Background: The current proposed model of colorectal tumorigenesis is based primarily on CpG island methylator phenotype (CIMP), microsatellite instability (MSI), KRAS, BRAF, and methylation status of 0-6-Methylguanine DNA Methyltransferase (MGMT) and classifies tumors into five subgroups. The aim of this study is to validate this molecular classification and test its prognostic relevance. Methods: Three hundred two patients were included in this study. Molecular analysis was performed for five CIMP-related promoters (CRABP1, MLH1, p16INK4a, CACNA1G, NEUROG1), MGMT, MSI, KRAS, and BRAF. Methylation in at least 4 promoters or in one to three promoters was considered CIMP-high and CIMP-low (CIMP-H/L), respectively. Results: CIMP-H, CIMP-L, and CIMP-negative were found in 7.1, 43, and 49.9% cases, respectively. One hundred twenty-three tumors (41%) could not be classified into any one of the proposed molecular subgroups, including 107 CIMP-L, 14 CIMP-H, and two CIMP-negative cases. The 10 year survival rate for CIMP-high patients [22.6% (95%CI: 7–43)] was significantly lower than for CIMP-L or CIMP-negative (p = 0.0295). Only the combined analysis of BRAF and CIMP (negative versus L/H) led to distinct prognostic subgroups. Conclusion: Although CIMP status has an effect on outcome, our results underline the need for standardized definitions of low- and high-level CIMP, which clearly hinders an effective prognostic and molecular classification of colorectal cancer.
Jass (2007) proposed a molecular classification of colorectal cancer based predominantly on five features: CpG island methylator phenotype (CIMP), microsatellite instability (MSI), KRAS, BRAF, and methylation status of 0-6-Methylguanine DNA Methyltransferase (MGMT). The new classification was composed of five molecular subtypes, with the largest group including mostly CIMP-negative, chromosomally instable (CIN), microsatellite stable (MSS) colorectal cancers (57% of cases). In addition, CIMP-low (CIMP-L), KRAS mutated, MGMT methylated, MSS/MSI-low (MSI-L) cancers were predicted in 20% of cases, while CIMP-H, BRAF mutated, MSI-H tumors in 12%, CIMP-H, BRAF mutated, chromosomally stable, MSS/MSI-L in 8%, and finally, the hereditary Lynch syndrome CIMP-negative, BRAF mutation-negative, chromosomally stable, and MSI-H cancers found in 3% of all cases. Indeed, these new subgroupings form the basis of the current model of colorectal tumorigenesis.
To date, the prognostic relevance of Jass's proposed groupings, particularly those arising in the sporadic context, has not yet been tested. As single molecular entities, KRAS mutations and MSI have been intensively investigated, while mutations in BRAF and analysis of CIMP are fewer (Andreyev et al., 1998; Boland and Goel, 2010). Less than a handful of studies have evaluated the prognostic relevance of MGMT (Shima et al., 2011). CIMP-H and MSI-H colorectal cancers seem to share similar features including proximal tumor location, mucinous histological type, poorer tumor grade, and BRAF mutation, but they may be inter-dependent in terms of their prognostic effects (Ogino et al., 2009; Sanchez et al., 2009; Dahlin et al., 2010). Patients with MSI-H cancers may benefit from a decreased rate of distant metastasis and longer survival time when compared to their MSS counterparts (Kloor et al., 2010) whereas patients with CIMP-H cancers particularly in the MSS context seem to have a considerably more unfavorable outcome (Ward et al., 2003; Dahlin et al., 2010; Kloor et al., 2010). Also, BRAF mutated cancers may lead to poorer survival time in MSS cancers only (Samowitz et al., 2006).
The aim of this study was first to classify a cohort of 302 colorectal cancers according to the proposed molecular classification based on CIMP, MGMT methylation, KRAS and BRAF mutation, and MSI and then, to test its prognostic value.
About 1420 primary pre-operatively untreated, unselected sporadic colorectal cancer patients treated between the years 1987 and 1996 were initially included in this study. Hematoxylin and eosin (H&E) stained slides were retrospectively collected from the Institute of Pathology, University Hospital of Basel, the Institute of Clinical Pathology, Basel, Switzerland, and the Institute of Pathology, Stadtspital Triemli, Zürich, Switzerland. From this larger subgroup, only 600 paraffin-embedded tissue blocks could be retrieved. Histopathological criteria were reviewed by an experienced gastrointestinal pathologist. The tumor border configuration (pushing/expanding or infiltrating) as well as the presence of peritumoral lymphocytic inflammation at the invasive tumor front were scored according to Jass (1986). Clinical data including patient age at diagnosis, tumor location, and follow-up were retrieved from patient records. Clinical outcome of interest was cancer-specific survival time. Censored observations included patients who were alive at the last follow-up, died for reasons other than colorectal cancer or were lost to follow-up. Patient characteristics are summarized in Table 1. The use of material for this study was approved by the ethics committee of the University Hospital of Basel.
Table 1. Patient characteristics (n = 337).
In order to identify regions for punching and DNA extraction, neoplastic, and adjacent non-neoplastic tissue areas were marked on the H&E slide by an experienced pathologist (A.L) with pens of two different colors. Only blocks with >70% tumor content were used for this purpose.
Genomic DNA was obtained from both primary tumors and adjacent non-neoplastic tissues using NucleoMag 96 Tissue Kit (Macherey Nagel) protocol and processed in the Xiril X-100 robot (Xiril, Hombrechtikon, Switzerland). Briefly, punched tissue was lysed in proteinase K. B-beads and MB2 buffer were added to the cleared lysate, shaken for 5 min at RT. The supernatant was removed and MB3 buffer was added followed by shaking and supernatant removal. The genomic DNA was eluted with MB6 buffer. Genomic DNA was amplified by PCR using AmpliTaq Gold polymerase (Applied Biosystems). KRAS (exon 2 codon 12 and 13) and BRAF (exon 15 codon 600) were amplified by a first and a nested PCR. Residual primers were removed using the EXOSAPit (Amersham). Samples were then subjected to direct sequencing of single-stranded PCR products using the BigDye® Terminator v1.1 cycle sequencing kit (Applied Biosystems, Foster City, CA, USA) and the ABI Prism® 3130 genetic analyzer (Applied Biosystems). All products were sequenced bi-directionally. Analysis of MSI status was based on the multiplex amplification of the five microsatellites (BAT25, BAT26, D2S123, D5S346, D17S250). An initial denaturation step at 95°C for 10 min was followed by 42 cycles at 95°C for 40 s, 54°C for 40 s, and 72°C for 60 s. For the analysis, 1 μl of the DNA weight marker ROX 500 (Applied Biosystem) was added and 10 μl of deionized formamide in 3 μl of the PCR amplified solution. DNA was denaturated by incubation for 2 min at 95°C. The POP-7 polymer solution (Applied Biosystem) was used for the electrophoresis on the ABI Prism® 3130 genetic analyzer (Applied Biosystems). MSS and MSI-L status were defined as instability at zero and one microsatellite, respectively. MSI-H was characterized by the presence of instability in 40% (≥2 markers; Umar et al., 2004).
DNA denaturation and bisulfite conversion were processed into one-step using the EZ-96 DNA Methylation-GoldTM Kit (Cat. No. D5007, Zymo Research Corporation) according to manufacturer's instructions. Briefly, 130 μl of the CT conversion reagent were added to 20 μl of each DNA sample in a conversion plate. The plates were sealed with the provided film and the conversion plate transferred to a thermal cycler running under the following steps: 98°C for 10 min, 53°C for 4 h, storage at 4°C. Four hundred microliters of M-Binding Buffer were added to the wells of a Silicon-A™ Binding Plate. The samples were transferred from the conversion plate to the wells of the Silicon-A™ binding plate and centrifuged at 3,000 × g for 5 min. Each well of the plate was washed using 400 μl of M-wash buffer. The samples were centrifuged at 3,000 × g for 5 min. 200 μl of M-Desulphonation buffer was added to each and the plate was placed at room temperature for 20 min followed by centrifugation (3,000 × g for 5 min). Two consecutive steps including washing (400 μl of M-wash Buffer) and centrifugation (3,000 × g for 5 min) were performed. The Silicon-A™ binding plate was placed onto an elution plate and 30 μl of M-Elution buffer was directly added to each well. 5 min later, the samples were centrifuged at 3,000 × g for 3 min to elute the DNA. For control of DNA methylation, Universal Methylated Human DNA Standard was used (Cat. No. D5011, Zymo Research Corporation).
For the first and the nested PCR, 50 cycles of amplification was performed. Two microliters of the modified DNA was added in a volume of 25 μl containing the dNTPs (0.2 mM final), PCR Gold Buffer (1× final, Applied Biosystem), PCR primers (0.12 μM), and 0.2 μl of Taq polymerase (ampliTaq Gold, Applied Biosystem). The nested PCR is performed under the same condition by addition of 1 μl of the amplicon in 25 μl of master mix.
Promoter methylation was assayed for the five CIMP-related genes [CRABP1 (HGNC: 2338), MLH1, p16INK4a, CACNA1G, NEUROG1] as well as for MGMT. For the first and the nested PCR, 50 cycles of amplification were performed. Primer sequences are listed in Table 2.
Three microliters of Sepharose beads were mixed together with 40 μl of binding buffer and 22 μl of water and mixed in an Eppendorf tube. Sixty microliters of this mix was added to 20 μl of PCR products in a 96 well plate and agitated at 1400 rpm for 5 min. The PyroMark Q96 Plate was filled with 0.3 μM of sequencing primer in 40 μl of annealing buffer. The washed were performed using the vacuum station according to the manufacturer instruction. For annealing the samples to sequencing primers, the temperature was increased to 80°C for 2 min and rapidly cooled to room temperature. Plates were then ready for processing in the PyroMarkQ96 instrument.
Pyrosequencing of the purified single-stranded PCR products and CpG site quantification was accomplished by the PyroMarkQ96 and related software (Qiagen). Four to six CpG sites were evaluated for each gene in both neoplastic and corresponding non-neoplastic tissue. Since this method is quantitative, each CpG site is assigned a percentage of methylation. The final CpG score for the tumor or non-neoplastic tissue is represented as the average percentage methylation across all CpG sites for that gene. A tumor-specific methylation score can then be assigned by subtracting out any background methylation from the adjacent non-neoplastic tissue from the tumor's CpG score. This method for calculation is summarized in Figure 1. Although the non-neoplastic mucosa is expected to be non-methylated, age-related methylation, and background can still occur (Issa, 2000). The threshold tumor-specific methylation score for considering a case as methylation positive was >30% (minimal difference between tumor and non-neoplastic mucosa). This cut-off score was based on the measured and theoretical percentage of methylation observed at different numbers of PCR amplification cycles using commercially available DNA (unmethylated and 100% methylated, Qiagen) and combinations of the two, resulting in varying degrees of methylation (0, 0.1, 0.3, 1, 3, 10, 30, and 100%). According to these findings, background methylation can be 10% suggesting that a minimal difference in methylation of 20% (10% for tumor and 10% for non-neoplastic) should be used to define methylation-positivity above background. Here, we have used a more stringent criterion of 30% to ensure with even greater certainty a significant degree of methylation. CIMP-H was defined as methylation in ≥4/5 gene loci, while CIMP-L and CIMP-negative were defined as methylation in one to three genes and no gene methylation, respectively.
Figure 1. Method of calculation used for determining methylation status. The pyrograms show percent methylation at five CpG sites in a colorectal cancer and its corresponding normal mucosa; the individual CpG scores are averaged for each. The mean percent methylation from the normal tissue is subtracted from the mean percent methylation of the tumor to give a tumor-specific methylation score. If this final score is ≥30%, then the tumor is considered methylated, otherwise it is considered negative for methylation.
Univariate survival analysis was performed using the Kaplan–Meier method and log-rank test (SAS V9.2; The SAS Institute, Cary, NC, USA). Re-classification of patients into prognostic molecular subgroups was performed using classification and regression tree (CART) analysis with survival status at 10 years follow-up as outcome of interest. To measure the classification error as a function of tree size, 10-fold cross-validation experiments were performed (DTREG Predictive Modeling Software, www.dtreg.com).
From the 600 cases initially investigated, molecular characterization for CIMP was possible in 337 patients. This was due to the lower quality of DNA which could be extracted from older paraffin-embedded tissues. The frequency of methylation using the proposed criteria were 16% for CDKN2A, 14% for CACNA1G, 17% for MLH1, 18% for CRABP1, 22% for NEUROG1. Twenty-four patients (7.1%) were CIMP-H, 145 (43%) CIMP-L, and 168 (49.9%) CIMP-negative. KRAS and BRAF mutational analysis could be made in 325 and 314 patients, respectively while MGMT and MSI analysis was possible in all 337 cases. Thirty-three percent of patients were methylated for MGMT and 16.6% had MSI-H tumors. All molecular features could be analyzed in 304 cases. The frequencies of KRAS and BRAF mutation were 30.5 and 13.3%, respectively while of MSI and MGMT methylation was 16.6 and 33.2%.
Tumors were then classified into each of Jass Groups 1–5 (Figure 2). In Jass Group 1, only six patients (2%) were CIMP-H, BRAF mutated and MSI-H, compared to the predicted 12%. In Group 2, there were five patients (2%) with CIMP-H, BRAF mutated MSS/MSI-L cancers, compared to the predicted 8%. Next, 13 cases (4%) could be classified into Jass Group 3 containing CIMP-L, MSS/MSI-L, KRAS mutated, and MGMT methylated tumors, rather than the predicted 20%. Group 4 remained the largest group with 45% of patients (n = 137) showing CIMP-negativity, MSS/MSI-L. Finally, Group 5 contained 18 patients (6%) with CIMP-negative, BRAF WT, MSI-H cancers. Interestingly, 41% (n = 124) of tumors could not be classified into any of the proposed groupings including the remaining 107 (35.4%) CIMP-L cases, 14 CIMP-H, BRAF WT (4.6%), and four CIMP-negative, BRAF mutated, MSI-H (1.3%).
Figure 2. Attempt to classify 302 colorectal cancers into the proposed Jass Groups 1–5. Forty-one percent of all cases could not be assigned to any one of these subgroups. In parentheses, the asterisk identifies the predicted percentage of patients belonging to each group.
The median survival time of the entire cohort was 63 (95%CI: 46–84) months. Patients with CIMP-H colorectal cancers were found to have a significantly lower 10 year survival rate [22.6% (95%CI): 7–43)] compared to both CIMP-L [34.8% (95%CI): 26–43] and CIMP-negative [43.4% (95%CI): 34–53] cancers (p = 0.0248; Figure 3A). This unfavorable prognostic effect occurred in MSS/MSI-L (p = 0.0532) and showed a trend in MSI-H (p = 0.2515; Figures 3B,C). In contrast, no difference in survival time was noted for patients with MGMT methylated or unmethylated tumors (p = 0.4966; Figure 3D).
Figure 3. Kaplan–Meier survival curves showing survival time differences for patients with CIMP-H, CIMP-L, and -negative tumors (A) in the whole patient cohort, (B) in microsatellite stable or instable-low (MSS/MSI-L) and (C) in microsatellite instable-high (MSI-H) cases, and (D) for patients stratified by MGMT status.
Of the 304 fully molecularly characterized patients, 302 had survival time information and were entered CART analysis. This approach was used to classify patients into prognostic groups using 10 year survival as the clinical endpoint (Figure 4A). BRAF gene mutation was identified as the most important parameter and classified as a single group. Patients with BRAF WT tumors were further discriminated based on CIMP status; patients with any methylation of CpG islands (CIMP-H and CIMP-L) formed a separate prognostic group. CIMP-negative patients were further subdivided by KRAS gene status. The remaining classification by MSI or MGMT methylation yielded little additional discrimination. The frequency of these subgroups is shown in Figure 4B. Ten year survival for the most important subgroups underline a rate of 10% (95% CI: 1–32; n = 30) for patients with BRAF mutated tumors, followed by 38% (95%CI: 29–47; n = 118) for BRAF WT, CIMP-H, or CIMP-L tumors, then 50% (95%CI: 32–62; n = 112) for BRAF WT, CIMP-negative, KRAS WT cases, and 55% (95%CI: 23–72; n = 42) for BRAF WT, CIMP-negative, KRAS mutated cases. Hence, three major groups of patients were identified: BRAF mutated, CIMP-H or CIMP-L, and CIMP-negative (p = 0.034).
Figure 4. (A) Analysis of the five molecular features using classification and regression tree analysis shows the hierarchy of most discriminating alterations and prognostic subgroups, namely subgroup 1: BRAF mutation, subgroup 2: CIMP-high, and CIMP-low and subgroup 3: CIMP-negative. KRAS, MGMT, and MSI contribute only little additional prognostic information. (B) Frequencies of each new subgroup.
Our results suggest that Jass's model of colorectal cancer cannot effectively classify patients from the institutes included in this study into molecular subgroups. Here, we analyze the reasons for this discordance.
We used pyrosequencing rather than MethyLight or methylation-specific PCR (MSP) to quantify methylation at CpG islands. This is a novel yet validated method for investigating CpG site methylation from paraffin-embedded tissues (Colella et al., 2003; Tost et al., 2003; Potapova et al., 2011). In contrast to MethyLight and MSP, each CpG site is assigned a percentage of methylation. This has several advantages; among others, it allows us to take into consideration the background methylation of the adjacent non-neoplastic tissue and assign a tumor-specific methylation score by subtracting out this signal. This is particularly interesting in the case of CDKN2A where age-related methylation can occur more frequently (Toyota et al., 1999).
In this study we evaluated the following five CIMP genes: CACNA1G, NEUROG1, CDKN2A, CRABP1, and MLH1. Not only has this same panel been used in previous studies (Ogino et al., 2006), but a comparison study of the performance characteristics of these genes has shown them to be reliable for the detection of CIMP phenotype (Ogino et al., 2007). Although we used a stringent criterion for determining methylation-positivity of each gene (minimal 30% difference between tumor and non-neoplastic CpG methylation), we nonetheless obtain rates comparable to those published by others. Our frequency of 16% for CDKN2A is slightly lower than that of Ogino and Nosho using MethyLight assays (29, 30%) but similar to Ahn et al. (2011) and also Yu et al. (2008) using pyrosequencing (16 and 20%, respectively; Ogino et al., 2007; Nosho et al., 2008). Our finding of methylation in 33% MGMT, 22% for NEUROG1, and 14% for CACNA1G is similar to the 38, 32, and 13% reported by Nosho and Lee while the 17% obtained for MLH1 is also within the expected range documented by others (6–28%; Ogino et al., 2007; Lee et al., 2008; Nosho et al., 2008; Ahn et al., 2011).
We defined CIMP-H and CIMP-L as at least four/five and one to three methylated genes, respectively. Dahlin et al. (2010) characterized CIMP-L and CIMP-H as hypermethylation in one to five and six to eight genes using the MethyLight method. Jover et al. (2011) considered CIMP+ as aberrant methylation in at least three/five genes (25% CIMP+ rate). Kim et al. (2010), also using pyrosequencing show a CIMP+ rate of 35.8% when considering hypermethylation of at least two/seven genes while Van Rijnsoever et al. (2003) report a 32% CIMP + rate referring to at least two/three methylated sites. Finally, Ogino et al. (2009) used an eight-marker panel and defined CIMP-H as at least six/eight methylated promoters by MethyLight assays. There is to date no consensus regarding the number of methylated genes to be included in the definition of CIMP.
Our frequency of CIMP-H and -L is 7.1 and 43%, respectively. Dahlin et al. (2010) evaluated three prospective European population-based cohorts (together termed the Northern Sweden Health and Disease Study, NSHDS) followed by a second expanded series (Colorectal cancer in Umeo Study, CRUMS) including 190 and 414 patients. Stratifying by MSS status, they report a 7.4 and 6.8% CIMP-H rate in the MSS and MSI tumors of the NSHDS and 3.0 and 8.8% CIMP-H rate for MSS and MSI tumors, respectively in the larger CRUMS. Therefore, although the frequency of CIMP-H in this study is lower than expected, it is in accordance with these larger European studies. More importantly, the poor prognostic effect observed here in patients with CIMP-H and CIMP-L tumors in comparison to those showing CIMP-negativity agrees with several works from other authors (Ward et al., 2003; Kim et al., 2009; Dahlin et al., 2010). In addition, our findings show no association of MGMT methylation with prognosis, a result which was also recently observed by Shima et al. (2011).
A recent review by Curtin et al. (2011), stresses that in contrast to the relatively straightforward determination of MSI tumor status, a consensus panel of CpG sites for CIMP determination has not yet been made. To date, studies evaluating CIMP have shown considerable variability in the selection of CIMP-related promoters, definition of threshold values, and variation in the number of methylated genes to define CIMP-L and CIMP-H. In this study 41% of all cases could not be classified into any one of Jass's five proposed molecular subgroups. Eighty-six percent of these unclassifiable cases were CIMP-L and 11% CIMP-H. This finding stresses again that the definition of CIMP status can significantly compromise the validation of a molecular classification of colorectal cancer based on three categories of CIMP. One possibility would be to evaluate CIMP-negative versus CIMP+ tumor, regardless of the degree of methylation. Supporting this further, our study here shows that in the case of BRAF wild-type patients, CIMP-L, and H cancers segregate together in CART analysis.
Although evidence suggests that CIMP not only plays a major role in the pathogenesis but also in the prognosis of patients with colorectal cancer, an effective classification is clearly hindered by the definition of high and low-level CIMP. The selection of promoter regions, number of CpG sites, analysis method and cut-off values leading to standardized definitions of CIMP status all warrant considerable investigation.
The authors would like to thank Dr. Andreas Papassotiropoulos, Biozentrum, University of Basel, for technical support on this project. This study was supported by the Krebsliga beider Basel (Gesuch 03-2007). The study sponsor did not have any role in the conception, carrying out or decision to publish this manuscript.
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Accepted: 16 January 2012; Published online: 27 February 2012.
Copyright: © 2012 Zlobec, Bihl, Foerster, Rufle, Terracciano and Lugli. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
†Inti Zlobec and Michel P. Bihl have contributed equally to this work.


