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Rubinstein-Taybi Syndrome (RSTS, MIM 180849) is a rare congenital disorder characterized by mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors. RSTS is caused by chromosomal rearrangements and point mutations in one copy of the CREB-binding protein gene (CREBBP or CBP) in 16p13.3. To date mutations in CREBBP have been reported in 56.6% of RSTS patients and an average figure of 10% has ascribed to deletions.
Our study is based on the mutation analysis of CREBBP in 31 Italian RSTS patients using segregation analysis of intragenic microsatellites, BAC FISH and direct sequencing of PCR and RT-PCR fragments.
We identified a total of five deletions, two of the entire gene and three, all in a mosaic condition, involving either the 5' or the 3' region. By direct sequencing a total of 14 de novo mutations were identified: 10 truncating (5 frameshift and 5 nonsense), one splice site, and three novel missense mutations. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1–170) and will probably destroy a Nuclear Localization Signal. Identification of the p.Asn1978Ser in the healthy mother of a patient also carrying a de novo frameshift mutation, questions the pathogenetic significance of the missense change reported as recurrent mutation. Thirteen additional polymorphisms, three as of yet unreported, were also detected.
A high detection rate (61.3%) of mutations is confirmed by this Italian study which also attests one of the highest microdeletion rate (16%) documented so far.
Rubinstein-Taybi syndrome (RSTS; MIM 180849) is a congenital disorder characterized by growth retardation and psychomotor developmental delay, broad and duplicated distal phalanges of thumbs and halluces, and a wide range of typical dysmorphic features. Facial dysmorphology includes down-slanted palpebral fissures, broad nasal bridge, beaked nose and micrognathia [1]. In addition, patients with RSTS have an increased, although not well documented, risk of tumor formation [2,3]. RSTS was shown to be associated with microdeletions and point mutations in the gene encoding the CREB-binding protein (CREBBP, also known as "CBP"), located in 16p13.3 [4]. CREBBP is a transcriptional coactivator and possesses acetyltransferase activity on lysine residues of histones and nonhistone proteins [5]. CREBBP partecipates in basic cellular functions, including growth, differentiation, DNA repair and apoptosis, regulating the expression of many genes [6]. The mutations found in RSTS patients vary from point mutations to relatively large microdeletions, which remove the entire gene, attesting that haploinsufficiency of this dosage-sensitive gene is the ultimate cause of the syndrome. More precisely, studies of patients with missense and splice-site mutations that affect only the histone acetyl transferase (HAT) domain of CREBBP demonstrated that loss of HAT activity is sufficient to cause the syndrome [7,8]. The related p300 protein, which is encoded by the EP300 gene on chromosome 22q13.2, shares homology with CREBBP and accordingly serves as a transcriptional coactivator endowed with a HAT domain [9]. Mutations of EP300 have been recently reported in a small subset (3.3%) of RSTS patients [10]. This figure and the low detection rates (from 40% to 56.6%) of CREBBP gene assessed by all mutations studies of RSTS patients suggest that other candidate genes might contribute to the pathogenesis of this syndrome [4,10-12]. We recruited 31 patients with consistent RSTS clinical diagnosis and we tested them by microsatellite segregation analysis, FISH, RT-PCR and direct sequencing to find mutations of the CREBBP gene. This multimethod approach allowed us to identify five deletions and 14 point mutations, accounting for the highest (61.3%) mutation rate so far assessed. Particularly FISH analysis was instrumental for detecting even subtle microdeletions proving to be a method suitable more than mutation analysis to disclose low level mosaic conditions.
We analysed samples of 31 unrelated patients sent to our laboratory with parental consent with the request of genetic analysis for Rubinstein-Taybi syndrome. Studies and procedures were in accordance with the ethical standards of the host institutions. The group consisted of 16 female and 15 male patients, aged 2 to 42 years. Clinical diagnoses were established by different Centers and eventually confirmed by the coordinating clinical Center (Dept of Pediatrics, University of Milan) based on clinical records and photographs, when no pathogenetic mutation could be found. Careful examination of the patients' phenotypes was done, and the presence of malformations and medical complications were confirmed or excluded.
Thirty subjects had a normal karyotype by Giemsa-trypsin banding at 450-band resolution; patient 38 showed a 46, XY, der(14)t(9;14)(p11.2;p11.2) karyotype.
Cell cultures, chromosome and interphase nuclei preparations
Phytohemagglutinin-stimulated peripheral blood lymphocytes were set up in culture from samples using Chromosome Kit "Synchro" (Celbio) and modified RPMI (Irvine Scientific) plus 5% fetal calf serum (Gibco). The cultures were blocked with colchicine after 72 h. Chromosome preparations were obtained using a standard technique.
Clone preparations
BAC clones RP11 95J11, RP11 461A8 and RP11 566K11 were supplied by Mariano Rocchi [13]; BAC RP11 1072J2 was purchased from the CHORI BAC PAC Resource Center (Oakland, USA). DNA was obtained starting from a single colony grown in 4 ml of LB medium supplemented with 20 μg/ml chloramphenicol (Sigma) following standard procedures.
BAC clones were labelled with digoxigenin-dUTP (Roche Diagnostic) using a nick translation kit (Roche Diagnostic). The FISH experiments were performed according to standard procedures [14]. The chromosomes were counterstained with DAPI in antifade (Vectashild), and then visualised using a Leitz DM-RB microscope equipped for DAPI and FITC/TRITC epifluorescence optics. The images were captured by means of a CCD camera (Hamamatsu 3CCD Camera, C5810) and visualised using Highfish software (Casti Imaging).
Analysis of FISH signals in mosaic condition
Almost 50 metaphases and 100 nuclei were scored for each sample in order to establish the mosaic condition. Only intact and undamaged nuclei free of cytoplasm were analyzed. Nuclei with low signal intensities, diffuse signals, or absence of signals on both homolog chromosomes were considered to be hybridization failures and were not scored. Two small focal (or paired) signals of the same color and the same intensity, separated by a distance of less than the area of one signal, were considered to be a split signal from one chromosome. Interphase nuclei with one large signal of the same color and increased intensity of fluorescence with the absence of a second hybridization signal in an interphase nucleus were considered to be overlapping (or over-position) of two signals and were not scored. Informative mosaic samples were defined as those in which more than 5% of the nuclei had a reproducible abnormal pattern of signals different from normal chromosomal signals.
Microsatellite segregation analysis
Fluorescent genotyping was performed as previously described [11]. The following fluorescently dye-labeled chromosome 16p microsatellite markers: MS4, MS2 and D16S3065 (from centromere to telomere) were used for segregation analysis from parents to probands. Fluorescence detection was performed on an ABI 3100 sequencer. ABI PRISM software (Genescan) was used for gel analysis.
RT-PCR analysis
RT-PCR analysis was performed as previously described [11] for patients 14, 16, 20, 25, 28 and 29 for whom mRNA was available.
Molecular analysis
The DNA sequencing of all coding exons of the CREBBP gene was performed as previously described [11]. Twentysix CREBBP PCR genomic fragments were amplified (see 1). The DNA sequencing protocol was updated for use with the BigDye Chemistry, Versions 2.0 and 3.1, and the ABI PRISM 310 and 377 Genetic analyzer systems (Applied Biosystems, Darmstadt, Germany). If a mutation or polymorphism was found, a second sequencing run was performed for confirmation. The origin of the mutation or polymorphism, whether de novo or familial, was established if parental DNA was available. Paternity testing was not performed due to legal restrictions. The Human Gene Mutation Database (HGMD) [15], recent publications [8,10-12], and the dbSNP database [16] were consulted to check whether sequence variations were previously reported or not. Missense mutations of patients 15 and 46 identified in this study were absent in 100 controls, while that carried by patient 23 was absent in 50 controls.
Additional file 1. Additional Table I. Twentysix CREBBP PCR pairs of primer for DNA sequencing of all coding exons of the CREBBP gene, as previously described by Coupry et al. 2002
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Clinical evaluation
Thirty-one Italian RSTS patients, whose main signs are reported in Table 1, were carefully clinically analysed. Sex ratio was F:M = 16:15. All patients had psychomotor/mental retardation, which ranged from mild to severe in 17 cases. Microcephaly was evident in 20 (64.5%); a subset (12 cases) accounting for 61.3% of RSTS patients manifested poor growth. The main facial features were specifically described and/or evident from photos (see Figure 1) and the overall facial gestalt was absolutely typical in all but one patient. As reported in Table 1, the typical large thumb was evident in 93% (27/29 patients), and in 11 cases it was also abducted; the hallux was large in 89% (26/29), and only in 4 cases it was valgus/varus. Only 11 individuals had major malformations of internal organs or limbs: congenital heart disease (patent ductus arteriosus, ventricular/atrial septum defects, bicuspid aorta) was reported in 6 of them, cryptorchid testes in 3, coloboma of the optic nerve, renal hypoplasia, duodenal malrotation and hexadactyly in one. In 5 patients supernumerary nipples were evident. Only in two cases (pt 16 and 17) lacrimal ducts stenosis and sensorineural deafness (pt 14 and 38) were signaled. In case 46 the presence of multiple epitheliomas was reported. In another single case (pt 15) Perthe's disease was found.
Figure 1. a Patient 16 (negative for CREBBP mutations); b patient 17 (c.3715_3716delAA in CREBBP gene); c patient 46 (c.4627G>T in CREBBP gene). The typical RSTS facial features are visible in the three patients.
Table 1. Main clinical signs of the thirty-one Italian RSTS patients.
Mutation analysis
We screened the 31 recruited patients for point mutations, small deletions or insertions, and large deletions and duplications of the CREBBP gene. First, by genotyping the polymorphic intragenic repeats MS4, MS2 and D16S3065 [11] plus one SNP (c.5454G>A, [12]) we could identify two deletions spanning the whole gene in patients 30 and 41. Both deletions affected the maternal chromosome. Figure 2 shows for patient 30: (A) the haplotype reconstruction attesting the lack of three maternally contributed intragenic polymorphic loci; (B) FISH of the CREBBP spanning BAC 1072J2 evidencing a signal of reduced intensity on one chromosome 16. By means of FISH analysis we detected three additional deletions, all in a mosaic condition. Two (pt 40, pt 66) affect the 5' of the gene, while one (pt 38), spans mainly the central region of the gene and its flanking 3' sequences. The last one is present in a structurally rearranged karyotype (see subjects in the methods section). The mosaic condition has been confirmed in two patients from which buccal smears were available. Scoring of CREBBP specific signals on both lymphocytes (> 150 cells- metaphases and nuclei) and buccal smears (>100 nuclei) gave comparable results in showing an average 20% of deleted cells in both cases. A fraction of 30% deleted cells was estimated on the third case for whom a sample of 300 cells from peripheral blood was scored. Current studies are in progress aimed to evaluating the extent and boundaries of all the deletions. These data will be reported elsewhere. A schematic view of the identified deletions mapped on the encompassed genomic CREBBP region is shown in Figure 3.
Figure 2. CREBBP deletion in patient 30 detected through: a genotyping of intragenic polymorphic markers (MS4, MS2, D16S3065 and SNP c.5454G>A) in the available family members allowing haplotype reconstruction; b Double color FISH analysis showing a signal of highly reduced intensity on one chromosome 16p for BAC 1072J2, specific for CREBBP (in red). The residual hybridization is accounted for by the size of the genomic clone higher than the deleted region. The control subtelomeric 16q BAC 566K11 shows a comparable signal on both chromosomes (in green).
Figure 3. Mapping of the five deletions on the CREBBP genomic region. Top: genomic organization of CREBBP with exons represented by black boxes and introns as connecting lines. The intragenic polymorphic loci are positioned across the gene. Middle: BAC clones used for preliminary FISH analysis, indicated by bars. Bottom: deletions are shown by thick lines; deletion ends containing the breakpoints, are represented by dashed lines.
Then we screened the remaining 26 patients for point mutations by direct sequencing of 26 PCR genomic fragments encompassing the complete coding sequence and splice sites of CREBBP. We identified 14 sequence alterations of pathogenic significance: all are listed in Table 2 and shown in Figure 4 in their location within exons encoding different CREBBP domains. Although the identified mutations are distributed across the whole gene without apparent hot-spots, six, including two missense (p.Tyr1482Cys; p.Asp1543Tyr), and four truncating mutations (p.Lys1239ValfsX14; p.Gly1479X; p.Asp1543GlnfsX39; p.Pro1655CysfsX89) are clustered within the HAT domain. Out of the remaining mutations, which map outside the HAT domain, five of eight are predicted to lead to premature translation stops upstream of the HAT region, thus indirectly spoiling its function. They comprise p.Arg370X and p.Arg424X in the N-Terminal Transactivation Domain (TAD), p.Gln662X in the CREB Binding Domain and p.Gln1118ProfsX13 and p.Arg1173X in the Bromodomain. The remaining three mutations, p.Arg14Gly in the 5' Nuclear Receptor Binding Domain, p.Ser2015AlafsX25 and p.Gln2022ArgfsX16 in the C-Terminal TAD, do not affect the HAT domain at all.
Table 2. Fourteen causative CREBBP mutations detected by direct sequencing.
Figure 4. Location of the 14 causative CREBBP mutations found in this study. Only exons are drawn to scale. The histone acetyl transferase domain and the plant homeodomain (PHD)-type zinc finger are indicated according to Kalkhoven et al. (2003), other domains according to Giles et al. (1997). Truncating mutations are in light-grey, missense mutations in dark-grey and the two previously reported mutations in italics.
Twelve of 14 mutations are novel, while p.Arg370X has been reported by several groups [8,10,11,17] and p.Arg424X has been also recently described [12]. As to the nine different single nucleotide substitutions they consist of five nonsense (pts 24, 35, 11, 32 and 34), three missense (pts 23, 15 and 46) and one splice site mutation (patient 20). Out of the five sequence alterations producing a frameshift in the reading frame, one is a 2 bp-duplication (pt 2) leading to the potential incorporation of 12 anomalous aminoacids, three are deletions sized 1, 2 and 7 nucleotides respectively (pts 22, 17 and 21) predicting 88, 13 and 15 anomalous aminoacids and one is a splice site mutation (c.4728+1G>A) affecting IVS 28 donor site. Analysis of this mutation with two different softwares, the Splice Site Prediction by Neural Network (BDGP) [18] and the SpliceView [19] indicated that the splice donor site was suppressed (predicted scores = 0%) and a novel candidate donor site 260 bp upstream the mutation was activated. The SpliceView software, also detected a near donor site, 104 bp upstream the splice mutation. We were able to identify CREBBP transcripts from patient 20 also including a smaller transcript, in addition to the normal one (Figure 5). Direct sequencing of the anomalous transcript confirmed the activation of the nearest upstream cryptic donor site predicted by the SpliceView software. The frameshift produced by missplicing should lead to the incorporation of 38 anomalous aminoacids.
