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NC elections board rejects Appalachian State early voting site
Appalachian State University may not have an early voting site on its main campus this general election, despite arguments from local and state elections officials that it would be more convenient for a younger voting crowd.
The N.C. State Board of Elections in Raleigh on Thursday denied an appeal from Watauga County Board of Elections member Kathleen Campbell, who presented the state board a different early voting plan than what a majority on the three-member Watauga board approved last month. The majority plan includes five early voting sites – with one about a half-mile walk or so from campus – but nothing on ASU proper.
That's a bad idea, Campbell asserted.
"The 26th Amendment to the U.S. Constitution prohibits such an abridgment of this specific group of voters," she wrote to the state board.
Gerry Cohen, recently retired special counsel to the N.C. General Assembly, supported Campbell's cause with his own letter to the board. "The majority of Watauga County's voting age population (students, faculty and staff) are on campus during weekdays," wrote Cohen, "and are in walking distance of the Plemmons Student Union," the early voting site Campbell proposed.
Elections records show Watauga County has the highest percent of student voters of any of North Carolina's 100 counties.
"It is as if the goal of the (prevailing) plan was to inconvenience the majority of the voters," Cohen said.
But state board member Paul Foley pointed out that the next-nearest early voting site approved by the Watauga Board is less than a mile from campus.
"The university has put dorms that are 0.6 miles away from the Student Center, but somehow your contention is that by putting a voting location 0.6 miles away from the Student Center, that somehow that disenfranchises students?" Foley said.
With college students more likely to be first-time voters, advocates such as Campbell have been sensitive to any perceived obstructions they might encounter – even walking distance, in this case.
Efforts to smooth the path for college-age voters grew more defensive in 2013, when the N.C. General Assembly passed a sweeping voting bill that will require voters to show photo ID at the polls starting in 2016. College ID cards will not be accepted, and with that change occurring under a GOP-controlled legislature, Democrats have contended it was a strength move to make voting less accessible to young people, who are more likely to favor Democrats.
The voting law also canceled one's ability to register to vote at early voting locations.
While a federal judge this month sided against groups including the NAACP and college students in a legal challenge against the myriad voting changes, newly filed appeals – including from the NAACP – are keeping that challenge alive.
UNC-Chapel Hill will have an early voting site this election; so will Wake Technical Community College.
ASU did have an early voting site in 2010. An attorney representing Campbell on Thursday told the state board that between the primaries of that year and 2014 (when the campus lacked an early voting site), early voting turnouts increased by about 40 percent in all age groups except 18-25, which saw a 12 percent decline.
Rhonda Amoroso, secretary of the state board, pointed out that she saw no affidavits from students who feel inconvenienced by the Watauga board's majority plan.
Bill Aceto, secretary of the Watauga board, said he lives near campus and sees no problem with the approved scheme. "It's very accessible," he said.
But he agreed with a wish from the state board to expand early voting hours at the county's most popular site, in downtown Boone and a half mile from campus. In a 4-1 vote, the state board approved a plan for Watauga's board to operate that site – at the county's administration building on King Street – from 7 a.m. to 7 p.m. during Oct. 27-31. The previous plan was 8 a.m. to 5 p.m.
Other early voting sites in that county will operate from 10 a.m. to 5 p.m.
Amoroso said she wanted the Watauga board to report back on the success of those hours. She didn't mince words when opining that low turnout is a bigger issue than voter obstruction.
"If we started to teach civics 101 and teach young people about their right to vote, when they're starting in grade school, we might not have this issue of people not knowing how to vote, what to vote, anything about voting," she said.
ASU will, however, have an Election Day voting site on campus.
Benjamin Brown writes for the NCInsider.com, a news service owned by The N&O.
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Temporary Road Closure In Upper Valley Due To Construction
POSTED: Tuesday, March 9, 2010 - 8:18am
UPDATED: Tuesday, March 9, 2010 - 9:40am
After months of delays construction of a roundabout in the Upper Valley is expected to be finished at the end of this month. But, in the meantime, the area is completely closed. That's on Country Club Road from Westside Drive to Upper Valley Road. Starting today and for the next two weeks, traffic is being re-routed. The project includes new drainage, custom artwork, street lighting, landscaping, and paving.
Comments News Comments
Forget the artwork, just get it done. School bus transportation has been affected by this construction and it's hard to understand why it's taken so long. These delays place unnecessary burden on working families that now have to arrangemnt alternative transport for their school age kids. But we keep on paying taxes...


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Steatohepatitis/Metabolic Liver Disease
Liver-specific ablation of Krüppel-associated box–associated protein 1 in mice leads to male-predominant hepatosteatosis and development of liver adenoma†
Article first published online: 27 AUG 2012
DOI: 10.1002/hep.25767
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 4, pages 1279–1290, October 2012
Additional Information
How to Cite
Bojkowska, K., Aloisio, F., Cassano, M., Kapopoulou, A., Santoni de Sio, F., Zangger, N., Offner, S., Cartoni, C., Thomas, C., Quenneville, S., Johnsson, K. and Trono, D. (2012), Liver-specific ablation of Krüppel-associated box–associated protein 1 in mice leads to male-predominant hepatosteatosis and development of liver adenoma. Hepatology, 56: 1279–1290. doi: 10.1002/hep.25767
- †
Potential conflict of interest: Nothing to report.
Publication History
- Issue published online: 4 OCT 2012
- Article first published online: 27 AUG 2012
- Accepted manuscript online: 8 JUN 2012 08:15AM EST
- Manuscript Accepted: 1 APR 2012
- Manuscript Received: 22 DEC 2011
Funded by
- Swiss National Science Foundation and the European Research Council
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
The liver is characterized by sexually dimorphic gene expression translating into sex-specific differences in lipid, drug, steroid hormone, and xenobiotic metabolism, with distinct responses of males and females to environmental challenges. Here, we investigated the role of the Krüppel-associated box (KRAB)-associated protein 1 (KAP1) epigenetic regulator in this process. Liver-specific KAP1 knockout (KO) led to strikingly sexually dimorphic phenotypic disturbances, including male-predominant steatosis and hepatic tumors with up-regulation of protein kinase B and extracellular signal-related kinases 1/2 mitogen-activated protein kinase signaling. This correlated with the sex-specific transcriptional dysregulation of a wide range of metabolic genes, notably those involved in retinol and sex hormone processing as well as in detoxification. Furthermore, chromatin immunoprecipitation followed by deep sequencing indicated that a number of dysregulated genes are direct targets of the KRAB/KAP1 repression system. Those genes include sexually dimorphic cytochrome P 450 Cyp2d9, glutathione S-transferase π, Cyp2a, Cyp2b, and Cyp3a gene clusters. Additionally, we identified a male-restricted KAP1-binding site in the fat-specific protein 27 gene, correlating with its male-predominant up-regulation upon Kap1 deletion, suggesting that the latter might be an important trigger in the development of male-specific hepatosteatosis and secondary tumorigenesis. Conclusion: This work reveals KRAB/KAP1-mediated transcriptional regulation as a central event in metabolic control hormones, drugs, and xenobiotics in the liver and further links disturbances in these processes with hepatic carcinogenesis. (HEPATOLOGY 2012)
Metabolism is orchestrated by complex gene-regulatory networks, and the liver is central to this process. This organ is characterized by sexually dimorphic gene expression, with numerous genes transcribed in a sex-dependent manner.1 In mice, examples of such genes include the male-predominant cytochrome P450 Cyp2d9, which encodes for a testosterone-16-α-hydroxylase inactivating the main male sex hormone and various drugs, and the female-predominant Cyp2a and Cyp2b genes involved in xenobiotic and drug metabolism.2 The sex-specific expression of these and other classes of enzymes results in the differential response of males and females to environmental challenges, with males displaying a higher predisposition than females for liver inflammation, cirrhosis, and tumors subsequent to infections or nonalcoholic steatohepatitis.3, 4
Sexually dimorphic gene expression in the liver is established by the sex-specific action of liver transcription factors.1 One of those, regulator of sex limitation (Rsl), belongs to the Krüppel-associated box zinc finger proteins (KRAB-ZFPs) family of tetrapod-specific transcription repressors, which counts between 300 and 400 members in mice and humans.5 KRAB-ZFPs are characterized by the presence of an N-terminal KRAB domain required for repression and a C-terminal array of DNA-binding zinc fingers (ZFs). Few have been assigned a physiological role in vivo, yet enough data are available to indicate that these proteins display a wide range of biological activities, from the control of imprinting to regulation of metabolic processes in neurons.6, 7
Whereas the role and gene targets of the vast majority of KRAB-ZFPs remain ill defined, how they repress transcription is comparatively well understood. Many KRAB-ZFPs likely bind DNA in a sequence-specific manner through their ZFs and recruit KRAB-associated protein 1 (KAP1; also known as TIF1β, TRIM28, and KRIP-1), which serves as their universal cofactor. KAP1, in turn, acts as a scaffold for a chromatin-remodeling complex comprising the histone methyltransferase SET domain bifurcated 1 (SETDB1), which catalyzes histone 3 lysine 9 trimethylation (H3K9me3), histone deacetylases (HDACs), nuclear remodeling factors, as well as heterochromatin protein 1. The formation of heterochromatin ensues, leading to epigenetic silencing.8
In the mouse, constitutive Kap1 knockout (KO) is early embryonic lethal, correlating with an absence of gastrulation.9 Deleting Kap1 in embryonic stem cells (ESCs) leads to loss of pluripotentiality, imprinting defects, and failure to silence endogenous and some exogenous retroviruses.6, 8, 10 In adult tissues, KAP1 regulates spermatogenesis and affects the management of behavioral stress.8, 11 Furthermore, inbred mice heterozygous for a null mutation in Kap1 were found to exhibit greater variance in body weight than wild-type (WT) littermates and, for some animals, liver steatosis, adipocyte hypertrophy, and impaired glucose tolerance.12
Here, we explored the role of KRAB/KAP1 in liver function. The analysis of the hepato-specific conditional Kap1 KO mouse revealed a sexually dimorphic metabolic syndrome, with male-predominant liver steatosis and tumorigenesis. This correlated with the sex-specific transcriptional dysregulation of genes involved in retinol, xenobiotic, and drug metabolism. The identification of KAP1-binding sites in the mouse liver further revealed that a number of the affected genes are direct KAP1 targets. This study thus unveils the important contribution of KRAB/KAP1-mediated regulation to liver function and metabolism.