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AJ McLean Net Worth
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AJ McLean Net Worth: AJ McLean is an American musician, dancer and actor who has a net worth of $45 million. A.J. McLean has earned his net worth as a singer in the group the Backstreet Boys. Born Alexander James McLean in West Palm Beach, Florida, in 1978, AJ McLean began acting when he was eight years old with a part in the 1986 movie "Truth or Dare". He and his mother moved to Orlando so AJ could continue pursuing his career, and he scored parts on "Welcome Freshmen", "Hi Honey, I'm Home!" and "GUTS". In 1993, McLean joined pop boy band the Backstreet Boys and dropped out of high school to be with the group. He was part of eight albums from 1996 to 2013 with the popular band, including "Backstreet's Back", "Millennium", "Black & Blue", "Unbreakable" and "In a World Like This". As a band, they have sold more than 130 million records around the world. He performed several times as himself in 2008, and worked with Ryan Tedder of OneRepublic and JC Chasez of 'N Sync. His solo album, "Have It All", released in 2010. McLean has appeared on several TV shows and movies, including "Static Shock", "Arthur", "Sabrina The Teenage Witch" and "This Is the End". In 2001, McLean went to rehab for substance abuse at the encouragement of fellow band member Kevin Richardson. As of 2011, McLean has been in rehab three times. He is the founder of the JNN Foundation that works to keep music in classrooms and raise money for diabetes research. He has been married to his wife, Rochelle Deanna Karidis, since 2011, and has one child.
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How A $300 Million Ponzi Scheme Landed Boy Band Mogul Lou Pearlman In Federal Prison
One Man Has Written Virtually Every Major Pop Song Of The Last 20 Years. And You've Probably Never Heard His Name

