Although microRNAs offer great potential as cancer biomarkers, effective clinical dignostics and tumor maker have not been verified to diagnose with colorectal cancer (CRC). The purpose of our study is to systematically assess the expression of miRNAs in matched cancer and normal tissue samples to identify promising diagnostic microRNA (miRNA) biomarkers for CRC.
In our study, we examined by Real-Time PCR the expression levels of 96 mature miRNA in 32 CRC patients with differently expressed tumors versus normal colon tissues. Using enter and stepwise variable selection methods separately, conditional logistic regression was conducted to identify miRNAs associated with CRC. The classification performance of these indicators was assessed under the Fisher discriminant analysis. Receiver operating characteristic curve analyses were applied to obtain diagnostic utility of the differentially expressed miRNAs.
In this study, we confirmed 11 overexpressed miRNAs with no less than twofold difference, and 85 downexpressed miRNAs with up to 0.5-fold difference in CRC from 96 aberrantly expressed miRNAs being identified by real-time PCR. Conditional logistic regression results confirmed that miRNA-378 and miRNA-145 expression profile was statistically significant. The error diagnosis rate of these two miRNAs are 0.194 and 0.113, separeately, showing by discriminant analysis.
MiRNA-145 and miRNA-378* are potential biomarkers for early detection of CRC, which may help in diagnosing CRC in early period.
Colorectal cancer (CRC) yields the second highest mortality rate in China, showing a high incidence trend. Early diagnosis and treatment of CRC is an effective way to improve patients' survival. However, most cases are diagnosed with CRC at late stages as current clinical diagnostics and tumor markers are inconvenient and population screening rates are low. Therefore, there is an imperative need to search for specific, sensitive biomarkers for the early diagnosis of CRC.
MiRNA is small, non-coding sighle-strand RNA, which contain of about 19 nucleotides to 25 nucleotides arising from one arm of longer endogenous hairpin transcripts. Growing studies suggests that microRNA (miRNA) plays an important role in colon disease process, including cell differention, development, proliferation and translation. Futhermore, misregulation of miRNA expression might contribute to human diseases. Evidence has shown that miRNA can work with the target mRNA 3′ non-transcribed with incomplete or complete pairing and negatively regulate gene expression in post-transcriptional level by degrading the target mRNA or inhibit translation .
There is increasing evidence that some miRNAs may be used as diagnostic biomarkers for CRC by identifying differences in miRNA expression of colorectal tumors and ajacent non-neoplastic tissues from patients. For example, E Bandrés et al. reported that miR-31, miR-96, miR-133b, miR-135b, miR-145, and miR-183 are the most significantly deregulated miRNAs and the expression level of miR-31 was correlated with the stage of CRC tumor . Calin et al. reported that one of the most upregulated miRNAs is miR-106a, which is consistently reported in six studies, and the five most downregulated miRNAs are miR-30a-3p, miR-139, miR-145, miR-125a, and miR-133a, which are consistently reported and differentially expressed in four studies; these miRNAs may actually be of clinical use as diagnostic/prognostic biomarkers or therapeutic targets . However, most of the screening studies have small sample with no prediction accuracy of candidate diagnostic biomarkers.
To determine much sensitive indicators, the present study examined the expression of 96 mature miRNAs in a panel of 31 matched pairs of tumoral and non-tumoral tissues by real-time PCR. Conditional logistic regression was used to screen the factors contributed to the occurrence of tumor, among which miR-145 and miR-378* were found being statistically significant. Futher analysis reveals miR-378* and miR-145 exhibits potential as a good diagnostic and prognostic marker.
To investigate whether miRNAs are differentially expressed in CRC versus normal colon tissues, surgical specimens of cancer tissue and adjacent normal mucosa were obtained from 32 patients with colorectal cancer who underwent surgery at The General Hospital of PLA Guangzhou Military Area between 2012 and 2013. Fresh CRC and adjacent noncancerous colorectal tissues, which were used as specimens, were obtained by experienced surgeons and examined by experienced pathologists. Surgery was performed to remove the primary tumor immediately after carcinoma was diagnosed. Incision was performed from the edge of the site by at least 2 cm. Tumor stage was classified according to the International Union against Cancer (UICC, 6th ed., 2002). Informed written consent was obtained from each patient, and research protocols were approved by the Medical Ethics Committee of the General Hospital of PLA Guangzhou Military Area.
RNA extraction was performed to obtain cryopreserved tissues and adjacent group-woven sliced tissues with liquid nitrogen, grinding into powerder using Trizol total RNA isolation reagent as per the manufacturer's protocal . Concentration and purity of isolated RNA were assessed by measuring the optical density at 260 (OD260) and 280 nm (OD280).
Isolated RNA was of high purity and integrity. A260/A280 ratios for the human genomic DNA extracted from spit were consistently within generally acceptable values of 1.7 to 2.0 . Reverse transcription-related operations were performed following the kit instructions.
Quantification was performed by real-time PCR using SYBR Premix Ex Taq TM (TaKaRa) for the most upregulated or most downregulated miRNAs. The primers for U6 were obtained from TaKaRa. PCR was performed in a real-time PCR system (Bio-Rad) with the following reaction conditions: Real-time PCR kit was operated in strict accordance with the manufacturer's instructions. The cycling program consists of 1× at 95°C for 10 min and 40× (15 s at 95°C) at 60°C, plus extension of 60 s, for a total of 40 cycles .
Default threshold settings were used as threshold cycle (Ct) data. The Ct is the fractional cycle number at which the fluorescence passes the fixed threshold . After calculating the Ct value, expression values were normalized to those for U6, which were calculated as ΔCt = Ct − CtU6 (expression of the relative expression profile). Therefore, ΔΔCt = ΔCt (tumor group) − ΔCt (control group) . Relative quantification of miRNA expression was calculated with 2-ΔΔCt method, which represents relative fold changes of miRNA expression.
The patients' demographics for continuous variables were reported as mean ± SD, while percentage, and frequency calculated for categorical variables. Paired Student's t-test was used to determine the level of significance (P < 0.05). Conditional logistic regression model was used to calculate odds ratio with 95% confidence interval to estimate association and control the potential confounding variables, confirming diagnostic use of miRNAs that contributes to CRC probability. Discriminant analysis for classification of tissues types  was performed to determine the discriminative ability of the screened miRNAs. Statistical analysis was performed using IBM SPSS version 16.0 software. P values of less than 0.05 were considered statistically significant.
The clinicopathological factors of the 32 (16 women) participants with CRC recruited to the study are showed in Table 1. The mean age of the respondents was 31.3 years (±5.6 SD). No participants showed evidence of disease complications. A total of 23 participants (71.9%) were within the age range of 60 years to 83 years, while9 patients (28.1%) were in the age range of 20 years to 60 years. In addition, 16 participants (50%) had stage II disease, while the other 16 (50%) were diagnosed with stages III and IV disease. Although Beştaş R et al. suggested that vascular endothelial growth factor (VEGF) expression is significantly correlated with advanced stage , we did not found any correlation in this study. Among nine patients reported VEGF, 4 patients (44.44%) were negative in VEGF and 5 out of them were positive. Loss of CK20 expression is associated with poorly differentiated carcinoma . Ten (31.3%) out of 31 patients were positive in CK20.
To identify miRNAs that are differentially expressed in tissues, we analyzed expression profiles of 1448 miRNAs, founding 497 miRNAs expression profiles showed statistical significance, in which 155 miRNAs have statistical significance in paired t-test and satisfied the strict condition of P ≤ 0.001.
To further validate the expression levels of these miRNAs, 31 patients were qualified and selected for performing qPCR validation phase. In the condition of fold chang >2.0 and P < 0.05, we gained a set of 96 miRNAs that were differentially expressed between the colorectal tissues and normal tissues, which were consistent with the results of TaqMan Human MicroRNA Array. Twelve miRNAs were upexpressed, while 84 miRNAs (has-miR-137, hsa-miR-133a, hsa-miR-143, hsa-miR-363, hsa-miR-4770, hsa-miR-490-5p, hsa-miR-133b, and so on) were deexpressed in tumors compared with those in normal tissues (adjusted P = 0.05) (Figure 1).
Fold change of 96 selected miRNAs further validated by TaqMan RT-qPCR. Twelve miRNAs (hsa-miR-130b, hsa-miR-203, hsa-miR-1974, hsa-miR-592, hsa-miR-200a, hsa-miR-429, hsa-miR-183, hsa-miR-182, hsa-miR-1290, hsa-miR-141, hsa-miR-135b, and hsa-miR-96) were overexpressed, whereas 84 miRNAs (hsa-miR-1, hsa-miR-145, hsa-miR-145*, and so on) were downexpressed in tumor tissues compared with those in normal tissues.
After a series of selection processes independently with enter method and conditional forward method in conditional logistic regression, we found nine statistically significant miRNAs in enter method, namely, miR574-3p, miR422a, miR490-3p, miR-374b, miR-133a, let7g, miR-378*, miR-9* and miR-378i.
On the other hand, we found seven statistically significant miRNAs, namely, miR-145, miR-363, miR-378*, miR-137, miR-100, miR-125a-5p, miR-143 in conditional forward method. This result was consistent with Pagliu A. et al.'s study who found that analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression . Besides, the expression levels of these miRNAs between CRC tissues and the neighboring noncancerous colorectal tissues were compared using qRT-PCR analysis. Preliminary results showed that the level of miR874-3p, miR-422a, miR-490-3p, miR-374b, miR-133a, let-7 g, miR-378, miR-9*, and miR-378i were all deregulated in the CRC tissues compared with the neighboring noncancerous colorectal tissues (all P < 0.05) (Figure 2).
Selected miRNA expression levels in CRC tissues and neighboring noncancerous tissues. Selected miRNAs showed statistical significance in conditional logistic regression analysis. (A) has-miR874-3p, miR422a, and miR490-3p expression levels in CRC tissues and neighboring noncancerous colorectal tissues. (B) has-miR374b, has-miR133a, has-let-7 g, has-miR378, has-miR9*, and has-miR378i expression levels in CRC tissues and neighboring noncancerous colorectal tissues.
To further screen the most contribution factors to CRC among these miRNAs, the variables above were used to analyze in the conditional logistic regression. The results indicated that miR-378* is the kept variable with statistical significance to distinguish CRC from normal tissues (P < 0.05; odds ratio = 4.6; 95% CI of odds ratio = 1.25 to 16.84). Similarly,miR145 is also the kept variable with statistical significance to distinguish CRC from normal tissues (P < 0.05; odds ratio = 4.21; 95% CI of odds ratio = 1.17 to 15.13) (Table 2). These results were consistent with those from the study of Zhang et al., who indicated that miRNA378 is a reliable, hemolysis-independent biomarker for CRC . We compared the expression of miR-378* in different clinical stages and found that miR-378* is downregulated in all stages. A previous study also proved that the expression of miR-378a-3p and miR-378a-5p was significantly associated with TNM stage . These results indicate that clinical stage may influence the expression of miRNAs (Figure 3).
Fold change of miR-378* and miR-145 in different clinical stages. Expression levels of miR-378* and miR-145 varied in different clinical stages.
To verify the diagnostic value of miR-378*, Fisher discriminant analysis was analyzed to predict the category and determine the diagnostic ability of miR-378*. After ln-gamma transformation of the sample data, the variables followed normal distributions and equal variance matrix for categories I and II.
Evidently, as shown in Table 3, true-positive rate is 80.65% and false-positive rate is 19.35%. The whole discriminant analysis results are listed in Table 3.
Area under the curve for the receiver operator characteristic function for miR-378* and miR-145 were 0.975 (95% confidence interval 0.923–1.00, p < 0.0005) and 0.996 (95% confidence interval 0.982–1.00, p < 0.0005) separately. At an optimal cut score of ≥3.80 and < −1.975(fold change 0.025) separately, sensitivity was 100% both and specificity was 60% and 98% separately. A score of −1.167 (fold change 0.833) or greater for miR-145 had 93.3% specificity but had sensitivity of only 93.8% (See Figure 4, Table 4).
Receiver operator characteristic curve for miR-378* and miR-145 for the predictor of CRC.miRNA-378* levels had areas under the receiver operator characteristic curve of 97.5% and 99.6% separately.
Interestingly, our results in CRC samples agree with those obtained by Faltejskova P et al., who found that the miRNAs functioning as tumor suppressors in CRC are miR-378, miR-375, miR-422a, and miR-215 from 667 miRNAs in a paire design study . Furthermore, Cui SY et al. found that microRNA-145 as a potent tumour suppressor that regulates multiple cellular pathways . Zhang GJ et al. also indicated that miR-378 is an independent prognostic factor that inhibits cell growth and invasion in CRC. Most important is HouY et al. suggest that microRNA-145 as ideal biomarker for the diagnosis of various carcinomas .
Notably, our current study showed that discriminant analysis based on expression data revealed that miR-378* can distinguish CRC from normal tissues. This result is important for the potential role of new molecular gene miR-378* in future diagnostic processes in the absence of effective early diagnostic biomarkers.
The different biological effects of any particular miRNA in different cells could be dependent of the cell-specific collection in target genes . miR-378 inhibits progression of human gastric cancer MGC-803 cells by targeting MAPK1 in vitro . miR-378 also promotes BMP2-induced osteogenic differentiation of mesenchymal progenitor cells . Furthermore, miRNA-profiling study proved that miR-378 was significantly upregulated in cachexia related to enhanced adipocyte lipolysis in human cancer . Notably, Panza A, et al., found that miR-145 is a novel target of PPARγ, acting as a tumor suppressor in CRC cell lines and being a key regulator of intestinal cell differentiation by directly targeting SOX9, a marker of undifferentiated progenitors in the colonic crypts .
Therefore, high-field miR-378* and miR-145 are powerful means for investigating early CRC signs and are promising sensitive tools to support medical diagnosis. Future validation of these methods is preparing planned on a prospective study. Thus, previous studies reveals that change of miR-378 expression has been previously reported in nasopharyngeal cancer. Yu BL et al. reported that repressing TOB2 expression would cause miR-378 to function as an oncomiR in nasopharyngeal carcinoma ; miR-378/ATP also binds Cassette Transporter G1-Signaling pathway .
In summary, our real-time PCR results identified alterations of miRNA expression in CRC with two down-regulated miRNAs (miR-378* and miR-145), which may be novel candidate biomarkers for CRC. Although, both miR-145 and miR-378* contribute to the probability of CRC, comparison between the roles of miR-145 and miR-378* in the CRC progression will give more information to the cell transcription mechanisms.
Further mechanistic studies focusing on miR-378* and miR-145 are required to investigate its underlying roles in the tumorigenesis of CRC .
Juan Peng and Zhengyong Xie contributed equally to this work.
The study was supported with the grant no. B2013313, the project of rapid rehabilitation of prospective randomized controlled study of laparoscopic and open colorectal surgery under the concept of operation, financed by Guangdong Province Medical Research Foundation.
We thank all patients and their families for their participation in this trial. We also thank Dr. Zhang for critically reviewing this manuscript.
ZYX and ZXY performed all the experimental work, prepared data for analysis, and helped with the manuscript; JP analyzed the data; JYC, ZHL and HXK coordinated the original collection of the samples. JP, ZYX and YXZ wrote the manuscript; HPY and YXZ supervised all the analyses and contributed insightful critique; LYC conceived and designed the current study. All authors participated in data interpretation and critical revision of the manuscript. All authors read and approved the final manuscript.