Figure 5. RT-PCR and bioinformatic analysis of the splice site mutation (c.4728+1G>A) of pt 20. a RT-PCR of the CREBBP fragment including Ex 28 and 29 evidenced an additional smaller fragment (NC: normal control). b bioinformatic analysis with Splice Site Prediction [18] and the SpliceView [19]: the physiological donor site is in bold; the de-novo donor site activated is underscored. c schematic diagram of the misplicing predicted to occur in this patient with the cryptic donor site underscored. On the left electropherogram of the normal donor site; on the right the electropherogram attesting activation of the cryptic donor site.
All three missense changes, p.Arg14Gly (pt 23), p.Asp1543Tyr (pt 46) and p.Tyr1482Cys (pt 15) were not previously reported. They were established to have occurred de novo and were found absent in 50 (p.Arg14Gly) and in 100 (p.Asp1543Tyr and p.Tyr1482Cys) healthy individuals, respectively. Furthermore all of them affect aminoacids that are highly conserved both through evolution and in the related p300 (Figure 6) [20]. p.Arg14Gly in the 5' Nuclear Receptor Binding Domain is predicted by PSORTII [21] to cause the destruction of a monopartite Nuclear Localization Sequence (NLS) (Figure 7). This NLS is a typical monopartite cluster of basic residues, with a conserved pattern starting with Pro, followed by Lys or Arg in 3 out of 5 residues (PKRAKLS) [22,23]. In addition the same software predicted another central bipartite Nuclear Localization Signal at 1591 (KKTNKNKSSISRANKKK). Both the NLSs are highly conserved in mouse CREBBP and in p300 protein. p.Tyr1482Cys and the p.Asp1543Tyr are both in the HAT domain. Finally we detected 18 CREBBP polymorphisms, including 12 single nucleotide polymorphisms (SNPs) and a 3'UTR 1 bp-duplication (see 2). Three of the sequence variations have not been previously reported, including two intronic SNPs (c.3983-22C>T, c.4560+14A>G) and the 3'UTR 7329+25dupC. Conversely the sequence variation (c.5933A>G), was reported in other patients with RSTS [11,12]. This substitution, causing the p.Asn1978Ser change in a conserved glutamine-rich region, downstream the HAT domain, has been inherited by our patient 22 by his apparently normal mother. The same patient was found to bear a de novo truncating mutation in the exon upstream the p.Asn1978Ser change (c.4963delC). We were able to establish that both mutations occurred on the maternal allele in a cis configuration (data not shown). Moreover we detected the same nucleotide substitution in one of 50 controls analysed.
Figure 6. Conservation of amino acids that are predicted by ClustalW [20] to change by three missense mutations identified in this study. a p.Arg14Gly of pt 23; b p.Tyr1482Cys of pt 15; c p.Asp1543Tyr of pt 46. The changed residues are conserved in man (GeneBank: Q92793), in mouse (GeneBank: P45481), in Drosophila melanogaster (DROM3A), in Caenorabditis elegans (CEL116) and in P300 protein.
Figure 7. Nuclear Localization signals (NLSs) predicted by PSORTII [21] analysis. a wild-type CREBBP with three putative NLSs (two monopartite and one bipartite) evidenced by squares: the affected Arg14 is marked in red; b Mutated CREBBP of patient 23 with Arg14Gly substitution with only one predicted NLS. The bottom panels show the cellular localization predictions of wt and mutated proteins.
Additional file 2. Additional Table II. Thirteen CREBBP polymorphisms detected by direct sequencing. The yet unreported variations are bolded.
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By investigating 31 RSTS Italian patients using approaches suitable to detect most types of CREBBP mutations we identified bona fide causative lesions in 19 subjects (61.3%), a score slightly higher than that recently reported [12]. Complementary application of FISH and microsatellite analysis allowed us to detect five microdeletions, (which refined FISH characterization will be published elsewhere) one of the highest microdeletion rate (16%) documented so far, a finding that emphasizes possible underestimation of CBP microdeletions in RSTS patients [24-26]. Data achieved using realtime quantitative PCR are consistent with this view [27].
Interestingly this is the first report describing mosaicism for CREBBP deletions, indicating the contribution of mitotic errors to this rare syndrome, that might exploit the same breakpoints of the highly unstable region around intron 2 of CREBBP evidenced in cancer [28-30]. It should be noted that in one case (pt 38) the CREBBP mosaic deletion is in the context of a rearranged karyotype, which may account for the complex phenotype of the patient.
By sequencing all exons and splice sites of the CREBBP gene, we identified on a total of 26 patients 14 different mutations, only two of which have been described [8,10-12,17]. Neither a predominant type of mutation nor clustering of mutations within the CREBBP gene are apparent. In agreement with previous studies, most mutations (11/14, >78%) predict premature stop codons [4,7,8,11,12,17,24]. Since RSTS is an autosomal dominant trait, it can be assumed that truncating mutations are disease causing mutations making superfluous to determine their de novo origin [10,11]. We also detected three putative missense mutations, in which the pathogenic role is much less clear. However, we were able to confirm the de novo origin of all three missense mutations which were found only once among 26 patients analysed and were never observed in a 100 normal controls (50 in the case of patient 23), ruling out that they are unreported CBP polymorphisms. Moreover, when compared with the murine CREBBP (Genbank: S66385) [31], which shows 95% identity across the whole 2441 aa length of the protein, all the three mutated residues were conserved (Figre 6). More generally their conservation, both phylogenetic, from fruit fly to C. Elegans, and in the related p300 protein highlights the functional importance of these residues in the protein. Interestingly, two missense mutations are in the HAT domain of CREBBP, where similar mutations were shown to be sufficient to cause the RSTS phenotype as they destroyed the acetyltransferase activity [7,8]. Furthermore p.Tyr1482Cys (patient 15) is in the postulated coenzyme A binding site (aminoacids 1459–1541). It may not be fortuitous that the phenotypic presentation of this patient strikingly overlaps the clinical presentation of a second patient (20), carrying a splicing mutation affecting the same domain. Application of RT-PCR allowed to document the deleterious consequence of the splicing mutation and to better interpret the patient's phenotype. Indeed both patients 15 and 20 are affected by severe mental retardation and complete absence of speech. The third missense mutation, p.Arg14Gly, found in patient 23, is localised in the 5' end of the CREBBP protein, where no other missense mutation has been reported. Aminoacids from 1 to 100 are known to be responsible for the Nuclear-Receptors binding (RAR, GR TXR) [32]. Moreover, according to the PSORTII software the resulting aminoacid change is predicted to disrupt a putative Nuclear Localization Signal. Functional studies of this mutant protein are in progress to determine whether the predicted NLS is necessary for the correct import of the protein into the nucleus. It should be noted that patient 23 has a mild phenotype, characterised by normal growth and absence of microcephaly. This peculiar phenotype might be accounted for by a reduced amount of CREBBP protein in the nucleus because of impaired translocation of the mutated product, rather than by a reduced binding to Nuclear-Receptors.
In this study we detected the c.5933A>G leading to p.Asn1978Ser change in patient 22, who carries also a de novo truncating mutation (c.4963delC). We were able to establish the cis phase of the two alterations on the maternal allele. The same p.Asn1978Ser change was found in a classic RSTS patient [11] and has been recently described as a recurrent mutation, in a patient displaying an incomplete RSTS phenotype [12]. We detected the same change in our patient 22's healthy mother, and subsequently in one of 50 additional control individuals who were studied: thus we infer it may be counted among CREBBP polymorphisms. Consistent with this view, the resulting amino acid substitution, located outside the HAT domain, affects an aminoacidic residue conserved in the mouse, but not either in fruit fly and C. Elegans, or in p300 (Figure 6). Interestingly, a different change of the same residue (p.Asn1978Asp) has been recently detected in an ovarian and a breast tumour from unrelated individuals. Mutation analysis in germline DNA which could be performed on one of the two individuals showed the same sequence alteration present in the tumours [33]. The authors emphasised that the individual carrying the mutation in the germline does not have the RSTS phenotype, as expected of someone with a CREBBP mutation. All the cumulated evidences indicate the affected CREBBP codon as a highly polymorphic site, resulting in a aminoacidic change which does not disrupt protein function sufficiently to cause RSTS or to predispose to breast and/or ovarian cancer. The overall data might help to interpret this sequence change and to keep it into account in genetic counselling.
Finally, we identified 13 additional sequence variations, which can be added to the list of known CREBBP polymorphisms (see 2). Interestingly our patients 16 and 25 share five different polymorphisms inherited from their parents, in agreement with a recent report [12]. Also our two families do not appear to be related, but extended genetic histories were not available.
By combining different techniques we identified a CREBBP mutation in 61.3% of RSTS cases, a mutation rate higher than that of a recent study [12]. Intragenic microsatellite markers and FISH analysis enabled us to identify one of the highest microdeletion rate (16%) documented so far [24-26,34]. No significant correlation could be established between different types of mutation and the clinical presentation and significantly, the patients proved negative to CREBBP mutation screening (both point mutations and deletions) represented the whole RSTS phenotypic spectrum. The overall mutation rate attested by our study and the fact that most CREBBP-negative patients did not display a mild or borderline RSTS clinical presentation provide further indirect evidence on the involvement of genes other than CREBBP in the RSTS phenotype. Indeed, a few CREBBP lesions might have been underestimated, as we ruled out silent exonic alterations affecting splicing enhancers (in the CREBBP-negative patients 14, 16, 25, 28 and 29), but not intronic alterations affecting splicing as analysis at the RNA level was precluded. Similarly the CREBBP promoter could not be tested, as direct sequencing was attempted, but raised technical problems. However the putatively missed CREBBP alterations likely do not cover the whole fraction of negative cases with a consistent RSTS phenotype. It may be that a few of the screened patients will turn out, upon a closer clinical examination, to have a different syndrome that resembles RSTS. However, considering the larger set of RSTS patients cumulatively ascertained by other groups, yet mutations were not found in more than half their patients as well [11,12]. The recent finding of only three mutations of the CREBBP homologue p300 in a series of 91 patients did not prompt us to screen this gene in our much more restricted cohort [10]. However genetic heterogeneity of RSTS patients is documented and lesions in other genes encoding for proteins that interact with CREBBP in various signal transduction pathways, should be considered.
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
AB: main investigator with a direct and coordinating role in experimental work; drafted the manuscript and approved the final version of it.
DM: involved in the collection and critical review of clinical data
CG, PC, FM: performed laboratory investigation concerning both mutation analysis and FISH screening and helped to draft the manuscript
SM e PC: involved in the set up of the mutation screening
LG, FA, MTD, MLGU, GN, MFB, FF: clinical geneticists providing selected patients with RSTS
AS: supervisor for patients recruitment and clinical diagnosis
LL: involved in design and coordination of the experimental work; drafted the manuscript and approved the final version of it.
All authors read and approved the final manuscript.
We would like to thank the patients and their families for contributing to this study, and our clinical colleagues for referring patients and clinical data, especially Dr Emanuela Lucci-Cordisco (Institute of Medical Genetics, Catholic University, Rome, Italy, pt 40); Dr Alice Pessagno (Department of Infantile Neuropsychiatry, G. Gaslini Children's Research Hospital, Genova, Italy, pt 38); Dr Giovanna Olioso (Divisione di Neuropsichiatria Infantile, Spedali Civili, Brescia, Italy, pt 23). The parents of the children depicted in Figure 1 have provided consent for the use of the images for publication. This work was supported by a grant from ASM (Associazione Italiana Studio Malformazioni).
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Petrij F, Dauwerse HG, Blough RI, Giles RH, van der Smagt JJ, Wallerstein R, Maaswinkel-Mooy PD, van Karnebeek CD, van Ommen GJ, van Haeringen A, Rubinstein JH, Saal HM, Hennekam RC, Peters DJ, Breuning MH: Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations.
J Med Genet 2000, 37:168-76. PubMed Abstract | Publisher Full Text
Breuning MH, Dauwerse HG, Fugazza G, Saris JJ, Spruit L, Wijnen H, Tommerup N, van der Hagen CB, Imaizumi K, Kuroki Y, et al.: Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3.
Am J Hum Genet 1993, 52(2):249-54. PubMed Abstract
Coupry I, Monnet L, Attia AA, Taine L, Lacombe D, Arveiler B: Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR.
Hum Mutat 2004, 23:278-84. PubMed Abstract | Publisher Full Text
Vizmanos JL, Larrayoz MJ, Lahortiga I, Floristan F, Alvarez C, Odero MD, Novo FJ, Calasanz MJ: t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia.
Genes Chromosomes Cancer 2003, 36:402-5. PubMed Abstract | Publisher Full Text
Schmidt HH, Strehl S, Thaler D, Strunk D, Sill H, Linkesch W, Jager U, Sperr W, Greinix HT, Konig M, Emberger W, Haas OA: RT-PCR and FISH analysis of acute myeloid leukemia with t(8;16)(p11;p13) and chimeric MOZ and CBP transcripts: breakpoint cluster region and clinical implications.
Leukemia 2004, 18:1115-21. PubMed Abstract | Publisher Full Text
Rozman M, Camos M, Colomer D, Villamor N, Esteve J, Costa D, Carrio A, Aymerich M, Aguilar JL, Domingo A, Sole F, Gomis F, Florensa L, Montserrat E, Campo E: Type I MOZ/CBP (MYST3/CREBBP) is the most common chimeric transcript in acute myeloid leukemia with t(8;16)(p11;p13) translocation.
Genes Chromosomes Cancer 2004, 40:140-5. PubMed Abstract | Publisher Full Text
Genbank [http://www.ncbi.nlm.nih.gov/Genbank/] webcite
Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG: A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors.
Cell 1996, 85:403-14. PubMed Abstract | Publisher Full Text
Ward R, Johnson M, Shridhar V, van Deursen J, Couch FJ: CBP truncating mutations in ovarian cancer.
J Med Genet 1996, 42:514-8. Publisher Full Text
Bartsch O, Rasi S, Delicado A, Dyack S, Neumann LM, Seemanova E, Volleth M, Haaf T, Kalscheuer VM: Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.
Hum Genet, in press.
2006, Jun 17
Pre-publication history
The pre-publication history for this paper can be accessed here:


