histone lysine methylation is intimately involved in gene regulation, influencing chromatin structure, a key element of the transcriptional status of a gene. Thus, H3K9me3 and H3K27me3 are typically associated with heterochromatin and gene repression, while H3K4me, H3K36me and H3K79me are associated with transcriptionally active regions, which are primarily located in the regions of euchromatin.
Histone methyltransferases are also components of large, multi-protein nuclear complexes that contain other histone-modifying enzymes and other regulatory proteins including histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and SWI/SNF complex components. The complex nature of these interactions ensures the appropriate regulation of transcription during the execution of multiple differentiation programs that are required for normal hematopoiesis. Furthermore, methylation of key transcription factors can alter their function, and profoundly influence the expression of their target genes. Impairment at any step can promote the process of malignant transformation.
The mixed lineage leukemia (MLL) gene encodes a PKMT that is the mammalian homolog of the Drosophila trithorax (Trx) gene. The methyltransferase (SET) domain of MLL is involved in methylating H3K4, a mark usually associated with gene activation. Chromosomal rearrangements involving the MLL gene, which is located at 11q23, are seen in both AML and ALL. MLL is fused to more than 50 different partner genes. These distinct fusions are associated with unique clinical characteristics and often a poor outcome [34]. Many of these MLL fusions result in loss of the SET domain, although the fusion proteins often retain their DNA-binding domain and can positively regulate MLL target genes, including the Hox genes, a class of proteins critical for the regulation of differentiation and self-renewal. In many cases, the MLL fusion partner brings gain-of-functions, for example, the MLL-AF10 fusion, where AF10 recruits hDOT1L, a H3K79 PKMT. H3K79 methylation is generally associated with high level expression of MLL target genes such as HoxA9, which promote leukemic cell transformation [52]. Other MLL fusion partners also interact with hDOT1L including AF9 [82], AF4 [7], and ENL [34, 79], among others. In the Okuda study, the expression of an enzymatically dead form of DOT1L, or knock down of DOT1L using siRNA, abrogated the leukemia promoting activity of MLL fusions.
Several therapeutic approaches have been taken to target MLL-induced leukemia [35], and given the role of DOT1L in MLL driven leukemia, efforts to target hDOT1L have been prioritized [6, 16]. Bernt et al. [6] provided direct evidence for the essential function of DOT1L in MLL-driven leukemia, as they found a significant reduction in the in vivo transformation of dot1L −/− cells by MLL-AF9. In the study by Daigle et al., the authors identified a highly potent and selective inhibitor of DOT1L, EPZ004777 that selectively killed MLL-driven leukemic cells with minimum effect on non-MLL-rearranged cells. EPZ004777 also significantly reduced the growth of subcutaneously injected MV4-11 (MLL-AF4+) cells in tumor bearing mice, suggesting that small molecule inhibitors of DOT1L may be useful in the treatment of MLL-induced acute leukemia.
The maintenance of gene activation promoted by the TrxG proteins is counteracted by the activity of the polycomb (PcG) proteins, which maintain gene repression. EZH2 is a catalytic component of the PcG repressive complex (PRC2), which mediates the trimethylation of H3K27 (H3K27me3) [43]. The H3K27me3 mark serves as the docking site for the Polycomb proteins, such as PC3, that are contained within PRC1, promoting the silencing of repressed target genes. EZH2 mutations are found in several hematologic malignancies, with loss-of-function mutations identified in patients with myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs) [20, 49] and T-acute lymphoblastic leukemia [51, 80]. Patients with these mutations appear to have a poorer than average prognosis, and these events identify EZH2 as a tumor suppressor protein. In contrast, gain-of-function mutations in EZH2, at a single tyrosine residue (Tyr 641) in the SET domain, are found in large B-cell lymphoma patients [46], supporting the notion that EZH2 can also function as an oncogene, consistent with prior reports that EZH2 is overexpressed in breast cancer and prostate cancer [13]. Furthermore, two recent studies demonstrated a role for EZH2 in promoting MLL-AF9 driven leukemia [48, 66]. Given the potential opposing roles for EZH2 in these disorders, it will be important to assess which malignancies are dependent on EZH2 function for their maintenance.
Another PKMT involved in AML is NSD1 (nuclear receptor-binding SET domain protein 1), which is fused to NUP98 by the cryptic t(5;11) translocation, which is seen in childhood AML [9] and adult AML [31, 67], and generally confers a poor prognosis. NSD1 methylates H3K36, which is generally an activation mark, and the NUP98–NSD1 fusion protein retains the PHD fingers and the SET domain from NSD1. Target genes of NUP98–NSD1 include the HOX and MEIS1 genes, which are normally repressed by H3K27 methylation. De-regulation of the target genes of NSD1 presumably leads to the transformation of myeloid progenitor cells and the development of AML [73].
Readers of methylation: PHD fingers
An example of a methyl lysine "reader" that is altered in cancer is the NUP98–JARID1A chimeric protein [74]. This fusion protein contains the PHD-containing domain of JARID1A, and Wang et al. demonstrated that the PHD domains of either the NUP98–JARID1A or NUP98–PHF23 chimeric proteins were essential for their ability to induce leukemia in several model systems. This effect seems to be induced by the sustained expression of several Hox genes, and also Meis1, Gata3 and Pbx1. The PHD domain in these fusion proteins recognizes the H3K4me3 mark, and when mutated there is no activation of these target genes, nor a leukemia phenotype. As these two translocations were identified in patients with AML [59, 71], this work implicates both the writers and the readers of activating histone marks in cellular transformation. These studies also support attempts to target these interactions in novel therapies for acute leukemia.
Protein lysine demethylases
Until the discovery of LSD1 (lysine-specific histone demethylase-1) and the JmJC-domain-containing histone demethylases, histone methyl marks were regarded as part of the permanent "epigenetic" signature [63]. However, the ability of demethylases to remove methyl groups from multiple histone substrates converts this mark from a stable form to a dynamic one. Recently, defining the role of these demethylases in normal and malignant hematopoiesis has triggered great scientific interest.
LSD1/KDM1A was the first demethylase to be identified [62]. It was shown to specifically demethylate mono- and di-methyl lysine in an amine oxidation reaction that uses flavin adenine dinucleotide (FAD) as a cofactor. Targets of LSD1 include H3K4 and H3K9, and its effects on these two critical substrates give it a central role in transcriptional regulation. LSD1 is highly expressed in AML [5, 39], suggesting that it could function as an oncogene, thereby representing a potential therapeutic target. Several recent studies identified a role for LSD1 in acute leukemia, as well as suggesting that LSD1 inhibitors could be useful in its treatment [29, 39, 61]. Using two different LSD1 inhibitors (tranylcypromine—TCP and a biguanide polyamine analog), Shenk et al. showed that inhibiting LSD1 activity promoted ATRA-driven differentiation of non-APL leukemic cells. Treatment of primary AML samples with ATRA and an LSD1 inhibitor (but not ATRA or the LSD1 inhibitor alone) ex vivo diminished the potential of these cells to cause leukemia in a NOD–SCID mouse model. Harris et al. analyzed 23 MLL rearranged leukemias and found a strong correlation between LSD1 expression and clonogenic or leukemia stem cell like features. Knock down of LSD1 expression in MLL-AF9 + AML reduced the expression of MLL-AF9 target genes, which was coupled to an increase in the H3K4me2/H3K4me3 ratio and a loss of leukemic potential. The effectiveness of two TCP analog inhibitors of LSD1 was shown using both murine leukemia models, and primary human AML patient samples.
UTX (Ubiquitously transcribed tetratricopeptide repeat, X chromosome) belongs to the Jumonji family of demethylases, which demethylate mono-, di- and tri-methyl lysine via a Fe2+ and α-ketoglutarate-dependent oxidative and radical attacking reaction [63]. Both UTX and Jumonji D3 (JMJD3) function as H3K27 demethylases, and both can regulate the expression of Hox genes [2]. Inactivating mutations in the UTX gene were identified in AML, CML, multiple myeloma and ALL [41, 70], implicating it in (normal and) malignant hematopoiesis. A function of UTX in leukemia was recently reported [37], as knock down of UTX expression in human and murine leukemic cells impaired their clonogenic potential and decreased their proliferation. Despite this insight, further work is needed to explore the normal functions of UTX, and determine how its demethylase activity contributes to the malignant phenotype.
While not itself a chromatin reader, writer or eraser, the recent link between metabolic processes and epigenetics has been cemented by the discovery of mutations in the isocitrate dehydrogenase (IDH) 1 and 2 enzymes in brain tumors [54] and subsequently in AML [3, 42]. These mutations generate a neomorphic enzymatic activity, which converts α-ketoglutarate (αKG) to 2-hydroxyglutarate (2-HG), the first identified oncometabolite. Reduction of αKG levels impairs the function of enzymes that require it as cofactor; these include the TET family of methylcytosine hydroxymethylases, and the JmJc-demethylases. Moreover, high levels of 2-HG competitively inhibit the catalytic activity of these dioxygenases [76]. IDH1/2 mutations were first connected to aberrant TET2 regulation in AML [22], but recently an effect of these mutations on demethylases was shown [40]. This work suggests that inhibitors of the mutant IDH1/2 enzymes could be useful in treating cancer and that blocking the effects of or production of 2-HG could similarly have a positive therapeutic effect.
Protein arginine methyltransferases
Protein arginine methyltransferases (PRMTs) catalyze the addition of one or two methyl groups from S-adenosylmethionine to the guanidino nitrogen atom of arginine (R), resulting in either mono or di-methylation, and based on their activity the PRMTs are classified into two groups: type I PRMTs, which include PRMT 1, 3, 4, 6 and 8 and catalyze the formation of asymmetric dimethylarginine, and type II PRMTs, which include PRMT 5, 7 and 11 and catalyze the formation of symmetric dimethylarginine. To date, ten mammalian PRMTs have been identified, but only eight of them have been shown to be enzymatically active. PRMTs are widely expressed and they often methylate within glycine and arginine-rich (GAR) motifs in substrates (except for CARM1/PRMT4). The cellular substrates of PRMTs include histones, and non-histone proteins such as transcription factors, heterogeneous nuclear ribonucleoproteins (hnRNP), proteins involved in DNA damage repair (Mre11), and signal transducers (e.g. growth factor receptors and their downstream effector molecules). Similarly, arginine methylation is implicated in regulation of many cellular processes including signal transduction, DNA repair, RNA processing, transcription regulation, translation and apoptosis [4]. Arginine methylation can potentially be modified or removed by protein arginine demethylating enzymes, which include peptidylarginine deiminase 4 (PAD4) and possibly Jumonji D6 (JMJD6) [12, 68].
Several studies suggest a role for PRMTs in leukemia. PRMT1 has been shown to be a critical component of the MLL-oncogenic transcriptional complex [14]. Direct fusion of MLL with PRMT1 enhanced the self-renewal capacity of primary hematopoietic cells, while knockdown of PRMT1 suppresses MLL-mediated transformation. Furthermore, during myeloid differentiation, PRMT1 methylates RUNX1 (aka AML1) within an RTAMR motif, which abrogates SIN3A binding, promoting the expression of two RUNX1 target genes, CD41 and PU.1, in primary human hematopoietic CD34+ cells [83]. This site of methylation is lost when RUNX1 is fused to ETO in t(8;21) AML. However, PRMT1 also interacts with and methylates the RUNX1/AML1–ETO fusion protein, which promotes its effects as an activator of transcription and promoter of cell proliferation [64].
PRMTs may also play a role in cancer development by regulating p53 function, and the expression or function of other tumor suppressor genes as well. p53 can be arginine methylated by PRMT5, and this may trigger p53-dependent G1 arrest, rather than apoptosis, in response to DNA damage due to specific changes in the expression of p53 target genes that are specifically required for each process[32]. A role for PRMT5 in the hematological malignancies was recently highlighted by two research groups: We showed that PRMT5 (aka JAK binding protein 1, JBP1) is a substrate of the mutant, constitutively active JAK2 kinases, such as JAK2V617F, the most common JAK2 mutation found in MPN. Phosphorylation of PRMT5 by JAK2 inhibits its enzymatic activity toward histone H4R3, and knockdown of PRMT5 promoted the erythroid differentiation of the human primary CD34+ cells [36]. This suggests that PRMT5 may block differentiation and serve as an oncogene.