text:
What is web3, and what does it have to do with sales enablement?
Software/tools
Nick Ziech
So, after watching all of the crypto ads at the Super Bowl last week, I started to wonder more about how real this web3 thing is.
I mean, if Coinbase can spend $14 million to put a QR code on the screen, the least I can do is understand the digital realm it's creating, right?
But after reading a bit about web3, it started to remind me of how we at Enablix talk about sales enablement, and how we believe it's going to change in the near future.
In this post, I'm going to outline how some of the main tenets of the potential web3 apply to SE, and how enablement managers should think about putting their teams in the best place possible going forward.
And while I'm not giving away any free bitcoin, I think there'll be some takeaways that will make reading worth it.
Note: For my discussion of web3, I'm relying on many sources - but primarily FreeCodeCamp's summary as well as the classic web3 Wikipedia Page.
Tl;dr: As web3 grows on popularity based on the idea of a decentralized, secure, and self-governing platform, sales enablement will continue to shift in a similar direction, with enablement materials available in all applications central to a sales reps' workflow while content creation will shift to be more heavily sales dependent
Also, in writing this, I'm becoming convinced that web3 doesn't solve any of the practical issues we face in web2. But that's besides the point.
There are a bunch of ways to answer that question - but I'd argue that the simplest definition is to contrast it with what web 1 and 2 were:
Web 1.0: Web 1.0 was basically the first version of the internet. Most people on the web consumed content, and the creators were typically developers who built websites that contained information in text or image format (anyone remember geocities?). Web 1.0 lasted approximately from 1991 to 2004.
Web 2.0: Today's web. We're all content creators sharing our thoughts amid several platforms that are primarily owned by a handful of companies. Infrastructure is largely centralized through a few big companies (Amazon, Google, Social Media Companies, etc.), and privacy is, well, "meh".
Web 3.0 is a little different. While the full definition of what web3 can be is pretty exhaustive, I'm going to boil it down to 3 things:
Self-Governing
Verifiable
In web 3, applications don't run on single servers in the cloud - rather they are powered by decentralized blockchain technology that potentially has the ability to create a much more secure and elastic framework for interactions.
How Does This Affect Sales Enablement?
Am I arguing that all sales enablement platforms are going to be built on the blockchain this year? No.
However, there are some pretty important parallels between how web3 could be constructed, and how sales enablement practitioners should be thinking about empowering their teams from old sales enablement strategies (we'll call it se2) to new ones (se3).
Let's break this down point-by-point:
The Future of Sales Enablement is Distributed
In web2, applications were powered by centralized "gatekeepers" that gave platform to content, whereas in web3 the application and infrastructure will be largely distributed among devices that use the app.
Similarly, in se2 (my term) sales and marketing collateral was hosted in standalone enablement platforms that sales reps would log into, but in se3 all collateral will be distributed among the sales applications that reps use daily.
Collateral, whether it be public facing assets, internal content, or training materials, is only going to get more important as seller-buyer relationships continue to go online and increasingly start outside of typical channels.
However, because of these changing trends, content needs are changing from "search for a big case study" to "what 15 second snippet can I send right now".
This means that content must be effectively distributed throughout the salesperson's day-to-day tools. Stop making reps log into standalone sales enablement tools, but integrate with their tools today. This means making collateral of all kinds available in:
Your CRM (Salesforce, Hubspot, etc.)
Messaging Tools (Teams, Slack)
Email (Gmail, Outlook)
Even your browser! Calendly does a great job of detailing what this should look like
Think less about the platform, and more about the salesperson workflow. You'll end up with dozens of places salespeople interact with their prospects - that's good, and it's also what distributed sales enablement looks like.
SE Materials Will Be Generated Primarily By the Sales Team
In web2, platforms governed what could be said and done within their apps, whereas in web3 the decentralized nature meant that the users themselves 'self-govern' the content
In se2, collateral came from sales enablement managers and PMM's who made material for the sales team. In se3, the content will be curated from the team's own interactions, making every prospect call and message a potential piece of content
Beginning in 2020, companies began to see how valuable sales and marketing content can be within the sales cycle, and began to heavily invest in creating collateral for their sales cycles'.
Unfortunately, this has turned enablement managers and PMM's largely into content centers.
However, there's no real reason that sales content needs to originate outside of the sales team. Every call - successful or otherwise, likely has multiple discussion points and places where new or seasoned reps can learn from.
Se3 will have content creation start with the sales team - prospect email replies, call recordings and interactions will be the source of >50% of content, both for internal sales training but also for external consumption.
Systems should be flexible enough to allow seamless two-way communication on content regardless of the type, where sales suggests ideas but also responds in real-time to content updates.
Writing about the things that prospects are talking about is not only a more sustainable pattern of content creation, it's going to be far more relevant to your target audience.
This shifts the role of SE manager and PMM to less of a content mill and more of a curator - taking sales suggestions and content beginnings and refining them into something suitable for a training or company Linkedin post.
Sales Enablement Collateral Will All Come From A Single Source of Truth
In web2, security risks and phishing attacks are prevalent, but web3 promises all transactions and credentials to be machine verifiable, impossible to have identities stolen or impersonated (whether or not that is true is dubious at best)
Similarly, in se2, reps are never 100% sure if they have the latest copy of a case study or presentation. In se3, reps will only ever have access to brand-approved and up-to-date material, without sifting through multiple versions of a doc
This one seems like a no-brainer, but it's still an ongoing issue for what feels like a heavy majority of enablement teams.
When marketing materials are all over the place, it's impossible for reps to consistently stay up to date on what the 'latest and greatest is'.
Let's quickly reiterate what doesn't work:
Sending out slack updates with latest copies that quickly get buried in other conversation
Weekly newsletters that never get read because everyone's inbox is flooded
Remote meetings where 45 minutes go by with no questions
A sharepoint site constantly updated by the team that becomes difficult to look at, let alone parse
When collateral access gets distributed, there won't be a reason for reps to store old copies on their machines, and it will be easy to control lineage and versioning from a single content source feeding these outlets.
Reps will have the ability to see full change logs for each piece of content, and be assured that all content is in line with what marketing wants to be shared.
All Aboard the Hype Train
Taking it back to how we got here… how realistic is this?
Well, as many have noted, the full online experience of web3 is still far away for most people, and I think it's safe to say the same is true of se3 as well. And while platforms will evolve to offer functionality even beyond what I've mentioned here, let's the order of importance for sales enablement:
People > Processes > Tools
So in a way, the real future of sales enablement isn't about the sales OR the enablement, but the friends we make along the way.
I'm sorry. I had to.
Nick is the Chief Marketing Officer at Enablix. When not writing articles, Nick spends his time learning about the world with his infant daughter, brewing beer, playing basketball, and cooking.
He doesn't do all those activities with his daughter, though, and he understands how the wording in the previous sentence may be confusing to some readers.
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TelevisionVideo
'NCIS: New Orleans' Season 1, Episode 12: 'The Abyss'
Posted byBy Ricky Riley | Published on January 13, 2015 CommentsComments (0)
NCIS: New Orleans season 1, episode 12: The Abyss airs tonight on CBS.
When a Navy admiral's daughter is the prime suspect in a double-murder case aboard a research boat, the NCIS team partners with the Coast Guard Investigative Service (CGIS) to work the case. Meanwhile, LaSalle tracks down his estranged brother.
NCIS: New Orleans is a drama about the local field office that investigates criminal cases affecting military personnel in The Big Easy, a city known for its music, entertainment and decadence. Leading the team is Special Agent Dwayne Pride, aka "King," a native of New Orleans who is driven by his need to do what is right. Working with Pride is Special Agent Christopher LaSalle, who plays hard but works harder; and Special Agent Meredith "Merri" Brody, a charismatic and tough interrogator who transferred from the Great Lakes office in search of a fresh start. Supporting them is coroner Dr. Loretta Wade, who is as eccentric as she is smart. This colorful city that harbors a dark side is a magnet for service personnel on leave, and when overindulgence is followed by trouble, Pride's team is at its best.
NCIS: New Orleans season 1, episode 12 airs Jan. 13 at 9 p.m. EST on CBS.
TagsNCIS: NEW ORLEANSNCIS: NEW ORLEANS cbsNCIS: NEW ORLEANS previewNCIS: NEW ORLEANS season 1
'NCIS: New Orleans' Season 1, Episode 16: 'My Brother's Keeper'
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'NCIS: New Orleans' Season 1, Episode 10: 'Stolen Valor'


