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Mononucleotide microsatellite instability and germlineMSH6 mutation analysis in early onset colorectal cancer
Loveena Verma*,a,
Michael F Kane*,b,
Cecilia Brassett*,c,
James Schmeitsb,
D Gareth R Evansd,
Richard D Kolodnerb,
Eamonn R Mahera,c
aSection of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham B15 2TG, UK, bLudwig Institute for Cancer Research, Department of Medicine and Cancer Center, University of California San Diego Medical School, 9500 Gilman Drive, La Jolla, CA 92093-0660, USA, cCambridge University Department of Pathology, Cambridge CB1 4QP, UK, dDepartment of Medical Genetics, St Mary's Hospital, Manchester, UK
Professor Maher, Birmingham.
Germline mutations in the MSH2 andMLH1 mismatch repair genes account for most cases of hereditary non-polyposis colon cancer syndrome (HNPCC). In addition, germline MSH2 andMLH1 mutations have been detected in patients with non-HNPCC early onset colorectal cancer. GermlineMSH6 mutations appear to be rare in classical HNPCC families, but their frequency in young colorectal cancer cases has not been studied previously. In a population based study of early onset colorectal cancer (<50 years) investigated for tumour microsatellite instability (MSI), we identified a subgroup of tumours with MSI for mono- but not dinucleotide repeat markers (m-MSI+ group). In contrast to tumours with classical MSI for dinucleotide markers (d-MSI+), the m-MSI+ group cancers were mainly left sided (6/7). As MSH6 mutations in yeast and human cell lines are associated with weak (and preferential mononucleotide) MSI, the complete MSH6 gene coding region was sequenced in blood DNA from the five m-MSI+ cases available for analysis. A germline nonsense mutation was identified in an isolated case of early onset colorectal cancer (age 43 years). These results support previous findings that germline MSH6mutations may not be associated with classical MSI and suggest a role for germline MSH6 mutations in isolated early onset colorectal cancer.
mononucleotide microsatellite instability
germlineMSH6 mutation analysis
early onset colorectal cancer
http://dx.doi.org/10.1136/jmg.36.9.678
Colorectal cancer (CRC) is one of the commonest cancers in the western world1 and genetic factors have been clearly implicated in its pathogenesis. Up to 5% of all cases have a recognisable dominantly inherited colorectal cancer susceptibility disorder such as familial polyposis coli (FAP) or hereditary non-polyposis colorectal cancer syndrome (HNPCC). In recent years there has been considerable progress towards defining the genetic basis for colorectal cancer susceptibility. FAP is caused by germline mutations in the APC tumour suppressor gene mutations, which characteristically produce a distinctive clinical phenotype including florid colonic polyposis. In contrast, HNPCC does not present a distinctive clinical phenotype and the clinical diagnosis of HNPCC depends on a combination of familial clustering of colorectal cancer, susceptibility to early onset and multiple colorectal cancers, and the presence of associated tumours such as endometrial, ovarian, and urothelial cancers.2 Formalised clinical criteria for the diagnosis of HNPCC ("the Amsterdam criteria") have been adopted widely and define a small group of patients with a strong family history of colorectal cancer.3 A major advance in colorectal cancer genetics was the mapping and subsequent identification of the molecular basis for HNPCC. Most classical HNPCC kindreds have germline mutations in the MSH2 orMLH1 mismatch repair genes.2 4-8 Cancers from these patients characteristically show a high rate of accumulation of DNA replication errors (RERs) in simple repeat sequences resulting in what has been called microsatellite instability (MSI, MIS, etc). InMSH2 and MLH1deficient tumours, such microsatellite instability has been observed in mono-, di-, tri-, and tetranucleotide repeats.9-12
MSH2 and MLH1 are human homologues of the E coli MutS and MutL components of the E coli MutHLS mismatch repair system.13 In this system, the MutS protein recognises mispaired bases in DNA and recruits other essential protein factors, such as MutL, that function in the mismatch repair reaction. The eukaryotic MMR system is more complex than the bacterial system.14 15 Eukaryotic MMR involves two different heterodimeric complexes of MutS related proteins. One is a complex ofMSH2 and MSH6(sometimes called GTBP in humans) that functions in repair of base-base mispairs and small insertion/deletion mispairs, and the other is a complex of MSH2and MSH3 which is involved in repair of insertion/deletion mispairs.16-18 Similarly, eukaryotic MMR involves two different heterodimeric complexes of MutL related proteins. One is a complex of MLH1 andPMS1 (PMS2 in humans) that functions in the bulk of mismatch repair and the other is a complex of MLH1 andMLH3 (PMS1 in humans) that appears responsible for only a small component of mismatch repair.19-21 The observation of partially redundant MutS homologue complexes and partially redundant MutL homologue complexes is consistent with the observation that the majority of HNPCC causing mutations are found in MSH2and MLH1. Mutations in these two genes encoding the common subunits of the MutS and MutL homologue complexes, respectively, would be expected to cause the greatest defects in mismatch repair.