Materials and Methods
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
Mouse Generation and Phenotyping.
Generation and genotyping of mice with a floxable Kap1 allele (Kap1fl/fl) and the albumin/Cre recombinase (Alb-Cre) mouse strain have been previously described.9, 13 Animals were housed in standard conditions with water and chow or high-fat diet (HFD) provided ad libitum (for details, see Supporting Materials). All animal experiments were approved by the local veterinary office and were carried out in accord with the European Community Council Directive (86/609/EEC) for care and use of laboratory animals. Phenotyping was performed on at least 8 males and females (for details, see Supporting Materials).
Histological Tissue Processing and Analysis.
Hematoxylin and eosine (HE) and Oil Red O (ORO) stainings were performed according to standard procedures. Histopathology evaluation, ORO scoring, and tumor occurrence analysis were done by a board-certified pathologist (F.A.). Hepatocellular lesions were classified as foci of cellular alteration, hepatocellular adenomas, and hepatocellular carcinoma (HCC) according to established criteria.14 For bromodeoxyuridine (BrdU) pulse-labeling, mice received 3 mg/mL of BrdU in drinking water for 6 days and the liver tissue was stained for BrdU (Oxford Biomedical Research, Kidlington, UK). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed with the Apoptag kit (Millipore, Bedford, Massachusetts, USA) according to the manufacturer's instructions.
Small-Scale DNA, RNA, and Protein Analysis.
Genotyping, RNA extraction and reverse-transcription, as well as protein, analysis were performed according to standard procedures as previously described, see Supplemental Methods.11
Microarray Analysis.
Mice (8-10 weeks old) were food-deprived at 07:00 a.m., and liver was isolated at 11:00 a.m. to 2:00 p.m. Total RNA was extracted with the mirVana kit (Ambion Biotechnology, Houston, TX) and treated with DNAse (Ambion), following the manufacturer's instructions. Three RNA pools from 9 mutant and WT male livers were prepared, whereas 3 individual female KO and WT livers were used separately. Microarray analysis was performed as previously described.11 Significantly deregulated genes (P < 0.05 by unpaired t test and fold-change ≥2) were used to interrogate the DAVID bioinformatic database.15
Chromatin Immunoprecipitation Sequencing and Chromatin Immunoprecipitation Polymerase Chain Reaction.
Liver chromatin was performed as previously described, with minor modifications.16 For chromatin immunoprecipitation (ChIP) sequencing, chromatin from 2 male and female Kap1fl/fl and 1 male and female Alb-Cre Kap1fl/fl control were prepared. ChIP with an affinity-purified rabbit polyclonal antibody, kindly provided by Dr. J.F. Rauscher,17 was performed as previously described.18 Details describing sequencing, read alignment, and subsequent analyses are provided in the Supporting Materials.
Statistical Analysis.
Body- and organ-weight measurements as well as plasma biochemistry were analyzed with the two-tailed Student t test or two-way analysis of variance (ANOVA), followed by Bonferroni's post-test. Contingency testing was done with Fisher's exact test. For statistical analysis of high-throughput data, see related paragraphs.
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
Generation of Hepatocyte-Specific Kap1 KO Mice.
We crossed Kap1fl/fl mice9 in a mixed C57/Bl6-Sv129 background with animals expressing Cre under the control of an Alb promoter.13 We confirmed the liver specificity of Kap1 deletion by locus-specific polymerase chain reaction (PCR), and determined that, in whole liver from mutant mice, KAP1 messenger RNA (mRNA) was reduced by more than 75% and protein was undetectable by western blotting, whereas immunohistochemistry confirmed that its loss was restricted to hepatocytes (Supporting Fig. 1). Histology combined with ORO staining further revealed that 8-10-week-old male Alb-Cre Kap1fl/fl mice, but not their female counterparts, suffered from mild liver steatosis (Supporting Fig. 1). These results suggested that loss of KAP1 perturbed metabolic homeostasis in the liver and pointed to possible sex-specific differences in this process.
Sex-Dependent Phenotypic Consequences of Hepatocyte-Specific Kap1 KO.
Because of this early finding and of known sex-related differences in metabolism and liver function in rodents and other mammals, including humans,1, 19 we followed a phenotyping protocol that separately examined male and female mice (see above). At 8-10 weeks of age, no differences in body weight, food intake, and plasma markers of liver function and lipid metabolism between mutant and WT mice were observed (not illustrated). However, histopathology revealed significant fat accumulation with small vacuoles in all 12 KO male livers, compared to only one third (4 of 12) of controls (Fisher's exact test; P = 0.0013; not shown), whereas females were exempt of this pathology. The steatosis noted in male KO mice was not the result of Cre, because no difference was observed between Alb-Cre Kap1wt/wt and Kap1wt/wt animals (not illustrated).
We then asked whether a metabolic challenge would accentuate the phenotype of male Kap1 KO mice. For this, we fed 10-week-old male and female Alb-Cre Kap1fl/fl and Kap1fl/fl littermates with HFD (60% calories from fat) or chow diet (CD) for 19 weeks. CD-fed Kap1 KO males displayed progressive hepatosteatosis characterized by increased liver weight and fatty change of mild to moderate degree at 6 months of age (Fig. 1B,C; Table 1). In contrast, control littermates exhibited minimal lipid accumulation in the liver, as revealed by ORO staining (Fig. 1B,C). These changes were not accompanied by weight gain and increased food intake and only by a trend to up-regulation of plasma markers of liver function (Fig. 1A,D; Table 1; and data not shown). Interestingly, Kap1 KO males displayed significantly lower plasma free fatty acid (FFA) concentration than littermate controls, suggesting an increased rate of hepatocytic FFA uptake after Kap1 deletion (Table 1).