text:
α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats
Tiebing Liang, John Spence, Lixiang Liu, Wendy N. Strother, Hwai Wen Chang, Julie A. Ellison, Lawrence Lumeng, Ting Kai Li, Tatiana Foroud, Lucinda G. Carr
Total gene expression analysis (TOGA) was used to identify genes that are differentially expressed in brain regions between the alcohol-naive, inbred alcohol-preferring (iP), and -nonpreferring (iNP) rats. α-Synuclein, expressed at >2-fold higher levels in the hippocampus of the iP than the iNP rat, was prioritized for further study. In situ hybridization was used to determine specific brain regions and cells expressing α-synuclein in the iP and iNP rats. Similar to α-synuclein mRNA levels, protein levels in the hippocampus were higher in iP rats than iNP rats. Higher protein levels were also observed in the caudate putamen of iP rats compared with iNP rats. Sequence analysis identified two single nucleotide polymorphisms in the 3' UTR of the cDNA. The polymorphism was used to map the gene, by using recombination-based methods, to chromosome 4, within a quantitative trait locus for alcohol consumption that was identified in the iP and iNP rats. A nucleotide exchange in the iNP 3' UTR reduced expression of the luciferase reporter gene in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the α-synuclein gene may contribute to alcohol preference in the iP rats.
Synucleins
Quantitative Trait Loci
Chromosomes, Human, Pair 4
Luciferases
Alcohol Drinking
Liang, T., Spence, J., Liu, L., Strother, W. N., Chang, H. W., Ellison, J. A., ... Carr, L. G. (2003). α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats. Proceedings of the National Academy of Sciences of the United States of America, 100(8), 4690-4695. https://doi.org/10.1073/pnas.0737182100
α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats. / Liang, Tiebing; Spence, John; Liu, Lixiang; Strother, Wendy N.; Chang, Hwai Wen; Ellison, Julie A.; Lumeng, Lawrence; Li, Ting Kai; Foroud, Tatiana; Carr, Lucinda G.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 8, 15.04.2003, p. 4690-4695.
Liang, T, Spence, J, Liu, L, Strother, WN, Chang, HW, Ellison, JA, Lumeng, L, Li, TK, Foroud, T & Carr, LG 2003, 'α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 8, pp. 4690-4695. https://doi.org/10.1073/pnas.0737182100
Liang T, Spence J, Liu L, Strother WN, Chang HW, Ellison JA et al. α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats. Proceedings of the National Academy of Sciences of the United States of America. 2003 Apr 15;100(8):4690-4695. https://doi.org/10.1073/pnas.0737182100
Liang, Tiebing ; Spence, John ; Liu, Lixiang ; Strother, Wendy N. ; Chang, Hwai Wen ; Ellison, Julie A. ; Lumeng, Lawrence ; Li, Ting Kai ; Foroud, Tatiana ; Carr, Lucinda G. / α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 8. pp. 4690-4695.
@article{008e7928b7064a6c997f3f2001f8303d,
title = "α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats",
abstract = "Total gene expression analysis (TOGA) was used to identify genes that are differentially expressed in brain regions between the alcohol-naive, inbred alcohol-preferring (iP), and -nonpreferring (iNP) rats. α-Synuclein, expressed at >2-fold higher levels in the hippocampus of the iP than the iNP rat, was prioritized for further study. In situ hybridization was used to determine specific brain regions and cells expressing α-synuclein in the iP and iNP rats. Similar to α-synuclein mRNA levels, protein levels in the hippocampus were higher in iP rats than iNP rats. Higher protein levels were also observed in the caudate putamen of iP rats compared with iNP rats. Sequence analysis identified two single nucleotide polymorphisms in the 3' UTR of the cDNA. The polymorphism was used to map the gene, by using recombination-based methods, to chromosome 4, within a quantitative trait locus for alcohol consumption that was identified in the iP and iNP rats. A nucleotide exchange in the iNP 3' UTR reduced expression of the luciferase reporter gene in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the α-synuclein gene may contribute to alcohol preference in the iP rats.",
author = "Tiebing Liang and John Spence and Lixiang Liu and Strother, {Wendy N.} and Chang, {Hwai Wen} and Ellison, {Julie A.} and Lawrence Lumeng and Li, {Ting Kai} and Tatiana Foroud and Carr, {Lucinda G.}",
T1 - α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats
AU - Liang, Tiebing
AU - Spence, John
AU - Liu, Lixiang
AU - Strother, Wendy N.
AU - Chang, Hwai Wen
AU - Ellison, Julie A.
AU - Lumeng, Lawrence
AU - Li, Ting Kai
AU - Foroud, Tatiana
AU - Carr, Lucinda G.
N2 - Total gene expression analysis (TOGA) was used to identify genes that are differentially expressed in brain regions between the alcohol-naive, inbred alcohol-preferring (iP), and -nonpreferring (iNP) rats. α-Synuclein, expressed at >2-fold higher levels in the hippocampus of the iP than the iNP rat, was prioritized for further study. In situ hybridization was used to determine specific brain regions and cells expressing α-synuclein in the iP and iNP rats. Similar to α-synuclein mRNA levels, protein levels in the hippocampus were higher in iP rats than iNP rats. Higher protein levels were also observed in the caudate putamen of iP rats compared with iNP rats. Sequence analysis identified two single nucleotide polymorphisms in the 3' UTR of the cDNA. The polymorphism was used to map the gene, by using recombination-based methods, to chromosome 4, within a quantitative trait locus for alcohol consumption that was identified in the iP and iNP rats. A nucleotide exchange in the iNP 3' UTR reduced expression of the luciferase reporter gene in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the α-synuclein gene may contribute to alcohol preference in the iP rats.
AB - Total gene expression analysis (TOGA) was used to identify genes that are differentially expressed in brain regions between the alcohol-naive, inbred alcohol-preferring (iP), and -nonpreferring (iNP) rats. α-Synuclein, expressed at >2-fold higher levels in the hippocampus of the iP than the iNP rat, was prioritized for further study. In situ hybridization was used to determine specific brain regions and cells expressing α-synuclein in the iP and iNP rats. Similar to α-synuclein mRNA levels, protein levels in the hippocampus were higher in iP rats than iNP rats. Higher protein levels were also observed in the caudate putamen of iP rats compared with iNP rats. Sequence analysis identified two single nucleotide polymorphisms in the 3' UTR of the cDNA. The polymorphism was used to map the gene, by using recombination-based methods, to chromosome 4, within a quantitative trait locus for alcohol consumption that was identified in the iP and iNP rats. A nucleotide exchange in the iNP 3' UTR reduced expression of the luciferase reporter gene in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the α-synuclein gene may contribute to alcohol preference in the iP rats.