Initial studies of MSH6 in HNPCC kindreds focused on kindreds in which tumours showed strong dinucleotide repeat instability and did not identify any mutations.8 22Studies in yeast showed that mutations in MSH6did not cause dinucleotide repeat instability but rather caused weak mononucleotide repeat instability and a marked increase in the rate of accumulation of base substitution mutations.14 18 23 Similarly,MSH6 mutant human tumour cell lines showed much weaker microsatellite instability than tumour cell lines in whichMSH2 or MLH1 were defective.14 24-30 Furthermore, studies withMSH6 mutant mice showed that they had markedly increased cancer susceptibility and that the tumours in these mice did not show repeat instability, which is similar to the results seen in yeast.31 These results suggested that mutations inMSH6 would probably cause cancer susceptibility but the tumours that arose might be distinct from those seen in kindreds inheriting MSH2 andMLH1 mutations, at least with regard to their microsatellite instability phenotype. Indeed, two germlineMSH6 mutations have been reported in non-HNPCC familial colorectal cancer kindreds.32 33 To investigate further the role of germlineMSH6 mutations in colorectal cancer susceptibility we have performed mutation analysis ofMSH6 in colorectal cancer patients with tumour mononucleotide microsatellite instability (m-MSI).
Patients and methods
Eighty-three patients with early onset colorectal cancer (age <50 years) were analysed for tumour RERs (microsatellite instability (MSI)) using a combination of mono- and dinucleotide microsatellite markers. Patients were ascertained randomly through a population based survey of colorectal cancer in eastern England and the results of MSI for dinucleotide markers on the first 33 patients aged 45 years or less have been reported previously.34
MICROSATELLITE INSTABILITY ANALYSIS OF COLORECTAL CANCERS
For each case (n=83), paraffin embedded tumour and normal tissue sections were obtained and analysed for microsatellite instability with CA dinucleotide microsatellite markers as described previously.35 In addition, MSI was assessed with two mononucleotide repeat markers chosen from BAT25, BAT26, and BAT40. Tumours were considered as showing conventional dinucleotide repeat instability (d-MSI) if two or more of five dinucleotide repeats tested showed instability and were considered as showing mononucleotide repeat instability also if one or more of two mononucleotide repeats showed instability. Tumours showing mononucleotide but not dinucleotide microsatellite instability were designated m-MSI+. We have used these two definitions of microsatellite instability to test the hypothesis that there might exist a class of tumours showing only mononucleotide repeat instability. Because all of the tumours designated d-MSI+, but only some of the tumours designated m-MSI+, would fall under the recently published definition of MSI-H,35 we have generally not used the MSI-H designation in this study to avoid confusion.