|Female KO CD (n = 7)
|Female WT CD (n = 8)
|Female KO HFD (n = 8)
|Female WT HFD (n = 8)
|Male KO CD (n = 10)
|Male WT CD (n = 7)
|Male KO HFD (n = 10)
|Male WT HFD (n = 9)
|BW (g)
|31.4 ± 1.4
|30.0 ± 1.4
|46.2 ± 2.2
|41.0 ± 2.6
|38.0 ± 1.4
|35.9 ± 1.5
|51.5 ± 2.2
|52.4 ± 1.2
|Body fat (%)
|27.6 ± 3.0
|26.1 ± 1.8
|48.2 ± 1.4
|41.6 ± 2.2
|23.0 ± 1.6
|23.3 ± 3.0
|39.4 ± 0.6
|38.6 ± 1.1
|Liver (% BW)
|4.1 ± 0.2
|3.8 ± 0.2
|4.0 ± 0.3†
|3.0 ± 0.2
|4.8 ± 0.2
|4.0 ± 0.2
|6.3 ± 0.4*
|5.3 ± 0.3
|6.3 ± 0.9
|6.4 ± 0.6
|10.9 ± 0.3
|10.3 ± 0.6
|4.7 ± 0.2
|4.4 ± 0.4
|4.5 ± 0.3
|3.8 ± 0.2
|Ovaries/testes (% BW)
|0.33 ± 0.03
|0.34 ± 0.03
|0.23 ± 0.02
|0.25 ± 0.04
|0.91 ± 0.03
|0.93 ± 0.03
|0.62 ± 0.02*
|0.72 ± 0.04
|Testosterone (ng/mL)
|3.8 ± 1.4
|2.2 ± 0.5
|1.3 ± 0.6
|4.5 ± 2.4
|Cholesterol (mM)
|4.8 ± 0.4
|4.5 ± 0.3
|6.0 ± 0.6*
|4.1 ± 0.5
|5.7 ± 0.2
|4.5 ± 0.3
|8.2 ± 0.4
|7.9 ± 0.4
|HDL cholesterol (mM)
|1.34 ± 0.25*
|1.67 ± 0.17
|2.11 ± 0.10
|1.98 ± 0. 17
|2.19 ± 0.09
|2.33 ± 0.11
|2.11 ± 0.10
|2.95 ± 0.08
|LDL cholesterol (mM)
|1.25 ± 0.55*
|0.86 ± 0.33
|0.73 ± 0.18
|0.38 ± 0.06
|0.44 ± 0.04
|0.24 ± 0.03
|1.10 ± 0.09†
|0.83 ± 0.06
|Triglycerides (mM)
|1.46 ± 0.13†
|1.20 ± 0.09
|1.15 ± 0.05*
|0.86 ± 0.03
|1.56 ± 0.15
|1.38 ± 0.16
|1.10 ± 0.08
|0.92 ± 0.09
|Total protein (g/L)
|63.4 ± 1.2
|63.1 ± 0.7
|68.2 ± 1.4*
|63.5 ± 1.8
|63.9 ± 0.7
|63.1 ± 1.3
|68.6 ± 1.4
|67.5 ± 0.7
|FFAs (mM)
|1.60 ± 0.40
|1.70 ± 0.21
|1.66 ± 0.14
|1.28 ± 0.09
|1.06 ± 0.11*
|1.75 ± 0.40
|1.50 ± 0.14
|1.77 ± 0.13
|252 ± 79
|173 ± 50
|342 ± 82†
|123 ± 18
|118 ± 19
|173 ± 67
|373 ± 58
|239 ± 72
|γGT (U/L)
|10.3 ± 2.1‡
|6.4 ± 1.4
|3.7 ± 0.4
|4.6 ± 0.5
|7.3 ± 0.6
|6.3 ± 0.6
|6.4 ± 0.5
|4.9 ± 0.6
|IL-1β (ng/mL/mg protein)
|4,355 ± 106*
|3,881 ± 91
|4,380 ± 140
|4,257 ± 180
|4,234 ± 195
|3,614 ± 164
|4,021 ± 241
|4,485 ± 184
|79.8 ± 5.8
|86.8 ± 4.3
|1,04.3 ± 20.0*
|66.8 ± 5.8
|72.5 ± 3.8
|67.1 ± 4.8
|1,14.5 ± 14.7*
|82.1 ± 5.1
|Total bilirubin (μM/L)
|2.7 ± 0.6
|2.2 ± 0.4
|2.7 ± 0.5
|1.5 ± 0.3
|1.6 ± 0.2
|2.1 ± 0.5
|2.4 ± 0.4
|1.3 ± 0.1
|Glucose (mM)
|15.8 ± 0.8
|16.1 ± 0.9
|17.0 ± 1.4
|16.4 ± 1.3
|17.5 ± 1.1
|18.7 ± 1.2
|17.9 ± 0.7
|19.1 ± 1.0
Upon HFD challenge, both Alb-Cre Kap1fl/fl and Kap1fl/fl males developed severe hepatic steatosis (Fig. 1C), but the liver was heavier in Kap1 KO animals, which also presented with a bigger epididymal fat pad and a decreased testis weight (Table 1). Although this latter trait suggested an impaired sex hormone balance, a condition also observed in humans in cases of severe liver steatosis,4 total plasma testosterone levels were not different between KO and WT littermates (Table 1).
In contrast to males, CD-fed females did not present significant liver lipid accumulation, although Kap1 KO animals showed plasma dyslipidemia and up-regulation of liver enzymes (Fig. 1A-D; Table 1). When subjected to HFD, Kap1 mutant females displayed a higher body weight than littermate controls, probably as a result of increased body fat content, as assessed by echo magnetic resonance imaging (Fig. 1A; Table 1). Furthermore, these mice were characterized by (1) a moderate degree of liver steatosis (Fig. 1C), (2) mildly elevated plasma cholesterol and triglycerides, and (3) significant up-regulation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), as well as a clear trend in the up-regulation of other plasma markers of hepatocytic dysfunction (Fig. 1D; Table 1). Nevertheless, Kap1 KO females were comparable to their littermates for food intake, physical activity, and energy expenditure (not illustrated).
Development of Hepatic Adenomas in Kap1 KO Males.
Anatomo-pathological examination indicated that male Alb-Cre Kap1fl/fl mice on HFD had a tendency to develop liver tumors that occasionally reached large size and formed nodular masses distorting the lobular contour (Fig. 2A,B). Hepatic adenomas were observed in 4 of 11 HFD-fed and 1 of 12 CD-fed males at 29 weeks, whereas no tumors were found in Kap1fl/fl littermates (n = 9 and n = 10 on CD and HFD, respectively). In 1 of the HFD-fed Kap1 KO males, a 2-mm diameter hepatocellular proliferative focus with features of solid carcinoma was observed. Consistent with the previously reported protective effect of female hormones,3 Kap1 KO female mice appeared largely to escape HFD-induced tumorigenesis, because only 1 of 10 HFD-fed KO females had an adenoma and no tumor was observed in WT (n = 10 on CD and n = 10 on HFD) or in CD-fed female KO mice (n = 10). To confirm these results, we analyzed the livers of CD-fed mice at ages of 53-72 weeks (Table 2). Macroscopic examination revealed that Kap1 KO mice presented with hepatomegaly (Table 2), and 9 of 15 (64%) male Alb-Cre Kap1fl/fl mice developed tumors, compared to 2 of 13 (15%; P < 0.024) WT controls, whereas females appeared partially protected against this process, with only 4 of 15 (27%) KO and 1 of 15 (7%) WT controls showing hepatocellular tumors (Table 2; Fig. 2C). Histopathological examination performed on a subset of animals (13-15 in each subgroup) confirmed that all tumors observed in Kap1-deleted mice were adenomas, whereas focal cellular alterations were detected in both control and KO mice. In addition, minimal infiltration by mixed inflammatory cells was noted in approximately one quarter of the animals, but no significant association with Kap1 status was found (not illustrated). We verified that similar results were obtained in a C57/Bl6 background (Supporting Fig. 2).
|Female KO CD (n = 15)
|Female WT CD (n = 15)
|Male KO CD (n = 15)
|Male WT CD (n = 13)
|40.1 ± 2.5
|46.2 ± 2.7
|43.9 ± 2.7
|45.9 ± 2.8
|Liver weight (% BW)
|5.1 ± 0.3*
|3.8 ± 0.1
|6.5 ± 0.7*
|4.5 ± 0.3
|Age (weeks)
|60.3 ± 3.9
|59.3 ± 1.6
|63.5 ± 1.6
|62.1 ± 2.0
|Liver IL-1β (ng/mL/mg protein)
|1,611 ± 95
|1,606 ± 63
|1,962 ± 32*
|1,674 ± 78
|Liver IL-6 (ng/mL/mg protein)
|1,178 ± 79
|1,258 ± 51
|1,504 ± 87*
|1,255 ± 47
|Liver TNF-α (ng/mL/mg protein)
|2,085 ± 161
|2,123 ± 156
|2,682 ± 128*
|2,360 ± 145
Although inflammation was not a prominent histological feature of Kap1 KO livers, we observed higher intrahepatic levels of proinflammatory cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in this setting (Fig. 1E; Tables 1 and 2). IL-6 and TNF-α contribute to hepatoprotection and induce hepatocyte proliferation during liver injury20 and have been implicated in the development of fatty liver and tumors in other mouse models of liver tumorigenesis.3 Because cytokine signaling involves several transduction pathways previously implicated in liver oncogenic transformation,21 we analyzed the activity of the mitogen-activated protein kinase (MAPK) pathway, the phosphorylation levels of protein kinase B (AKT), as well as the expression levels of phosphatase and tensin homolog (PTEN), key regulators of the phosphoinositide 3-kinase (PI3K) pathway (Fig. 2D,E). Total levels of p38 MAPK were similar in WT and KO animals, irrespective of their genetic background. However, levels of phosphorylated p38 were increased in KO livers. As an expected corollary, there also was a significant hyperphosphorylation of extracellular signal-related kinases 1/2 (ERK1/2) MAPK and MAPK kinase 1 in KAP1-depleted tissue (Fig. 2D,E). Furthermore, tumor tissue harvested from Kap1 KO liver displayed a marked up-regulation of both total and phosphorylated ERK1/2, despite normal levels of activity of other components of the MAPK pathway. Additionally, we observed AKT hyperphosphorylation in tumor tissue, despite normal total protein levels. These results suggest that amplification of ERK1/2 and increase of AKT signaling play a prominent role in the development of adenomas in Kap1 KO livers. In contrast, there was no significant change in the phosphorylation status of Jun N-terminal kinase/stress-activated protein kinase (JNK/SAP) nor abnormalities in PTEN levels (Fig. 2D).