text:
Heat oil add mustard seeds, cumin seeds, pinh of hing, curry leaves, garlic and saute till garlic gets light golden color.
Add chopped onion and fry till onion gets light brown color.
Add red chilli powder, garam masala and cook for about a minute.
Add chopped tomatoes and jaggery or sugar, mix, cover and cook for 3 to 4 mts till tomatoes becomes soft.
Add some water and salt mix.
Add roasted peanut powder, mix and cook for 2 mts.
Garnish with corriandar leaves.

subset: commoncrawl


text:
Female Vocalists
This tag describes any musical artist with a female singer as the centerpiece of the vocals. This tag is not limited to any one musical genre or era, and includes artists ranging from Billie Holiday to Lady Gaga.
Pierce the Veil
Tagged: Post-hardcore Emocore Experimental Emo Post Hardcore
The Mynabirds
Tagged: Indie Pop Indie Female Vocalists Singer-songwriter American
Obscure Sphinx
Tagged: Post-metal Sludge Polish Experimental Sludge Metal
Tagged: Alternative Rock Rock Hard Rock Female Fronted Metal
Theatres Des Vampires
Tagged: Gothic Metal Vampiric Metal Black Metal Gothic Metal
Larval Stage Planning
Tagged: J-pop Female Vocalists Japanese Anime I've Sound
Larval Stage Planning
Tagged: J-pop Female Vocalists Japanese Anime I've Sound
Tagged: Try Under 2000 Listeners Indie Groove Bay Area
Канцлер Ги
Tagged: Bard Menestrel Russian Fantasy Post-huipizdacore