DETECTION OF MUTATION IN MSH6
Mutations in hMSH6 were detected by amplifying individual exons and flanking intron sequences by PCR using the primers devised from the sequence of thehMSH6 genomic locus (Genbank accession number U73732-U73737). Primer details are available on request. PCR set up was performed with a Tecan Genesis 100 Robotic Workstation and PCR was performed on Perkin Elmer 9600 and 9700 PCR instruments. The PCR products were sequenced on an ABI 377 sequencer (Perkin Elmer/Applied Biosystems) with standard M13 forward and reverse primers and Big Dye terminator chemistry using reagents obtained from Perkin Elmer/Applied Biosystems. In some cases it was necessary to resequence PCR products using primers that prime on internal regions of a PCR product. Analysis of the sequence chromatograms was carried out using Sequencher (Gene Codes Corp, Ann Arbor, MI) as well as by visually examining printed chromatograms to detect sequence changes and heterozygous nucleotides.
YOUNG ONSET COLORECTAL CANCER: FREQUENCY AND CHARACTERISTICS OF TUMOUR MICROSATELLITE INSTABILITY
Eighty-three patients with colorectal cancer diagnosed before the age of 50 years were ascertained from a population based study and analysed for tumour MSI with dinucleotide microsatellite markers. An Amsterdam criteria family history of HNPCC was present in two patients. Seven of 83 (8.4%) patients had d-MSI+ tumours (defined as instability at two or more of five dinucleotide markers). This group with classical MSI comprised the two cases with HNPCC (Amsterdam criteria), one patient with a non-HNPCC family history, and four isolated cases.MLH1 and MSH2mutation analysis was performed in the seven cases with d-MSI+ tumours and germline MLH1 mutations were identified in the two HNPCC cases only.
Sixty-one of 76 cancers without d-MSI were analysed for mononucleotide repeat instability at two mononucleotide markers chosen from BAT25, BAT26, and BAT40. Microsatellite instability was detected in at least one of two mononucleotide markers (m-MSI+) in seven of 61 cases (11%). Four of these m-MSI+ cases were sporadic cases, while the remaining three came from patients whose families contained two first degree relatives with colorectal cancer but did not satisfy the Amsterdam criteria for HNPCC.
The clinicopathological features of d-MSI+, m-MSI+ only, and MSI- tumours were compared. There were no differences in mean (SD) tumour size (4.8 cm (1.6), 5.5 cm (2.3), and 4.2 cm (1.6) respectively), histological differentiation, or lymph node involvement. However, d-MSI tumours were significantly more frequently right sided in location than those without d-MSI+ (5/7 v 15/60). Tumours with m-MSI+ phenotype differed from d-MSI+ tumours by being mainly left sided (6/7 v 2/7). We postulated that m-MSI+ tumours might have MSH6 mutations.
To enable accurate mutation analysis in patients with m-MSI+ tumours, we developed a set of primer pairs for PCR amplification and sequencing of the 10 exons and flanking intron sequences ofhMSH6. Sequencing of the completeMSH6 gene coding region was performed in the five m-MSI+ cases for whom peripheral blood DNA was available (two familial and three sporadic). A number of putative polymorphisms were characterised (table 1). These included a number of silent changes, one that caused a Glu to Gly substitution at codon 39 (exon 1), and a number of substitutions, insertions, and deletions in introns. In cases where these changes were suspected to affect either the function or expression of MSH6, their allele frequency was determined by analysing DNA from 20 normal controls. In all cases, the detected sequence change was sufficiently common to be considered a polymorphism. However, in one m-MSI+ case, we detected a heterozygous germline nonsense mutation (C642G, Tyr214Ter) (fig 1). Translation of the mutant sequence would be predicted to result in the synthesis of a truncated protein containing only the 213 N-terminal amino acids of the 1260 amino acid long MSH6 protein. Functional studies inSaccharomyces cerevisiae have shown that this truncated protein would be inactive in mismatch repair (unpublished data). The proband presented at the age of 43 years with a left sided, moderately differentiated, 5 cm diameter adenocarcinoma of the large bowel. He was an only child with no family history of cancer. Attempts to determine if there was loss of the wild typeMSH6 allele in tumour tissues were uninformative owing to insufficient quantity and quality of tumour DNA.