In B cell lymphomas, Aggarwal et al. [1] showed that a constitutively active cyclin D kinase can phosphorylate MEP50—a regulatory factor of PRMT5 and enhance the PRMT5/MEP50 complex activity. Thus, several epigenetic enzymes appear to be oppositely affected by mutations in leukemia versus lymphoma. This likely reflects differences in their pathogenesis.
PRMT6 has been shown to antagonize the ability of MLL to methylate H3K4 [27], suggesting a potential involvement of PRMT6 in regulating hematopoietic processes. Few studies have examined the involvement of PRMTs in normal and malignant hematopoiesis; however, these histone-modifying enzymes may also contribute to the pathogenesis of human leukemia in additional ways.
Histone acetyltransferases: the writers
Lysine acetylation involves the transfer of an acetyl group from acetyl-CoA to lysine residues, to form ε-N-acetyl lysine. The lysine acetyltransferases (KAT), or histone acetyltransferases (HAT), are called writers, while the histone deacetylases (HDAC) are the erasers; the "readers" of ε-N-acetyl lysine containing motifs are the bromodomains, an evolutionary conserved, protein-interaction module. Histone acetylation is associated with a more accessible chromatin state; acetylation of lysine neutralizes its positive charge, thereby diminishing its interaction with (negatively charged) DNA. Less compact chromatin state, i.e. euchromatin, is more accessible to transcription factor binding and is generally associated with gene transcriptional activation.
Seventeen histone acetyltransferases have been identified in humans thus far; they are members of five different families of proteins: the Gcn5-related N-acetyltransferases (GNATs), the MYST acetyltransferases (MOZ, Ybf2/Sas3, Sas2, Tip60), p300 and CBP, the transcription factor TAF250, and the nuclear hormones SRC1 and SRC3. Mutations in the HATs have been identified in B-cell lymphoma and relapsed acute lymphoblastic leukemia and aberrant acetylation of cancer-related genes observed in hematological malignancies [47, 55]. Bromodomain proteins have recently been described as new therapeutic targets in acute myeloid leukemia [85]. We will focus on the MYST and p300/CBP proteins, in this review, for the role they play in hematological malignancies.
The p300/CBP (CREB Binding Protein) family of HATs generally contains three cysteine-histidine rich regions, a bromodomain, HAT domain and PHD motif. p300 and CBP are distinct proteins that are usually associated with gene activation [78] and are referred to as co-activators. They interact with aspects of the basal transcriptional machinery to induce a more open chromatin conformation as a result of the acetylation of lysines within the histone tails (K12 and K15 in H2B, K14 and K18 in histone H3, and K5 and K8 in histone H4). Regulation of transcription can also be achieved through the acetylation of non-histone proteins.
Presumably inactivating mutations in the human CREBBP and EP300 genes have been identified in non-Hodgkin lymphoma, both in follicular lymphoma (FL; ~41 % of cases) and diffuse large B-cell lymphoma (DLBCL; in ~39 % of cases); these mutations primarily affect the histone acetyltransferase (HAT) domain. These missense mutations prevent p300 or CBP from acetylating the BCL6 transcriptional repressor, a PTM that diminishes its function, and from acetylating pro-apoptotic p53 molecule, a PTM that promotes its function. As a consequence, BCL6 becomes constitutively active, repressing p53 function in the germinal centers [57]; p53 activity is further reduced by the lack of its acetylation. Restoring the acetylation of BCL6 and p53, using HDAC inhibitors, may represent a promising therapy for p300/CBP mutant B-cell non-Hodgkin lymphoma [55].
In another study, mutations in the CBP gene were found in 18 % of relapsed acute lymphoblastic leukemia (ALL) patients. These mutations generally affect the HAT domain, reducing CBP's acetyltransferase activity, which leads to impaired histone acetylation (H3K18) and diminished expression of CREB target genes, such as the glucocorticoid receptor responsive genes. Current ALL therapy includes administration of the glucocorticoid dexamethasone, and ALL cell lines harboring CBP mutations were resistant to treatment with dexamethasone. The class I/II HDAC inhibitor vorinostat was able to increase the sensitivity of these cells to dexamethasone, suggesting that HDAC inhibitor treatment may be useful for some patients with ALL [47].
Among the non-histone substrates of p300, we recently showed that acetylation of the AML1–ETO oncogene plays a crucial role in its ability to trigger the development of AML. AML1–ETO and p300 physically and functionally interact, leading to the acetylation of AML1–ETO on K24 and K43, an event that helps activate the expression of the AML1–ETO target genes involved in self-renewal. Mutation of lysine 43, but not K24, abrogates the ability of AML1–ETO to induce leukemia in vivo. Promising results were achieved after the ex vivo treatment of AML1–ETO9a, a AML1-ETO spliced variant, but not MLL–AF9, driven leukemia cells with the p300 inhibitor Lys-CoA-Tat before the cells were injected into recipient mice. It appears that the acetylation of K43 provides a docking platform for bromodomain containing proteins, which can help promote gene activation by AML1–ETO [75]. These data suggest that targeting p300 or the docking of proteins to K43 acetylated AML1–ETO could be a promising mechanism for developing novel therapeutics for some patients with AML.
The MYST family of proteins may account for as much as 30 % of all histone acetylation, making them critical for the appropriate remodeling of chromatin. The monocytic leukemia zinc finger (MOZ) protein contains two PHD domains and a HAT domain. MOZ can bind AML1 and leukemia mouse models demonstrate that Moz plays a critical role in hematopoiesis, with lack of Moz down-regulating the level of c-Mpl (a target of AML1), HoxA9 and c-Kit. Moz null mice die on embryonic day 15 from pancytopenia [33], suggesting a role for Moz in hematopoietic stem cell (HSC) maintenance. The HAT activity of Moz is required for the maintenance of HSC integrity, as mice lacking the HAT function of Moz have fewer HSCs and progenitor cells [56]. Additionally, the MOZ gene is involved in several chromosomal translocations in leukemia. The first identified translocation fused the MOZ PHD motifs and HAT domain with the entire CBP protein, leading to aberrant histone acetylation, and cell transformation [8, 15]. Another fusion protein, MOZ–TIF2, contains the zinc finger motif of MOZ, which allows it to bind nucleosomes at regulatory loci, and the CID domain of TIF2, which allow it to recruit CBP. It is this recruitment, and the HAT activity of CBP, that is thought to be at the heart of the aberrant activation of cancer-related genes seen in these cells [19]. The same mechanism of transforming activity of the MOZ–p300 fusion protein, found in two patients with AML, M5 (acute monocytic leukemia) has been postulated. These fusion proteins may have double the normal level of acetyltransferase activity [11].
Histone-modifying "writers"; their function and reported alterations in leukemia
Translocations (MLL–AF9, MLL–AF10, MLL–AF4); MLL2 mutations in Kabuki Syndrome and prostate cancer, MLL–MLL3 mutations in bladder cancer
HOX genes
Aberrant Recruitment, over-activity
H3K79me, HoxA9
Gain-of-function mutations (Y641F/N), over-expression
Nuclear receptor-binding SET domain-containing protein 1 (NSD1)
Translocation (NSD1–NUP98)
HOX genes, MEIS1
Component of the MLL complex
ITGA2B, SPI1, MLL and AML1/ETO target genes
Over expression
p53, H4R3, H2AR3
Promotes AML1/ETO oncogenicity
Id1, Cdkn1A, Erg1
Translocations (MOZ/CBP, MOZ–TIF2, MOZ–p300); CBP recruitment
MPL, HOX genes, HOXA9, KIT
Histone phosphorylation
Gain-of-function mutation (JAK2V617F)
Tumor suppressor genes
Loss-of-function mutations
HOXC8, HOXA9, MYT1, CDKN2A, WNT target genes, Retinoic acid target genes
Loss-of-function mutations in lymphoma, mutations in medulloblastoma; mutations in bladder cancer
BCL6, p53, H3K18
glucocorticoid receptor responsive genes
Reduced expression, interaction with c-Myb and TEL
Multiple lysine residues in H2A, H3, H4
The bromodomains: the readers
The bromodomain (BRD) is the only protein module that can recognize and bind ε-N-acetyl lysines within histones. It is widely conserved among species, taking its name from the Drosophila Brahma protein structural domain [65]. So far 61 bromodomain containing proteins have been identified, which either have HAT activity or are factors involved in chromatin remodeling. Bromodomains are composed of 110 amino acids that are folded in a left-handed bundle of four alpha helices, with an external hydrophobic pocket that reads the acetylation mark. Flanking marks, such as acetylation or phosphorylation, can modulate the binding of bromodomains to combinations of PTMs present on ε-N-acetyl lysines and other histone marks [72].
Targeting of the epigenetic machinery has recently gained favor [23] and the bromodomains are undoubtedly attractive targets. They have a "druggable" functional pocket and they powerfully translate the histone marks they recognize by recruiting transcriptional coactivators.
Thus far, the best example of targeting a bromodomain in cancer has come from studies of BRD4, a member of the bromodomain and extra-terminal (BET) family of proteins, that is involved in a translocation in the rare NUT midline carcinoma tumor [85]. BRD4 has also been implicated in promoting the growth of MLL-AF9 driven AML [85], based on a shRNA library screen. A crucial role for Brd4 in the survival and proliferation of MLL-AF9+, NrasG12D + murine leukemic cells was demonstrated. In an important advance, recipient mice transplanted with these cells were found to have a survival advantage if treated with the BET protein inhibitor JQ1 [23]. Interestingly, leukemia cells are more sensitive to JQ1 than are the normal cells, suggesting some specificity of the drug for proliferating or malignant cells. JQ1 represents the first drug therapy to target a chromatin reader; it is a membrane soluble molecule that binds the hydrophobic pocket that recognizes acetylated lysines. Inhibition of Brd4 rapidly reduces the expression of c-Myc, and its target genes, inducing differentiation and slowing cell proliferation.
Histone-modifying "erasers"; their function and reported alterations in leukemia
K demethylation
Over expression
Hox genes
K methylation level
Point Mutations, neomorphic activity
K deacetylation
Gene repression of tumor suppressor genes
K demethylation
Loss-of-function mutations; deletions and nonsense mutations in Kabuki Syndrome, mutations in medulloblastoma, prostate cancer and bladder cancer
HOX genes
Histone deacetylases: the erasers
Histone deacetylases (HDAC) are grouped into three distinct families of proteins. Class I HDACs are widely expressed and they include HDAC1, 2, 3 and 8. Class II HDACs include HDAC 4, 5, 6, 7, 9a, 9b, and 10; they are expressed in a cell-specific manner. Class III HDACs are Sir2/Hst homologs; they are called Sirtuins (1, 2, 3, 4, 5, 6, 7) and their structure and enzymatic mechanism is totally different from class I and class II HDACs. They are NAD+ dependent and they are not inhibited by class I or class II inhibitors. HDAC proteins counteract HAT activity; they are associated with transcriptional repression, forming macromolecular complexes with corepressor molecules, such as N-COR, but also transcription factors and nuclear receptors that sit on gene regulatory elements [24]. Histone acetylation is deregulated in transformed cells, resulting in downregulation of tumor suppressor gene expression (due to promoter hypoacetylation) and oncogene over-expression (due to histone hyperacetylation at similar regulatory regions) [44].
Histone-modifying "readers"; their function and reported alterations in leukemia
Histone phosphorylation
Phosphorylation of serine/threonine residues in histones has been studied for all histones, especially H3S10. More recently, histone tyrosine phosphorylation has been found, for the mutant JAK2 kinase [17]. Mutant and wild type JAK2 is found not only in the cytoplasm of hematopoietic cells, but also in the nucleus, where it phosphorylates histone H3 at tyrosine 41 (H3Y41). Phosphorylation of H3Y41 prevents the binding of HP1α, thus reduces the recruitment of this repressive mark to regulatory regions of target genes, which include the LMO2 gene, resulting in an abnormal upregulation of LMO2 expression. This link between JAK2 and LMO2 expression and between signaling pathways and chromatin represents another instance of how aberrant signaling pathways can affect chromatin structure and further reinforce aberrant patterns of gene regulation. How to take advantage of this knowledge therapeutically is the challenge for the coming years.
Recent studies have found overexpression of or mutations in a number of epigenetic modifying enzymes, including those impacting histones, and those that impact on DNA itself. Learning how these abnormalities contribute to the malignant process will help guide our strategies to target the epigenetic abnormalities that characterize cancer, as these may be much more amenable to changes than the fixed genetic abnormalities. Properly designed clinical trials will help advance our knowledge of how to introduce and then combine these types of therapies.
We thank the members of the Nimer lab, especially Sarah Greenblatt and Guoyan Cheng, for their helpful comments and thoughtful discussions on this manuscript. The work has been supported by an LLS SCOR grant and an NCI R01 grant to SDN.