text:
SACAC Basketball Season 3 is upon us and is broken down into 3 pillars:
1. Season 2 CBL http://www.sacac.com/node/41990
Who: Boys and Girls divisions, 11U, 13U, 15U & 18U
When: January 17th – May 31st
Assessments: Saturdays, January 17th & 24th from 1-2pm in the Singapore American School ES Gym C/D. Please try to attend at least one assessment.
Once signups and assessments are completed, teams will be organized and assigned practice and game schedules.
Practices: Twice a week from Mondays to Fridays, usually Mondays and Wednesdays or Tuesdays and Thursdays ; 4:30-6:00 or 6:00-7:30pm in the Elementary School Gym.
This season SACAC Basketball has the 4:15 gym time slot guaranteed 3 days a week; M,T & TH while WED & FRI are available if it does not rain. If rain occurs, SAS Softball gets the gym and practice will either be delayed, re-scheduled or possibly cancelled depending on coaches discretion.
Games: Sundays from 9am-1pm, starting February 8th - May 17th, with Playoffs on May 24th and Championships on May 31st
2. Season 3 Pre-Spring Break - January 17th – March 16th (Saturdays or Mondays, days/times vary by program) http://www.sacac.com/node/41954
3. Season 3 Post-Spring Break – March 30th – May 30th (Saturdays or Mondays, days/times vary by program) http://www.sacac.com/node/42012 (
Who: ANYONE!
Where: SAS, Elementary School Gym C/D
When: Saturdays and Mondays, starting January 19th – May 31st
The Pre and Post-Spring Break sessions are Skills and Development sessions broken down into programs that offer something for all ages and skill levels:
1. K thru' 2 is our "Learn to Play" program and will be focusing on basics and rules of the game, basketball stance and skills with games & full court scrimmages during every session.
2. Girls' Skill Development was developed so young girls can learn from an experienced role model in a comfortable setting whilst picking up the game and developing confidence.
3. Boys' Skill Development is Aimed to introduce the sport to young boys in a comfortable environment, Coach Pathman will run through the fundmentals of the game through fun and exciting drills and games!
4. Senior Girls' Skill Development will focus on basketball skills development, team play, basketball education, and organized positive fun.
5. Seniors' Elite Skill Development is a program customised program and training that will be of a high level. With Coach Pathman's experience as a professional basketball player and having played at the highest level, he will reveal the secrets to being a great player and what took him there.
6. Jump Start with Laura Schuster and Coach Pathman is for all kids who have interest in ball sports yet have not found the entry level to maximize his or her development or the desire to play basketball.
Register now!! http://www.sacac.com/user (SACAC.COM)
No seasons tentatively.
No seasons tentatively.
No seasons tentatively.
|Ended on
|10/11 Qtr 2 Basketball
|Feb 19, 2011
|10/11 Qtr 3 BASKETBALL
|May 21, 2011
|10/11 Summer Basketball Camp
|Jun 23, 2011


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Aliens vs. Predator Swarm DLC Trailer
Check out two new multiplayer maps for six different modes, as well as two new survivor maps in the new downloadable content for Aliens vs. Predator!
by Dan Mihoerck on
Did you enjoy this video?Sign In to Upvote
played em already there awesome !!
I never saw what problems they had with this game. Watching the review... their biggest concern was the lack of fluid movement with the aliens and predator. I respectfully disagree. I mean really, problems with controls is just an opinion. I personally have never had a problem with them.
i really dont see whats so bad about this game. its avp for god sakes!!
Most underated game of the year.
nice , im buying this. its only $7.
facepalm, they should already included these maps in the beginning, and heres advise to the avp makers, make the buy price lower, and give it some patches/fixes on the game, that will make teh game revelutionary!!!
". . . wow, let's entertain what's left of our buyers, and give them a few more maps! yeah! that'll really get more ppl to buy our sucky game! . . ."
^^^TO THE MAKERS OF THE GAME^^^ please stop. ur making fools out of urselves...
must have the map pack
shame we have to pay for these when they should have included them for free in a patch.
well the game only started out with like 4 maps maybe 8 if u include survivor so it makes sense that they would bring them out so fast
Cool video! Such an underrated game.


text:
Weekdays at Noon on 92.3 KTAR
KTAR Middays
Head rush: Common sense wins in NYC war on soda
New York City's soda ban on cups larger than 16 ounces was set to take effect Tuesday. Until a judge put a stop to it.
New York Supreme Court Justice Milton Tingling struck down the ban saying it was, "arbitrary and capricious."
Tingling pointed out the inconsistencies in the ban pushed by Mayor Michael Bloomberg. He wrote, "It applies to some but not all food establishments in the city. It excludes other beverages that have significantly higher concentrations of sugar sweeteners and/or calories."
For example, convenience stores could sell large sodas, but restaurants and movie theaters could not. Tingling also wrote that because patrons could get refills on 16- ounce cups the ban wouldn't be effective.
But the most important part of Tingling's decision reeled in Bloomberg's power. The Mayor's Office said the City Board of Health has broad powers to "better the public health." The New York Times explained:
That interpretation, the judge wrote, "would leave its authority to define, create, mandate and enforce limited only by its own imagination," and "create an administrative Leviathan."
Had this ban gone into effect, the ramifications would have been much larger than a 20-ounce soda. New York City's government would have limited almost any product a business can and cannot sell at will as long it bettered the public health.
Could donuts and double cheeseburgers be next? What about sugary sports drinks or candy bars? Once power is taken away, it is hardly ever given back.
Perhaps the best course of action the city could take is refusing to pay the health care costs of individuals who refuse to take care of themselves.
That may never happen, but at least sometimes common sense still wins.
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On Demand
- December 10, 2014 - Hour: 1Mark Curtis and Stacey Brooks talk about the CIA Senate Intelligance Report, Uber, Airplane Etiquette, Medical Marijuana laws.
- December 9, 2014 - Hour: 1Mark Curtis and Stacey Brooks: Phoenix protests with Paul Penzone, Mark Whalberg pardon, CIA report released, People mad because man NOT eaten by snak
- December 8, 2014 - Hour: 1Mark Curtis and Stacey Brooks discuss UVA/Rolling Stone Scandal, and a valley mother who lost her children to DCS.
- December 3, 2014 - Hour: 1Charles Barkley speaks for common sense Americans and Do you leave your teen home alone overnight?
- December 2, 2014 - Hour: 1The robots will destroy humanity and whats up with calorie counts at the movies and gas stations?
- December 1, 2014 - Hour: 1You decide if Ray Rice's wife is lying or not and why in the world have orthodontics become so expensive? Two fathers weigh in...


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Publishing Content Strategist & Copywriter – Chicago
Location: Chicago, IL
Ref#: 40563
Our leading technology client needs a Content Strategist & Copywriter to plan, create, and organize creative and copy for their ecommerce websites for their downtown office. The Content Strategist & Copywriter reports to the Lead Content Strategist and will work closely with content developers, copywriters, publishers, marketing, legal, brand, and other stakeholders to ensure that …
Associate Product Manager, Ecommerce – Chicago
Location: Chicago, IL
Ref#: 40560
Our international technology client is looking for an Associate Product Manager to join their Direct-to-Consumer mobile products team. You will have the opportunity to actively participate in all aspects of the product lifecycle, from conception, to launch, to end of life. The ideal Associate Product Manager candidate will have experience with how creative vision and …
Programmer – Remote
Location: New York, NY
Ref#: 40519
Our client, a super awesome author, coach and TV host, is seeking a WordPress Developer to assist with all websites, security, and optimization. Must be familiar with the Genesis theme! Start date ASAP. This can be part time and remote. This is an amazing opportunity!!
All digital, marketing, & creative staffing agencies are not created equal.
All employment firms are not created equal. What makes Artisan Talent special is that we've combined the service of a boutique firm with the reach of a national staffing agency. Our specialty? Filling the digital, marketing, & creative staffing needs of major corporations, interactive agencies and small non-profits. We're an award-winning agency that loves matching skilled talent with the perfect creative, digital and marketing opportunity.