hMSH6 polymorphisms
Detection of a germline MSH6 mutation by sequence analysis. The upper panel shows the sequencing chromatogram from the region of exon 4 containing codon 214 from a wild type control DNA. The DNA and predicted protein sequence are shown above the chromatogram. The lower panel shows the sequencing chromatogram from the same region of a patient DNA sample containing a heterozygous nucleotide at nucleotide 642 of the cDNA sequence. The mutant DNA sequence and predicted mutant protein sequence are indicated above the chromatogram.
The analysis of tumours for MSI using standard microsatellite markers provides a screening strategy for targeting patients with possible germline MLH1 orMSH2 mutations. Thus, the overwhelming majority of tumours in HNPCC kindreds withMSH2 or MLH1mutations show MSI. However, the specificity of MSI analysis is reduced by phenocopy tumours in which both alleles ofMSH2 or MLH1 were inactivated by somatic events. Early age at cancer diagnosis is a characteristic feature of inherited cancer susceptibility and a high frequency of MSI and germlineMSH2/MLH1mutations has been described in patients with very early onset (<35 years) colorectal cancer.36 However, the incidence of MSI and germlineMSH2/MLH1mutations is low in moderately young cases (35-49 years)34 36 37 suggesting the possible involvement of other genes in these cases. Germline MSH6mutations have not been reported in classical HNPCC kindreds, but the presence of a MSH6 mutation in a Japanese HNPCC family which did not meet Amsterdam criteria led to a suggestion that the phenotype of germline MSH6mutations might differ from those of MSH2 orMLH1 mutations.33 Thus there were no cases of early onset (<50 years) colorectal cancer in the Japanese family and extraintestinal (endometrium, ovary, and pancreas) cancers were prominent. A further germlineMSH6 mutation was also reported from Japan in a 62 year old man with rectal cancer and two colonic adenomas, a weak non-HNPCC family history of gastrointestinal tumours, and MSI in the tumours.32 These results are similar to those obtained with mutant mice where MSH6 mutant mice developed cancer at later ages than eitherMSH2 or MLH1mutant mice.31 38 39
Although it seems unlikely that the MSH6truncating mutation we identified could not be pathogenic, this possibility should be considered. However, we note that expression of an N-terminal fragment of yeast MSH6 (that closely corresponds to what would be produced by the human mutant gene we describe) fails to complement the MSH6mismatch repair defect in in vitro studies (Das Gupta and Kolodner, unpublished data). Long term follow up of the proband and his children may provide further information on the pathogenicity and penetrance of this mutation. The finding of a germlineMSH6 mutation in an isolated case of young onset colorectal cancer further expands the phenotype ofMSH6 mutations and should prompt further studies of the role of these mutations in early onset colorectal cancer. Recently, Shin et al 40 analysed Korean HNPCC families and 45 sporadic early onset (<40 years) cases for mutations of the mononucleotide repeat in the MSH6gene. They reported frameshift alterations in two of 44 suspected HNPCC cases in whom MSH2 orMLH1 mutations had not been detected, suggesting that MSH6 mutations might be found in early onset cases. In this study we targeted these cases with m-MSI for MSH6 mutation. Although this approach is logical, further research is required to determine if germline MSH6 mutations can be associated with d-MSI or MSI negative tumours. The results ofMSH6 mice knockout studies would suggest that the latter possibility could occur. A germlineMSH6 mutation was only found in one of the five m-MSI+ tumours analysed. Although this finding clearly shows the potential significance of m-MSI, the four cases withoutMSH6 mutations could result from somatic inactivation of MSH6 or failure to detect a germline mutation (despite sequencing of the completeMSH6 coding region). Alternatively, germline or somatic mutations in other mismatch repair genes could be implicated in this group; in familial colorectal cancer we found a single m-MSI+ tumour in a patient with a germline MSH2mutation (unpublished observation). Our findings and a report of germline MSH6 mutations in Dutch familial colorectal cancer families41 indicate a need for further studies of tumour MSI and germline MSH6mutation analysis in familial and isolated colorectal cancers.