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Brain Age: Train Your Brain in Minutes a Day! cunoscut si sub numele de Dr. Kawashima's Brain Training: How Old Is Your Brain in regiunile PAL sau Daily DS Brain Training în Coreea de Sud, este un joc video de puzzle edutainment. A fost dezvoltat și publicat de Nintendo pentru Nintendo DS. Nintendo a declarat că este un produs de divertisment "inspirat" de munca lui Ryuta Kawashima în neuroștiințe.

A fost lansat mai întâi în Japonia și mai târziu în America de Nord, Europa, Australia și Coreea de Sud. A fost urmată de o continuare intitulată Brain Age 2: More Training in Minutes a Day !, și a fost urmată ulterior de două reproiectări și Brain Age Express pentru serviciul DSiWare al Nintendo DSi, care folosește puzzle-uri populare din aceste titluri, precum și câteva puzzle-uri noi, și Brain Age: Concentration Training  Nintendo 3DS. O nouă tranșă din serie, Dr Kawashima's Brain Training for Nintendo Switch, pentru Nintendo Switch, a fost lansată în Japonia la 27 decembrie 2019.

Brain Age prezintă o varietate de puzzle-uri, inclusiv teste Stroop, întrebări matematice și puzzle-uri Sudoku, toate concepute pentru a ajuta la menținerea activă a anumitor părți ale creierului. A fost inclus în Touch! Generations, o serie de jocuri video, o serie care prezintă jocuri pentru un public de jocuri mai casual. Brain Age folosește touchscreen-ul și microfonul pentru multe puzzle-uri. A primit atât succes comercial, cât și critic, vânzând 19,01 milioane de exemplare în întreaga lume (începând cu 30 septembrie 2015)și a primit mai multe premii pentru calitatea și inovația sa. Au existat controverse cu privire la eficacitatea științifică a jocului. Jocul a fost lansat ulterior pe Nintendo eShop pentru Wii U în Japonia la mijlocul anului 2014.