text:
Ho Yeah!
Episode Reviews (7)
Ho Yeah! Baby
This is one of the best episodes of Season 5, and one of the few from this season I'd argue is a KOTH classic. It has something most of this season didn't. LAUGHS, and lots of them. Sure there have been some great plots, or character episodes, but this one was just what a comedy should be. Hilarious. The naivety of Hank and Peggy really make this episode work. Cotton's quick appearance is good for a couple of laughs and then there is Alabaster. Probably the best guest character of the season, and one of the best of the series. It was nice to enjoy an episode because of how funny it was, which I wish more KOTH episodes were.moreless
Hank has a new co-worker, Tammi. Just another one of Bucks replacements for Debbie. But Tammi refuses his advances and turns to the Hills for help. Hank and Peggy work to make a better life for Tammi, but turns out she has a tendency to 'get around'.
In brief, this episode made me fall in love with the series all over again. It is a different situation for the Hills and I think it was a great line to cross. It shows the innocence of the characters that makes it the most interesting. In front of there face, a hooker is making her way around Arlen, and all the Hills want to do is get her life on track and have no idea about her secert life. When the Hills discover the Tammi's lifestyle, they do not hesitate to defend her and help her out. This episode shows the love in there hearts and the pure goodness of the characters. Not only the funniest episode I've seen, but also the nicest.moreless
One of the best episodes of the season.
When Hank gets a new co-worker at work- Tammy. Peggy helps her to get her quilification, Tammy is then invited to stay at the Hill house. It then turns out she is going out on dates but is selctive as no one seems to last for more than 1 hour. Evantually Hank unknowningly becomes a pimp. Then one of Tammy's former pimps comes to the neighbourhood and wants Tammy back. In the chase Hank squares up to him and he flees.
In my opinion this is one of the best ever King of the hill episodes. It is one again where Hank and Peggy are lured into something they didn't know was happening. Comic Genius.moreless
one of my favorites
Hank's new coworker, Tammy, is not exactly the sharpest tool in the shed. He and Peggy both start liking her, until Hank learns what exactly it is Tammy does; she's a prostitute, and her pimp, Alabastor, thinks Hank is stealing her, and he is not about to let her go without a fight.
Great episode. The realization for hank, when he realizes Tammy is a prostitute is one of the funniest moments of the series, I'd say. And him acting like a pimp to ward off Alabastor was also hilarious. The whole episode has a lot of hilarious moments, and is definitely one of their best, I think. So because of all of this my final grade is of course going to be an A+moreless
Very much like a comedy.
I have to say this is a silly episode of King of the Hill. But it was an episode that was really entertaining and it was fresh from the other normal storylines the show usually circles itself around. My favorite highlights had to be the entire time where Hank is oblivious to the fact that he has a hooker living with him. Even more funny is that Peggy is even dumber for not noticing suttle details. She is always in over her head and she got what she deserved. I also thought that the confrontation with Tammi's pimp and Hank was really entertaining. I personally wanted Hank to knock him out, but I guess you can't have everything. Thank you.moreless
Hank & Peggy try to help out their newest squatter: Hank's co-worker Tammi, who just so happens to have a secret life. Hank & Peggy get a new wardrobe! Hank faces down a flashy dresser from OK City! Are we gonna see Hank & Peggy gettin' jiggy wit it?
Hank and Peggy try to help out their newest squatter in the person of Hank's lovely (but not too bright) new co-worker Tammi, who just so happens to have a secret life. Hank and Peggy get a new wardrobe. Hank faces down a flashy dresser from OKC. Watch Hank and Peggy gettin' jiggy wit it!
Big AWWWW! I 'heart' Hank & Peggy Hill and their big love for other people. Even if they're hoes. Rising above his own reservations, Hank allows Tammi, who currently lives in her car, to stay in the rec room until she 'gets on her feet'. Well that turns out to be …difficult…as staying OFF her feet is exactly how she's supplementing her meager income from the propane company.
Peggy tries to help Tammi obtain her GED, raise her literary sights, and otherwise uplift her life. In turn, Tammi buys Hank a kick-a** hat and gives Peggy a total makeover. In Hank's words: "you look HOT!" Says Peggy: "We look like a couple of movie stars!"
Tammi's secret life comes out of the closet when her pimp, Alabaster, travels all the way to Arlen from Oklahoma City (OKC to those in the know) to "get his Ho back." And that's when Hank reveals a side of himself I didn't expect to see! Says Hank: "She's my ho, now!"
Watch this episode–it's great.moreless
The Hills show their compassion in a way that would seem out of character for this couple in the first few seasons of the show.
That Peggy invited Tammi to live with them after such a short acquaintance isn't too unusual for her - but that it took mere moments for both Peggy and Hank to forgive Tammi for using their home as a base for her operations is absolutely out of character for both of them. I think Hank's reaction was particularly out of character given how long it took for him to warm up to Luann and SHE'S related.
Don't get me wrong, I was really happy about the way Hank and Peggy came to her rescue. I haven't seen any episodes since this one with Tammi in them - I'm new to watching King of the Hill and I've started with the first season and I'm making my way through them one season at a time - does Tammi show up again? I hope so - and Renee Zellweger sounded both cute as a button and a little hardened as well. She did a fabulous job!


text: We spent 5 nights at Cactus Cove in late February. We Stayed in the "Honeymoon Suite" which is around the corner from the other two suites. We saw all 3 and they were all very nice. Sally, the hostess is charming. My wife is a vegetarian and so a vegetarian version of each breakfast was made. We liked the idea... More


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You can now invite anyone to meet at your favorite Starbucks.
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32 year old woman | Forest Hills, NY, USA | Seeking men 25-39 within 20 miles of Flushing, NY
Rock Star in sheep's clothing
Me: ~By night, I fight crime... Oh, how I wish that were true. I suppose that's not a good way to start: lying. Sigh...So no, though I do wear a lot of black, I do not fight crime. I'm actually a Daylight Management Consultant... which is way less exciting than fighting crime. My job is just a job, right now. I'm still looking for the thing I can do all day, and still love doing. I am also a singer, but lately that involves mainly karaoke. I can be girly at times (i hate spiders, but who doesn't!) but I can still teach a truck driver a new word or two. I'm looking for my partner in crime (fighting?). I would like to find someone who has passion for something, and is willing to share the things that make them proud and some of the things that don't. If you can make me laugh loud enough that it is embarrassing, you get extra points... though admittedly that's not hard to achieve! I think in metaphors and song lyrics. I find that my brain has a better time processing new information when I can relate it to something I already understand. So in an effort to find someone like-minded, here is the perfect description of the person I am looking for, as described in the song lyrics of Andy Grammer's The Pocket: I'm looking for a four-course meal that isn't based in base desire I'm looking for a (guy) that knows the soul is more than an appetizer I'm looking for a shining light that likes to fight and persevere I'm looking for a (guy) that wants to make me part of his atmosphere Submitted from mobile
Book club , Coffee and conversation , Business networking , Dining out , Hobbies and crafts , Movies/Videos , Museums and art , Music and concerts , Exploring new areas , Performing arts , Playing cards , Shopping/Antiques , Travel/Sightseeing , Wine tasting
Other types of exercise
I exercise 1-2 times per week.
I have Cats
I have two cats, Maggie and Luna. They are absolutely crazy, but I love them! One day I would really like to have a dog, but I don't think it would be fair right now since I am out so much, and have no one to help care for it.
Prime rib, medium rare, au jus with mashed potatoes. Finding things in old boxes at my parents house. My bedspread and squishy pillows. The Walking Dead.
I really like to read (mostly romance, paranormal fiction, or a good murder mystery), and go to the movies. I love when other people cook for me :) I am always up for live music or stage shows, and I will kick your butt in karaoke any day, all day.
I just read Chuck Palahniuk's latest, Damned. Love his writing. Still have no idea how to say his last name. I also read Life of Pi. I found it captivating, once I got through the first 3rd. Curious how it translates to film...
Z{{Cta}} {{#if HasMoreInfo}} ?{{CtaSecondary}} {{/if}}
|What she is looking for
|5'7" (170cms)
|5'10" (177cms) to 8'0" (243cms)
|Body type:
|Slender, About average, Athletic and toned
|No preference
|Light brown
|No preference
|Occasionally, Daily, Yes, but trying to quit
|Social Drinker
|Social Drinker, Moderately
|Sales / Marketing
|No preference
I'm starting a new job right now, actually, but I will be the Commercial Business Development Manager for a solar shade manufacturer. Be still your beating heart, I know.
|$35,001 to $50,000
|$35,001 to $50,000, $50,001 to $75,000, $75,001 to $100,000, $100,001 to $150,000, $150,001+
|Never Married
|Never Married
|Have kids:
|Wants kids:
|Not sure
|Someday, Not sure, Probably not
|White / Caucasian
|White / Caucasian
|Spiritual but not religious
|Spiritual but not religious
I would say I am more philosophical than spiritual. I try to learn about all different forms of religion, and through my singing, have been introduced to many differing opinions about what the truth really is. I have my own opinions about it too.
|Bachelors degree
|Bachelors degree, Graduate degree, PhD / Post Doctoral


text:
Results 1 to 3 of 3
Thread: Sketchbook Spam
August 10th, 2012 #1
Sketchbook Spam
Is there an issue with spam bots on the forums currently? My new sketchbook thread seems to be receiving post that have no context from users who've been registered to the site for a day. If you browse my sketchbook, you'll notice the following users may in fact be bots: Iamoreira0, Rezsdg4fsa, uutt8907.


text:
Denver Pioneers at Southern Miss Golden Eagles Basketball
Tue, Nov 27, 2012 7:00 pm
Reed Green Coliseum, Hattiesburg, MS
Sorry, this event has already taken place. Please see similar events below.
|Tweet | State Guides | Gift Certificates | Policies | Blog | About Us | TicketMasters sold out |


text:
Saving His Business
Updated: 01/10/2005 - Knives are drawn as the owner of a local tobacco store defends his livelihood.
Updated: 01/10/2005 - Knives are drawn as the owner of a local tobacco store defends his livelihood.
Updated: 01/09/2005 - A shooting leads to an almost four-hour standoff in Machesney Park.
Updated: 01/09/2005 - In December there is the proposal, but in January there is the discussion.
Updated: 01/10/2005 - Danfoss will contribute water systems and other donations in the coming weeks to help tsunami victims.
Updated: 01/07/2005 - The quality of an American college education isn't dropping, but the numbers of international students taking advantage of it are.
Updated: 01/07/2005 - It's a case that touches our emotional core, a painful story that's difficult to comprehend of a newborn baby left outside in the cold of December to die.
Updated: 01/07/2005 - A Rockford man is hospitalized after a hit and run accident early Friday morning.
Updated: 01/06/2005 - Some were prepared, but many others made a mad dash to the store once the flakes started to fall.
Updated: 01/06/2005 - Gov. Doyle says Thursday he can save the state about $11 million and he's called the Legislature into special session to help him do it.
Updated: 01/06/2005 - According to federal figures, O'Hare International Airport in Chicago remained the nation's most delayed airport through November.
Updated: 01/05/2005 - A group of automaker supply firms looks to give the stateline a jobs jolt.
Updated: 01/05/2005 - President Bush has taken his push for medical liability reform to Illinois.
Updated: 01/05/2005 - The Rock County Sheriff's Department made an interesting discovery Tuesday. They found a man hiding in the crevasse of an old, hollow tree.
Updated: 01/05/2005 - Rockford firefighters were out in the snow battling an early morning house fire.
Updated: 01/05/2005 - Next week, the pastor at Rockford's Memorial Baptist will pitch in with medical relief in the Southeastern Asia city of Galle.
Updated: 01/04/2005 - A neighborhood on the city's East Side is suffering from murky water flowing out of their taps.
Updated: 01/04/2005 - The Winnebago County Health Department says a child has tested positive for bacterial meningitis and is currently being hospitalized.
Updated: 01/04/2005 - A Rockford man is charged with the possession of explosive devices.
Updated: 01/04/2005 - Officials say six people have applied to take over the chairmanship of the Illinois Republican Party.
Updated: 01/04/2005 - Tuesday's the day Barack Obama gets sworn in as a U.S. Senator.
Updated: 01/04/2005 - A mobile home fire kills a Rockford man.
Updated: 01/04/2005 - Two local agencies are continuing their efforts after speaking with a pastor in the heart of devastation in Sri Lanka.
Updated: 01/04/2005 - The first winter storm of 2005 made driving conditions a bit slippery Tuesday.
Updated: 01/04/2005 - This is the first day commuters are a part of the new Illinois Tollway.
Updated: 01/03/2005 - Every day we hear stories of heroism in Iraq, but we don't always hear about the work going on here at home, of the countless individuals standing in solidarity working to make sure our troops overseas have everything they need.