To assess the contribution to the observed phenotype of hepatocyte proliferation and hepatic cell death, we performed BrdU pulse in 35- and 68-week-old mice and found that hepatocyte proliferation was comparable between KO and controls (Fig. 2F). Similarly, histological examination and TUNEL staining in KAP1-depleted livers did not reveal any significant signs of cell death in Kap1 KO livers (data not shown).
In summary, these results indicate that loss of KAP1 in the liver leads to sexually dimorphic phenotypes, with males exhibiting progressive steatosis and age-related tumorigenesis and females suffering from a less dramatic syndrome with mild metabolic defects, including obesity and steatosis, revealed only upon exposure to an environmental stress.
Sex-Specific Gene Dysregulation in Kap1 KO Liver.
We performed gene-expression profiling in livers from CD-fed 8-10-week-old WT and mutant male and female mice, choosing this young age to minimize the potential effect of compensatory changes. Loss of KAP1 led to at least 2-fold dysregulation of 170 and 149 genes in male and female mice, respectively. Interestingly, less than 50% of the deregulated genes were common to the two sexes (Fig. 3A), suggesting that the KRAB/KAP1 system targets different genes in males and females. Gene ontology (GO) analysis of 2-fold dysregulated transcripts (Supporting Table 1) indicated that loss of KAP1 affected genes encoding protein endowed with oxidoreductase activity involved in xenobiotic metabolism by Cyp450 as well as the pathways of retinol, drug, and arachidonic acid metabolism (Fig. 3B). Additionally, GO terms and Kegg pathway analyses singled out genes relevant for steroid hormone biosynthesis and metabolism, peptidase inhibitor activity, and peroxisome proliferator receptor signaling in male KO mice, contrasting with genes linked to pheromone binding in their female counterparts. Approximately 50% of genes with the highest fold-change differed between male and female mice. For example, the most highly up-regulated genes in males belong to the phenobarbital-inducible Cyp2b family, whereas in females, those include serine peptidase inhibitor, Kazal type 3 (Spink3), keratin 23 (Krt23), and Cyp2d9 (Fig. 3C). We verified that the transcriptional changes noted upon Kap1 deletion were not the result of the mixed genetic background of the mice or Cre expression (Supporting Fig. 2).
KAP1 Controls Expression of Rsl-Target Genes.
Female-restricted changes in Cyp2d9, sex-limited protein (Slp), and major urinary proteins (Mups) are hallmarks of the Rsl loss-of-function phenotype.5 Though we could document both Cyp2d9 and Slp derepression in female Kap1 KO livers (Fig. 3D), Slp appeared affected to a far lower extent than reported in Rsl-deleted female mice, although a direct comparison is difficult owing to differences in the mouse strains used in the two studies. Furthermore, we observed a down-regulation, rather than an up-regulation, of Mups in Kap1 mutant mice at both RNA and protein level (Fig. 3D and Supporting Fig. 3), suggesting that either Rsl2-mediated female-specific repression5 is not mediated by KAP1 or that Mups are indirect KAP1 or Rsl targets.
KAP1 Binding Sites and KAP1-Related Chromatin Modifications in the Mouse Liver.
To better understand the molecular mechanisms of KAP1-mediated gene-expression control in the liver, we performed ChIP followed by deep sequencing on male and female WT and KAP1-depleted nuclei, using an antibody directed against the RBCC domain of KAP1.8 False-positive peaks originating from nonhepatocytic cells present in the samples were minimized by following a protocol optimized for hepatocyte-centered ChIP experiments,16 and data obtained in Kap1-deleted hepatocytes served as a control sample for peak calling. We identified 7,158 and 5,223 KAP1 peaks in male and female livers, respectively (Fig. 4A), a number comparable to that extrapolated from genome-wide KAP1-binding studies previously performed in other tissues.22 Surprisingly, few of the identified peaks (∼10%) were common to males and females (Fig. 4A), consistent with the observed sex-specific gene dysregulations induced by the Kap1 KO (Fig. 2). KAP1 peaks were significantly enriched in the vicinity of transcriptional start sites (TSSs; Fig. 4B).
We then searched the nearest peak for each of the genes dysregulated at least 1.5-fold upon KAP1 removal (Supporting Table 1). We observed that relatively few of them had a KAP1-binding site in the gene body (less than 20%; not shown); however, the average distance between both up- and down-regulated genes and the nearest KAP1 peak was significantly shorter than for all protein-coding genes present on our Illumina chip (Fig. 4C). Furthermore, these peaks were usually found just upstream of the TSS of deregulated genes (Fig. 4D). This suggests that KAP1 might directly control many of the genes perturbed in its absence, but that it may not always be through repression.
Surprisingly, for several genes expressed and deregulated in a sex-discriminating fashion, KAP1 binding was found in both males and females (Figs. 3 and 5). These included peaks in the promoter of the male-predominant Cyp2d9 and Slp genes, both strongly up-regulated in Kap1 KO females, and in the glutathione S-transferase π (Gstπ) cluster, a late-phase drug-responsive gene preferentially expressed in males, with strong down-regulation upon KAP1 removal. Of note, the Gstπ cluster bears a male-specific KAP1-binding site downstream of the locus that could explain sex-biased dysregulation. Moreover, we identified putative KAP1-binding sites in an intron of the gene encoding fat-specific protein 27 (FSP27), which plays a role in lipid droplet formation23 and was strongly up-regulated in male KO livers, and in the gene encoding for the cellular homolog of the viral Casitas B-lineage lymphoma proto-oncogene (c-Cbl), a regulator of various tyrosine kinase signaling pathways24 up-regulated in KO livers of both sexes (Figs. 3E, 5, and 6A). We also identified KAP1-binding sites in a cluster of phenobarbital-responsive, female-predominant Cyp2b genes that were up-regulated in males and down-regulated in females upon loss of KAP1 and in clusters of other xenobiotics-processing Cyp450 genes, such as Cyp2a and Cyp3a (Figs. 3E, 5, and 6A, and Supporting Fig. 4).
KAP1 recruits the SETDB1 histone methyltransferase, which induces deposition of the H3K9me3 repressive mark, and HDAC-containing complexes, which result in histone deacetylation.17 We thus compared the presence of the relevant chromatin marks in WT and Kap1 KO liver at both the nearest KAP-binding site and the promoter of a few genes suspected to represent direct KAP1 targets. Loss of KAP1 correlated with a loss of H3K9me3 at the binding site for genes up-regulated in Kap1-mutant livers, such as Cyp2d9 in females and fsp27, c-Cbl, or the Cyp2b cluster in males. However, for male down-regulated Gstπ, Cyp2d9, or Slp, no change in H3K9me3 at the KAP1-binding site was detected. Notably, gain of H3K9me3 at the male KAP1-binding site in the fsp27 locus in the female liver suggests local chromatin changes that could be the cause of mild female up-regulation of the corresponding transcript. Finally, an increase in H3Ac at the promoters of Cyp2d9 in females and Fsp27 in males coincided with gene dysregulation; however, this was not the case for all tested KAP1-target loci (Fig. 6B,C).
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
The present work reveals the prominent role of KRAB/KAP1-mediated regulation in the control of liver metabolism and endo- and xenobiotics-detoxifying genes. The liver-targeted KO of KAP1, the universal cofactor of KRAB-ZFPs, resulted in a markedly sexually dimorphic phenotype in mice, which included male-predominant steatosis and hepatic tumors. This correlated with sex-specific transcriptional dysregulation of a wide range of metabolic genes, notably those involved in retinol and sex hormone processing as well as in detoxification. An examination of KAP1 genomic binding sites in the liver and of chromatin marks at the promoters of some of these genes further revealed that a number of detoxifying genes, such as Cyp2d9, Gstπ, and the Cyp2a, Cyp2b, and Cyp3a gene clusters, are direct KAP1 targets. Moreover, loss of KAP1 binding at the fsp27 locus was associated with the male-predominant up-regulation of its product.
Male liver-specific Kap1 KO mice displayed early-onset hepatosteatosis and age-related development of liver adenomas, whereas their female counterparts exhibited milder metabolic disturbances revealed only by an HFD challenge and had lower incidences of liver adenomas than their male counterparts. This correlates with the reported resistance of the female liver to environmental insults, which has been attributed to its greater ability to inactivate toxins and neutralize reactive oxygen species, and to the protective action of estrogens against inflammation and steatofibrosis, including during the course of chronic viral hepatitis.19, 25 Our results suggest that these mechanisms are influenced by KRAB/KAP1-mediated transcriptional control.