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Each year Tufts University School of Dental Medicine holds the Bates-Andrews Reseach Day to honor George A. Bates, an alumnus who taught Tufts medical and dental students. The student research societies sponsor "Bates Day" annually, and it features
- Student table clinics showcasing research conducted during the preceding year
- Commercial exhibitor displays
- Student and faculty photography and arts & crafts exhibitions
Bates-Andrews Research Day gives students an opportunity to share their accomplishments in fields of special interest with the rest of the Tufts community. Since the 1930's Bates Day has promoted student research and thereby enhanced the opportunities for professional growth of students, alumni and faculty.
- Download the 2014-2015 abstracts
- Download the 2012-2013 abstracts
- Read about Bates-Andrews Research Day 2013
Awards given:
Faculty members judge student presentations and several prizes are awarded as described below.
- 1st place (1st, 2nd, or 3rd year dental students): ADA/Dentsply Student Clinician Program Award for Best Overall Predoctoral Table Clinic (winner will present at the annual ADA convention)
- 2nd and 3rd place (1st, 2nd, or 3rd year dental students) students will present at the annual Greater New York or other regional meeting, and receive $100
- 4th year dental students: Andrews Society Award for the Best Scientific Research Presentation by a Senior (winner receives $100)
- Postgraduate students: Bates Society Award for Best Postgraduate Table Clinic (winner receives $100)
- Omicron Kappa Upsilon (OKU) Research Award for Public Health Research (the award is for $1500 to be used to fund that student's summer research project)
- Bates Day OKU Award (OKU faculty vote to award a deserving student presenter $200)
- Proctor & Gamble Travelling Fellowship Award ($1500 to help defray costs to the annual American Association of Dental Research meeting – student must already have his/her abstract accepted by the AADR)
All students who received Student Summer Research Fellowships from Tufts University School of Dental Medicine are required to present at Bates Day. Graduate students and students who did research at other institutions are encouraged to participate.