text:
- District 514 Residents:
- $125 per semester hour
$135 per semester hour effective Fall 2015 Semester
- Online Classes:
- $125 per semester hour
$135 per semester hour effective Fall 2015 Semester
- (in- and out-of-district, out/international students)
- District 514 Residents, age 65 or older:
- FREE for credit classes only
- Out-of-District Illinois Residents
- $270 per semester hour
$290 per semester hour effective Fall 2015 Semester
- (NOT authorized by their Community College Board for partial tuition payment)
- Out-of-State Residents/International Students:
- $310 per semester hour
$335 per semester hour effective Fall 2015 Semester
- Community Education Activities and Professional Development Institute:
- *Varies
* Cost is associated with the class and not on a credit hour basis.
If you reside in an Illinois community college district that does not offer a program available at ICC, you may be eligible for a district chargeback of an inter-district cooperative agreement from your legal or home district. Please contact your home district community college for the applications, and once approved by your home district, immediately submit it to ICC to ensure your account balance is adjusted to reflect the in-district tuition rate. District chargeback applications must be approved by your home district Board of Trustees and should be submitted at least 30 days before the beginning of the semester.
All district chargebacks, inter-district cooperative agreements, and miscellaneous agency authorizations must be completed and received by the Student Accounting Office in Enrollment Services. All authorizations must be completed and received prior to the tuition due date of the semester. Illinois Central College reserves the right to change tuition and fees without notice.
Prior to enrollment:
- Make arrangements with Financial Aid
- Submit all agency charge authorizations through Enrollment Services
- Clear past due college accounts
Any required course fee is listed with each course in the class schedule published each semester. Many noncredit classes such as crafts, recreation, and Institute seminars are not supported by tax dollars – instead, participants pay the cost. We reserve the right to change fees and tuition without notice.


text:
DOJ preparing corruption charges against NJ Sen. Menendez
National drug trial for transplant patients shows promise
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The Supreme Court's conservative majority voted Wednesday to free wealthy donors to give to as many political candidates and campaigns as they want, further loosening the reins on giving by big contributors as the 2014 campaign moves into high gear.
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Ram Man looks awesome! Thanks Veebs!
DeviantArt Gallery
Week Daze - my webcomic
The Return to Anwat Gar
Ram Man looks awesome! Thanks Veebs!
MOST WANTED MOTUC figures: Ice Armor He-Man, Sagitar, Fang-Or, Major Header, Granita, Great Black Wizard, Despara, Quakke, Master Sebrian, Tuvar, Bahdrah, Stridor, & Snake Mountain.
MOST WANTED PCS statues: Mer-Man, Whiplash, Buzz-Off, Sy-Klone, Ram Man, Tri-Klops, & Two-Bad.
*My iTrader Feedback
*My MOTU_Maniac Feedback Thread
I wasn't all that impressed with all the pics we'd seen at shows and whatnot prior, but that review really did a good job of selling him.
Matty, Great Black Wizard figure please!
This is absolutely the best Ram-Man EVER!!!!
200X fan? Classic fan? What does that mean? I'm a MotU fan!!!
Does Fwoosh have a review page up for Ram Man yet?
My Feedback Rating Thread http://www.he-man.org/forums/boards/...43#post2936643
My Ebay ratings http://feedback.ebay.com/ws/eBayISAP...k&myworld=true
My Custom MOTUC's http://www.he-man.org/forums/boards/album.php?u=36694
Wow... "runs to fwoosh to view reviews" Rammy is sweeeeet!
Sale/Trade//Feedback//MOTU Customs// MOTUC Albums//MOTU Fans Puerto Rico Chapter
I got lazy...So here is a link to my NON MOTU Collection!
Collection and NON MOTU Customs
XBOX ONE Gamertag: Avenger12PR
PSN: Avenger12PR
Best MOTUC figure...EVER!
Jii Dee regarding Matty's view on MOTUC Collectors: "Here be whiny surrender monkey dragons".
MOTUC NEEDS: Sssqueeze, Dragstor, Saurod, Blast Attack, & Lord Masque.
That figure is pure Metal.
Your support means more research for the Myostatin-challenged.
I want this version!
DeviantArt Gallery
Week Daze - my webcomic
The Return to Anwat Gar
WISHLISTKarg ~ Crita ~ Despara ~ Fang-Or ~ Kittrina ~ Darius ~ Sorceress of Serpos Teela ~ Lodar ~ Hunga The Harpy Great Black Wizard ~ Staghorn ~ Lady Slither ~ Artilla ~ Ra-Jarr ~ Major Header ~ Vultak ~
Crimson Fury ~ Kex Queen ~ Hawke ~ Red Beast ~ Angast ~ Delora ~ Quakke ~ Lord Masque ~ Zilora ~ Three-Beast Robowoman ~ DC He-Man ~ DC She-Ra ~ DC Stratos
Ram Man is out of this world. Great first look, Veebs!
I am happy and sad about Ram Man. I'm happy to finally be getting him and happy his quality is good. I'm sad that no figure released after Ram Man will bring me as much joy as getting Ram Man. MOTUC is all downhill for me after Ram Man. After him and Jitsu, Mantenna and Two-Bad are my last must haves. That's not to say that there aren't still more figures I want. But I am extremely cherry picking now.
"There's only one Master of the Universe and it's He-Man." - Stephen Colbert
"The heart has its reasons of which reason knows nothing." - Blaise Pascal
Barring unforseen QC issues (which often show up in these reviews, so things look hopeful), Rammy seems just about perfect. I'm getting used to the squint, and am very glad he is the same height as the other figures. Much as I love Filmation, I always felt Rammy should have been a bit bigger, eye to eye with the other characters. I think this is about the perfect size, with his bulk being his massive girth.
This one looks like a winner on par with things like Trap Jaw and Bow as far as setting the standard goes. And I would splurge for a cardback colored version, maybe an out of sub bonus figure like She-Ra 2.0. They paid a premium to make him with all the nw molds, might as well squeeeze some extra money out of them as there appears to be a good demand for this variant.
"I will use this power for all the good that can be done, to work for peace, to encourage virtue, and above all, to preserve life in all its forms..." Superman
"Wheresoever on earth he dwells, man is prey to two weaknesses: the need to pray and the need to love."-Marquis de Sade
"It is not by reasoning or by our understanding that we have received our religion; it is by external authority and command."-Michel De Montaigne
Heretical Vintage Purist and Non-Fan Extraordinaire!
Anyway, on to Ram Man:
...well wait, I'm not sure what to say! He's just so obviously awesome that I can't think of much beyond "awesome!" He's got everything the original had sans his immobility, and it even looks like he's got a good range with the legs, considering the skirt (though the skirt is segmented so perfectly that I may end up cutting it anyway).
One question though: Can he hold other weapons? Looks like the hole in his hand is the same size, but I can't tell. I wana see if you can shove a spear in there.
"Since you got here by not thinking, it seems reasonable to expect that, in order to get out, you must start thinking." ~ Tock, the Watchdog
Alexx has a blog?! Come on in and check out Toys and Tomfoolery! You won't regret it...until the next morning.
I hate RAM MAN....waste of a slot....Bring on Jitsu!!!!!!
MY Feedback Thread : http://www.he-man.org/forums/boards/...d.php?t=191572
And for different versions, I would have preferred the Vintage toy MAA over the one we got, darker green and dark green furries, but we at least got a semi correct colored armor set with SMAA. But I myself would have preferred a Filmation MAA, which I made as a custom from a Palace Guard buck, some paint and MAA accessories. And I am currently working on my Dragstor custom, I would love an official version, but if he never makes it to production, I'll be happy with my custom, and at least with my custom the official version can stay MOSC. But Two-Bad & Mantenna would pose greater challenges and need of more parts than I want to commit to right now, being personal customs, if they were client customs, then that would be different.
Recent.... Lizard Man
Wanted.... NA She-Ra, Jitsu....
Needed.... Dragstor
Oh man, did I forget to use these [sarcasm][/sarcasm] again? Sorry....
He looks fantastic! I can't wait, already have his spot on the shelf picked out
Other than picking up Mekaneck, that will complete the Heroic Warriors for me (well I may get Sy-klone if I could find him really cheap, couldn't squeeze him into the Matty sale). I'm glad that he is wide and thick but not 200X huge (and really glad he's not 200X toy short. Awful figure, lol).
My list of "essentials" is a bit longer:
Two-Bad (last evil warrior I need to feel complete)
Tung Lashor
Horde Troopers (don't let me down, Toyfair 2013)
And despite always saying that I don't want variants, I'm starting to feel more and more like NA Skeletor falls on my essentials list. Plus I want to see what the Horsemen do with him.
Oh and of course Crita!
I'm probably leaving a few out, but my list of essentials is a bit longer and growing
Queen Crita avatar by Emiliano Santalucia
We were specifically told that Dare would not be in 2014-2015, see the words straight from Scott here: http://forums.mattycollector.com/eve...808#9101046808
If these guys came out...
Horde Troopers
Tung Lashor
NA Skeletor
...the line could end and I would be satisfied in the end.
The Blonde Teela Thread
The Cloak and Dagger Evil-Lyn Thread
Sagitar (Jetlag) Horde Wraiths Azdar Belzar Chazdar Cloak and Dagger Evil-Lyn 200X Teenage Prince Adam 200X Teenage Teela 200X Sorceress General Rattlor (MYP) 200X King Randor and Queen Marlena 200X Battle Armor King Randor and Battle Armor Queen Marlena Ice Armor He-Man WMD Roboto
Am I the only one who thinks the second head is not only a bit unnecessary, but also doesn't look right on his shoulders? There's a great big gap between his chin and the armour.
Most-wanted MOTUC: Granita - Hunga the Harpy - The Melog - Melaktha - Vultak - Dylamug - Crita - Sprag, Sprocker and Spritina - the Twiggets King Ahgo
Great figure, 2013 starts great with Ram Man, Jitsu and Snake Face...
Ram-Man looks aweesooome!!
Why the black belt? a 200x element?