What specific mechanisms account for the accumulation of fat and tumor development in the Kap1-deleted male liver remains to be determined. We observed a male-predominant, Kap1 deletion-induced up-regulation of FSP27, correlating with a male-restricted strong KAP1-binding site in the body of this gene. FSP27 promotes fat droplet formation in adipocytes and its hepatocytic overexpression results in hepatosteatosis.23, 26 This phenotypic abnormality, which represents an early sign of hepatocyte suffering common to many pathological circumstances, has been linked to increased liver damage, inflammation, and development of HCC in other mouse models.3 Interestingly, KAP1 KO mice displayed an up-regulation of liver levels of proinflammatory cytokines IL-6 and TNF-α, which is a sign of response to hepatocyte damage. Aberrant activity of signaling pathways downstream of these cytokines have been linked to increased fat accumulation in hepatocytes and development of liver tumors, and our results suggest a role of the MAPK and AKT pathways in the increased incidence of tumors in Kap1 KO animals.3 The early development of hepatosteatosis resulting from derepression of fsp27 in KAP1 KO males may be one important trigger in a cascade of events leading to the development of liver steatosis and tumors in these mice.
Indirectly, our analyses suggest that xenobiotic stress, which, if prolonged, can lead to tumorigenesis,27 might contribute to the observed phenotype. In Kap1-deleted livers, we measured a dysregulation of drug- and xenobiotic-metabolizing phase I genes, such as members of the Cyp2a, Cyp2b, and Cyp3a families, of phase II and III genes, such as Gstπ and θ, and of genes coding for various UDP-glucuronosyltransferases required for the conjugation of molecules that need this modification for efficient excretion.2 We identified KAP1-binding sites in the vicinity of several of these genes, suggesting that they are direct targets of the transcriptional regulator.
The combined results of our transcriptome and chromatin analyses exclude a simple model for KAP1 action, whereby a given KRAB-ZFP would tether the cofactor to specific sequences, with secondary heterochromatin formation and gene silencing. Some sexually dimorphic genes, such as the male-predominant Cyp2d9, Gstπ, and Slp, carry KAP1 signatures inconsistent with such a model. For instance, the Cyp2d9 and Slp genes are Rsl1-targeted, male-predominant genes up-regulated upon Kap1 KO only in female mice. However, KAP1 was detected at similar sites, such as the promoter of Cyp2d9, in liver chromatin from both sexes. Also, KAP1 binds upstream of the Gstπ locus in both males and females, whereas this gene is highly expressed in the former and strongly repressed in the latter. These observations might reflect the effect of sex-specific dominant factors counteracting the repressing influence of KAP1 or sex-differential, post-translational modifications of the transcription regulator. KAP1 small ubiquitin-like modifier (SUMO)ylation appears to be required for its corepressor activity, whereas phosphorylation stimulates its chromatin-opening properties.8 In the case of Cyp2d9, it could be that phospho-KAP1 keeps the promoter accessible for transcription factors in males, whereas SUMO-KAP1 recruits SETDB1 and heterochromatin protein 1 to close it down in females.
It is generally acknowledged that KAP1 exerts its gene-repressor activity through an interaction with DNA-binding KRAB-ZFP family members. It will be important to identify the mediators of its activity in the liver; however, it remains that our data strongly suggest that KAP1 sometimes acts as a transcriptional activator, rather than as a repressor. Future studies should explore this possibility, which challenges the current view of KAP1 function.
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
The authors thank the Histology Core Facility at Ecole Polytechnique Fédérale de Lausanne (EPFL), the National Center of Competence in Research Genomics Platform at the University of Geneva, and the EPFL Transgenic Core Facility for technical assistance, Jacques Rougemont for bioinformatics support, and Juergen Ripperger, Walter Wahli, Gianpaolo Rando, and Kristina Schoonjans for their discussions. Computations were performed on the Vital-IT facility of the Swiss Institute of Bioinformatics.
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
- 1Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol 2006; 20: 2613-2629., .
- 2Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 2009; 76: 215-228., .
- 3Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140: 197-208., , , , , , et al.
- 4Sex hormones and risk of liver tumor. Ann N Y Acad Sci 2006; 1089: 228-236., , , , , .
- 5Regulator of sex-limitation (Rsl) encodes a pair of KRAB zinc-finger genes that control sexually dimorphic liver gene expression. Genes Dev 2003; 17: 2664-2674., , , , , .
- 6In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol Cell 2011; 44: 361-372., , , , , , et al.
- 7PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease. Cell 2011; 144: 689-702., , , , , , et al.
- 8KAP1 protein: an enigmatic master regulator of the genome. J Biol Chem 2011; 286: 26267-26276., .
- 9Mice lacking the transcriptional corepressor TIF1beta are defective in early postimplantation development. Development 2000; 127: 2955-2963., , , , , .
- 10KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 2010; 463: 237-240., , , , , , et al.
- 11KAP1-mediated epigenetic repression in the forebrain modulates behavioral vulnerability to stress. Neuron 2008; 60: 818-831., , , , , , et al.
- 12Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise. Genome Biol 2010; 11: R111., , , , , , et al.
- 13Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem 1999; 274: 305-315., , , , , , et al.
- 14Liver, gallbladder, and exocrine pancreas. In: Ulrich M, ed. International Classification of Rodent Tumors: The Mouse. Hannover, Germany: Springer; 2001: 59-86., , , , , , et al.
- 15Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4: 44-57., , .
- 16Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet 2006; 38: 369-374., .
- 17Targeting histone deacetylase complexes via KRAB-zinc finger proteins: the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the Mi-2alpha subunit of NuRD. Genes Dev 2001; 15: 428-443., , ,
- 18KRAB-zinc finger proteins and KAP1 can mediate long-range transcriptional repression through heterochromatin spreading. PLoS Genet 2010; 6: e1000869., , , , , , et al.
- 19Sex differences in nuclear receptor-regulated liver metabolic pathways. Biochim Biophys Acta 2011; 1812: 964-973., .
- 20NF-kappaB and STAT3—key players in liver inflammation and cancer. Cell Res 2011; 21: 159-168., .
- 21The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 2010; 29: 4989-5005., , .
- 22ZNF274 recruits the histone methyltransferase SETDB1 to the 3′ ends of ZNF genes. PLoS One 2010; 5: e15082., , , , .
- 23A physiological role for fat specific protein 27/cell death-inducing DFF45-like effector C in adipose and liver. Biol Pharm Bull 2010; 33: 346-350..
- 24Cbl: many adaptations to regulate protein tyrosine kinases. Nat Rev Mol Cell Biol 2001; 2: 294-307., .
- 25Female hepatology: favorable role of estrogen in chronic liver disease with hepatitis B virus infection. World J Gastroenterol 2007; 13: 4295-4305., , , , , , .
- 26Fat-specific protein 27 regulates storage of triacylglycerol. J Biol Chem 2008; 283: 14355-14365., , , , , , et al.
- 27Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 2005; 19: 1646-1653., , , , , , .
Supporting Information
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
Additional Supporting Information may be found in the online version of this article.
|Supporting Information Figure 1.
|Supporting Information Figure 2.
|Supporting Information Figure 3.
|Supporting Information Figure 4.
|Supporting Information
|Supporting Information Table 1.
|Supporting Information Table 2.
Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.