subset: commoncrawl


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Unbelievable! See details here:
Dustin's Gun Blog: Unbelievable - Attempt at Ammunition Ban in Arizona!
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Unbelievable! See details here:
Dustin's Gun Blog: Unbelievable - Attempt at Ammunition Ban in Arizona!
Great... now when I get there I'll have to lug all of my ammunition along with me. Come on AZ residents, please jump on this.
Actually if you did that they'd probably throw you in jail for being an illegal ammo dealer because you would have too much ammo on you to be a casual ammo user :twak:
Mississippi is trying to push that same law through the house. They say it is to help LE. :confused:
ArizonaShooting.com :: View topic - Ammo Ban bill filed!
And this from the state that's home to Dillon Precision.:mad: I've got to believe that Mike Dillon is all over this as this bill would effectively put reloaders out of business. I don't think it's any small coincidence that these bills have all surfaced in what I tend to think of as "gun friendly" states. Tennessee, then Mississippi and now Arizona. These yahoos are thinking that if they can get one rural state to go along with this nonsense, a whole bunch of others will follow suit. Have no doubt about it, I'm afraid that a lot of us are going to see this crop up in our own home states and we need to jump on this like ugly on an ape. This legislation would have devastating effects on the shooting sports. Please, if one of these bills pops up in your home state, don't assume that it's such an asinine piece of legislation that it can't possibly pass. Get on your legislators immediately and let them know that this cannot be allowed to happen.
Good on everybody for quickly contacting your government reps and letting them know what you think. If this ever shows up in Ohio I'll be sure to do the same. I can only hope that it doesn't slip through somewhere else, making it's adoption that much easier for all the other states....
I still don't understand the "but THEY are doing it!" mentality. If someone jumped off of a bridge......all the politicians would follow.
Can we say - once more - "creeping incrementalism"?
Seems like it to me and as ever, the real sense or logic within such proposals is non existent. Crazy - is one of the more polite words to consider :frown:
They should be less concerned about serial numbers on ammo and more concerned about their border with Mexico. What a time waster.
Doesn't surprise me. I think we are going to see many more attempts to either effectively outlaw ammunition or make it so expensive that most of us won't be able to afford it.
They have filed HB3359 in Washington State to do the same thing. I have notified my Reps and senator in Olympia my feelings and urged them to vote against it.
I believe this is a consentrated effort by the Pro-Crime groups to limit guns to the Law abiding people.
I would recomend anybody in a state that is trying to pass such a law to notify your reps in the state gov how you feel about the laws.
I didn't hear about that in WA. I'll have to contact my representatives. And probably stock up on ammo. I don't know why I don't have thousands of rounds sitting around yet.
Writing my senator/reps right now...anyone who has info to help shoot this down let me know.
You've got to be kidding me. There is no way this will pass. The funding ALONE to build the database would be astronomical. My God... Walmart can barely keep ammo in stock during the warmer months!!
They have to keep the record on file for 3 years? Ha! Yeah right. This would bankrupt the state. Do these sponsors have any idea how much ammo is sold here?! If it drives up the cost of ammo and subsequently kills the entire hunting industry here the state will take a huge hit financially.
My letters are going out right now. This is.. well.. its almost the dumbest thing I've ever heard. I can understand why they might think this is a good idea but wow. Theory and practice are two different things. The road to hell is paved with good intentions and politicians. Which is really like saying the road to hell is just paved with politicians.
hmmmm lets see.... they are all Democrats. Why am I not surprised?
I am a democrat (please don't yell at me) .... and even I find this outrageous, insulting and STUPID!


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Why are we asking this question now?
England have been eliminated from the Cricket World Cup, being played in the West Indies. The defeat by South Africa on Tuesday, which confirmed their removal in the second stage of the tournament, known as the Super Eights, was particularly inept. South Africa won by nine wickets, bowling out England for 154 and then scoring the runs they required for victory and a place in the semi-finals in fewer than 20 overs. Although South Africa should be applauded for managing to approach their peak in a crunch encounter, it was the culmination of an appalling World Cup and a dire winter in general for England.
In the previous six weeks (it is the longest sporting competition ever devised) their cricket had been fitful at best but was usually dire. They won four matches in all - unconvincingly, against such cricketing giants as Canada, Kenya, Ireland and Bangladesh - but lost to all the more traditionally accomplished opponents, New Zealand, Sri Lanka, Australia and South Africa.
This failure has been exacerbated by a long winter of defeat: starting in the one-day Champions Trophy in October, continuing with the Ashes in Australia when they lost 5-0 and broken only by winning a triangular one-day series in Australia.
But wasn't the nation rejoicing when England regained the Ashes in 2005?
Indeed it was, and the elation was entirely justified, although the combination of MBEs and OBEs that were awarded to each player and members of management might have over-egged the Ashes pudding.
Two things should be borne in mind when reflecting on that English triumph. The Ashes series comprises Tests, which consist of two innings a side spread over five days, while the World Cup is a limited-overs competition consisting of 50 overs a side played on one day. For some reason nobody has yet satisfactorily explained that England have become much better at Test cricket. Despite their thrashing by Australia in their defence of the Ashes during the winter, they remain the number two ranked team in the world.
For more than a decade they have struggled with the shorter version. The frequent suggestion that they treat it too lightly has been rejected just as often, though not with overwhelming conviction.
How have we done since 2005?
The 2005 victory infused the England team with a misguided belief that they could beat anybody. This meant in turn that they took their eye off the ball, sometimes, given the quality of their fielding, all too literally.
In both long and short forms of the game, they have struggled for consistency, which represents a state of nirvana for professional sportsmen. A Test series in Pakistan was lost, though that was followed by a highly commendable and improbable drawn rubber in India. In both cases, however, the corresponding one-day series were lost, auguring badly even then for the World Cup.
At home last summer, England were desperately poor against Sri Lanka, drawing a Test series they ought to have won and being roundly defeated 5-0 in the one-day matches. This was followed, however, by Test victory against Pakistan (and a drawn one-day series).
So, who is to blame?
Fundamentally, the players, who have not been helped at various intervals by injuries to key colleagues. But these are part of sporting life. The vultures which have been circling around the head of the coach, Duncan Fletcher, for months, look ready for a messy kill. Any search for culpability may also alight on the chairman of selectors, David Graveney, and less probably but not impossibly on the captain, Michael Vaughan.
It is generally accepted that the Zimbabwe-born South African resident Fletcher, upon whom British citizenship was conferred after the 2005 Ashes, is one of the most proficient technical coaches in the world, and it has been said without much exaggeration that he can spot a glitch in batting method with the naked eye at 100 paces. England have indubitably improved under his tenure. At one point leading up to the Ashes victory, they won six successive Test series.
However, Fletcher has attracted criticism for his wariness, often but not exclusively with reporters, and his confrontational approach to officials if things are not going his way. He has been coach to the same team for much longer than any of his rivals and it is felt that he may be past his shelf life.
The evidence of the winter is fairly conclusive. The results alone have been poor, but when a group of England players, including the talismanic Andrew Flintoff, were fined for a late night boozing binge earlier in the World Cup, it suggested that the management might have lost control.
There is a mood abroad that the chairman of selectors should at long last be paid a proper salary rather than be a well-meaning amateur. It would seem premature and a case of jerking knees to sack Vaughan. As the feted Ashes-winning captain, he spent much of the subsequent period injured, missed the Ashes defence when Flintoff made a porridge of the job and was rushed back for the World Cup.
What happens next?
It is already happening. In the wake of the disastrous Ashes campaign, the England and Wales Cricket Board established a review committee, under the chairmanship of Ken Schofield, the former chief executive of the European golf tour. This includes several former England players, including Angus Fraser. Nominally, the panel will scrutinise the performances of Team England in the past four years. In reality it will examine the wreckage of the past winter and make recommendations accordingly.
At the very least a lessening of the authority of the coach with an increase in powers for the selectors' chairman, and perhaps the appointment of a team manager, can be expected. The ECB has promised that the recommendations will be acted on. It is intended that Schofield will produce the results before the First Test of the 2007 summer on 17 May - but by then Fletcher might already have gone.
Who could replace Fletcher?
Three candidates stand out. Tom Moody, the Australian coach of Sri Lanka, has taken the team into the World Cup semi-finals. He lives in Worcester, but is thought to have accepted in principle the role of coach with Western Australia. John Wright, the New Zealander who coached India to the last World Cup final, has the experience, knowledge and correct approach. But the favourite may be Peter Moores, the director of the National Academy, who was successful at Sussex. He has sound qualifications, a likeable temperament - and Englishness.
October 2006: Eliminated in first stage of the ICC Champions Trophy, known as the mini World Cup, after defeats to India and Australia
November 2006 to January 2007: Lost 5-0 in the Ashes series in Australia, having regained them in summer 2005. England held them for one year and 97 days having been without them for 16 years and 142 days
February 2007: Won the Commonwealth Bank triangular, one-day series after a dreadful start, by beating Australia three times in a row
March, April 2007: Eliminated from second stage of World Cup after losing four matches to stronger nations
Should Duncan Fletcher go?
* England have lost their way under his stewardship after a disastrous winter, finishing with early exit from the World Cup
* Now 58, he has been in the job almost eight years, and may be out of touch with a new generation of players
* His departure would also see the demise of the men directly appointed by him, who must shoulder some responsibility
* He moulded England into a combative unit capable of beating any side in the world, including Australia
* It is possible that the present crop of players will improve under Fletcher and are merely finding their international feet
* The system that produced the players from easygoing county cricket is more worthy of blame than the international team's coachReuse content