redpajama_set_name: RedPajamaWikipedia


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The Baker Institute Student Forum Research Committee promotes and showcases original policy research by Rice University undergraduate students through the publication of an online journal, The Rice Cultivator: A Student Journal on Public Policy.
The Rice Cultivator is currently soliciting submissions for the 2013-2014 edition. Submissions are due Jan. 1, 2014. For more information, please refer to the section below or contact the editors at thericecultivator@gmail.com with any questions or concerns.
BISF will sponsor periodic events and workshops designed to introduce students to the research process and help students better understand how to prepare research for publication. Sign up for the BISF listserv to receive announcements of these events.
Research Committee Members, 2013-2014
Rohini Sigireddi
Sophia TonNu
Kira Clingen
BISF Student Journal
The Baker Institute Student Forum publishes an annual student journal, The Rice Cultivator: A Student Journal on Public Policy. This journal offers exceptional Rice undergraduates an opportunity to publish their original research. We encourage all Rice students to take advantage of this unique opportunity to contribute to and enhance the public dialogue about important public policy issues.
The Rice Cultivator publishes articles on various areas of public policy, including health, sustainability, energy and science as well as economics, international relations, religion, education and politics. Students from all academic disciplines are encouraged to submit their work.
In addition to research articles, The Rice Cultivator publishes a News & Views section and a Book Review section (contingent on submissions). The News & Views section features short briefs of 300 to 600 words on current national or international policy issues. The briefs should summarize and analyze a topical event or issue, and may provide some editorial or evaluative comment. The Book Review section features critical evaluations of recent books on a range of topics related to public policy. We have a list of suggested titles, or you may suggest a book of your own choosing. Ideas include "Field Notes on a Catastrophe" by Elizabeth Kolbert, "Age of Turbulence" by Alan Greenspan or any recent book on the wars in Iraq and Afghanistan wars. Suggested length for book reviews: 750 to 1,000 words.
Submissions for the 2013-2014 edition of The Rice Cultivator should be sent as Microsoft Word documents via email to thericecultivator@gmail.com by Jan. 1, 2014.
Each submission will undergo a review and revision process. If you have a promising research article, you may submit it for consideration even if it is still a work in progress or a rough draft.
You will receive an email confirming the receipt of your submission within two days. If you do not receive a confirmation email, do not assume that the editors have received your paper and please email for confirmation.
Format and Style
There are no length requirements for articles. Most submissions range from 15 to 25 pages. For submissions more than 50 pages long, the Research Committee will work with the author to edit and shorten the article.
Submissions should be double-spaced with standard font and margins.
Students may follow their academic discipline's conventions for citations (please specify which citation style you use in your submission), but Chicago style (author-date) is the preferred style.
Tables, charts, graphs or data set information may be included in the body of the article or at its conclusion.
Timeline and Submission Deadlines
Submissions are accepted on a rolling basis throughout the year. The editors will work to review submissions as soon as possible, but will not confirm the acceptance/rejection status until after the submission deadline has passed.
Learn More about Research Opportunities at Rice
Office of Fellowships and Undergraduate Research
Rice Center for Civic Engagement
Rice Social Sciences Undergraduate Research Enterprise


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One Big Self
By C. D. Wright
One Big Self (Paperback)
Availability: NOT IN STOCK - Usually arrives in 7 - 14 business days
Published: Copper Canyon Press - April 1st, 2007
This long form, investigative poem freed me of how I saw poetry. It gave me permission to do what I wanted. The collage of the anecdotes and prison protocol Wright creates is where poetry can go if you let it expand further and further. This is the hybrid form at its best; this is where she created a new genre we're lucky to have.
Crush (Yale Series of Younger Poets)
By Richard Siken
Crush (Yale Series of Younger Poets) (Paperback)
By Richard Siken, Louise Glück (Foreword by)
Availability: On Our Shelves Now
Published: Yale University Press - April 11th, 2005
These poems are the dizzy hangover of a night spent with someone you know you shouldn't have. Abrasive in form, Crush begs you to start reading but won't let you stop or even slow down, no matter what. This is where you learn about poetry's velocity. You won't get off this ride unscathed, trust me.
Why Does the World Exist?: An Existential Detective Story
By Jim Holt
Why Does the World Exist?: An Existential Detective Story (Paperback)
Published: Liveright - April 8th, 2013
This is a book that makes you take breaks (in a good way). It freaked me out. Here the concepts of "nothing" and "infinity" make me want to hide and just go back to dumb YouTube videos on loop. But inevitably I return to this book because maybe in secret I want to be scared by philosophy.
Cathedral (Vintage Contemporaries)
By Raymond Carver
Cathedral (Vintage Contemporaries) (Paperback)
Published: Vintage - June 18th, 1989
This collection of Carver's short stories never stays on my shelf; I need it close by. This is poverty, alcoholism and love stripped to their barest, the portraits so intimate you feel like a voyeur, but why look away? I have the last line of "Vitamins" tattooed on my arm if that means anything.
Kindertotenwald: Prose Poems
By Franz Wright
Kindertotenwald: Prose Poems (Paperback)
Published: Knopf - March 19th, 2013
These prose poems changed my life. Every line drags you further into a place you've been afraid to go or didn't know you needed to. This is Franz Wright at his most startlingly brutal. It's as if he's holding up a mirror you've been avoiding and saying, Look at what you are.
Last Bus to Wisdom: A Novel (Two Medicine Country)
By Ivan Doig
Last Bus to Wisdom: A Novel (Two Medicine Country) (Paperback)
Published: Riverhead Books - August 16th, 2016
Published in 2015, this was the last of Doig's books, every one of which I have loved. Doig writes of the American West, and he paints the big sky and the stalwart people into his stories so beautifully that you will know each place and person as though you had grown up there.
Picnic, Lightning (Pitt Poetry Series)
By Billy Collins
Picnic, Lightning (Pitt Poetry Series) (Paperback)
Published: University of Pittsburgh Press - January 29th, 1998
Reading the poetry of Billy Collins feels like talking to an old friend. He takes the mundane, the everyday circumstances, and turns them to extraordinary thoughts to ponder and appreciate.The irony in life is his toolbox.
Crossing to Safety (Modern Library Classics)
By Wallace Stegner
Crossing to Safety (Modern Library Classics) (Paperback)
By Wallace Stegner, Terry Tempest Williams (Introduction by), T.H. Watkins (Afterword by)
Published: Modern Library - April 9th, 2002
I found myself re-reading page after page of this beautiful novel to savor the beautiful artistry of Stegner's writing. I felt as if I were there, while the events unfolded and the characters made themselves known to me. This story of friendship, marriage, hopes and dreams will not disappoint. When you finish this one, read ANGLE OF REPOSE, for which Stegner won the Pulitzer prize.
Straight Man: A Novel (Vintage Contemporaries)
By Richard Russo
Straight Man: A Novel (Vintage Contemporaries) (Paperback)
Published: Vintage - June 9th, 1998
I love Russo's ability to weave heartbreak and humor into a wonderful tale that we can all relate to. The protagonist is an English professor at a small, underfunded college who is facing down life's challenges as he tries to save his department and himself. STRAIGHT MAN is witty, compassionate and unforgettable.
The Archivist: A Novel
By Martha Cooley
The Archivist: A Novel (Paperback)
Published: Back Bay Books - April 8th, 1999
In THE ARCHIVIST by Marta Cooley, the life and poems of T.S. Eliot reverberate in the lives of an archivist of Eliot's letters and his poet wife. This beautifully written novel confronts many of the enduring literary themes of our twentieth century experience—the struggle to move beyond guilt and find redemption; the role of both religion and art in helping us make sense of our patterned existence in the face man's aggression against his fellow man. THE ARCHIVIST is an unconventional, sophisticated novel that encompasses so much of what it means to be human.


Succulents are having a moment because they're beautiful and they have a rep for being easy to grow. You can kill these hardy little plants, though, if you don't play by their rules. Here are some tips for keeping them happy.
Succulents are native to arid regions, so they hate moist soil. Pot them in a potting mix that drains quickly, because wet dirt will rot their roots. You can buy special potting mixes for succulents, or alter regular potting soil by adding vermiculite or perlite to it to improve aeration and drainage. Remember, good dirt makes good plants.
Yes, we know you want to put a collection of succulents in that perfectly rusted metal trough you nabbed at an estate sale. The one with no drainage holes because it wasn't meant for plants. But you'll have to water that collection of plants lightly, and with precision, or you'll end up with a bunch of drowned succulents. Make it easy on yourself and use containers with holes in the bottom.
Succulents store water in their foliage and stems so they don't need as much water as other plants do. Water them only when the top two inches of the soil is dry. Too much water will rot their roots and turn them into a squishy mess. Overwatering kills more succulents than underwatering, so be stingy with the watering can. TIP: Place your pot of succulents in a shallow pan of water, leave it till the water wicks up through the drain hole in the pot, then remove the pot. This saturates all the soil, not just the edges or top few centimeters.
Succulents are tough, but they still need a little love from you. During the spring and summer, they'll need water about once a week. Check them regularly for aphids, spider mites and mealy bugs that will make a meal of your precious plants. If they're in containers, repot them annually with new soil because salts from tap water build up in the dirt and harm the plants.
Unlike their cactus kin, succulents can't take extreme heat. Succulents do best with moderate temperatures between 70 and 90 degrees, so put them by a window indoors, or on outdoors on a covered patio or beneath trees in the summer. Freezing temperatures will kill them, which is why for most of us they're houseplants.
Succulents need a 50-50 mix of sunlight and shade. Full sun burns their leaves, but too little sun makes them rangy and frail. A quick rule of thumb is that green, yellow or variegated succulents like more shade, while red, gray, and blue ones, or the ones covered in spikes, like more sun. If they're outdoors, put them in a spot that gets morning sun and afternoon shade. If you're growing succulents indoors, put them by a south-facing window to get the bright light they need to be Instagram bait.
Colorful succulents, like aeoniums, paddle kalanchoes and some varieties of sempervitum and echeveria, need at least six hours a day to maintain their rich hues. Less sun causes them to revert to boring green and elongate. Heat and extreme cold (but not freezing cold) bring out the deepest hues, so most varieties will be their most colorful in the spring when they'll get warm, sunny days and chilly nights.
Most succulents go dormant during the winter and stop growing. They're resting, waiting for spring and summer when they'll grow like crazy. Don't fertilize them and water just enough to keep the pot from drying out completely, because they're extremely susceptible to root rot when they're dormant. Don't worry, they'll be fine. The water and nutrients stored in their leaves will keep them alive till they wake up in the spring.
Even houseplants need a summer vacation. Give your succulents some time outdoors in the spring and summer. Let them get rained on because rainwater contains oxygen and trace minerals a plant can't get from chlorine-laden tap water. They'll benefit from air circulation they can't get inside, too. Do not put your indoor succulents in full sun, though, because sudden light change can burn their leaves.
Fertilize them once a week from spring to early fall, their growing season, with a 10-10-10 organic fertilizer diluted to half strength. Don't fertilize them in the winter when they're dormant. Sleeping people don't need food till they wake up. Sleeping plants don't either.