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(In)Appropriate Behavior From Dysfunctional Siblings in New Drama
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You might have seen our earlier reports regarding the facelifted Indigo eCS and just as expected it has been revealed. The Indigo eCS has been facing tough competition from the Maruti Dzire and more recently the Honda Amaze. The eCS in its last generation was getting old and lacked the features and ... read more
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Porsche Boxster comes in the Convertible category of cars. Porsche Boxster's engine has a displacement of 3387 CC while its transmission is of Automatic type. The fuel type of the car is Petrol. Porsche Boxster has a mileage of 0.0 Km/L. Porsche Boxster's dimensions are 4329X1801X1292 mm (length X width X height). Porsche Boxster costs Rs. 77,95,000 (ex-showroom, New Delhi) ... read more
Used Cars
Tata Indigo XL Classic Petrol (2008)
78900 kms run, Feb 2008 manufactured, Tata Indigo XL (yes.... its an extra large car) in excellent condition and single owner driven. This stretch sedan is an elegant luxury lounge and is the longest Indian car in its segment, much bigger than a normal Indigo or Indigo CS, having a length of 4377 mm, width of 1620 mm, height of 1540 mm and wheel base of 2650 mm. It has a high ground clearance of 165 mm, with a very large trunk (boot) capacity of 450 litres and fuel tank of 42 litres. It has a 14 ... read more
|Registration no: MH12 EM 6721
|Colour: Burgundy
|City: Pune
|Asking Price: 2,00,000
Tata Indigo Marina GLS BS-III (2007)
First class condition Well maintained Full Insurance Multipal choise fuel (PETROL/CNG) A good average of 22-24 KMPL 220-230 Kilometers with full tank of CNG Large dikky ... read more
|Registration no: GJ 5 CJ 2212
|Colour: Grey
|City: Surat
|Asking Price: 2,25,000
Upcoming Cars
Tata Megapixel
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User Reviews
Hyundai Verna Fluidic Reviews
Hyundai Verna engine ensures high performance that results in no vibration even at the speed of 140kmph and it can touch 195 kmph of highest speed. Hyundai Verna Fluidic 1.4L petrol engine delivers a mileage of 17.43 kmpl which is quite appreciable figure. Also, the fuel tank capacity of New Hyundairead more
Toyota Corolla Altis 2011 - 2014 Reviews
Driving this car for last three years. An awesome package of power and performance. Low maintenance cost. Features are very useful. Tank like built. Only fuel efficiency is a concernread more
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New Car Dealers
Urs Kar Service Centre (P) Ltd ( Tata)
Ch-47, Dewans Road Near Double Tank, Lakshmipuram 570 004, Lakshmipuram
Phone: 0821 - 2333776
Phone: 0821-2333432
Mobile: 9844065169 / 9845607686
Republic Hyundai ( Hyundai)
Commerce House, Line Tank Road, Sharda Babu Street, Commerce House
Phone: 0651-2301134
Phone: 0651-3091325
Used Car Dealers
Mithal Used Car Dealers
10-1/5/A/52, Masab Tank, Near Golconda Hotel, Hyderabad - 500028.Hyderabad, Masab Tank
Phone: 040 - 32999197
Mobile: 9441038719
Avis Motors
Opposite Mahaveer Hospital Lane, Shantinagar, Masab Tank, Hyderabad - 500028Hyderabad, Masab Tank
Phone: 040-65532555
Mobile: 9246538326


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New Sod lawn dying
I have a small 1200sft backyard lawn. I put new SOD lawn in februry 2010 with bolero plus (Dwarf Fescue + 5% blue grass). The lawn came up fine till April and then grass started turing brown.
Naively I put in scotts turf builder #2 & then ironite (1 whole 20lbs bag!!) probably I put too much of these. Now in 2 months grass is turing brown there are some dead patches.
I am wondering if any one can please advice what can i do for spreading brown patches, will this parch ever become green again or is it gone for good?
Needless to say I am new to gardening & love to work in my lawn, but i dont know what to do.
You probably will have to learn this one the hard way. There's no way to undo the effects of the fertilizer, etc. at this point.
Keep the remaining grass well watered so the sod continues to root well. Then wait until fall, put down seed in the bare spots, cover it with top soil, and water it well for a couple weeks (you cannot plant grass seed at this point of the summer, especially in a hot climate). Hopefully by next spring after the seed has had a chance to germinate all winter, the damage will not be so visible. At least the grass seed will have a good base in which to grow consisting of the dirt from the dead sod.
How did you prepare the ground before you put the sod down? Was it nearly smooth? Or were there rocks, twigs, etc.?
How did you apply the fertilizer? I hope it was with a spreader (one with wheels) with the correct setting and not with a hand spreader or just by throwing it.
Whoa, hold on a second. The advice of seeding a Bolero Plus lawn isn't exactly great. Here's how I would handle this situation.
First of all, are you on a sprinkler system? If not, I would seriously consider a system if you're wanting to keep a lawn in any kind of consistent shape. They're actually not that difficult to install yourself.
Second, do you want it to remain Bolero Plus? If you do then I would strongly suggest NOT seeding it. The problem with seeding is that Bolero Plus has the potential of a 6 foot root system whereas any seed you buy at a local store is usually never going to get to 1 foot little long 6 so you will always have grasses competing against one another.
If you want to remain Bolero Plus, I have a feeling that the problem you had initially lies in your soil preparation. If you planted your sod right on top of good old San Jose soil then you essentially planted it in clay.
I live in San Jose and have had to learn about the soil the hard way. If you run a ph test on the soil, it looks great, in fact it's fantastic but the fact remains, it's still clay. If you planted just in San Jose soil then you might as well rip up the entire mess because you will be fighting it forever. There will be constant brown spotting and all sorts of growing pains.
So I would suggest doing some soil removal if you have to because in this soil, you want amendment at about 70/30, meaning 70% amendment and 30% regular soil. It might seem high but go out and dig down about 6 inches and grab out enough soil to form a ball about the size of a baseball. Check out the consistency and you'll see what I'm talking about. If you rub your finger over the ball does it seem like the soil breaks loose easily? I bet it doesn't.
That's NOT what you want to plant sod into. So I suggest no less and 18 inches of amended soil. Also add in a good lawn fertilizer as your mixing in the amendment. Try to save enough prior to finishing to add another inch or two on the top because you want to tamp down this stuff, just a little, don't want it compacted but you want some of the air out of it too. That's what you'll use the 1 or 2 inches of left over for, to recover what you tamp down.
Now, when you lay the sod, have a very large bucket or something that you can place the entire roll of sod into. Fill it with water and sink the sod into it so that the water covers it completely. You'll see the air bubbles finally stop once it's soaked through. Don't be afraid to be a little rough on the soil side of the sod because the dirt that holds it together isn't always the best stuff to plant with.
(Repost possibly?)
Roll it out, tamp it down lightly. If the roll is moving around then you need to figure out a way to move it around until it stops moving. After you roll it all out, don't be afraid to water it, in fact a good soaking won't hurt at all. You also need to water it every day for about two weeks. I water my grass every day but it's simple because everything is electronic and I don't usually waste water. Good luck!


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I cant fault Riad Dar Othmane, I went with a friend and had a great time. Hassan (the riad owner) couldnt do enough for us. We were greeted with Orange Juice, Mint Tea and Water, which was great as it was 45 degree heat when we arrived! He also gave us a map and showed us around outside and made sure we didnt get lost. We got a really good price, and as there werent many other guests Hassan upgraded us for free. It's a good location, a reasonably easy 10 min walk to the main square. The riad overall was quite simple, but there's so much to do in Marrakech there's no reason to stay indoors. The room had air con, was clean and our beds were made daily. The breakfast was fine (tea, juice, bread and pancakes). Although small and quite basic, the riad was a beautiful and cosy place to stay after a busy day in the city.
- Reservation Options:
- TripAdvisor is proud to partner with Booking.com, Priceline and Odigeo so you can book your Riad Dar Othmane reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
- Also Known As:
- Riad Dar Othmane Marrakech


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Rescue your productivity from email overload!
A recipe for breaking free from the social trapping of electronic messaging
Art as a Reflection of Rising Economic Inequality
Monet, Matisse, and Picasso are fetching record breaking prices at auction
VIDEO: Overcoming the fear of failure is the new challenge of the modern manager
"The way we see failure is still very immature"
Priceline, Expedia and the Online Travel Agency Oligarchy
It's going to be harder than ever for hotels to capture their fair share of today's online travel customers
Greening up the city: challenges for real estate
On the occasion of the international real estate show MIPIM held in Cannes, Professor Ingrid Nappi-Choulet presents her analysis
The Old Girls Club: Gender Quotas and Women as Role Models
Men have a multitude of role models in upper-level positions to choose from in terms of designing their career paths. Women, on the other hand, have a much harder time identifying useful role models
VIDEO: Can you get great results from a virtual team?
Teamwork: you're only as close as you feel
Can we measure social entrepreneurship activity globally?
A bird's eye view to compliment case-based studies to take in
Has Netflix Got What it Takes to Dominate in France?
An Interview with Serge Hayat, co-President of ESSEC's Media and Entertainment Chair
Intangible Assets: How Should Organizations Measure and Report on Them?
Weighing-in on a debate that still divides the experts


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60 percent want Bush tax cuts extends, 28% don't
I've moved from the 60% to the 28%. While the latest Rasmussen poll finds that 60% of voters want Bush tax cuts extended because of the lousy economy, 28% don't want them extended. I've come to the conclusion that if Americans were stupid enough to give Obama a free pass on his first term failure, then lets give him and the rest of the Marxist Democrats what they want so they own it. Let the Bush tax cuts expire, let sequestration happen, and see how the economy 'takes off.'
http://www.fireandreamitchell.com/2012/11/12/60-percent-want-bush-tax-cuts-extends-28-dont/Political PollingTaxesPolitical Polling,Taxes
A new Rasmussen Reports national telephone survey shows that 60% of Likely Voters believe the government should extend the variety of tax cuts, including those implemented during the George W. Bush administration, past the end of the year. Just 28% believe Congress and the president should let those tax cuts expire. Another 12% are undecided.
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West Yarmouth Vacation Rentals(20)
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Recent West Yarmouth Reviews
The perfect place
Such a dream! The listing was accurate in describing this property, yet modest in how wonderful it is. The place was clean to a sparkle and had Christmas decorations (even stockings by the fireplace) for our holiday visit. The owner was so easy to work with and quick to reply before and during our stay. This property felt "like home" instantly and will surely be a favorite place to return to in the future.