text:
Q: Display two messages at the same time with SwiftMessages pod I'm using the SwiftMessages pod to display messages in my app.
(https://github.com/SwiftKickMobile/SwiftMessages)
I would like to display two messages at the same time, by example, one at the top, one at the bottom.
In the Readme, it's written:

Multiple instances of SwiftMessages can be used to show more than one
  message at a time. Note that the static SwiftMessages.show() and other
  static APIs on SwiftMessage are just convenience wrappers around the
  shared instance SwiftMessages.sharedInstance):
let otherMessages = SwiftMessages()
SwiftMessages.show(...)
otherMessages.show(...)

So, I taken some of the demo code and I tried with multiple instances:
override func viewDidAppear(_ animated: Bool) {
    super.viewDidAppear(animated)

    let error = MessageView.viewFromNib(layout: .TabView)
    error.configureTheme(.error)
    error.configureContent(title: "Error", body: "Something is horribly wrong!")
    error.button?.setTitle("Stop", for: .normal)

    let status2 = MessageView.viewFromNib(layout: .StatusLine)
    status2.backgroundView.backgroundColor = UIColor.orange
    status2.bodyLabel?.textColor = UIColor.white
    status2.configureContent(body: "Hello")
    var status2Config = SwiftMessages.defaultConfig
    status2Config.presentationContext = .window(windowLevel: UIWindowLevelNormal)
    status2Config.preferredStatusBarStyle = .lightContent

    let notification = SwiftMessages()
    SwiftMessages.show(view: error)
    notification.show(config: status2Config, view: status2)
}

but just the first message (error) appears.
What is wrong ?

A: Move the line
let notification = SwiftMessages()

out of viewDidAppear to make it a member variable so that it's retained long enough to display the message.