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jfoj: regarding the t-stat in the bottom of the expansion tank, I replaced that when I did my wife's cooling system overhaul, so that is relatively new as well.
OK so I did the test leaving work yesterday. It was about 40-something degrees out or so, when the car started up, the temp read 23C. I find this pretty odd considering that translates to 73.4F? Maybe the coolant never gets below a certain temp? seems odd though.
Anyways, I started my car at 1:11pm, and around 1:15pm, my needle was dead center, and the temp reading was only 75C (so this shows you how much temp variation there is when the needle is dead center!)
In less than 10 minutes total time, my car was up to 95C and steady there the entire time I was driving, saw it go to 96 once and down to 94, but it stayed pretty steady at 95C.
I replaced my thermostat when I did the water pump around 100K I think. I am now almost at 170K.
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Part of being the runner up-turned- favorite is handling both expectancies and devils. This is not a new charge for the Miami Heat nonetheless it doesn't mean they are immunized to one side effect, either. Odds
The Heat has generally gotten off to a strong beginning to the season, blowing away their competitors most nights and successful at least three games so far that pretty effortlessly could've been losses. So what happened Tuesday against the Golden State Warriors was portion regression to the mean and part regression to 2011. Scores
This time the Heat didn't get the clutch shot and didn't execute under stress. And for all his talk about performing with a rather more free psychological perspective and putting in the hours to work on his post game, LeBron James looked like the lost and initial guy from last June in that annoying 4th quarter.
Coming from 17 points down the Warriors came back to beat the Heat 111-106 in overtime. It's a thrilling night for the Golden State fans including owner Joe Lacob, who ripped off his suit coat and stamped around the sidelines down the stretch like a university coach. It was a season highlight film type win for the Warriors, who had lost 5 straight games and were struggling with scoring and wounds.
The Warriors' greatest player, Monta Ellis, missed 16 shots and had 9 turnovers. A couple of the team's starters, Stephen Curry and Andris Biedrins, didn't play with injury and another, Kwame Brown, ended the game in the locker room. The game's hero, Nate Robinson, had 24 points but also missed 8 of 12 shots and had some absolutely mindless plays across the game.
Golden State entered the fourth quarter down 12 points and shot just 36% with five turnovers in the period. They only shot 31 % with 12 turnovers in the whole 2nd half. On their last 4 possessions of regulation the Warriors had 2 turnovers and, regardless of having thirteen seconds, were unable to get a shot off on the last possession.
And they won the set!
"That game was there to be had," Heat coach Erik Spoelstra asserted. "We needed 3 defensive stops."
In fact the Heat got plenty of defensive stops. They'd too many turnovers, 22 of them, but it was fairly survivable mainly because they kept the Warriors to forty percent shooting general and forced twenty turnovers of their own.
The Heat (8-2) lost for a similar situation they lost to the Dallas Mavericks in the Finals and the same reason they'd their earlier loss of the season against the Atlanta Hawks, when they scored just 42 points in the second half. When under stress, their offense is still a soft place and it still starts with James.
After scoring 23 points on 9-of-16 shooting after 3 quarters, James didn't even attempt a shot in the fourth quarter even as his team's offense was hemorrhaging around him. Wade ended with 34 points and looked formidable for much of the night. But he was 1-of-8 shooting in the fourth quarter, the results of missing three games with a foot injury clearly catching up with him, and there was no assistance.
But at some particular point the Heat and James are going to have to find a rhythm in tough fourth-quarter circumstances. Tues. wasn't simply a missed chance, it had been a reversal.
"It was clearly a distinct game than we've been playing," Spoelstra recounted. "That will adjust."


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Two Metalworkers, Daguerreotype by unknown photographer, 1855; digital images courtesy of the Getty's Open Content Program
Click on any image to enlarge
It was quite a month! Late in the January our crazy weather kept me iced-in for two days, but that Thursday I was able to get to Athens to spend three days attending the wonderful Henry D. Green Symposium of the Decorative Arts. This year's theme was "Connections: Georgia in the World."
Because of the weather, flights were cancelled, so speakers were slightly out of order. A speaker from Rhode Island was unable to get out of her state; a flight South would not happen until the day after the Symposium closed, but her paper was delivered by an excellent substitute.
This was the seventh Green Symposium, but it was my second. I attended the one just prior (2012), and I knew then that this gathering of scholars (including many Independent Scholars – hooray!) from all over the country, is where I wanted to be again in 2014.
The Green Symposium is held every two years, and in the intervening years the Georgia Museum of Art publishes the most recent Symposium presentations in a soft cover book form. I have all but one of these fine publications. This year I purchased the latest book, the 2013-issued "Homecoming."
That publication includes two articles related to my research on Georgia photographers and their associates. One article is on the Geechee people and their culture as depicted in the beautiful hand-tinted lantern slides made from Orrin Sage Wightman's photographs taken in Glynn, McIntosh, and Liberty counties Georgia. The other is about Atlanta's Lycett Studios and in particular, china artist William Lycett, who I recognize also as an amateur photographer and a landlord to a series of Atlanta photographers.
On Saturday, we were privileged to have Daniel Ackermann, Associate Curator at the Museum of Early Southern Decorative Arts (MESDA), speak. MESDA http://www.mesda.org/ is part of Old Salem Museums and Gardens, in Winston-Salem North Carolina. http://www.oldsalem.org/
Ackermann shared some wonderful news with us. I knew their database was coming online, eventually, but I did not know that their Craftsman Database had come online, digitized through a partnership with University of North Carolina at Chapel Hill. As of New Year's Day – in January 2014 – it was available for use and this is exciting news indeed!
You will note that the Museum itself includes
decorative arts objects from the three regions of the early South: the Chesapeake, the Low Country and the Backcountry and includes objects from North and South Carolina, Virginia, Maryland, Kentucky, Tennessee, and Georgia.
And the Craftsman Database is a
Collection of primary source information on nearly 85,000 artisans and artists practicing 127 trades in the early South.
And it
Contains information [that was] gathered through primary research in public and private records about artisans [who were] working in the South before 1861.
It includes information on craftsmen of color and women. In fact, it is
A significant resource that offers unparalleled access to documentation about women and African Americans, both enslaved and free. And because each craftsman's record is linked to a specific geographic location and date, the database enables a clearer understanding of the migration of craftsmen in the South.
So, you ask, what in the world does this have to do with photographers?
As you may remember reading in this blog, many Georgia photographers were also jewelers and/or silversmiths and/or watchmakers (see my previous post "Jeweler-Photographers, Photographer-Jewelers, and a Dentist or Two" at http://wp.me/p3wX4F-97 ).
Daguerreotype portrait of a watchmaker seated at table with watches, 1840-1860; DAG no. 1195, LC Prints & Photographs Division
Early Georgia photographers were also artists, miniaturists, portraitists, sign painters, etc. Some were also carpenters and frame makers. The Database includes needle workers, cabinetmakers, surveyors, builders, blacksmiths, potters, glass makers, plasterers, and so much more. In addition to slaves, indentured servants and apprentices are included. And there may be more than one "card" entry per person. It is up to you to make the connections. I have already located one early daguerreotypist who I knew had trained as and became a jeweler (he later became a dentist – silver, silver, and silver again!).
You can access the Craftsman Database on the menu to the left on the link given above, and you can even download a PDF of their Detailed Index of the MESDA Subject Database if you like.
I have come across photographs of Georgia furniture-makers, etc. and their names may possibly be here. I want to know about the subject of the photograph, but only if I can afford to spend the research time involved. This Database can make researching some of those early photographs a bit easier.
Have fun with this great resource, whether you seek information on early American artists or craftsmen or on your ancestors, or on a sometime photographer.
After my previous Tuesday Tips post, "Newspapers & Indexes Off-the-Beaten- Path," I was contacted about the availability of some Valdosta newspapers. I had not known about these. I certainly will use these indexes to search for information now that I know where they are.
This nice addition to those "off the beaten path" Index Sources comes via Deborah S. Davis, Archivist at Valdosta State University's Archives and Special Collections. Thanks Deborah!
Valdosta, 1885 Bird's Eye View
A companion to the issues of the Valdosta Times, 1905-1912, found on the Digital Library of Georgia's South Georgia Newspapers site http://sgnewspapers.galileo.usg.edu/sgnewspapers/search would be GENDEX, which is a notebook of vital records in the Valdosta Daily Times from 1868-1945. Copies are at the South Georgia Regional Library, The Lowndes County Historical Society Museum, and the Valdosta State University Archives.
For death notices/obituaries, engagement, wedding, and birth announcements from 1945-1964, see the Valdosta Daily Times Vital Records Index at http://tinyurl.com/odpkso6
That index is ongoing and will be brought up through 1993.
Information on the index to The Valdosta Daily Times from 1994 and after, and on the VSU Archives annual index to the Times (they create an annual index), can be found here http://tinyurl.com/lvg7jex
Also of interest, complements of Valdosta State, are two other Indexes. There is an index to the Southern Patriot (a progressive newspaper covering Civil Rights and the Labor Movement published in South Carolina, 1942-1973) http://tinyurl.com/nr7b92t and there is an index to the Valdosta State student newspaper, the Campus Canopy, for 1935-1942 (called the Campus Canopy through 1969, and renamed The Spectator in 1970) http://tinyurl.com/lptjr3g
On his site The Ancestor Hunt, Kenneth R. Marks has compiled an excellent"Summary of Alabama Online Historical Newspapers." This includes many free and some subscription sites (subdivided by city name) holding digital copies of the state's newspapers. I certainly plan to refer to this list – Georgia and Alabama often shared photographers. http://tinyurl.com/lvhajwa
Marks and others have noted that many, many freely accessible newspapers were added to the Library of Congress Chronicling America site recently http://chroniclingamerica.loc.gov/
Newspapers added from the South include those for Maryland, D.C., North Carolina and South Carolina. Georgia is not covered well at all on CA, but we are very lucky – we have the wonderful Digital Library of Georgia newspapers online and free.
That is "all the news" I saw "fit to print" for this week. I really hope you find something useful here to help you in your own Hunting and Gathering.
© E. Lee Eltzroth and Hunting & Gathering, 2014. Unauthorized use and/or duplication of this material without written permission from this blog's author is prohibited. The piece can be re-blogged, and excerpts and links may be used, provided that full and clear credit is given to E. Lee Eltzroth and Hunting & Gathering, with appropriate and specific direction to the original content.