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The Via Francigena is a historical itinerary leading to Rome from Canterbury. At the beginning of the 11th century mainly, a multitude of souls "looking for their Lost Heavenly Home" took the habit of travelling across Europe. This route bears witness to the importance of the practice of pilgrimage in medieval times; the pilgrim was to travel mostly on foot (for penitential reasons), covering about 20-25 Km a day,and was driven by a fundamentally devotional reason: the pilgrimage to the Holy Sites of Christianity.


JOHNSON CITY, Tenn. (AP) Tray Boyd III scored 24 points, tying his season high, as East Tennessee State got past Western Carolina 81-74 on Saturday. Bo Hodges added 20 points for the Buccaneers.
Boyd III hit 6 of 9 3-pointers. Hodges also had seven rebounds and three blocks for the Buccaneers.
Isaiah Tisdale had 13 points for East Tennessee State (23-8, 13-5 Southern Conference). Mladen Armus added three blocks.
Kameron Gibson had 23 points for the Catamounts (7-24, 4-14). Marcus Thomas added 15 points and seven rebounds. Marc Gosselin had 13 points and 11 rebounds.
The Buccaneers improve to 2-0 against the Catamounts for the season. East Tennessee State defeated Western Carolina 91-69 on Jan. 26. The Buccaneers and the Catamounts next take the floor in the Southern Conference Tournament.


At last year's Superbooth, we spoke to one of the original designers of the Synton Syrinx - Felix Visser - lovely chap. They were showing their new key bed technology - which was their primary focus of their booth - its a variant of MPE with pressure, and key position sensing. As a result they needed an instrument to demonstrate it. So they "knocked up" a demo unit based on their original Syrinx synth design. We had a chat with Felix.
It seems that there was so much interest in the synth part, that they have been working on that part of it since last year. This will be on show again at Superbooth which starts on Thursday this week - we will of course be there to find out what we can.
There's more info on the Syntonovo web page.


Higher education has its own accounting and financial management challenges. At Parms + Company, we understand the ins and outs of college and university auditing, foundation auditing and research grant compliance. Our wide experience with higher education clients gives us the perspective to help you and your learning institution.
Want to explore ways the Parms team can help your institution? Contact us to learn more.


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Asylum and refugee status is available to persons seeking protection in the US because they fear returning to their home country. If you qualify for asylum or refugee status, you can apply for permanent residence (i.e.: a "Green Card") and remain in the US permanently.
Asylum is a form of protection from removal to a country of feared persecution that allows an eligible refugee to remain in the US and eventually to become a lawful permanent resident.
Any person (including illegal aliens) can apply for asylum within one year of arriving into the US unless circumstances in your home country have changed or extraordinary circumstances caused you to apply after one year.
In general terms, a refugee is an individual who is outside of their home country who can demonstrate that because of their race, nationality, political opinion or social affiliation they may be subject to persecution if they return.
What is the procedure to come to the United States as a refugee?
You must receive a referral to the US Refugee Admissions Program for consideration as a refugee.
You will apply for status and be interviewed abroad by a USCIS officer.
You may include your spouse and unmarried children under 21 years of age, and sometimes even other family members.
When you are approved as a refugee, you will receive a medical exam, a cultural orientation, help with your travel plans, and a loan for your travel to the United States. After you arrive, you will be eligible for medical and cash assistance.
Within 2 years of your arrival you can file for your spouse and unmarried children under 21 to join you.
You can work in the United States as soon as you arrive in the US. You will use your I-94 until you receive formal permission to do so (EAD).
If you believe that you or a loved one will qualify for asylum or are seeking refugee status, please call and talk too a Los Angeles County Immigration Attorney at Vincent W. Davis & Associates. We are a dedicated group of attorneys dedicated to finding you safe haven in the US if at all possible. One of our Immigration Attorneys will explain all of your legal options so that you can make an informed decision about your potential asylum or refugee case.


From La Paloma Lodge in the Osa Peninsula, I headed to Monteverde Lodge via a plane and road transfer. After my stay at La Paloma I had high expectations about the next location that Costa Rica Expeditions had recommended.
Fortunately my expectations were met. The lodge was in a good location just on the edge of town with easy access to a supermarket (which I used to grab some snacks) and coffee shops (including one that I had lunch at one day). The lodge was surrounded by a well-maintained garden and on the edge of the garden was the rainforest.
The temperature was great – not too hot or cold. Rain would come and go as you would expect in a rainforest. The one surprise was the wind which was non-stop. This was an odd experience high winds make me think of a coming storm whereas here they're normal and mean nothing.
The staff at Monteverde Lodge were great with the woman (I've forgotten her name) at reception a real standout for being helpful and patient. The room I got was clean and comfortable with nice balcony overlooking the rainforest. For me, this sort of arrangement is paradise. The only surprise, and I don't mean this as a negative in any way, is that a scorpion had decided to settle into the folds of the curtains. No problem though, the front desk sent a couple of guys over with a glass to scoop it up. It looked easy when they did, but I had never dealt with scorpions before so I was happy to have someone else handle it.
Some of the activities I signed up for included a guided walk in the Monteverde Cloud Forest, a night hike into the nearby Ecological Sanctuary, and a trip to the Frog Pond (a series of terrariums reproducing the environment for the frogs each contained.
Breakfasts were made to order and were very tasty, but as is typical with Costa Rica the options were similar to what you'd find in North America e.g. eggs, pancakes, french toast.
Monteverde Lodge was also very quiet. I didn't hear other guests at night (even though I typically go to bed early in preparation of early morning hikes). Nor did I hear the rain or wind neither of which are a problem during the day, but can make for a fitful night for me. Curiously I'm actually pretty sure I don't have perfect hearing and yet sounds at night always seem loud to me.
So Monteverde Lodge gets a thumbs-up for me and Costa Rica Expeditions once again lives up to expectations.


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"Trump Forest" Blooms to Counter "Trump's Monumental Stupidity" and Attack on Earth
"As the planet heats up towards critical tipping points, we simply can't afford his ignorance"
Andrea Germanos, staff writer
Dan Price (l) and Adrien Taylor (r), seen here planting a seedling, are co-founders of the Trump Forest initiative. (Photo: TrumpForest.com)
Want to help counter President Donald Trump's war on climate action and combat climate change? Help plant Trump Forest.
The brainchaid of climate scientist Dan Price and sustainable cap company founder Adrien Taylor, the Trump Forest initiatve launched last month with a batch of 1,000 trees planted in Christchurch, New Zealand.
The new website lays out the initiative's impetus like this:
U.S. President Donald Trump doesn't believe in the science of human-caused climate change. He wants to ignore one of the greatest threats to healthy life on Earth.
Trump wants to bring back coal despite scientists telling us we cannot afford to burn it, and despite economists telling us there's more money and jobs to be made in renewable energy.
So we're planting a forest to soak up the extra greenhouse gases Trump plans to put into our atmosphere.
We're planting a global forest to offset Trump's monumental stupidity.
How it works: an individual or business makes a donation to a local tree planting group indicating that it's in honor of Trump, and then sends the receipt on to the folks at Trump Forest who will track and map the growing "forest."
"We know Trump likes his things: Trump Tower, Trump Golf, Trump Vodka and so on. We thought he might like Trump Forest too," Taylor said in a press statement announcing the launch.
Price said he felt like "we had to do something" to counter "Trump's extremely dangerous incompetence."
"The world's most powerful man doesn't believe in science, and that should be concerning to everyone around the globe," Taylor added.
The Trump Forest website points specifically to the president's executive order last month to roll back the Clean Power Plan, thereby threatening United States' ability to meet the targets set out in the historic Paris climate accord.
Price called such action "completely unacceptable in a modern scientifically literate society. We cannot stand by and watch as he attempts to derail effective action and recent progress."
He and his co-founder hope their initiative can help make up for the damage in terms of greenhouse gas emissions the Clean Power Plan rollback would unleash.
Here's how they explain the science behind their approach:
If the Trump Forest covers an area of 100,000 square kilometers (37,000 square miles), about the size of the U.S. state of Kentucky, it will offset the additional carbon in the atmosphere if the Clean Power Plan is removed.
Then at least, the backward steps of the Trump administration will be negated until a sane, logical government, that bases its decisions on scientific advice wins the next election.
"As the planet heats up towards critical tipping points, we simply can't afford his ignorance," Taylor said.
Lindsey Graham Excoriated for Equating Trump Accountability With Divisive 'Vengeance'
World, Climate, Solutions
Donald Trump, Environment, People Power