redpajama_set_name: RedPajamaStackExchange


text:
Are top tennis players actually tougher than the rest?
I used to play a lot of tennis. I used to play all the year round, Christmas Day included. The only time of the year I didn't play was Wimbledon fortnight. That was partly because the sight of the top pros would make me want to throw my racket in a skip. The same TV action that was making me feel like giving up was having the opposite effect on people who never played. They were burrowing under the stairs for their equipment, racing down to public parks to give it a go as if their tennis ability was just an old muscle that needed to be re-awoken. Presumably some while later they were wondering why their slice backhand didn't go within an eighth of an inch of the net and then dip sharply before hanging a sharp right like Roger Federer's did. Then they'd give up again until the following year. And they still didn't realise just how mind-bogglingly good the best tennis players are. I know Tim Henman never won a grand slam but the abuse he came in for in this country came mainly from people who staggered down the park once a year rather than the people who knew just how tough it is to prevail in the upper reaches of this sport.
Watching Murray only just overcome Wawrinka last night was a salutary reminder that there can't be many sports that require more of the competitors than men's professional tennis. It's you and you alone, using personal reserves of stamina, concentration, athleticism, touch, power, nerve, cussedness and geometric aptitude that most of us couldn't summon for three minutes, let alone four hours and more. I've hit maybe twenty tennis balls in my life that connected with the sweet spot and went not just roughly but exactly where I wanted them to go. These people are doing it ten times a minute. There's not a split second for coasting or allowing their brain to switch off and their body do the work. They have to be pushing the other guy back a millimetre at a time, putting his feet in slightly the wrong place, forcing him into the tiny hurry that will produce the crucial error. If they don't do that he will do the same to them. And when you don't win, as happened to Stanislas Wawrinka last night, you just put your racket in your bag and go back to the dressing room, vowing to do better next time. He'll probably be out playing doubles today. Remarkable, as Dan Maskell was wont to say.
Posted by David Hepworth at 12:40 pm 9 comments:
A man of property
I've just found this. It shows my grandmother Lois (left), my great-grandfather Smith Taylor and a cousin who used to live with them.
It's unusual in that it's not a studio picture but it seems too good to be an amateur snap. Obviously whoever's taking it has had instructions to include as much of their house as possible. What I don't understand is that the back of it is a postcard with a space for "a half penny stamp". They must have been posted to friends and relatives to show off.
Posted by David Hepworth at 10:06 am 5 comments:
Let us now praise Another Nickel In The Machine
Jude Rogers, fellow member of the Society For Mooching Around Old London Pubs With Literary Associations, sent me a link to Another Nickel In The Machine, one of the best blogs I've seen in ages. It combines three of my favourite things - London, history and serendipity - in one endlessly browsable package. I've just been looking at the piece about Errol Flynn and his 15-year-old girlfriend Beverly Aadland at the Lido Club in Swallow Street. It also shows you the house in Castelnau in Barnes where he went to school and a YouTube clip of him on a panel game with Neil Young's father. How could anyone resist?
Is death just the start for the Michael Jackson industry?
A few hours after the death of Elvis Presley in 1977, as his family were sitting around Graceland shocked and weeping, Colonel Tom Parker turned up. He hadn't been closely involved in Presley's affairs at that time, preferring to spend his time gambling. It was Parker who galvanised the shattered family with the words "this changes nothing".
Even he can't have known how right he was. When Presley died there was no etiquette for handling the death of a rock superstar. The media weren't sure if they were dealing with a washed-up has-been or a figure who was still relevant. I don't think Downing Street felt the need to make a statement. "People" magazine, America's foremost title about entertainment and celebrity, could have put his face on the cover but didn't, reasoning that he no longer meant that much to the average American. I happened to be in Memphis that year and visited Graceland to look at the grave. You could just walk into the grounds. There were no conducted tours and very few souvenir shops. The massive resurgence of interest in Elvis took some time to gather. The Elvis impersonators in their white suits took a while to get their act together. Dead Elvis was eventually more popular and more profitable than Live Elvis but it wasn't immediate.
When John Lennon was shot three years later the news organisations were primed by the Presley experience. The wall-to-wall coverage of his death was encouraged by the fact that he was both British and American, therefore both nations claimed some kind of ownership of him, politicians and public moralists could persuade themselves he was a key thinker for our times, his murder threw up all kinds of questions about random violence and the levers of the media were being pulled by people who had grown up adoring the Beatles and everything they stood for. At the end of December 8th 1980, after having gone through a day of hacking out tributes, a remark of Annie Nightingale's on the TV set me bawling. I wasn't crying for John Lennon, of course. I was crying for myself. Lost youth, good times, perspective, all that kind of thing. These things trigger something in us that needs to come out eventually. The Princess of Wales was not a rock star but the reaction to her death was on the scale of Lennon's but this time with a previously unfamiliar hysteria thrown in. Even the people who were flinging roses at her hearse in the Finchley Road on that mad day probably think better of it now. But at that time there was a pent-up desire for an extravagant, apparently un-British show of emotion. It was the kind of thing that used to be sublimated via religion or dancing round the maypole. In the TV age it was delivered via the box.
Judging by the way that Google almost broke yesterday under the strain I think it's fair to say that Michael Jackson's was the first death of a massive star in the internet age. TV and radio suddenly look and sound very quaint, huffing and puffing in the wake of the story, trying to assemble talking heads to say anything meaningful; even as they are talking people are coming up with new angles and implications. What happens to the kids? Where does this leave the London shows? Are his mother and father speaking to each other? Do you think these shows will actually happen in some strange animatronic form? How long will Sony leave it before the TV ads start? Bet they're glad they didn't auction the personal effects a month or two back. Does McCartney get the ATV catalogue back? I hear the funeral is going to be Muslim. What religion was he? Will Neverland be reopened to the public? How many people are working on one-shots right now? And so on.
Is there anything wrong with that? Well, it doesn't represent us at our most worthy but it does represent us at our most human. In the wake of any death in any family human beings have a huge desire to just sit down and talk about it. They may be talking about the deceased. They may be grasping the opportunity to talk about something they rarely talk about, which is life. They may just want to gossip. Thanks to the internet you can now take a seat in the world's largest living room with millions of souls who are similarly fascinated and listen to discussions you might not wish to instigate yourself. Because a lot's changed since Colonel Parker's pronouncement in 1977. Parker was essentially a small-time thinker. Thirty years later, with the technology at the disposal of the entertainment industry, death can be just the beginning. I'm sure there are people working on it right now.
This post is also on The Word site. I've written a piece about Michael Jackson which is in today's Independent.
Why I don't use book shops much
I usually buy books online. I tend to get scolded at dinner parties for the damage I'm thereby doing to my friendly neighbourhood bookstore. I fear that bookstores, friendly or otherwise, may be damaging themselves without help from me. On Radio Four this morning I heard an extract from a book called "The Junior Officers Reading Club". Having your book read on Radio Four is the publishing equivalent of a Radio One record of the week and therefore you'd expect the trade to be at least slightly poised.
Finding myself in the King's Road this afternoon I went into a branch of one of Britain's biggest book retailers, a place I might reasonably expect to find such a book. I enquired on the ground floor. Years working on the other side of the counter have taught me how to be a good customer. My presentation goes like this. "They're reading a book on Radio Four this week. [I'll confess, I half anticipated that I wouldn't have to go any further than this. I was wrong. ] It's called something like The Junior Officers Reading Club." There's a slight flicker of recognition on his face but he has to look it up on their computer system (which probably means he's looking on Amazon). He tells me it's downstairs in History. Obvious place, really, for a book about serving in the army in contemporary Afghanistan. The tyranny of categories kicks in, which is half the problem for book retailers, as it is for record retailers. You don't just have to work out where it is. You have to work out where they think it is which is based on what they think it is. These are not problems for you and Google.
I go down to History unaccompanied. If I'd asked after the Bovril in my local Sainsbury the assistant would have taken me to it. That's how they roll. Seemingly this does not apply to the spending of £16.99. I look – and bear in mind I'm a world-class looker – on the table where the big-selling military books are displayed. No sign. I ask another assistant. I've been sent down from upstairs etc etc. Again there's that faint gleam of recognition from him. I'm starting to wonder if they coach that gleam. He looks on the system which assures him that the book is present in the store. He takes me over to the place where it is assigned to live. He looks without success. He goes back to the desk to check whether it's actually been "put out" (because there's a whole world of difference between in-stock and on-sale). As he does so I look down and see the book. One copy, which means either there have been lots of sales and the staff haven't noticed or they have ordered one copy which suggests their buying could be keener.
Then I thank him. How English am I? What am I thanking him for? He didn't know what I was after or help me find it. In fact most of my time in the shop I was dealing with the difficulties of being in the shop. In a shop they've often hidden what you want behind lots of things they think you want. It's a bit like going to the office. Most of the time in the office you're dealing with problems that only arise because you're in the office. On the occasions I complain in a shop I invariably end up saying "you are confusing your problems with mine. If you hadn't introduced a system to make your life easier you might be making my life easier." Anyway, I bought the book. More fool me. I should have just ordered it on Amazon. It would probably have been home ahead of me.
A few years ago I did a presentation at a meeting of the Institute of PRs. Don't laugh. I concluded by saying that in the near future all providers of information would be replaced by just two things. One was Google, an unparalleled way of pulling information towards you. The other was what I like to call the House Hippie. House Hippies know everything. They are Google with skin. When I worked in retail there were a few House Hippies. They were often terrible with customers but they knew more about the stock than the most sophisticated retrieval system. If something was a Radio Four book they bloody well knew. I stand by what I said, particularly when it applies to PRs, who seem to recruit a remarkable number of people who have a passion for anything but communication. They long ago stopped informing people of anything. In this maybe they are just recognising the reality of the world against which I came up this afternoon. Any information of any interest you find out yourself. The only people worth consulting are experts. And if a shop has a range of stock which is so wide that the staff can't be expert in it, they mustn't be surprised if we go to the digital shelf and help ourselves.
(This over-long post was written in a hospital corridor waiting for a family member's x-ray to come back. Slight fracture.)
Posted by David Hepworth at 9:30 pm 16 comments:
I love radio. Why doesn't it love me?
I love radio. If I was going to do away with all media but one it would be radio I'd hang on to. Over ten years ago in the vanished kingdom of more money than sense I felt I ought to get one of these new fangled digital radios. I went to John Lewis where they had a couple of tuners on sale. Things hadn't yet reached the stage of portables. I bought a Technics tuner for what I think was the best part of a thousand pounds. Yes, you read that correctly. I'm not a complete dolt when it comes to setting up audio equipment but I could never entirely get it working to my convenience. I quickly gained the impression that the stations had been clustered for the convenience of the media owners rather than the listener. Later on I realised that the government were flogging off so much "spectrum" that the signal was getting worse all the time. Many hi-fi people say it's now actually worse than FM. But just as they were going quiet on the subject of audio quality they were starting to talk up the range of radio services that were going to be offered. However no sooner had these stations opened up than they were cutting back or closing. There was not enough advertising around to finance niche services and so everybody had to cluster in the middle of the road or go out of business. The promised internet radio revolution never happened either because the more popular sites became the more they had to pay for bandwidth and music rights. Then the recession gave Channel Four an excuse to change their mind about launching a radio station and suddenly a medium which was positioning itself for dramatic advances was abandoning its weapons and tiptoeing away in the dead of night.
There are maybe ten radios in our house. That's not counting the devices we've got that are capable of receiving radio signals. Some are portable. Some are fixed. A handful are digital. Most are analogue. Because of the digital delay it is impossible to do what I'd like to do, which is listen to the same programme while moving from the kitchen to the dining room. The only solution to that is to switch the digital radio to analogue. Because some clown is promoting club nights on pirate radio from the top of a nearby tower block it's difficult to get proper FM reception on Radio Four in my area. To get round these problems, and to save my family anguish, I decided to listen to the Twenty20 World Cup Final on the internet via my iTouch. I fired it up and tuned it to Five Live only to be told that (presumably because of rights issues) this was one broadcast they were not able to bring me. Since last year we have been trying to turn off anything in the house that uses "stand-by" power overnight. This applies to digital radios. It means that every morning when I make my way downstairs in traditionally fragile state I have to bend down to the plug to turn on our very lovely digital radio at which point it emits a piercing "meee" sound to announce it is ready to be switched on. This lowers my scene somewhat.
I realise that the proposed "digital switchover" ought to save me at least some of those problems but there's a part of me that agrees with Libby Purves's scorching column in The Times in which she lays into the radio industry and the government for a succession of blunders, technological letdowns and high-handed digital decrees that have left people with the feeling that this is an industry that only enters their life in order to take something precious away. (I might also bundle into this battered parcel of discontent the fact that Simon Mayo will no longer be on Five Live because the latter is moving to Manchester, as perfect a case of tail wagging dog as I can call to mind right now.) I also agreed with my old friend Trevor Dann of the Radio Academy when he said on this week's Broadcasting House that the radio industry needs to come up with a product that adds something to people's enjoyment rather than curtailing it. How it's going to happen I have no idea. Identifying with the listener (make that "customer" for a while) might prove very difficult. What we don't wish to hear any more of are their problems.