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LEGO Architecture Students Will Design Acoustic Shell for Outdoor Chamber Music Concerts
The toy manufacturer teams up with an Italian architecture summer school to offer hands-on building experience.
The LEGO Architecture Studio set is going to be launched in Europe on August 1st. To celebrate, they are teaming with an Italian architecture summer school and classical music event ("Villa Pennisi in Musica") to offer architects and students a hands-on building experience with the new set.
The LEGO Architecture Studio set provides the essential tools and methods for experimenting with the topic of architecture. It includes over 1,200 monochromatic white and translucent LEGO bricks plus a handbook with inspiration and insights. Based on examples and real-life cases of architectural principles, the book invites the exploration of various topics within the process of architecture using the LEGO brick.
This summer school will be part of a program of classical music master classes, architectural workshops and chamber music concerts held next month in an ancient villa, which has been owned by the Pennisi family since the 19th century. It was once a hotel with famous guests including Wagner, and is now a family house as well as a space where arts and music mix with the surrounding woods and plants of the garden.
This summer, a group of youngsters led by architects, lighting designers and acoustic engineers, will design and build an acoustic shell for outdoor chamber music concerts. During the event CMMKM Architects will be hosting a workshop on the design process and the basic principles of architecture in LEGO forms. Students and architects will get a hands-on opportunity to explore concepts and discover new insights by constructing 3D LEGO models of the acoustic shell.
The workshop will also teach the students about all the different aspects of a live classical music event production, including building the stage, acoustic design and lighting design. The LEGO Architecture team has been excited to see how the new set is proving to be a great tool for exploring new building and design solutions. It really sparks the imagination of young architects and those interested in architecture and design.
The team sent a Studio set to CMMK Architects, who began experimenting by creating new models of their acoustic shell. They came back with impressive models of varied solutions for building the shell in August.


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The Chief Executive Officer of Oncor says the company has a new procedure for installation of smart meters after two house fires in Arlington last week. Robert Shapard says old wiring in two homes could not support the new smart meters. The company now cuts power to the house while the meters are being installed…then as the change is made…electricians check the wiring to make sure there aren't any problems.
Oncor Changing Smart Meter Installation After FiresAugust 24, 2010 8:04 AM
One Comment
Cutting power to the house is done at the transformer. In older neighborhoods, the transformer is located on the pole. So a bucket truck will have to be present with each smart meter installation, unless the neighborhood has underground utility, in which case the transformer is inside a ground-level box located between homes. Either way, a lot of work is involved to cut power before a meter is installed.
And then an electrician has to check wiring, which means replacement of wires. Some homes will have to be rewired between the meter and main breaker box to accommodate the new meter, and this will be at homeowner expense. Most likely when a problem is detected, the solution will also require installation of a new breaker box.
The question is, will the electric company back off the meter install? Or will they red tag the electric service until customers pay money to update their service? Thus leaving some homeowners without power.
What makes the situation worse is that Oncor is a foreign company selling Americans a smart meter manufactured in China. So the American working man is being forced to pay for the Chinese meter, at the same time big companies like Oncor are telling us that the American worker is 'the problem.'
The smart meter issue needs to be put on the ballot before Oncor burns down the house of another American worker.
My mother had the "new smart meter" installed about a month ago.Since then she has had trouble with the lights blinking on and off.So on this past Friday(sept 17) she called TXU about the problem.They sent Oncor out late that evening while she was gone.Imagine the suprise she had when she returned home late with groceries and NO POWER! A note was on her front door saying….lugs in meter base need to be replaced fire hazard call back when repairs are made we will restore serv.After several calls to TXU ,ONCOR(representatives were very rude)she was told that she needed to find an electrician to fix problem at her expense.My mother is disabled and elderly and my sister who also lives with her is disabled.Because this was after hours more fees were charged..a total of$1483.66 to fix this problem that was caused by ONCOR because they decided to put in "smart meter"If there was a problem with lugs,was this not noticed when they were installing "smart meter" or simply that problem didn't exist until installation of "smart meter"? So here it is 1:35 Monday afternoon and still no power.We are waiting for inspection then we can notify Oncor to have power restored.This is so wrong.These older homes are not equipped to handle these "smart meters".So why put them in homes that are older and most likely are senior citizens living there and they are on fixed incomes.Something is so wrong with this picture.Do we still live in the United States of America?Are these "smart meters" going to join the list of many other recalled items from China?
Thanks. Been working as an electrician for a little while now so this post is very useful.
Smart meters fires are now occuring in Houston as well through Centerpoint. I had to pay $875 after a smart meter caused a fire at the meter box. I was told by Centerpoint that the meter box needed to be up to date and they denied my claim. I know of someone whose appliances burned out following a surge caused by a smart meter install. I wound up using an attorney who was able to recover my costs. He is now specializing in these cases since they are popping up all over the country causing property damage and physical harm. Contact Brad Leigh at the Leigh Law Firm (281) 419-3476.
We are investigating the extent of this problem and concerned that someone could be seriously injured or killed if North Housotn pole Line and Centerpoint Energy continue to install these meters on older homes that don't have the wiring to handle the new "smart-meters." NHPL has a very lucrative contract with CenterPoint to install more than 2,000,000 of these meters around town. They are supposed to hang a tag on the meter if the wiring isn't sufficient, but of course they don't get paid to hang tags they get paid to install meters and theiein lies the problem. Our website is woodlandsinjurylawyer.com, but we handle cases all over Texas and would be happy to visit with anyone who has experienced a fire or other injury as a result of the smart meter installations.
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2 Bunches asparagus
2 Red peppers, cut into small dice
½ Cup toasted pine nuts
½ Pound fresh sliced Deli Ham, thickly sliced - try Kings Spiral Sliced Smoked Ham
4 Large Kings Organic Eggs, hard boiled, chilled then chopped
½ Pound Manchego cheese, flaked
1/3 Cup Sherry wine vinegar
1 Teaspoon coarse mustard
2 Small garlic cloves, minced
1 Teaspoon dry leaf KINGS Organic Fresh Thyme
½ Teaspoon Spanish smoked paprika
½ Teaspoon salt
½ Teaspoon pepper
2/3 Cup olive oil
Preheat oven to 400 degrees
1. Roast asparagus in oven until fork tender, chill.
2. Cut thick sliced ham into 1" matchstick pieces.
3. Arrange asparagus on a large platter, top with red peppers, pine nuts and ham…chill until needed.
4. Combine ingredients for dressing in blender or bowl of food processor …blend until smooth and creamy.
5. To serve drizzle with dressing just before serving…divide on individual plates, garnish with chopped egg and flaked Manchego.
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SPDIF on cdrom to SPDIF on Digi Crossover
Has anybody tried running the spdif out of a cdrom to a digital crossover like the Behringer DCX2496 or something similar?
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We tailor every seminar to the needs of the university's program. Below are the seminar options.
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FULL-DAY SEMINAR (7 hours) + one year of access to OpEd Project National Network of Mentor-Editors. The highly-interactive, energetic full day seminar is built on a series of exercises, scenarios and experiential learning around thought leadership, and is designed to make participants think more carefully and more expansively about what they know and why it matters. We explore how to present ideas quickly and powerfully under pressure; the source of credibility; the components of powerful, evidence-based argument; the difference between being "right" and being effective; and strategies for making a greater impact, including how to escape a pigeonhole, how to preach beyond the choir, and the value of seeing your argument as part of a bigger picture—and yourself as part of a larger public conversation. We review techniques and tools of persuasion that appear in some of history's most powerful arguments (speeches, essays and op-eds that have changed the world), and we discuss strategies for pitching ideas (anywhere). Participants leave with an op-ed draft, and will have ongoing access to OpEd Project resources, events and mentors.
TWO-DAY (FULL + "TRANSLATION") SEMINAR + one year of access to OpEd Project National Network of Mentor-Editors: The two day seminar combines a full day seminar (see above) with a second day of guided work and hands-on individual feedback, in which we bring one or several OpEd Project mentors to work directly with seminar participants on their op-ed drafts, accompany them in exercises designed to expand the way they think about their particular expertise, and help them "translate" scholarly research into the lingua franca of public debate. The second day, also called our "translation" seminar, gives participants the opportunity to share their ideas and arguments—sketched and drafted in the full seminar, and fleshed out overnight—with each other in a language that is broadly accessible (and perhaps not previously available to them), which serves to foster community among colleagues and cross-pollination of ideas. The goal of this second day is to ensure all participants act on the ideas they generated in the first day, and leave with a solid op-ed which they will submit for publication. Participants will have ongoing access to OpEd Project resources, events and mentors.
CREATING PUBLIC INTELLECTUALS: FELLOWSHIP MODEL: The OpEd Project's fellowship model is intended for individuals and organizations that are committed to working for bigger results over the course of a year, and it's goal is to transform women (and in some cases, minority men) academics and professionals with knowledge and expertise that would be of public value into public intellectuals. Participants convene quarterly (or at regular intervals), for a total of four seminars throughout the year: an initial full- or two-day OpEd Project "thought leadership" seminar that begins the fellowship; two mid-year seminars led by OpEd Project staff and Mentor-Editors, which focus on areas of common interest and scholarship and are designed to stimulate cross-pollination of ideas, find connections between participants' areas of focus and current newshooks, and generate concrete op-ed results; and a final convening to recognize the accomplishments of the participants. In between these quarterly seminars, OpEd Project mentor-editors oversee the group throughout the year, leading weekly (non-obligatory) check-in chat sessions, as well as a monthly conference call designed to encourage and support participants in reaching their goals. Fellowship participants are asked to set individual goals of producing a set number of op-eds during the program year (minimum of one per quarter), with the support of our mentors, to reach an ambitious collective result. By partnering with us in this way, universities and organizations strengthen their internal community of experts, enhance these experts' voices and contribution to public knowledge, and also increase their institution's public presence.