This Citizens' Statement on Question 4 was written by an independent panel of 20 Massachusetts voters through the Massachusetts Citizens' Initiative Review Pilot Project.
The panel of 20 was formed from a pool of 10,000 randomly-selected Massachusetts voters using a scientific method to ensure it is representative of the overall electorate (based on place of residence, party affiliation, age, gender, educational attainment, and race and ethnicity). Over four days in late August 2016, the panel heard from the campaigns supporting and opposing Question 4 and relevant policy experts, deliberated among themselves with the help of professional facilitators, and produced this Citizens' Statement.
The views expressed in the Citizens' Statement are solely those of the Massachusetts CIR panel. They are not the opinions or positions of Representative Hecht, Tisch College, Healthy Democracy, the Commonwealth of Massachusetts, or any government agency.


The mission of the Diversity & Inclusion Committee is to ensure that traditionally underrepresented groups work at every level to advance our position as a leader in the ABA-wide effort to build a legal community that reflects the wider communities we serve.
By Safie Da Costa Soarès – February 12, 2019 | Advice for new litigators who need to know everything law school and bar study didn't teach them.
By Stephanie Francis Ward – February 12, 2019 | Demystifying the process for lawyers considering serving in the judiciary.
By Jennifer Selitti and Tracey Telemaque – February 4, 2019 | Are you suffering from Vicarious Trauma? For many lawyers and judges (as well as jurors, courtroom personnel, and others), the violent, disturbing, and unsettling reality they witness inside and outside the courtroom as part of their profession can become debilitating. Vicarious trauma, also called compassion fatigue or secondary trauma, is a form of post-traumatic stress disorder. Attorney Jennifer Selitti discusses how to recognize when we are effected by vicarious trauma, and how to best cope with it.
Read the latest Diversity & Inclusion newsletter and access our newsletter archive.


Our parks are managed through partnerships between City of Bradford MDC (Parks and Green Spaces) Friend and Community groups, Parish and Town Councils. By Working Together we aim to create "safe, clean and active communities" where we can enjoy "better health and better lives".
Parks and Green Spaces will always try to be positive and flexible in the way we Work Together and will always seek to involve people in how parks are managed and developed. As a service we take responsibility for our performance and in delivering value for money.


Hours ago, USA Today printed an op-ed by Senator Ted Cruz, one of the top-tier GOP presidential candidates. Cruz is known for speaking the truth and shooting straight with the American people.
The boldness and logic of Cruz's op-ed demonstrate his fearless credentials as a pro-life leader who will fight to end taxpayer funding of the barbaric abortion giant.
Planned Parenthood has performed more than a million abortions over the past three years, and its work accounts for nearly one-third of all abortions in the United States.
For far too long, Planned Parenthood has hidden behind the well-crafted charade that that it exists to protect women's health. In reality, it is in the business of killing unborn children on an industrial scale. Despite what Planned Parenthood contends, abortion procedures, not women's health, are its lifeblood. Hundreds of thousands of annual abortions generate nearly 40% of Planned Parenthood's clinic revenues. Simply put, Planned Parenthood is the nation's largest abortion profiteer. For every woman who gets prenatal care at Planned Parenthood, the organization reports more than 15 abortions. For every woman who is referred for adoption assistance, there are more than 150 abortions.
The abortion industry places more value on killing babies than it does on the sanctity of human life, and under no circumstance should it receive taxpayer funds. This is more than a mere fiscal matter — this is a moral issue. How we handle this issue reflects who we are as Americans and what we value most — either the lives of the most innocent and the health of our nation's mothers, daughters and sisters or the fiscal solvency of an industry that exists to abort babies.
For these reasons, I intend to lead the fight in the United States Senate to defund Planned Parenthood, even while investigations continue. The time for show votes is over. Funding the federal government does not require funding Planned Parenthood. But basic decency and our committment to the right to life does require that we stop taxpayer funding of abortions and any trade in baby parts.
To read the entire op-ed, visit USA Today's page here.


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Home » Progressive Metal
In Case You Missed It…..Demonstealer – This Burden Is Mine
In case you missed it is our new regular feature which highlights outstanding albums, from the last 5 years, which may have passed you by. Who: Demonstealer Album: This [...]
CONCEPTION – Listen To New Song, "By The Blues"
Reactivated Norwegian progressive metallers CONCEPTION, who feature in their ranks former KAMELOT singer Roy Khan, have released a new song called "By The Blues" [...]
KATATONIA Present Their Second Single From CITY BURIALS Album
Following the announcement that KATATONIA will be returning with a brand-new album, City Burials, on April 24 via Peaceville Records, and the release of the album's [...]
CONCEPTION To Release Album State of Deception on April 3rd!
Legendary Norwegian progressive / power metallers Conception are set to release the album State of Deception on April 3rd 2020, their first full length offering in over two [...]
Edinburgh Metal Veteran TOMMY CONCRETE (ex-The Exploited ) Prepares To Release New Album Via UK label Trepanation Recordings!
Edinburgh heavy music veteran Tommy Concrete (The Exploited / Man Of The Hour) prepares to release his upcoming album, Unrelaxed 2, via UK label Trepanation Recordings. [...]
AEONS – The Rovers Return Pub, Douglas, Isle of Man – 16th November, 2019
The Isle Of Man. A proper pub. Plenty of Guinness. An evening of top class, A-fuckin-grade, progressive, technical metal. Who's in? WE WERE! The Isle of Man's [...]
AEONS – A Tragic End – Album Review
The Isle Of Man. Not exactly a destination renowned for metal – never mind technically audacious, progressively-minded heavy metal – but that's the sphere [...]
Anacrusis: 'Suffering Hour', 'Reason', 'Manic Impressions', 'Screams and Whispers' re-issues now available via Metal Blade Records
This autumn, Metal Blade Records will re-issue Anacrusis' classic albums: Suffering Hour (September 27th), Reason (September 27th), Manic Impressions (November 15th), [...]
Eremit – Carrier Of Weight – Album Review
An expansive, restless, hypnotic, endless bludgeoning of beautiful, doom/sludge inflected noise, the term 'atmospheric' doesn't come close to describing the [...]
SYMPHONY X Announce June UK Tour Dates!
New Jersey's progressive metal masters SYMPHONY X are hitting the UK, as part of a wider European tour which will take place throughout May and the beginning of June this [...]


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Txangurru (hiszp. Changurro) – grupa dań kuchni baskijskiej przyrządzanych z rozdrobnionego mięsa jeżokrabów gatunku Maja squinado (bask. Centola).

Krab Maja squinado jest skorupiakiem bardzo cenionym za swoje delikatne mięso, co sprawiło, że jest jednym z najbardziej cenionych produktów w kuchni baskijskiej i hiszpańskiej. Danie może mieć formę terryny, w której oprócz pieczonego mięsa krabiego znajdują się, jako dodatki takie warzywa jak: cebula, pory, pomidory, a jako uzupełnienie niewielka ilość brandy lub białego wina. W innej wersji podobna mieszanka umieszczana jest w skorupie kraba i zapiekana w piecu (w tej wersji nosi nazwę Txangurro a la donostiarra, czyli z San Sebastian).

Przepisy na txangurru są w niektórych przypadkach przygotowywane z okonia morskiego, bez zmiany nazwy samej potrawy.