A thought about speeches
In the course of attending a lifetime of speech days I have finally realised you can tell a good speaker from a mediocre one without actually hearing a word of what they're saying. The poor speaker looks at their notes. The good speaker looks at their audience. The poor one thinks you're listening to hear what they're going to say. The good one knows you're listening to them because they're interesting to listen to.
Let us now praise "A Point Of View"
A Point Of View is one of the best things on Radio Four. It consists of wise old heads talking about current affairs. Because they're wise old heads, what they generally say is a variation on a theme of "this is not so new" or "pull yourselves together".
It's on early on Sunday morning, thereby ensuring the wisdom never reaches anyone under the age of 35. In the past it's featured the likes of Brian Walden and Katherine Whitehorn. The series that finished recently was done by Clive James. In the last one he managed to involve Kim Jong Il, MP's expenses and the botched election for the Oxford Poetry Professorship. You can read it here and even listen to it here.
I listened to it for the fourth time while walking home from the Tube last night. What's refreshing, particularly amid the humbug and prudery of our present media, is his recognition that God-given talent can reside alongside tawdry behaviour and that many of the great poets of yesteryear were imposing themselves on teenage girls even when they were at the age when they might have been better off delivering "A Point Of View". That in itself should not have disqualified them from lecturing on poetry because, as he points out:
good poets are often frail people, and people who are not frail are seldom good poets.
Is this why footballers always take the money?
It must be odd being a professional footballer at the best of times. It must be even odder when they're on their annual holidays, knowing that at any time a phone call may come with the news that in a couple of weeks they're to report at an entirely new place of work. This may even be in a different country. There will be no time for a fond farewell to erstwhile team mates. This isn't just an upheaval for the player. It probably involves their wife, children, parents and courtiers in tearing up roots that have barely had time to bed down.
I've had a distant glimpse of this since a young family friend joined the fitness staff of a major football club. Promotion or relegation at the end of a season means that the manager moves. Depending on the budget at the new club or the disposition of the incoming manager at the present club the fitness staff might find themselves staying or moving, sometimes hundreds of miles, sometimes to a different country, always at a few day's notice. Nobody, of course, is complaining that this makes the job intolerable but it might help explain why whenever football people are offered a large amount of cash they tend to take it.
How much does it cost if it's free?
This American Life is an excellent radio programme/podcast produced by Chicago public radio. This is popular all over the English-speaking world. But the more popular it is, the more it costs Chicago public radio. This is a classic example of the economics of the web, the exact opposite of the economies of scale that we traditionally believe in. Now they're having to make appeals like this one.
This is what you can do with your 39th game, Scudamore.
In case Richard Scudamore is thinking of reviving the idea of the 39th game, may I make a suggestion. As I understand it, the idea behind the 39th game was to access previously untapped markets, encourage valuable shirt sales and stay one step ahead of the NFL, the IPL and the other competing leagues across the world who are after the same leisure pound and big TV rights deals. When he suggested it at the beginning of last season he was shot down in flames. One of the many sound objections was that teams couldn't waste their time flying halfway round the world in the middle of an already hectic season.
I have a plan which gets round that problem and puts the Premier League in touch with a section that their whole future depends on. The 39th game should be played in England in front of under-18s only. Just kids. No corporates, no season ticket holders, just the young people that everyone professes to be so worried about.
Nobody who's seen that stat about the average age of a supporter at the Stretford End rising from 17 to 47 in the last forty years can doubt that the people the Premier League has lost contact with are young people who no longer go to top rank games unless they've got a wealthy and/or indulgent parent with a season ticket.
In the past few years under-age club nights and rock gigs have proved a massively popular boost to the live music business, putting artists in touch with their most passionate fans and planting the seeds of a lifelong interest in gig-going. Surely football would reap even more benefit from under-18s Saturday. It would look and sound totally different on TV, do more good than all those embarrassing football in the community photo-calls we see on MOTD2 and might even turn our current feelings about top footballers from seething envy to something approaching affection.
What could possibly be wrong with that? It ticks every box. All except the one that says football's highly paid bureaucrats should get an all-expenses paid jolly-up to somewhere warm where their sponsors wish to interest the locals in their lager and internet gambling.
Open University Cricket
I've been quite enjoying Empire Of Cricket, the BBC-2 Sunday night series, for the clips of Bradman's final duck, Botham's Headingley innings, the tie between the West Indies and Australia and old faces like Shane Warne, Clive Lloyd, Richie Benaud, Neil Harvey and many others. What's quickly become tiresome is the narrative spine of the series, which seems to have been cobbled up by a sociology lecturer looking for a way to justify his grant for a planned jaunt round the cricket grounds of the world. Each episode is devoted to a country and each country becomes an example of a theme. In England it's class distinction, in the West Indies it's racial discrimination, in Australia it's nationalistic self-confidence; presumably the series will continue in this vein. Those are obviously powerful elements of the story but the focus on them, which no doubt ticks a box somewhere, comes at the expense of any feeling for the things that interests me far more. How does the game operate in all those countries? What does amateur cricket feel like in Antigua or Sri Lanka? Is it taught in schools? What kind of status do the great heroes of the game enjoy in those places? What's it like to go to a game of cricket there? What does the grass smell like? Are they as sentimental about it as we are?
We'll have lived in this house twenty-one years on Saturday. I'm not a big one for birthdays and anniversaries but I'm feeling oddly sentimental about this fact.
We were telling somebody about it yesterday. "Do you like your house?" he asked. Well, it has one unique feature. It has been Our House so long that it ceased being something you could assess the likeability of decades ago. After twenty-one years we are intimately familiar with its every noise, creak, sticking door, loose tile and eccentric flushing action. We can find our way around it in pitch darkness.
When we moved in the two kids were small enough to have barely any recollection of the previous place and the third had yet to come along. There's a lot taken place under its roof, whose slates, I note, could do with a little attention. I note also that a digit has dropped off the house number, meaning couriers have to use their powers of deduction. There are many improvements we would make if we were in the first flush of ownership. But it's strange how your view of house ownership changes in twenty-one years. We don't cast envious eyes on anyone else's pile or think life would be better if we had more space or a rural address.
Somebody asked the other day if we would ever move. While I was thinking about it, the GLW issued a statement on our behalf. We would only move, she said, if the neighbours moved out and were replaced by people we didn't get on with. She's right. Of course.
Where the media is not going
Rupert Murdoch has said he can see a future without printing presses. He's already planning to charge in some way for access to some of News International's websites. Does he know what he's doing? I would guess that he doesn't entirely but he knows he has to do something involving revenue rather than expenditure. The alternative is watching his print business drain away.
The reactions of the digerati are predictable, whether they're represented by Michael Wolff on his news aggregator (polite way of saying leecher) Newser or Jeff Jarvis on the Guardian Media Talk Podcast. It won't work, they say. If Rupert would only hang on a year or two, listen to his users and change his corporate culture a new dawn would eventually break in which News International would no longer be looking at a declining market.
I can't get over the blithe confidence of these guys. It's the same airy faith that it will all work out I find in anyone who works for a publicly-funded organisation or gets their money from a very large vault rather than from customers or advertisers. You can't help but think that if they really knew a radically new way of doing things they would be out there raising the finance to launch the big game-changer. Because if they're right there must be an enormous opportunity.
Rupert Murdoch probably doesn't know what's happening. I certainly don't. I am however prepared to stick my neck out and say what I'm pretty sure is not going to happen.
* "New models" are not going to be cooked up in universities or think tanks.
* The decline in ink and paper advertising revenue is not going to be replaced by digital advertising revenue. Not now, not tomorrow, not ever.
* You can not blame this crisis on the short-sightedness and penny-pinching of all newspaper proprietors large and small.
* Since the internet abolished scarcity you can not get a premium on advertising revenue in premium environments.
* If users don't eventually pay in some way there will not be anything worth paying for.
Now tell me what is going to happen.
Joining the unprofessionals
On Friday night we watched "My Life In Verse" in which comedian Robert Webb "went on a journey" in search of e.e.cummings. This search brought him to the feet of Clive James, who used to present this kind of thing himself. Webb is no doubt a talented guy but he suffers from the same affliction as all funny guys when called upon to present a TV programme; he's not comfortable sitting and listening.
On Saturday afternoon former jockey Willie Carson was sent into the weighing room to interview the jockeys before the Derby. Clearly heartsick that he was no longer competing himself, he struck an uncomfortably chippy note so pronounced that one of his interviewees asked why he was shouting at him.
On Saturday evening former footballer Steve Claridge had the job of anchoring Five Live's football phone-in "606" and experienced such difficulty managing the callers that in the last fifteen minutes of the programme the switchboard was jammed with people having a go at him.
Are we living through an experimental period when nothing is presented by anyone who knows about; a) the subject; b) presentation; c) ideally, both?
Or is this the shape of the BBC to come?
A vinyl weekend
When records were rare and precious and the concept of replacing them utterly foreign, every scratch, every cigarette burn on a cover, every mark that the spindle made on the label (above) was like a dagger to the heart. Now that any record can be replaced with a few clicks, it does the heart good to see each ancient bruise.
Tapping up a rich Auntie
I'm sure there's never been an ideal time for the BBC to reveal how much it's paying its top radio talent but right now must be the worst time of all. The argument about having to pay top dollar in order to compete with offers from commercial rivals never did hold water. Where else could John Humphreys and Chris Moyles hope to earn a fraction of what they do presenting daily shows on a publicly-funded national broadcaster? But now that the commercial tide has gone out their, er, packages are going to look even more anomalous.
So who else are they going to give a whistle to?
In Saturday's Cup Final Chelsea's Florent Malouda let go a shot that hit the bar, bounced down over the line and then back into play. Neither the ref nor the other officials thought it was a goal and so they carried on. TV replays showed that it was a goal but thankfully it wasn't controversial. Chelsea held on to their lead and won the cup. This gave rise to the usual arguments about "modern technology". (Football people's belief in "modern technology" is about as well-grounded as 17th century villagers' belief in witchcraft.)
It works in cricket and rugby, they say. Well, in those sports it works far from perfectly and both games have one characteristic that football doesn't. When a decision needs to be made in cricket and rugby the ball is dead. In the Malouda case play was continuous and the only person who can stop play is the ref, who saw nothing wrong with it. So who would stop the FA Cup Final so that a TV replay could be consulted? Guus Hiddink? Roman Abramovich? One of the players? A representative of a Chinese gambling syndicate?
The technology may well work but somebody has to provide the interval for it to do that work. If you allow anyone other than the ref to be the arbiter of all decisions about how play is conducted you're letting in all manner of madness.
We hate it when our friends become successful, particularly in magazines
To the Museum of London at the Barbican last night for a party to mark Time Out's donation of forty years of its archive to the Museum. The public will eventually be able to search every back issue over that period. As Tony Elliott, the founder of the magazine, pointed out, there are whole areas – pub-rock, fringe theatre, alternative education – that have waxed and waned over those forty years and would have no historical record at all were it not for their coverage in the pages of the magazine.
To celebrate this occasion Tony Elliott had invited many of the people who had contributed to the magazine's glory days and played a part in shaping the city's view of itself. I spotted Miles, Jeff Dexter, Alan Parker, Pearce Marchbank and there were many more I wouldn't recognize. On one level it was AbFab come to life. Maybe I've just got an acute nose for this but I also caught the whiff of mild resentment that always seems to hover over any reunion of media people; no matter how graciously the boss behaves, somebody still thinks their contribution was never properly recognized, their byline hijacked, another stood in their precious ration of the light and they were condemned to a life of obscure jobbing while somebody else got his place in the sun.
If the enterprise didn't work they all seem satisfied that it didn't beat the odds. To bend a line from Alan Bennett, they are united in the magnificent equality of failure. But if it succeeds they never ever forgive.
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James Baldwin // "Most people live in almost total darkness...people, millions of people whom you will never see, who don't know you, never will know you, people who may try to kill you in the morning, live in a darkness which...if you have that funny terrible thing which every artist can recognize and no artist can define...you are responsible to those people to lighten. And it does not matter what happens to you. You are being used in the way a crab is useful, the way sand certainly has some function. It is impersonal. This force which you didn't ask for, and this destiny which you must accept, is also your responsibility. And if you survive it, if you don't cheat, if you don't lie, it is not only...your glory, your achievement, it is almost our only hope...because only an artist can tell, and only artists have told...what it is like for anyone who gets to this planet to survive it. What it is like to die, or to have somebody die; what it is like to be glad... The trouble is that although the artist can do it, the price that he has to pay himself and that you, the audience, must also pay, is a willingness to give up everything, to realize that although you spent twenty-seven years acquiring this house, this furniture, this position, although you spent forty years raising this child, these children, nothing, none of it belongs to you. You can only have it by letting it go. You can only take if you are prepared to give... It is a total risk of everything, of you and who you think you are, who you think you'd like to be, where you think you'd like to go...everything, and this forever, forever."