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April 3, 2014
Drivers whose medical exams were conducted by the late Dr. Paul Besdansky, Garden City, Ga., need to get a reexamination, says the Federal Motor Carrier Safety Administration.
Besdansky was in failing health toward the end of his life and was not conducting proper exams, the agency said.
Spokesman Duane DeBruyne said the agency believes some 3,000 drivers have certificates signed by Besdansky. Most reside in Florida, Georgia, North Carolina and South Carolina.
They must be re-examined and submit a new certificate to the state agency that issued their license and to their employer.
Certificates that were signed by Besdansky will be invalid on May 2.
FMCSA is asking law enforcement personnel to immediately tell the driver and the agency when they see a certificate signed by Besdansky.
For more information go to the FMCSA Southern Service Center at [email protected].
We offer e-newsletters that deliver targeted news and information for the entire fleet industry.
The expert, Mark Betner from CITGO, will answer your questions
The expert, Rence Oliphant from Hendrickson, will answer your questions
Timken Adds A Wheel End Parts Line
Eaton Expands Flex Reman Transmission Lineup
ARI Adds Custom Dashboards to Fleet Management System
TruckTech+ Provides Diagnostics to Fleets and Dealers


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Follow-up on 2011 Report:
Status of Actions Taken to Reduce Duplication, Overlap, and Fragmentation, Save Tax Dollars, and Enhance Revenue
GAO-12-453SP: Published: Feb 28, 2012. Publicly Released: Feb 28, 2012.
Additional Materials:
- Full Report:
- Accessible Text:
(202) 512-4300
Janet A. St Laurent
Office of Public Affairs
(202) 512-4800
What GAO Found
GAOs specific assessment of progress as of February 10, 2012, showed that 4 (or 5 percent) of the 81 areas GAO identified were addressed; 60 (or 74 percent) were partially addressed; and 17 (or 21 percent) were not addressed. Enclosure I presents GAOs assessment of the overall progress made in each area. GAO applied the following criteria in making these overall assessments for the 81 areas. We determined that an area was:
addressed if all actions needed in that area were addressed;
partially addressed if at least one action needed in that area showed some progress toward implementation, but not all actions were addressed; and
not addressed if none of the actions needed in that area were addressed.
As of February 10, 2012, the majority of 176 actions needed within the 81 areas identified by GAO have been partially addressed. Specifically, 23 (or 13 percent) were addressed; 99 (or 56 percent) were partially addressed; 54 (or 31 percent) were not addressed.
Streamlining federal efforts, reducing government costs, and enhancing revenue collections can offer financial and other benefits. Today, and concurrently with this report, GAO issued its second annual report to Congress in response to the statutory requirement that GAO identify federal programs, agencies, offices, and initiatives with duplicative goals or activities. That report identifies 51 additional issue areas and numerous actions within those issue areas that, if implemented, may further improve programs effectiveness and efficiency, achieve cost savings, and enhance revenues.
Opportunities exist for the Congress and federal agencies to continue to address the identified actions needed in our March 2011 and February 2012 reports. Collectively, these reports show that, if the actions are implemented, the government could save tens of billions of dollars annually. A number of the issues are difficult to address and implementing many of the actions identified will take time and sustained leadership.
Why GAO Did This Study
In March 2011, GAO issued its first annual report to the Congress on potential duplication, overlap, and fragmentation in the federal government. The report also identified opportunities to achieve cost savings and enhance revenues. We identified 81 areaswhich span a wide range of government missionswith a total of 176 actions that the Congress and the executive branch could take to reduce or eliminate unnecessary duplication, overlap, and fragmentation or achieve other potential financial benefits. We also presented areas where programs may be able to achieve greater efficiencies or become more effective in providing government services. In many areas, we suggested actions identifying some new options, as well as underscoring numerous existing GAO recommendationsthat policymakers could consider. This status report provides an overall assessment of progress in implementing actions for the 81 areas, as well as an assessment of each of the 176 suggested actions.
As of February 10, 2012, the Congress and the executive branch had made some progress in addressing the majority of the 81 areas that we identified, including the implementation of all actions in 4 areas; however, additional steps are needed to fully implement the remaining actions to achieve associated benefits. GAO suggested a wide range of actions for the Congress and the executive branch to consider, such as developing strategies to better coordinate fragmented efforts, implementing executive initiatives to improve oversight and evaluation of overlapping programs, considering enactment of legislation to facilitate revenue collection, and examining opportunities to eliminate potential duplication through streamlining, collocating, or consolidating program efforts or administrative services.
For more information, contact Janet St. Laurent at (202) 512-4300, or email@example.com and Zina Merritt, at (202) 512-4300 or firstname.lastname@example.com.
Jun 24, 2015
Federal Real Property:Current Efforts, GAO Recommendations, and Proposed Legislation Could Address Challenges [Reissued on June 24, 2015]GAO-15-688T: Published: Jun 16, 2015. Publicly Released: Jun 16, 2015.
Jun 16, 2015
Federal Real Property:Continued Efforts, Legislation, and Implementing GAO Recommendation Could Address ChallengesGAO-15-689T: Published: Jun 16, 2015. Publicly Released: Jun 16, 2015.
Jun 3, 2015
Indian Gaming:Regulation and Oversight by the Federal Government, States, and TribesGAO-15-355: Published: Jun 3, 2015. Publicly Released: Jun 3, 2015.
May 26, 2015
U.S. Postal Service:Improved Management Procedures Needed for Parcel Select ContractsGAO-15-408: Published: Apr 23, 2015. Publicly Released: May 26, 2015.
May 21, 2015
Federal Vehicle Fleets:Leading Practices for Managing Fleet OperationsGAO-15-644T: Published: May 21, 2015. Publicly Released: May 21, 2015.
May 20, 2015
Human Capital:Update on Strategic Management Challenges for the 21st CenturyGAO-15-619T: Published: May 20, 2015. Publicly Released: May 20, 2015.
Older Adults:Federal Strategy Needed to Help Ensure Efficient and Effective Delivery of Home and Community-Based Services and SupportsGAO-15-190: Published: May 20, 2015. Publicly Released: May 20, 2015.
May 18, 2015
Regulatory Guidance Processes:Selected Departments Could Strengthen Internal Control and Dissemination PracticesGAO-15-368: Published: Apr 16, 2015. Publicly Released: May 18, 2015.
Apr 27, 2015
Facility Security:Federal Protective Service's and Selected Federal Tenants' Sharing of and Response to Incident InformationGAO-15-406R: Published: Apr 27, 2015. Publicly Released: Apr 27, 2015.
Apr 20, 2015
2020 Census:Recommended Actions Need to Be Implemented before Potential Cost Savings Can be RealizedGAO-15-546T: Published: Apr 20, 2015. Publicly Released: Apr 20, 2015.
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I have seen the future....
View Single Post
Registered User
Join Date: Jul 2004
Posts: 575
Re: I have seen the future....
Originally Posted by
Read the thread on PhysX and see how important it really is. 3DVision requires a new monitor, surround three new monitors and a second card. Cuda is worthless unless you fold. All I see are marketing gimmicks. No one cares for eyefinity either. Where are the real performance numbers? You know that thing we actually buy these things for in the first place?
Why do we even let nvidia focus members post on these forums? Corporate shills are what they are. Stick to the nvidia official forums where you belong!
CUDA's foundation isn't gaming, its made for programmablity of different applications to GPU's, there is a lot more things in the world outside of gaming that need performance that a CPU, even multiple CPU's can't provide with out a huge cost to return ratio. As a side note CUDA does come in handy to port PC applications to GPU's because of its similarity in programming calls and language, and this is why physX was ported to CUDA, it gave immediate benefits, to owners of nV products. That was a better way to showcase their technology then porting over to OpenCL or direct compute since it would have been a year or so later we would have had to wait. On ATi's front its going to more then 2 years most likely.
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'Tis the season for New Year's resolutions. As we ring in 2015, many will vow to lose weight, get organized or learn something new, and according to StatisticBrain.com, the third most popular resolution is to spend less and save more. This year, Allstate is encouraging its customers to stick to their resolutions and take the time to tone up their finances.
"In order to spend less and save more, Americans need to evaluate their priorities, set goals and stick to them," said Bill Kavanaugh, senior vice president, Allstate Financial, and CFP® CERTIFIED FINANCIAL PLANNER™. "Remaining diligent throughout the year, not just immediately following the New Year, may mean you should seek advice from a financial professional who can help you develop a comprehensive annual game plan."No Comments »


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Nanticoke Car DealerChange City
Nanticoke Car Dealer
Find multiple listings of Nanticoke car dealers at the Autobytel.com website. Look for your future new or used automobile by manufacturer, value, type, or production year. Browse our giant catalogue of Nanticoke car dealerships; which have their entire supply of new and used automobiles listed at Autobytel.com. We can be your resource as you go through the transaction of purchasing a car. Sort through various costs on new and used vehicles, see pics of cars, read informative articles, review vehicle information, and find the actual value of autos at the Nanticoke car dealership.
Times have changed and the need for visiting Nanticoke car dealerships has been rendered obsolete. With the advent of the internet; Nanticoke car dealers can now list their entire inventory online at numerous locations like Autobytel.com. There is an increasingly greater number of shoppers that use the web to explore all the vehicle choices available on the market today. When a shopper has decided on an automobile; they browse through the line-up of nearby Nanticoke car dealers. Chances are they will land at an all encompassing website like Autobytel.com. Visit our site to see free vehicle pricing information from a couple of Nanticoke car dealers.
Finding one Nanticoke car dealership that is trustworthy can be a huge burden off your shoulders. You might think that in the car buying process, you will only visit that Nanticoke car dealer lot once. Often times Nanticoke car dealers have so many more resources available to the consumer that you're likely to make a return visit. Established Nanticoke car dealerships not only specialize in vehicle sales; they have a myriad of other services to offer such as: car repair, parts sales, and auto leasing, just to name a few. So there is a chance that you will be visiting that Nanticoke car dealer often for something like warranty service. That's why it is a good idea to form a close bond with the Nanticoke car dealership in the event that you need to use one of their multiple services.
Find a reputable dealer by searching the Nanticoke car dealerships database online at Autobytel.com Peruse accounts given by shoppers of Nanticoke car dealers to find out valuable details. Having these critiques from past patrons are a great resource when searching through the many Nanticoke car dealerships.