Przypisy

Kuchnia baskijska
Potrawy z ryb i owoców morza


Discussion in 'Birds' started by johnaalex, Aug 15, 2009.
First day of my trip to South Africa and we stayed at Palazzo Hotel in Johannesburg. The hotel is part of a massive complex along with a casino and a very good bird garden.
Shots taken using my Sigma 150 2.8.
Now that first one is just plain weird, disturbing even. Great shots, though.
Lovely set. I would be in heaven at that hotel.
Hey - evolution has a lot to answer for! Don't take it out on the poor bird :biggrin:!
If you like birds then South Africa would be heaven for you, let alone this place - thanks for the comment.
Stunning ! Beautiful and rich colors !
Love that saddle-billed stork. We have two at our zoo. Beautiful birds.


text:
<?php

namespace DvsaMotTest\Model;

use Dvsa\Mot\Frontend\Test\TestCase;

/**
 * Class LocationSelectTest.
 */
class LocationSelectTest extends TestCase
{
    public function testInitialState()
    {
        $locationSelect = new LocationSelect();

        $this->assertNull($locationSelect->submit, '"submit" should initially be null');
    }
}

redpajama_set_name: RedPajamaGithub


As with most consulting contracts I find I receive something less than expected. In fact, I have come to expect not more than around 75-80% of the intended deliverables from intellectual service firms. I am happy to say that Phoenix Consulting was different.
The work performed was on point and encompassed the vast majority of the intended information. I found the work thorough, well organized and substantive. The fact that the work was completed on time and on budget was an added surprise. You did a great job.
Thanks to you, we have been able to transition from a local to a regional distributor in a very short amount of time. Your evaluation and one-on-one training of our existing staff has been invaluable in advancing our company foreword. I am appreciative of both the results and the professional and methodical approach you used to obtain these results.
I credit your strategic planning sessions with our ability to stay focused and keep our expansion plans on track even during these times of economic uncertainty. As someone who has had a chance to put your specialized consulting to the test, I would recommend your services to any company in any industry.
Larry met face-to-face with my management and sales staff and myself. He also conversed with me personally on many occasions concerning the needs of my company. Larry was most flexible in his methods of contact using telephone, e-mail, faxes and mail/courier services. His flexibility was paramount in the execution of our project together.
Some of Larry's strengths that have contributed to our success are his excellent resources, contacts and on-going recommendations. I am very pleased with the exemplary results Larry has produced. He has done for Mid America Frame what he said he would do.


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April 19, 2019	 Posted by	Leo Stevenson Gear, Gear News
SEGA has announced 10 more titles coming to the Mega Drive Mini. Some of the biggest games that ever appeared on the Mega Drive are included as part of the mini console and will join the likes of Sonic the Hedgehog, Ecco the Dolphin and Castlevania: Bloodlines.
The Mega Drive Mini is based on the "original Model 1 Mega Drive which launched in Oct. 1988 in Japan" and is only 55% the size of the original. The mini console will include 40 games, of which we know 20 of them.
All of the games are being ported by M2 who is a developer well known for emulation and ports of classic games.
The 10 newly announced games today are;
Castle of Illusion
World of Illusion
Thunder Force III
Super Fantasy Zone
Shinobi III
Contra: Hard Corps
Landstalker
Many gamers will have fond memories of Castle of Illusion and EarthwormJim; two of the best platformers of their time. This second batch of 10 announced titles also includes Sonic the Hedgehog 2.
The previously announced titles are;
Ecco the Dolphin
Castlevania: Bloodlines
Space Harrier 2
Dr Robotnik's Mean Bean Machine
At launch, the Mega Drive Mini will cost $139.95 AUD and it will include the mini console, 40 games and two replica Mega Drive controllers.
It will be available on September 19, 2019.
Tags: SEGA
Yakuza 6: The Song of Life demo is playable now
Get ready to go back to Kamurocho and party in[...]
Team Sonic Racing is coming to PC, PS4, Switch and Xbox One later this year
SEGA has just announced Team Sonic Racing for PC, PS4, Switch[...]
At SXSW today, SEGA unveiled some brand-new details about the[...]


Milwaukee, Wis.-based Roundy's Inc. will have two executives on hand for the Jefferies Global Consumer Conference later this month.
Roundy's CEO Robert Mariano and CFO Darren Karst will present at 1 p.m. at the conference in Nantucket, Mass.
The audio portion and slides of the presentation will be broadcast live over the internet hosted at the "Investor Relations" section of Roundy's website and will be archived online through July 2.
Roundy's is a leading grocer in the Midwest with nearly $4 billion in sales and more than 18,000 employees. Founded in Milwaukee in 1872, Roundy's operates 159 retail grocery stores and 98 pharmacies under the Pick 'n Save, Rainbow, Copps, Metro Market and Mariano's Fresh Market retail banners in Wisconsin, Minnesota and Illinois.


NEW YORK - As tens of thousands of visitors from around the world flocked to the New York Times' annual Travel Show this weekend, they had a chance to learn about the island at the booth staffed by the Curaçao Tourist Board and hotel properties.
"This is a great place to meet people planning to go to Curaçao," said André Rojer, North American marketing manager for the Tourist Board who led the delegation of hotel representatives and Tourist Board staff.
Rojer added that taxi-roof displays, advertising in subway stations and online and social media campaigns are also a part of the promotion strategy.
The #RightNowInCuracao Instagram campaign was very popular. People were asked to submit photos of themselves related to Curaçao. Thumbnail prints of those photos were then posted on a board to make a beach collage.
Attendees considering Curaçao are also interested in niche travel experiences, according to Rojer.
Diving, Jewish heritage, African-American, family and honeymoon considerations are among the specialty experiences Curaçao provides. Curaçao is also a popular destination for LGBT travel. With 17 members, Curaçao has the largest number of International Gay & Lesbian Travel Association members in the Caribbean.


Tewksbury, MA – July 21, 2016 – On New Year's Eve 1975, Dr. Hugh Mahoney, his wife Ruth, and their fifteen-year-old son John were murdered in their Tewksbury home. Family and friends found themselves disempowered and bewildered. In many ways, this tragic event forever changed our community.
Maureen Mahoney, surviving daughter, is passionate about tackling domestic violence and violence against children in our community. Last year, Maureen mobilized the Mahoney Tribute Committee to coordinate a well-attended memorial and community awareness event at Tewksbury Country Club. Speakers highlighted the impact of violence on our community and four local violence prevention programs were awarded grants.
The Mahoney Tribute Committee remains committed to ending violence that impacts the most vulnerable members of our communities. On October 19, 2016 the Mahoney Tribute Committee will be hosting Voices Against Violence at the Tewksbury Country Club at 6:00 o'clock in the evening.
"When a child, vulnerable teen, or adult lives in fear and their daily lives consist of thwarting another's anger they lose the ability to function with a rational, clear mind. Chronic abuse ruins a life. Voices Against Violence will address ending violence that occurs in the home," remarks Maureen Mahoney.
This year's event will feature Middlesex County District Attorney Marian Ryan. D.A. Ryan has spent her entire career prosecuting serious cases across the county at both the trial and appellate level. She created the office's county-wide Workplace Safety and Violence Prevention Program and lectures and leads workshops on the teen dating violence and anti-bullying.
Along with Maureen Mahoney, Voices Against Violence will also feature the executive director of the Center for Hope and Healing Isa Woldeguiorguis and Jody Marchand of Westford. Each speaker will discuss their personal stories of surviving violence and overcoming tragedies and hardship.
The event will continue a community dialogue on violence prevention and also raise funds to grant to nonprofit organizations. Tickets are $50 and proceeds from the event will benefit local programs supporting violence prevention efforts.
For more information on the event, including sponsorship opportunities, please visit www.glcfoundation.org.
The Mahoney Tribute Committee is a component fund of the Greater Lowell Community Foundation.
Girls gathered at Girls Inc., on Friday to paint birdhouses.
Hugh and Ruth Mahoney and their son, John, were shot to death in their Whipple Road home on New Year's Eve in 1975. They were discovered by one of their three daughters, Maureen Mahoney.
To recognize the 40th anniversary of her family's slaying and honor their memory, Mahoney organized a tribute night last October that also raised money for four local nonprofit agencies whose goal is to stop domestic violence.
The initiative will continue this year on Oct. 19, with a theme of "Voices Against Violence," with attention on children. October is Domestic Violence Awareness Month.
Since her parents' and brother's deaths, Mahoney, who now lives in Florida, has learned about the murderers' pasts from police.
Read more at the original Lowell Sun article here.
After a year of advocating to put an end to domestic violence, culminating in a tribute event on the 40th anniversary of her parents' and brother's death, Maureen Mahoney accepted an unsung-hero award last week in Washington, D.C.
Eva Murillo was a crime-victim advocate from California.
Mahoney, whose family is from Tewksbury, accepted the award at the annual Congressional Victims' Rights Caucus on Wednesday. The VCR awards were founded by Reps. Ted Poe of Texas and Rep. Jim Costa of California. Along with 72 bipartisan members, the representatives act as a voice before Congress for victims of violence.
Moulton nominated Mahoney because of her effort to organize the Dr. Hugh, Ruth, and John Mahoney Tribute Night. The event remembered her parents and brother decades after they were murdered during a New Year's Eve robbery in 1975, and raised money to fund programs for three nonprofit agencies and the Tewksbury Police Department to work toward ending domestic violence among youths.
On Dec. 31, 1975, three armed men entered the Mahoney home and fatally shot the doctor, his wife and their son. Mahoney, 21 at the time, and her two sisters came home that night and discovered the scene. She raced to the police station. Many residents of Tewksbury and Greater Lowell remember the crime, which shocked the community. Three men were charged with the murders six months later.
Mahoney, who now lives in Florida, is going to continue the tribute night in her family's memory, and this year the focus will be on child maltreatment within domestic violence, she said.
Mahoney said research has shown that childhood domestic violence has led many children to get involved with gangs and drugs.
"They're into all kinds of trouble in life because they were beaten down physically, emotionally, spiritually," she said.
Bringing nonviolence home is Mahoney's goal.
This year's tribute night is scheduled for Wednesday, Oct. 19, at the Tewksbury Country Club.
Maureen Mahoney recently received an award at the Congressional Victims' Rights Caucus Awards ceremony, where the honorees are some of the most committed people in their field. Their work and advocacy have inspired meaningful changes that should never be forgotten. Each year the VRC has the privilege of honoring those unsung heroes who have dedicated their lives to advocating on behalf of crime victims. Among those present at the ceremony, were Congressman Ted Poe, Congressman Jim Costa and Congressman Seth Moulton.
Mahoney was presented with the "Eva Murillo Unsung Hero Award." This award honors the memory of Eva Murillo, a prominent crime victim advocate in the state of California. Murillo, who passed away in 2005, was best known for her twelve years of distinguished service to the Kings County Victim Witness Assistance Program, where she pioneered efforts to help women in abusive relationships.
The honoree is a crime victim or survivor, who has experienced a personal tragedy and triumphed over adversity. This award recognizes a person who has utilized his or her experiences as a crime victim or survivor to promote public education and awareness, public policy development, and/or greater awareness about crime victims' rights and needs. Through his or her efforts, the recipient has given hope to other crime victims and survivors.
The award was granted a result of the work Mahoney has been doing with domestic violence, that is, funding programs with the non-profits in the greater Lowell area who are aggressively addressing domestic violence and child abuse. The awardee would be someone who has experienced violent crime and is taking positive action to address it in the community.
The event was on April 13, 2016. A live video recording can be found here.