"Adopting this irresponsible proposal would exacerbate the global warming that now turbocharges weather systems ranging from always-dangerous tropical cyclones to once-benign rainstorms. Increasingly high-powered storms are leaving a trail of tragedy, from the massive hurricanes that struck Houston and Puerto Rico last fall, to the flooding of Ellicott City, Maryland in May. Polls show that 50 percent of Americans believe that global warming will harm them personally, and 75 percent think it will harm future generations. Extreme weather, wildfires, tick-borne diseases and other worsening climate-related scourges are already impacting American families, homes and businesses.


text:
Steve Baker's appointment provides huge reassurance that Brexit remains on course
Jonathan Isaby is Editor of BrexitCentral
When writing my morning email to BrexitCentral subscribers yesterday (if you're not receiving it, you can get if for free by clicking here), I wrote that I was unnerved by the news that David Jones had been sacked as a minister at the Brexit Department, while fellow minister Lord Bridges (who had expertly steered the Article 50 legislation through the Lords) had decided to quit his post. Bridges had reportedly found relations with Downing Street strained, while there was no obvious reason for firing the former Cabinet Minister Jones just a week before the Brexit negotiations are set to begin.
And when I learned later yesterday morning that Brexit Secretary David Davis had not even been made aware by the Prime Minister in advance that she was about to remove the man who was effectively his deputy at this critical time, that only added to my concerns.
This came on top of an onslaught from a variety of continuity Remain backers (pushed in many media outlets) – a point made by Hugh Bennett in his piece yesterday – while on Monday night the Prime Minister's new Chief of Staff, Gavin Barwell (who had lost his Croydon Central seat last week) had included people being "angry about Brexit" among the reasons for the Conservatives' electoral failure.
While he might seek to justify that experience in his London constituency, that is not the message I have picked up from conversations with numerous Tories, both elected and defeated, that I have had over the last couple of days. In many seats Brexit was deemed a positive for the party – look at the kind of seats they gained (and others they nearly won) in the Midlands and North of England. Meanwhile, in much of the country it was deemed an irrelevance. "Brexit wasn't an election issue – that was the problem," one MP told me, noting that Labour's acceptance of leaving the single market had neutralised the EU as an issue and caused voters to consider other matters when casting their ballot.
So, like may BrexitCentral readers, I was feeling in need of some reassurance that the Government's Brexit agenda was still on track. So, too, were a number of Brexiteer Tory MPs and yesterday morning many of the 80 or so members of the European Research Group, chaired by Steve Baker, gathered in Committee Room 14 for a meeting with (now reappointed) Brexit minister, Robin Walker, and Greg Hands and Mark Garnier from the Department for International Trade. The MPs present were assured that government policy had not changed and that the agenda of February's White Paper – outside the single market and customs unions, British law again being supreme etc – very much remained in place.
Guido Fawkes reported Steve Baker as describing the meeting as "hugely encouraging" and Baker himself then tweeted:
"The language of 'hard' vs 'soft' Brexit is so misleading. We need a good, clean exit which minimises disruption and maximises opportunity. In other words, we need the 'softest' exit consistent with actually leaving and controlling laws, money, borders and trade and that means delivering on the white paper so the Department for International Trade can get on with improving UK and global trade."
Quite right too. And then later in the afternoon came arguably the best news that any doubter of the Government's intentions could have received: Baker himself was joining the Government as a minister at the Department for Exiting the European Union. He played a huge role during the referendum as Co-Chairman of Conservatives for Britain and since in that role chairing the European Research Group, where he brought together Conservative and – significantly – DUP MPs supporting the Government in the delivery of Brexit from the backbenches. It is an appointment which sends a very clear signal that there will be no compromising on the fundamentals of Brexit as set out in the White Paper.
And while we have seen further unhelpful interventions from Remain-backing former Prime Ministers Sir John Major and David Cameron over the last 24 hours, today's Telegraph suggests that the current incumbent remains resolute. Its splash today opens with the news that "Theresa May has signalled she will not compromise over Brexit despite growing demands for a change in approach in the wake of last week's election result."
I, for one, am feeling far more optimistic than I was 24 hours ago.
Tags: David Cameron, David Davis, David Jones, European Research Group, Gavin Barwell, Greg Hands, Jonathan Isaby, Mark Garnier, Robin Walker, Sir John Major, Steve Baker