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Helicopter Crashes in Downtown Seattle, Killing 2, Injuring at Least 1 [UPDATED]
A helicopter belonging to Seattle news station KOMO crashed on Tuesday morning near Fisher Plaza, near the famed Space Needle.
A helicopter belonging to Seattle news station KOMO crashed on Tuesday morning near Fisher Plaza, near the famed Space Needle.
A lot more than bragging rights could be on the line when filling out your bracket for the NCAA Tournament.
Don't blink. You may miss history.
The 2014 Winter Olympics came to a close on Sunday with the host nation on top of the medal standings. Here's a recap of the final weekend of the Sochi Games:
Canada's women's hockey team beat the United States in overtime in the gold medal game on Thursday. Here's a recap of all the day's action in Sochi:
An elaborate opening ceremony lasting more than three hours marked the start of the 2014 Winter Olympics in Sochi, Russia on Friday.
The economy is having a love affair with Valentine's Day.
The Seattle Seahawks and Denver Broncos each won their respective conference championship games on Sunday to advance to Super Bowl XLVIII in New Jersey on Feb. 2. Here's a recap of Sunday's action:
Attention NBA scouts: keep your eye on Easton Gamoke.
Two of these ('Lone Survivor,' 'Her') aren't technically opening this weekend, but they are expanding to many more theaters. That, along with the year's first Hercules flick (yup, there's another one coming in July) and the recent slew of high-quality holiday releases, make for a very crowded cineplex.
Unless you've been living in an extremely well-insulated cave, you know it's insanely cold across the country.
The holiday movie season is in full swing already, leaving precious few screens available for anything new. This weekend we only get one big film opening. If you like the previous installments in this franchise, you should probably get a kick out of this one as well.


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Jon McCormack is an Australian-based electronic media artist and researcher in computing. He holds an Honours degree in Applied Mathematics and Computer Science from Monash University, a Graduate Diploma of Art (Film and Television) from Swinburne University and a PhD in Computer Science from Monash University. He is currently Professor of Computer Science, an ARC Australian Research Fellow and director of sensiLab at Monash University in Melbourne, Australia. His research interests include generative art and design, evolutionary systems, creativity, visualisation, interaction design, machine learning, L-systems and developmental models.
Since the late 1980s McCormack has worked with computer code as a medium for creative expression. Inspired by the complexity and wonder of a diminishing natural world, his work is concerned with electronic "after natures" – alternate forms of artificial life that may one day replace the biological nature lost through human progress and development.
His artworks have been widely exhibited at leading galleries, museums and symposia, including the Museum of Modern Art (New York, USA), Tate Gallery (Liverpool, UK), ACM SIGGRAPH (USA), Prix Ars Electronica (Austria) and the Australian Centre for the Moving Image (Australia). He is the recipient of 16 awards for new media art and computing research including prizes at Ars Electronica (Austria), Images du Futur (Canada), New Voices, New Visions (USA), Alias/Wavefront (USA), The John Lansdown Award for Interactive Media (Europe/UK), Nagoya Biennial (Japan) and the 2012 Eureka Prize for Innovation in Computer Science. The monograph, Impossible Nature: the art of Jon McCormack, was published by the Australian Centre for the Moving Image in 2005 and documents McCormack's creative achievements over the last 15 years.


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You can now invite anyone to meet at your favorite Starbucks.
Limited-time feature
40 year old man | La Crescenta, CA, USA | Seeking women 26-42 within 15 miles of Glendale, CA
We are usually picky for the wrong reasons
One day a farmer's donkey fell down into a well. The animal cried piteously for hours as the farmer tried to figure out what to do. Finally, he decided the animal was old, and the well needed to be covered up anyway; it just wasn't worth it to retrieve the donkey. He invited all his neighbors to come over and help him. They all grabbed a shovel and began to shovel dirt into the well. At first, the donkey realized what was happening and cried horribly. Then, to everyone's amazement he quieted down. A few shovel loads later, the farmer finally looked down the well. He was astonished at what he saw. With each shovel of dirt that hit his back, the donkey was doing something amazing. He would shake it off and take a step up. As the farmer's neighbors continued to shovel dirt on top of the animal, he would shake it off and take a step up. Pretty soon, everyone was amazed as the donkey stepped up over the edge of the well and happily trotted off! Life is going to shovel dirt on you, all kinds of dirt. The trick to getting out of the well is to shake it off and take a step up. Each of our troubles is a steppingstone. We can get out of the deepest wells just by not stopping, never giving up! Shake it off and take a step up. NOW -------- Enough of that crap . . . The donkey later came back and bit the hell out of the farmer who had tried to bury him. The gash from the bite got infected, and the farmer eventually died in agony from septic shock.
Coffee and conversation , Movies/Videos , Museums and art , Exploring new areas , Nightclubs/Dancing , Playing sports , Travel/Sightseeing , Volunteering , Wine tasting
Swimming, Walking / Hiking, Weights / Machines
I exercise 3-4 times per week.
I don't believe in astrology
I like Dogs
Middle of the Road
Maui, San Diego, Spain, Socal desert, NYC
University of California, Berkeley, Berkeley, CA
Favorite music: Jazz, rock TV shows: most shows on the travel channel Foods: Japanese, Italian, any type of fusion
international travel, wine tasting/road trips, bookstore sipping coffee, beaches, scuba diving, movies, painting (usually on canvas, not my wall)
Up in the Air by Walter Kirn
Z{{Cta}} {{#if HasMoreInfo}} ?{{CtaSecondary}} {{/if}}
|What he is looking for
|6'0" (182cms)
|5'2" (157cms) to 6'1" (185cms)
|Body type:
|Athletic and toned
|Slender, About average, Curvy, Athletic and toned
|No preference
|No preference
|No Way
|No Way, Occasionally, Yes, but trying to quit
|Social Drinker
|Never, Social Drinker, Regularly
|Medical / Dental / Veterinary / Fitness
|No preference
I'm a physician in San Fernando Valley
|No preference
|Never Married
|No preference
|Have kids:
|No preference
|Wants kids:
|Not sure
|Someday, Probably not, No, but it's OK if my partner has kids
|Asian, Pacific Islander
|Asian, East Indian, Latino / Hispanic, Middle Eastern, Native American, Pacific Islander, White / Caucasian, Other
|Christian / Other
|No preference
|No preference
|PhD / Post Doctoral
|No preference
What I've learned outside of school is way more valuable. Perhaps I should get my money back.


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Regime Ultra Family
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NBC Sports to Air NOTRE DAME Football Marathon New Year's Day
NBC Sports Network kicks off the New Year with 10 hours of Notre Dame Football programming this Tuesday, Jan. 1, 2013, at noon ET.
With No. 1 Notre Dame heading to the BCS National Championship, NBC Sports Network will re-air the team's Sept. 22, 13-6 win against rival Michigan, followed by an encore showing of Onward Notre Dame: South Bend to Soldier Field, a special NFL Films-produced behind-the-scenes look at Notre Dame Football. Onward, which debuted in October, features the Fighting Irish and head coach BrIan Kelly as they prepare to face Miami at Soldier Field, home of the Chicago Bears, a game Notre Dame won, 41-3.
At 3 p.m. ET, NBC Sports Network presents Notre Dame's 20-13 overtime victory over Stanford, followed by the team's thrilling triple overtime victory, 29-26, over Pittsburgh at 5 p.m. ET. Coverage continues with Senior Day and the Fighting Irish's 38-0 shutout win over Wake Forest at 7 p.m. ET. The programming block concludes with an encore showing of Undefeated: 2012 Notre Dame Football Season in Review, a look back at the Fighting Irish's magical season and look ahead to the team's upcoming appearance in the BCS National Championship. Undefeated premiered on NBC on Sat., Dec. 22.
NBC Sports Network's Jan. 1 Notre Dame Football Programming (subject to change):
Time (ET)
Tues., Jan. 1
Michigan at Notre Dame Re-Air
2 p.m.
Onward Notre Dame: South Bend to Soldier Field
3 p.m.
Stanford at Notre Dame Re-Air
5 p.m.
Pittsburgh at Notre Dame Re-Air
7 p.m.
Wake Forest at Notre Dame Re-Air
9 p.m.
Undefeated: 2012 Notre Dame Football Season in Review
Notre Dame Football on NBC scored its most-watched season in seven years. The Fighting Irish averaged 4.4 million viewers and a 2.8 household rating for their seven games on NBC, up 69% and 67%, respectively, versus last year (2.6 million viewers and a 1.7 household rating). The 4.4 million average viewers this year is the best for Notre Dame Football on NBC since 2005 (5.2 million), while the 2.8 rating is the best since 2006 (3.0).
The NBC Sports Group and the University of Notre Dame began their landmark Notre Dame Football relationship in 1991, and have renewed their partnership numerous times, the latest in June of 2008 through 2015. NBC has the media rights for up to eight Notre Dame home games annually, including one off-site home game airing in primetime each year. Since 2010, NBC's Notre Dame games have been streamed live on NBCSports.com and, beginning in 2012, on the NBC Sports Live Extra app for mobile devices and tablets. During the 2012 season, NBC experienced its most-watched season since 2005 with viewership of Notre Dame Football averaging 4.4 million viewers and a 2.8 household rating, up 69% and 67%, respectively, over 2011.
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