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Rabbits Are Roadkill On Rt. 37 Lyricsfrom Album (MySpace Records Volume 1) by A.F.I.
AFI (A Fire Inside) is an American alternative rock band from Ukiah Ukiah, California , California, formed in 1991. They have consisted of the same lineup since 1998, lead vocalist Davey Havok, drumme [more..]
All lyrics are property and copyright of their respective authors, artists and labels. All lyrics provided for educational purposes only.
On LyricsInfo.org you can find lyrics, album names, artist overviews, history, current and past members of bands, listen and watch videos.


text:
HBO Boxing Credits (PlayStation)
Published by
Developed by
Official Site
Critic Score
100 point score based on reviews from various critics.
User Score
5 point score based on user ratings.
HBO Boxing Credits
Other Games
In addition to this game, the following people are listed as working on other games. No more than 25 people are listed here, even if there are more than 25 people who have also worked on other games.
Jack Scalici, 84 other games
Christopher Cosby, 77 other games
Brett Gow, 65 other games
Brian Regan, 63 other games
Matthew Canonico, 55 other games
Leigh Busch, 49 other games
Scott Jenkins, 47 other games
Rick Fox, 45 other games
James Dima, 38 other games
Christopher Maher, 38 other games
Eric Hendrickson, 36 other games
Martin Glantz, 35 other games
Brian Alcazar, 35 other games
James Ackermann, 35 other games
Jameel Vega, 33 other games
James Johnson, 29 other games
Scott Douglas, 28 other games
James Craddock, 27 other games
Lisa Koch, 26 other games
John Meehan, 25 other games
Damon Redmond, 25 other games
Andrew Webster, 25 other games
Daren Chencinski, 25 other games
Lloyd Thompson, 23 other games
Michael Jerchower, 23 other games
People who have worked on this game have also collaborated on the creation of the following games:
Dave Mirra Freestyle BMX, a group of 39 people
Dave Mirra Freestyle BMX 2, a group of 30 people
Dave Mirra Freestyle BMX: Maximum Remix, a group of 30 people
Legends of Wrestling, a group of 27 people
BMX XXX, a group of 24 people
Mary-Kate and Ashley: Magical Mystery Mall, a group of 23 people
Shadow Man, a group of 23 people
Aggressive Inline, a group of 23 people
Blast Lacrosse, a group of 23 people
Jeremy McGrath Supercross 2000, a group of 20 people
All-Star Baseball 2000, a group of 19 people
Re-Volt, a group of 19 people
All-Star Baseball 2002, a group of 18 people
South Park, a group of 17 people
Turok: Evolution, a group of 17 people
Vanishing Point, a group of 16 people
NFL QB Club 2001, a group of 16 people
All-Star Baseball 2001, a group of 16 people
Freestyle Street Soccer, a group of 16 people
All-Star Baseball 2003, a group of 15 people
South Park Rally, a group of 15 people
All-Star Baseball 2005, a group of 14 people
ZooCube, a group of 14 people
ATV: Quad Power Racing, a group of 14 people
Trickstyle, a group of 14 people
Credits for this game were contributed by Kabushi (179515)


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This Macbook decal (sticker) can be applied to any smooth surface - laptop, tablet, car, fridge, window, wall, shower/bath, outside.. anywhere you can think of that has a smooth surface! They look great on Macbooks and always work with or around the apple logo.
Our Macbook decals (stickers) are made from high quality adhesive vinyl which is fully removable however not reusable.
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Banksy is a pseudonymous English graffiti artist, political activist, film director, and painter. His satirical street art and subversive epigrams combine dark humour with graffiti executed in a distinctive stencilling technique. Apache helicopter.
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Brandeis IBS offers and encourages students to accept dynamic internship opportunities to enhance their skills and hands-on experience. Academic credit can be earned for internships as long as the work is related to the student's degree, and as long as the student signs up for credit prior to the start of the internship. No tuition is charged for summer internships for full-time students.
Learn more about the internship process or learn more about our Internship Awards Program for students with unpaid opportunities. For a list of available internships, current students can visit GradLeaders to browse and apply.


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Travis Holcombe
Travis Holcombe
Eclectic 24
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BBC World Service
BBC World Service
Left, Right & Center
Weekly half-hour program providing "A civilized yet provocative antidote to the screaming talking heads of political debate" streaming & podcasting at KCRW.com.
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Madeleine Brand hosts Press Play, examining the latest ideas and trends shaping our world and Los Angeles. Streaming & podcast daily at KCRW.com.
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I found this article on the Delaware County Paranormal research site:
Fort Mifflin was built as part of the colonial defenses during the Revolution. It was built on top of an unfinished British fort. In 1777, when Howe approached Philadelphia, there was a battle there. The colonists were vastly outnumbered on both sides of the river by the British and Hessian troops.Fort Mercer, on the Jersey side, has its own revenants of this battle.
For five days the British pounded the fort. Finally, they overran and set fire to the fort. The Colonials fled.
The fort was rebuilt after the war. Confederate POWs as well as Union Soldiers awaiting trial for crimes were kept here during the Civil War, and ammunition was stored here into the twentieth century. In 1962, it was turned over to the city of Philadelphia.
Some of the inhabitants from the forts military history remain. There is a phantom lamplighter that patrols the Soldier's Barracks at sunset, lighting oil lamps outside that no longer exist. He is most often seen on the second floor. One night, the two guard dogs cowered and barked at "something" on that second floor.
In the center of the main area of the fort are the ruins of the Commandant's House. Ghosts of Union and
Confederate soldiers have been seen in and around the ruin. We have captured a green mist in this area:
During a recent visit our camera equipment would not work on one side of the interior of this building and the door slammed behind us when we exited. There was no way this door could have moved by itself, as we found when we tried to recreate the event. we reported the evnt to the staff, who informed us that this has happened on at least two other occasions known to them.
Visitors have also reported seeing a woman's face in the window of the officer's quarters. This is believed to be the "Screaming Woman" of the fort, Elizabeth Pratt. The story is that Elizabeth mourns her daughter, who had married an unacceptable man and become estranged from her family. They never nmade amends, and the daughter died very young of a disease. Elizabeth was inconsolable. She killed herself on the one year anniversary of her daughter's death. A new book about the paranormal history of the fort is due out on October 18, 2008. This book will reveal new information about Elizabeth Pratt and show how the screaming woman can not be Elizabeth Pratt, but may be another Elizabeth who became critically ill at the fort. I have my own theories about the identity of the screaming woman and am currently researching the possibilities.
On different occasions, the police have been summoned to the fort because passers by believed someon was being attacked on the grounds. Nothing unusual was ever found. The screams always occur at around 3:15 am. The scream was heard on the first night of our first Fort Mifflin investigation in April of 2001.
The blacksmith shop is the home of the ghost of Jacob Sauer, the blacksmith of the fort around the time of the Civil War. He has been heard still working in his shop. On at least one occasion, tools have been observed swinging on their hooks. The doors to the shop often open and close of their own accord.
Near the Artillery Shed, the ghost of a civil war soldier has been seen, still at his post, and just to the east of the shed, a revolutionary soldier called "Amos" still remains at his.
The Casemates served as shelters and also prison cells. In the casemates, be on the look out for Melvin, Alexander, Michael, and the Faceless Man. Alexander and Michael haunt the entrance. They were guards, and faithful ones, who still remain at their post. In one corner of the dorrway to the casemates is the faceless man. he is said to sit and sew, glancing up at people who pass. Where is face should be is a black void. This is believed to be the spirit of William Roberts, who we have encountered several times in the casemates.
During our visits to the fort, we have asked for the spirits to tell us
their names. We recorded the name "Howe" or "Howell" in response to this request. On another occasion, I requested the name of a spirit
who identified himself as a Union guard. He said his first name was "Nate". I asked for his last name, and he responded, but less clearly. You may
view these responses on YouTube: Nate
Interest in the fort has always been high, and even more so since it was featured on TAPS. I have received many photos over the past decade from people who have captured what they feel what spirit activity at the fort:
These pictures were taken by ,Carly Waddell , at Ft. Mifflin in October of 2008 and show that the fort,as we have seen ourselves, is active during the day as well!
These pictures were taken in the corridor leading to Casemate 5, at Ft. Mifflin on Feb. 25, 2001 at around 1:20 AM, with an HP PhotoSmart 315 digital camera. The photographer is Steve Norris The photo on the left has a part of his blue glove on the right side of the frame.


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Fall is all about hardware, exposed zippers, studs, satchels, drawstring bags, and metallics. Make your person fashion statement in these fierce and attractive boots which are the hottest trend of the season.
cheap michael kors
This many years Spring 2010 Assortment by Michael Kors was pretty. It featured a strong demonstrate of pastels, blacks, and whites. Mr Kors stated, "I've by no means accomplished pastels before; I constantly felt they were a bit as well saccharine. But they seem correct for spring. That's what it's all about." He added, "We don't want it to search like an previous lady at a backyard celebration," I don't think there is any danger of his designs appearing old. They were vibrant and breathed youth.
Lets say you have wished a Michael Kors Astor Satchel and you see it in shops for $298. You can get that exact same bag from a specific discounted cheap michael kors website for $100. Would you get the keep bag or the a single you identified on the web?
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And, we've acquired all the fitted caps over there, gotta assistance the Yankees – you know New York's our team. I enjoy hats that are tiny far more informal with the classic type, like the Gatsby's. Really like the non-fitted baseball caps, the snapbacks. Also, the ones with stretch.We've got 'em any way you want 'em.
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My pals and I undertaking these little issues now and they're paying out off big. In fact, my cost savings account is more substantial than it has ever been, and I am earning significantly less funds than ever. Hmmmm.
On the other hand, I see nothing at all wrong with acquiring a significantly less expensive bag that's reminiscent of the type of a couture brand. A high quality leather bag is a top quality leather bag no matter who tends to make it-as long as you're not stamping LV monograms on it (except if of program you're Marc Jacobs).