text:
Rejuvenating the Leftie Spiel
Professor Irwin Corey at Village Vanguard in time for an acceptance speech
There are at least 250, 000 people reportedly headed this way, from all over, to express an opinion regarding the occupying power that takes over Manhattan for four days starting Monday.
There is only one of Irwin Corey, and he is already here.
"HowEVER!" said Professor Irwin Corey, the World's Foremost Authority, as he contemplates the leadership of these United States. Whenever Irwin Corey takes a breath and says "HowEVER!"—and he's been saying it for more than 60 years now, in and out of places like the Village Vanguard—you know that he's off on a new lunatic spiel of non sequitur, ultra sequitur, and/or parabolic sequitur that makes no sense whatsoever except that it makes perfect sense.
"Our country?" he said. "One of the reasons Russian ballerinas and Cuban baseball players defect to the United States is because the United States is the most defective country in the world."
"Presidents?" the Professor said, or exploded, "I remember them all. George Washington was one of our first presidents. He was known as the father of his country, an amazing feat considering that decent transportation was at a minimum at that time. Our government put up a tremendous erection in his honor, but it wasn't Jewish because it had a little tip at the end.
"The best president we ever had was Millard Fillmore. Two weeks after he was elected, he went on vacation. Four years later they looked and found that he was dead. One of the good things about our presidents is that most of them are dead.
"Bush? I'd rather be a son of a bitch than a son of a Bush," said the little old silken-haired political philosopher, and he'll be saying it again, and many other things along the same lines, during four nights next week at the historic Village Vanguard, Seventh Avenue at Perry Street, in tribute to the Republican National Convention. Lorraine Gordon, widow of Vanguard founder Max Gordon, brought him in.
At the Vanguard he'll be wearing his no less historic attire of black tie and four-foot-long-trailing tuxedo over sneakers, but now, interview time, we find him at his day job—well, nights and matinees job—as Court Clerk in Larry Gelbart's "Sly Fox" at the Ethel Barrymore on Broadway. Here in his dressing room between shows last Saturday, he's again in a tuxedo, but without the long tails or the sneakers.
There was a time when you could not turn on the tube without catching Irwin Corey assaulting the brains and laughter glands of Steve Allen, Jack Paar, Johnny Carson, Ed Sullivan, Merv Griffin, Dick Cavett, Jackie Gleason—and this, mind you, given that Irwin Corey was perhaps the most overtly, unapologetically radical radical (read: old leftist) ever to hit the airwaves—if you could grasp the wit within those house-of-mirrors sequiturs.
So imagine what he'll do with Bush, once he gets going. As for instance: "Did you know that until 1824 this country had no popular vote? And they're going to bring democracy to Iraq?
"Bush was the one that said: 'Seventy-five percent of the people in Iraq want peace and security… and when we find those people we're going to bring them to justice.' He SAID that!"
A visitor to the dressing room during all this was Dr. Martha Friedman, psychotherapist, author of "Overcoming the Fear of Success" and a friend of Corey's since, they reckoned, 1948, when they had had children in the same nursery school.
"This man," Friedman remembered, "came and sat down next to me while there was a fight going on at a parents-and-teachers meeting, the way there usually was. He said: 'Is that person speaking a good guy or a bad guy?' I said, 'A bad guy.' He stood up and started to denounce her. I thought I was sitting next to a crazy man. He offered to give me a lift home. When we go out, there's a block-long Cadillac sitting there. I let him drive me home, and we've been friends ever since."
She also remembered this: "My husband Chick was in the construction business. At one time he ran out of money, and was very depressed. Irwin came by and said: 'What's the matter?' The matter was that Chick couldn't meet a payroll. Irwin said: 'That's all?'—and pulled $2,000 out of his pocket. It saved us, and when we could, we gave it all back."
The Professor, there in his dressing room, came in at the end of the story with a flourish: "… and it wasn't $2,000—it was $5,000!"
He can give the exact date of his very first appearance at the Village Vanguard: October 20, 1942.
Had Max Gordon discovered him?
"Well, nobody discovered me. I was there all the time. I was in a play with Woody Guthrie and Burl Ives, and Guthrie was found in a bar, all mushed out, so I had to take his place. For Max Gordon, I auditioned three days, and on the Friday he said: 'You've got the job.' After four weeks, Paul Petrov, who did the murals on the walls of the Vanguard, was standing next to Gordon, who pointed to me and asked Petrov: 'What do you think? Is he funny?' Petrov said: 'How much are you paying him?' Max said: 'Forty dollars a week.' Petrov said: 'He's funny, keep him.' I got a raise to $60 a week.
"Then I got into 'New Faces of 1943.' I missed the first show at the Vanguard, so Max took back $10. I said: 'I don't need this [the Vanguard], so he gave the money back, and for four weeks I was making $60 uptown and $60 downtown—$120 a week! We moved into an apartment where the Longacre Theater is now, and men kept calling and asking: 'Is Mary there?'… 'Is Louise there?'… 'Is Clara there ?'… 'Is Gloria there?'"
Irwin Corey and his wife Fran have a son named Richard, who's a painter, and a grandson named Amadeo—"for Modigliani"—who, at seven, is something of a poet and an artist himself. Evidence, freely supplied by grandpa: One poem—"My kitten has / two green eyes / one tale / four feet"—and one gold-star-winning school paper, with drawings, on What Lives in Washington Square Park: "Cockroaches, Squirrels, Lady Bugs, Butterflies, Spiders, Birds, Trees, Ants, Snails."
On the dressing-room mirror, reproductions of two famous photographs: That naked, napalmed little girl running, screaming down a road in Vietnam, and the pistol being fired, blank range, into the head of a suspected member of the Vietcong. "The man who shot him used to live next to us in Great Neck. He was a general. He had nine children," said Irwin Corey—who doesn't forget or forgive anything.
Next to all that is a photo of Fidel Castro.
"[John] Kerry is Jewish, you know. Robert De Niro is Jewish. His mother is Jewish, so he's Jewish. Stallone is Jewish, same way. Elvis Presley's mother was Jewish. Castro's mother was Jewish. Her name was Ruiz, a Jewish name. Disraeli was Jewish. Jesus was Jewish.
"But Moses wasn't Jewish. He was Egyptian, and not only Egyptian, but black. And he created the Jewish religion."
In his dressing room, Corey acted out Moses hurling the tablets and thus shattering the Ten Commandments.
The sneakers?
"That started when somebody stole my shoes one day at the Vanguard. And then everybody copied it. Woody Allen, everybody."
The HowEVERs?
"That started when I fell off the stage at the Vanguard" — hands indicating an eight-inch drop—"and got back up and started over with 'HowEVER…'"
Lots of people have copied that too.
Irwin Corey was, he declared, born in Brooklyn on July 29, 1914, though elsewhere you can find a 1912 date he ascribed to "when I went to get a driving license as a kid" and added two years to his age.
In any event, consider this. The man has been doing eight Broadway shows a week at the Ethel Barrymore. He had planned to use the dark night on Monday to hit the Vanguard at 8 p.m., scheduling the other performances next week for midnight. Had "Sly Fox" not announced its closing for this Sunday, August 29, on Wednesday of next week Professor Irwin Corey would have done a matinee and an evening performance and then headed downtown to take his midnight whacks at George W, Bush & Co. At age 90, apparently, Corey will be able, after all, to take it just a little easier. Okay, so 250,000 people are on their way thisaway. HowEVER…