Southern California Soaring Academy is the premier glider flight school in Southern California and is located at Crystalaire airport (46CN) in the high desert of Los Angeles, just over 1 hour driving time from L.A.
At Crystalaire nearly everyday is flyable. Tucked against the north side of the San Gabriel mountains the best year round soaring in the U.S. is found here. We are the only glider port in L.A. County.
Take the Hwy 138 exit toward Palmdale.
Continue on Hwy 138 about 26 miles.
Turn Left on 165th Street E.
Take the Palmdale Blvd, Hwy 138 East exit.
Continue on Hwy 138 East for 5 miles until 47th St. E.
Turn Right to follow Hwy 138.
Continue on Hwy 138 for 15 miles.
Watch for our sign on the corner.


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Immigration reform in California may pave the way for the rest of the U.S.
Louis Brandeis, the famous Supreme Court Justice who dedicated himself to public service, once said that California was a "laboratory of democracy."
Right now, many different bills are pending that would grant Californian undocumented immigrants rights they wouldn't have in many other places in the country (the right to practice law and to have a driver's license are among the biggest). They need to be signed by Gov. Jerry Brown before they become law.
Brown has said of the forthcoming legislation that "hopefully, it will send a message to Washington that immigration reform is long past due."
California leads in more ways than one. While taking a strong stance on positive immigration reform, the state also has the highest number of immigrants of any state in the country. This has the side effect of making some of the harsher federal immigration policies unpopular in the state.
One such federal policy is Secure Communities (SCOMM), which requires law enforcement to hold an arrestee and do a check against an ICE database. If the person arrested comes up as deportable, they are then deported in most cases. These deportations are not kept to serious cases, either. In one case, a woman was deported after she was arrested for a minor traffic incident.
SCOMM is a problem, and a severe one at that, because it discourages undocumented immigrants from going to the police when they are victims of a crime, thus leaving them without protection and without the feeling of safety in their own communities. This was perfectly illustrated when Lucy Allain, an undocumented immigrant, told her story of being sexually assaulted at the age of 14. The sexual assaulter knew she was undocumented and held that over her head to keep her silent, threatening the deportation of herself and her family if she said anything.
It's good that California is leading the way and introducing legislation to counteract them altogether. Hopefully the rest of the nation follows California's lead soon.


FinancesOnline, one of the most respected and reliable analytical B2B review platforms, chose Tap2Pay among top 20 Payment Gateway solutions. According to their detailed Tap2Pay overview, our product has become a two-time winner of the following awards given out by the B2B experts: the Rising Star 2018 and The Great User Experience 2018.
The Rising Star award under their top payment gateway solutions speaks for itself. Even if a company has not yet gained a sizeable market share, Tap2Pay addresses a big market does it in a solid way and has a number of strong competitive advantages. In the case of Tap2Pay, those are good customer traction, innovative technology that opens new sales channels for online business. All of them serve to help our customers start selling and accept payments more effective, smooth with high conversion. It brings us much pleasure to learn that Tap2Pay succeeds in this and that Finances Online thinks so, too.
The Great User Experience Award is given for noticeable and constant progress in quality user experience improvements, and this is also something Tap2Pay excels at. From the onset, Tap2Pay's mission was to provide its customers with the most easy-to-use and secure platform for accept payments. Every day our team of professionals does their best to develop everything necessary to make it happen.
According to FinancesOnline review, with Tap2Pay, you sell and get paid instantly, within the messenger platform. It streamlines the buy and pay process for customers, which greatly improves their user experience and satisfaction. Tap2Pay has a dashboard where you can view all the information you need to manage your business, such as customers' demographics, payment methods, and shipping addresses.
With Tap2Pay, you can communicate with your customers and sell your products at the same time, turning each conversation, each query, into a business opportunity. And once they are ready to make that purchase decision, they do not have to fill up the forms or exit the system to go to your website or online store. Tap2Pay lets you access your products and complete the purchase within the messenger app. It speeds up the whole process and you get paid quickly, which is good for your sales.
Please visit FinancesOnline.com to post your own review of Tap2Pay. We invite everyone to experience our product and take full advantage of its features. We are ready to make your selling process more efficiently. Try Tap2Pay now.


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Museum Celebrates 10th Anniversary of Quadracci Pavilion with Calatrava Exhibition
Posted on July 25th, 2011
Milwaukee Art Museum exhibition honors Santiago Calatrava masterpiece
Milwaukee, Wis. – July 25, 2011 – It has been named the sexiest building in the world, featured in TV ads and shows and Hollywood movies, and it has transformed the city of Milwaukee. In September, the Milwaukee Art Museum celebrates the 10th anniversary of its iconic building, the Quadracci Pavilion, with the exhibition Building a Masterpiece: Santiago Calatrava and the Milwaukee Art Museum.
Designed by internationally renowned architect Santiago Calatrava, the Quadracci Pavilion was the Spaniard's first completed commission in the United States. In 2001, it was named TIME Magazine "Best Design of 2001."
"The exhibition features watercolors and models by the architect—works of art in themselves—that track the evolution of the building's design," said Chief Curator Brady Roberts. "The watercolors have a stream-of-consciousness-like quality, as the imagery flows from humans to sails, to Lake Michigan, to uncanny representations of Windhover Hall, imagined at the very outset of Calatrava's design process in the mid-1990s. His models reveal the complex development of the moving wings of the Burke Brise Soleil, one of the most spectacular architectural elements in the world."
Building a Masterpiece further highlights the construction of the entirely custom-made project, a testament to Milwaukee's tradition of precision manufacturing and craftsmanship, through photographs, drawings, and models. Visitors will also be invited to submit their favorite photographs of the Museum—of its interior as well as its exterior. The best of these will be included in the exhibition, demonstrating how significantly the building has brought a sense of pride in, as well as international attention to, the city.
Building a Masterpiece: Santiago Calatrava and the Milwaukee Art Museum will be on view September 8, 2011, through January 1, 2012.
ABOUT THE MILWAUKEE ART MUSEUM


text:
Richard Hell and the Voidoids: Blank Generation 12" (new)
Tags: · 70s · 77 & KBD · hcpmf · new york · reissues · spo-default · spo-disabled
After establishing his reputation as founder of legendary bands the Heartbreakers and Television, Richard Hell went onto to lead the Voidoids which included Robert Quine (Lou Reed, Tom Waits, John Zorn), Ivan Julian (Matthew Sweet) and Marc Bell (aka Marky Ramone). Along with the Ramones, Television, Blondie and Talking Heads, Hell and his band helped to define the early New York "first wave" punk scene. The group's landmark 1977 debut Blank Generation is an iconic album chock full of attitude and blistering performances that has influenced countless rock bands in its wake. It clearly followed its own template and still sounds as unique and abrasive today. The title cut became a slogan and an anthem and later was emulated by the Sex Pistols for their track, "Pretty Vacant" while additional standouts come in the form of "New Pleasure," "Betrayal Takes Two" and "Another World."