Spectacular, comfortable, spacious and immaculate
Vacationing in this beautiful, fabulously decorated, clean and comfortable home is a MUST. The waterfront views are stunning from every angle. The owners are considerate and thoughtful and think of every way to make your stay memorable, relaxing, and perfect. From the professional kitchen to the wide picture windows, to the spacious decks and the immediacy of the ocean, you will never want to leave. Within walking distance to the downtown area (filled with restaurants and local shops) and far enough away from crowds, the home is in a private area with walkable and bike-friendly streets. I highly recommend this property to a large family or a group of friends getting together for a reunion. Each room has plenty of space, and common areas are abundant. Then there are nooks and crannies for reading, writing, and game playing. . . and to top it all off, you're fewer than fifty steps from the beach. We'll go back again and again and again, each time thrilled to be there!
Beautiful Location, Enjoyable Stay!
Dear Brian and Gail, It was a great week at your lovely home, perfect for relaxing away the last few days of summer. The weather was perfect, too! Your home is so comfortable and all the unique touches made it extra special - you thought of everything. Thank you for the gifts and your tips and advice. It was my first visit to Cape Cod and so enjoyable - I was very fortunate to have found you!


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Come out for one of the most unique beer experiences around. Tour not only the Christian Moerlein production facility, but also the 1850's John Kauffman Brewery as well. Taproom @ Christian Moerlein 1621 Moore St. Cincinnati, OH 45202
Come out for one of the most unique beer experiences around. Tour not only the Christian Moerlein production facility, but also the 1850's John Kauffman Brewery as well. Taproom @ Christian Moerlein 1621 Moore St. Cincinnati, OH 45202
Stay tuned for the announcement of the winners of 4 of these posters signed by all the collaboration brewers! #cbw15 pic.twitter.com/HUad1gjPG4
Happy Sunday & the last day of Cincinnati Beer Week makeup events. Where are you still finding #BlackTart? #cbw15 #overtime
Some Cincinnati Beer Week #tbt love for you! 2013 Fountain Square CBW kickoff! #cbw15 #cbw13 pic.twitter.com/3IC2puvuKR
We are still in @CincyBeerWeek #overtime, with more reschedule events on the calendar this week. Check it on the app or website! #cbw15
LAST CALL for your pictures of Cincinnati Beer Week 2015! You can win a #BlackTart poster signed by… instagram.com/p/zevdk0Idtv/
You can see these great rescheduled Cincinnati Beer Week events in our calendar at cincinnatibeerweek.com #cbw15 #overtime
Thank you to everyone who participated in Cincinnati Beer Week, whether as a attendee, volunteer, venue, wholesaler, or supplier! #cbw15
We'd also wish our friends at @nycbeerweek a great beer week! New York's beer week begins as ours is wrapping up, starting on 2/20/15 #cbw15
So you will be able to experience these great events on makeup dates over the next week thru March 1st! #cbw15
Some great events rescheduled due to the record-breaking, severe weather we unexpectedly experienced last week. #cbw15
Though this is officially the last day of the 2015 Cincinnati Beer Week, don't stop checking the calendar & website next week! #cbw15
Hope everyone is enjoying the last official day of the 2015 Cincinnati Beer Week! What beers are you celebrating with? #cbw15
Carpe Diem! TODAY is the LAST official day of the Cincinnati Beer Week! Enjoy great events & make it count! cincinnatibeerweek.com/events/2015-02… #cbw15
RISE AND SHINE! It's the last day of Beer Week - get out and make it count! Cheers to all for such a great week!
Lots of great events today! Just a reminder to call the venue before heading out to confirm it has not been affected by bad weather! #cbw15
Today, weather in Greater Cincinnati calls for a 100% chance of @CincyBeerWeek & a 100% chance of awesomeness. cincinnatibeerweek.com/events/today/ #cbw15
Only a few more days to get your @CincyBeerWeek @untappd badge! cincinnatibeerweek.com/2015/02/2015-c… #cbw15 #untappd
@brewnas @RivaWCPO @WCPO @NeroWCPO @zac_pitts Registered on-premise/off-premise venues are on our website: cincinnatibeerweek.com/venues/ #cbw15
We are more than halfway through @CincyBeerWeek! But you've still got many great events ahead! Today's events: cincinnatibeerweek.com/events/today/ #cbw15


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World's Largest Aftermarket Motorcycle Parts and Accessories Superstore!
Input the part number and quantity to add a part directly to your cart.
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It would be nice if it hold the air pressure reading when removed
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Great gauge / very accurate
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List any tickets you may have that you wish to give away or that you really need and hope someone has. Also, list info for EVENTS you'd like to share that others may like. *For Scottsdale, Phx, Tempe, Peoria, Glendale, etc. BE FRIENDLY!
Website: http://txtmovieclub.com
Location: Arizona
Members: 1175
Latest Activity: 42 minutes ago
Started by Shari K. Green on Wednesday. 0 Replies 0 Favorites
Started by j24young Jul 18, 2011. 41 Replies 25 Favorites
VIP rarely has hard passes. Usually you get on a list...
I will call first just to see if they still have some left
© 2015 Created by txtMovieClub.


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The Socialist International's (SI) meeting on the Arab Spring, scheduled to span two days, started in İstanbul on Friday.
The Special Committee on the Arab World meeting is being hosted by the main opposition Republican People's Party (CHP) on March 23-24 in İstanbul. The meeting started today at 10 a.m.
Representatives and leaders of SI member countries, as well as bloggers from Tunisia, Egypt, Libya and Syria, are expected to participate to the meeting.
Releasing a written statement on the meeting on Thursday, CHP Deputy Chairman Faruk Loğoğlu told the Anatolia news agency that the meeting was organized to discuss social-democratic approaches to the transformation process in the Arab world and to discuss the Syrian regime's recent bloody crackdown on protesters in that country.
A Turkish Airlines flight from Istanbul to Sao Paulo makes emergency landing in Casablanca.
President Erdogan has said that he plans to visit Iran but will be watching the developments in Yemen
Turkish dailies on Monday focused on the main opposition CHP party's interal primary elections.
The 300-million Turkish lira vessel will serve for at least 30 years.
Presidential system is the right thing for Turkey, says Turkish PM Ahmet Davutoglu
Armenian experts talking to The Anadolu Agency believe the two historically hostile countries could start a new phase after 2015.
Alimoglu said the NGO would occasionally dispatch doctors from Turkey to Gaza for difficult cases that Gazan doctors could not treat or that required competencies not available in the enclave.
Prosecutors said the Tuvalu-registered 5,095 deadweight tonne ship Kanton was being held in the Ukrainian port of Kherson. They said the crew could go to jail for up to three years and the ship could be seized.
Yalcin Akdogan said the support for the solution process is beyond AK Party's electoral base.
Saudi King shares information with Turkish President about military operation and airstrikes against Houthis.
-Minister of Economy Nihat Zeybekci says Turks and Tatars have blood ties, and so need to further each others' interests.
Turkish dailies on Friday mainly focus on the latest developments on Tuesday's deadly plane crash in the French Alps plus the escalating crisis in Yemen
A campaign to train Syrian opposition forces to fight hardline ISIL militants, which was due to start this month, has been delayed by Washington, Turkey's foreign minister said on Friday.
The legislation has sparked fierce criticism from opposition parties who say the ruling AK Party is becoming more authoritarian. Members of Turkey's restive Kurdish minority say the law could be used to target them.
The rocket that was fired by Syrian government forces across the Turkish border on March 24 exploded in the Reyhanlı district of the southern province of Hatay.
Turkey's biggest and Europe's third biggest Synagogue unveils 46 years later over restored for Jewish population


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Catherine Zeta-Jones
Michael Douglas Wears His Wedding Ring in France
Originally posted 08/31/2013 11:30AM
Ring it on!
Despite reps confirming that Michael Douglas, 68, and Catherine Zeta-Jones, 43, "are taking some time apart to evaluate and work on their marriage," the actor was photographed wearing his wedding ring at a press conference for his film Behind the Candelabra in Deauville, France, on Saturday.
"He was adorable," a source tells PEOPLE. "He was simply amazed at how well received the film was. I think this is really the first real audience screening since Cannes and he was awed."
Douglas, who the source says "was in an exceptional mood," was very friendly to the other people in attendance.
Duhamel Delivery Alert! Fergie and Josh Are Finally Parents – and Catherine Zeta-Jones and Michael Douglas Split
Originally posted 08/31/2013 09:00AM
It was the vacation photo that went viral – and wowed PEOPLE readers. A pic of former Marine Jesse Cottle, a double amputee, being carried by his wife, Kelly, was inspiring as a portrait of unconditional love and support.
Here are the five stories that sparked the strongest reactions from readers this week – the news that made you happy, sad, laugh out loud, angry and even saying "Wow."