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Only one Jeep garage
Anyboby know of JK forum that would be like (or close to WK2jeeps?)
Im looking for tsbs and other cool stuff like we have here for the WK's
Better yet... have jeep garage expand branch of a JK section? :D
Been to other sites and see lots of good info... just none as cool as here.. couldnt find any DIY sections etc...
Any interest from JG or other members to expand the JK (wrangler) section more like the WK(2) forums?
I'll sign on to help maintain it:eek:
Re: Only one Jeep garage
would love to.....just need more JK owners...LOL
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text:
Location Properties L.C. 785-764-6370
Visit website 1037 Vermont Street, Lawrence, KS 66044
- Phone: 785-764-6370
This business appears in: Real Estate, Property Management, Real Estate Agencies
11543 Location Properties L.C.
Well I loved the building, the location, and the first landlord we got. The second landlord was hard to get in contact with when almost every appliance in the apartment seemed to break (From obvious years of use) I just wish they had dated or had a better keep up with the appliances. Overall I loved living here.


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I'm not sure, but I am happy not to leave it in the car when I go there in future.
This is a discussion on Question about the VA restaurant carry law within the Concealed Carry Issues & Discussions forums, part of the Defensive Carry Discussions category; Now that VA has concealed restaurant carry, will I be fine if I carry concealed in a place that is more like a bar than ...
Now that VA has concealed restaurant carry, will I be fine if I carry concealed in a place that is more like a bar than a restaurant and not drink? I ask this because I remember reading somewhere that VA does not distinguish between a bar and a restaurant when they issue license to serve alcohol.
I'm not sure, but I am happy not to leave it in the car when I go there in future.
This is what I understand.
Virginia does not recognize a difference between a "Bar" and a Restaurant that sells beer to be served on site. Therefore, you can CC at all of those places now, however it is a crime to consume. You can carry at a bar no problem, just no drinking.
That is what I heard. Consuming is not a big deal to me since I don't drink anyways. I just want to make sure I can carry if I go out with some old friends when I'm back in VA visiting. I was hoping Handgunlaw.us would have been updated but the old statue is still in the places off limits to carry section still.
The commonwealth of virginia does not, strictly speaking, have bars. Any such place must sell enough food to qualify as a restaurant/pub.
I believe 51% of profit must come from non alcohol sales.
You're O K to CC if there is no sign. You can't consume unless you OC.
"The Constitution is not an instrument for the government to restrain the people; it is an instrument for the people to restrain the government".
Patrick Henry
In some states and jurisdictions establishments may serve alcohol and not serve food - hence, a bar.
In VA if you sell alcohol to consume on premises you must also serve food - hence, a restaurant that serves alcohol (no bars in VA).
Some Virginia laws as of July 1, 2010:
People who legally carry firearms openly already may enter restaurants that serve alcohol and may drink.
A new law allows concealed carry, but prohibits concealed handgun carriers from consuming alcohol in a club or restaurant.
A concealed gun carrier who violates the law by consuming alcohol can be charged with a class 2 misdemeanor punishable by up to six months in jail and a $1,000 fine.
A restaurant owner may refuse service to gun carriers and prohibit them from entering with their weapons, concealed or not.
Gun owners can also be charged with trespassing for brining their weapons into establishments that post signs prohibiting them.
Another new law - People who don't have concealed weapons permits may stow their firearms in the glove compartment or a container in their vehicle.
Our Constitution was made only for a moral and religious people. It is wholly inadequate to the government of any other"
~John Adams
"The Constitution is not an instrument for the government to restrain the people; it is an instrument for the people to restrain the government".
Patrick Henry
You will be fine if you carry concealed in a place that is more like a bar than a restaurant and not drink.
In Virginia, most public places where you would likely go that serve alcoholic beverages for on-premises consumption are a restaurant or club.
FWIIW -- the % of sales needed for for a beer, or wine and beer license is less than for for a mixed beverage license, for a restaurant.
The relevant law:Note: this law only applies to restaurants and clubs as defined in § 4.1-100."J3. No person who carries a concealed handgun onto the premises of any
restaurant or club as defined in § 4.1-100 for which a license to sell and
serve alcoholic beverages for on-premises consumption has been granted by
the Virginia Alcoholic Beverage Control Board under Title 4.1 of the Code of
Virginia may consume an alcoholic beverage while on the premises. A person
who carries a concealed handgun onto the premises of such a restaurant or
club and consumes alcoholic beverages is guilty of a Class 2 misdemeanor.
However, nothing in this subsection shall apply to a federal, state, or
local law-enforcement officer."
[emphasis added]
LIS > Code of Virginia > 4.1-100Most places where alcoholic beverages is sold are either restaurants or clubs. However, there are some other places where alcoholic beverages can be sold and consumed -- Day Spa, Meal Assembly Kitchen, Mixed Beverage Caterer, Airplane, Boat, Train, Amphitheater, Motor Sports Facility, Special Event, Banquet Facility, Bed and Breakfast, Canal Boat, Equine Sporting Facility, Gourmet Brewing Shop, Motor Car Sporting Facility, Museum.....
"Club" means any private nonprofit corporation or association which is the owner, lessee, or occupant of an establishment operated solely for a national, social, patriotic, political, athletic, or other like purpose, but not for pecuniary gain, the advantages of which belong to all of the members. It also means the establishment so operated. A corporation or association shall not lose its status as a club because of the conduct of charitable gaming conducted pursuant to Article 1.1:1 (§ 18.2-340.15 et seq.) of Chapter 8 of Title 18.2 in which nonmembers participate frequently or in large numbers, provided that no alcoholic beverages are served or consumed in the room where such charitable gaming is being conducted while such gaming is being conducted and that no alcoholic beverages are made available upon the premises to any person who is neither a member nor a bona fide guest of a member.
Any such corporation or association which has been declared exempt from federal and state income taxes as one which is not organized and operated for pecuniary gain or profit shall be deemed a nonprofit corporation or association.
"Restaurant" means, for a beer, or wine and beer license or a limited mixed beverage restaurant license, any establishment provided with special space and accommodation, where, in consideration of payment, meals or other foods prepared on the premises are regularly sold.
"Restaurant" means, for a mixed beverage license other than a limited mixed beverage restaurant license, an established place of business (i) where meals with substantial entrees are regularly sold and (ii) which has adequate facilities and sufficient employees for cooking, preparing, and serving such meals for consumption at tables in dining areas on the premises, and includes establishments specializing in full course meals with a single substantial entree.
See: License Types & Costs
There is no law against CC in any such places except restaurants and clubs as defined in § 4.1-100.
So, other than restaurants and clubs there is no restriction on CC and drinking in places where alcoholic beverages are sold.
Also, in restaurants and clubs there is no restriction against OC and drinking alcoholic beverages.
Μολὼν λαβέ
I'm just one root in a grassroots organization. No one should assume that I speak for the VCDL.
I am neither an attorney-at-law nor I do play one on television or on the internet. No one should assumes my opinion is legal advice.
Veni, Vidi, Velcro
There is a thread running on OCDO about an idiot Richmond bartender blogging about what he will do to anyone he sees carrying in his establishment.
Here is a link to the thread:
"Gun owners can also be charged with trespassing for brining their weapons into establishments that post signs prohibiting them."
Unless the law was changed, I think one has to be asked to leave first, and if you refuse then you are subject to trespass.
That was the answer that I got when I asked the Va. State Police.
Don't believe what you hear and only half of what you see!
-Tony Soprano


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Department of Psychiatry Faculty
Erin E. Bonar, Ph.D.
Contact Information
Primary Programs/Services:
- Postdoctoral Fellowship, University of Michigan, Addiction Research Center
- Ph.D., Clinical Psychology, Bowling Green State University
- Clinical Psychology Internship, VA Ann Arbor Healthcare System
- M.A., Clinical Psychology, Bowling Green State University
- B.S., Psychology, Northern Kentucky University
Clinical Interest:
- Substance use disorder treatment
- Motivational interviewing
- Cognitive behavioral therapies
Research Interest:
- Prevention and treatment of substance use disorders in diverse populations of adolescents, emerging adults, and adults.
- Understanding and reducing substance use and concomitant risk behaviors (e.g., HIV risk behaviors), and related negative consequences for both individuals and communities.
- Developing, improving, and evaluating interventions focusing on substance use and related risk behaviors in community settings.
Academic Appointment:
- Assistant Professor, University of Michigan, Department of Psychiatry
- Adjunct Assistant Professor in Psychology in LS&A
Recent or Representative Publications:
- Cunningham RM, Polshkova S, Chermack ST, Blow FC, & Walton MA. Alcohol and energy drink use among adolescents seeking Emergency Department care. Addictive Behaviors, 2015;43:11-17
- Bonar EE, Cunningham RM, Chermack ST, Blow FC, Barry KL, Booth BM, & Walton MA. Prescription drug misuse and sexual risk behaviors among adolescents and emerging adults. Journal of Studies on Alcohol and Drugs,2014;75:259-268
- Bonar EE, Walton MA, Cunningham RM, Chermack ST, Bohnert ASB, Barry KL, Booth BM, & Blow FC. Computer-enhanced interventions for drug use and HIV risk in the emergency room. Journal of Substance Abuse Treatment, 2014;46:5-14.
- Bonar EE, Whiteside LK, Walton MA, Zimmerman MA, Booth BM, Blow FC, & Cunningham RM. Prevalence and correlates of HIV risk among adolescents and young adults reporting drug use: Data from an urban Emergency Department in the U.S. Journal of HIV/AIDS and Social Services, In Press