Let us know what you think by clicking on the emoticons at the bottom of every story.
Michael & Catherine: Their Marriage Ups & Downs
Originally posted 09/24/2013 12:10PM
See the challenges and victories they've faced in their nearly 13 years as husband and wife
Michael Douglas Set to Return to Where He First Met Catherine Zeta-Jones
Originally posted 08/28/2013 04:40PM
Michael Douglas is about to take a sentimental journey back to the place where he first met his wife, Catherine Zeta-Jones.
As PEOPLE broke the news that the couple have separated, the Wall Street Oscar winner was in France, where he was spotted having dinner with friends at La Petite Maison in Nice on Tuesday night.
A source tells PEOPLE that the 68-year-old has been spending time in the South of France with his billionaire friend Jean Pigozzi, but will be flying out in a couple of days to attend the Deauville Film Festival in northern France.
Michael Douglas and Catherine Zeta-Jones Separate
Originally posted 08/28/2013 07:30AM
Michael Douglas and Catherine Zeta-Jones haven't been photographed together since April 22. They've walked red carpets solo, vacationed separately with their kids, and in recent days, Douglas has been relaxing on a yacht off the coast of Sardinia – with Zeta-Jones at home in New York.
So what's really going on with one of Hollywood's most celebrated couples? In this week's new cover story, two close confidantes tell PEOPLE that they've decided to take time apart: "They're taking a break," one source says.
Neither star has filed for divorce or moved toward a legal separation, sources say.
This Week's Best Dressed Star Has a Leg Up on the Competition
Originally posted 07/20/2013 09:05AM
See what sexy gown nabbed the top spot on our Most Loved Looks list
Catherine Zeta-Jones Stuns at First Red-Carpet Appearance Post-Treatment
Originally posted 07/12/2013 11:45AM
Catherine Zeta-Jones is back – and she looks more jaw-dropping than ever.
The Welsh actress, 43, wowed on Thursday night as she strolled the red carpet for the Red 2 premiere in Westwood, Calif., in a strapless, lacy black dress that showed off her fit physique.
It was one of Zeta-Jones's first public appearances – and her first on a red carpet – since voluntarily checking in to a treatment facility for further help managing her Bipolar II disorder, which she first revealed in 2011.
Catherine Zeta-Jones Returns Home from Treatment
Originally posted 05/23/2013 10:30AM
Catherine Zeta-Jones is home from treatment for her Bipolar II disorder, after having checked herself into a facility last month for what her husband described as a "10,000 mile check-up."
The Oscar-winning actress was spotted out driving in New York on Tuesday.
Zeta-Jones, 43, bravely revealed her diagnosis in 2011, telling PEOPLE at the time, "This is a disorder that affects millions of people and I am one of them."
She continued, "If my revelation of having Bipolar II has encouraged one person to seek help, then it is worth it. There is no need to suffer silently and there is no shame in seeking help."
Catherine Zeta-Jones Returns Home from Treatment for Bipolar II Disorder
Originally posted 05/20/2013 09:45PM
Michael Douglas is hard at work in Cannes to promote his HBO film, Behind the Candelabra, but he is ready to be back home with his wife, Catherine-Zeta-Jones, who just completed her ongoing treatment for Bipolar II disorder.
"She comes home tomorrow," he told PEOPLE on Monday. "She's doing a really good job of getting balanced. I'm proud of her."
The actress, 43, entered treatment for the second time in April as Douglas, 68, was beginning to generate praise for his role as the flamboyant piano player and vocalist, Liberace.
Michael Douglas Says Kissing Matt Damon in Behind the Candelabra Was 'Comfortable'
Originally posted 05/12/2013 09:00PM
Many dream of kissing Matt Damon, but Michael Douglas is one of the lucky few who has actually done it. But for him, it was simply part of the job.
"Once you get that first kiss in, you are comfortable," Douglas, who stars as pianist Liberace in HBO's Behind the Candelabra, tells New York magazine in its latest cover story (on newsstands May 13).
"Matt and I didn't rehearse the love scenes. We said, 'Well – we've read the script, haven't we?' "
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Latest Exciton Stories
Physicists at the University of California-San Diego say they've created speedy integrated computer circuits capable of working in very cold environments. The circuits, built with particles called excitons, can operate at commercially cold temperatures, bringing the possibility of a new type of extremely fast computer based on excitons closer to reality, researchers said. The accomplishment follows the team's demonstration last summer of an integrated circuit capable of working at 1.5 degrees...
Physicists at UC San Diego have successfully created speedy integrated circuits with particles called "excitons†that operate at commercially cold temperatures, bringing the possibility of a new type of extremely fast computer based on excitons closer to reality.
EDMONTON, Aug. 5 /PRNewswire/ - Exciton Technologies Inc.
New research by a team of University of Toronto scientists could lead to substantial advancements in the performance of a variety of electronic devices including digital cameras.
Researchers at the Harvard School of Engineering and Applied Sciences (SEAS), in collaboration with researchers from Worcester Polytechnic Institute (WPI), have demonstrated, for the first time
Research led by the University of Warwick has found a way to use doughnut shaped by-products of quantum dots to slow and even freeze light, opening up a wide range of possibilities from reliable and effective light based computing to the possibility of "slow glass".
By Xu, Zhihua Zang, Huidong; Hu, Bin Organic semiconducting materials have demonstrated attractive light-absorption and photocurrent-generation functions due to their delocalized pi electrons as well as intra-molecular and inter- molecular charge separation processes.
Imagine a technology that would not only provide a green and renewable source of electrical energy, but could also help scrub the atmosphere of excessive carbon dioxide resulting from the burning of fossil fuels. That's the promise of artificial versions of photosynthesis, the process by which green plants have been converting solar energy into electrochemical energy for millions of years. To get there, however, scientists need a far better understanding of how nature does it, starting...
Unsurpassed exciton distances, lifetimes may lead to new form of optical communication.
- To play, gamble.
- To impose upon; delude; trick; humbug; also, to joke; chaff.
- A deceitful game or trick; trickery; humbug; nonsense.


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Everything is positive!!! - Anonymous
well-equiped and new apartment with balcony, walking distance to the old-town, parking nearby - Anonymous
Beautiful and calm place, view to the bay and sea, even from the studio, beach is close enough (about 2 minuites). Mediterrean atmosphere, nice house with good style, clean and brand new furnitures, very friendly and helpful owner. We had a wonderful holiday there, thank you. - Anonymous


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Get the Best Priced Buick Apollo Valve Cover Gasket
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Buick Apollo Replacement Valve Cover Gasket Information
Search our online valve cover gasket catalog and find the lowest priced discount auto parts on the web. We sell wholesale to the public. We offer high quality new, OEM, aftermarket and remanufactured Buick Apollo Valve Cover Gasket parts. We specialize in a wide-variety of high-quality car parts and accessories for your car, truck or SUV. Call toll free to order or place your order online via our secure checkout system. Our online parts catalog uses real-time inventory, so you can be assured the parts you buy are in stock at the time of ordering. Most orders are shipped the same day. They are available for the following Buick Apollo years: 1975, 1974, 1973, 75, 74, 73. This part is also sometimes called Buick Apollo Valve Cover Gaskets. We stock valve cover gasket parts for most Buick models including Park Avenue, LeSabre, Regal, Riviera, Lucerne, Century, Super Series 50, Super, Electra, Roadmaster, Rendezvous, Gran Sport, Reatta, Special, Centurion, GS 455, GS 350, Skylark, Wildcat, Estate Wagon, Skyhawk, LaCrosse, Rainier, Enclave, Terraza, Invicta, GS, Allure, Sportwagon, GS 400, Commercial Chassis, Special Series 40, Special Series 40A, Limited, Somerset, Opel and Somerset Regal.
We stock these Valve Cover Gasket brands for the Buick Apollo: Felpro and VR Gaskets.
73 1973 Buick Apollo Engine Mount 4.1L 6 Cyl Left Energy Suspension
75 1975 Buick Apollo Exhaust Manifold Gasket 4.1L 6 Cyl Felpro
75 1975 Buick Apollo Engine Harmonic Balancer 4.3L V8 Dorman
75 1975 Buick Apollo Head Gasket 5.7L V8 VIN: H Mr Gasket
73 1973 Buick Apollo Intake Manifold Gasket Set 5.7L V8 VR Gaskets
75 1975 Buick Apollo Oil Cooler 4.1L 6 Cyl Hayden
75 1975 Buick Apollo Oil Filter 4.1L 6 Cyl VIN: D 1BBL Fram
75 1975 Buick Apollo Oil Pump 4.1L 6 Cyl Sealed Power
75 1975 Buick Apollo Piston Ring Set 4.1L 6 Cyl Sealed Power
75 1975 Buick Apollo Timing Chain Center 5.7L V8 VIN: H Cloyes
74 1974 Buick Apollo Timing Cover 5.7L V8 Spectre Performance
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