LV and EM thank the West Midlands NHS Executive for financial support. This work was also supported by National Institutes of Health grant GM50006 to RK.
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Journal of Medical Genetics


Thirsk & Malton – Page 7 – Thirsk & Malton Labour Constituency Labour Party. For the many, not the few..
Our constituency is one of the largest geographical areas in England, stretching fifty miles from Filey on the East coast to the market town of Thirsk, and from the North York Moors to the Yorkshire Wolds.
In addition to the austerity, and the employment problems facing most parts of the country, we face the imminent threat of our beautiful rural area being turned into an industrial landscape by large scale fracking.


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Political leaders face border challenges
Leadership Politics Women
Nations need clear values to strike a balance between liberty and national security
Political leaders must contend with both the physical and virtual challenges that nations' borders present, according to Janet Napolitano, President of the University of California and former US Secretary of Homeland Security.
Napolitano said political and business leaders and policymakers needed to establish clear values that would uphold people's democracy in an age where nations face many threats.
When speaking at a London Business School Leadership Institute and Alumni Mining Club event, Napolitano said: "In my view, the successful management of borders depends on the answer to a fundamental question: how do we stay true to the values of open, free and democratic society while also ensuring national security?
"We live in very difficult and challenging times and the ability to identify complex problems and bring to bear complex solutions are the competencies that help effective leadership, both in the political and policy realms, and the private sector."
The event was hosted by Randall S. Peterson, Professor of Organisational Behaviour and Academic Director, Leadership Institute, London Business School, which brings academics and practitioners together to put leadership research into practice.
Napolitano urged society to make a clear distinction between security and immigration policies. She said that doing so would be "one important step to ensuring our values are preserved".
She also discussed the world's fight against extremism, pointing to the controversy in February 2016 when Apple's CEO Tim Cook refused to help the FBI break into an iPhone belonging to an alleged Islamic fundamentalist.
Syed Farook and his wife, Tashfeen Malik, were accused of killing 14 people and injuring 22 in a shooting at his San Bernardino, California, workplace last December. Cook claimed that co-operating with the FBI would "threaten the security" of Apple customers.
Napolitano said: "Apple and the FBI are an effective illustration that when you're in a leadership role, and security is in your portfolio, you have to deal with issues like these, day in day out.
"We need powerful international partnerships to counter violent extremism. Third party partnerships, the private and the non-profit sector all have a part to play.
"Security is a complicated issue that drives right to the heart of our values. There's no denying that sometimes the balance is very difficult to strike."
Napolitano added that schools, colleges and universities can help tackle radicalisation. "Educational institutions offer opportunities for transformation. As more people take up education, it gives me confidence that open and free societies will trump extremism."

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Vlachopoulos joins Novi Beograd; Ivovic stays at Pro Recco
Angelos Vlachopoulos (Brescia) Photo: AN Brescia/FB
Novi Beograd continued composing a "dream team" for the new season.
Novi Beograd's newest addition is Greek Angelos Vlachopoulos. He will leave Brescia after the end of the season and arrive at the club, which will host the next three editions of the Champions League Final Eight.
Before he was contacted by Novi Beograd, Vlachopoulos had already made an agreement with Olympiacos, the club he played for until 2016. But, things have been changed in a short time.
In an interview with the Greek website aquafeed24.gr, Vlachopoulos confirmed that he would come to Novi Beograd.
"Everything changed in a very short time. I consider Olympiacos my "home" and that fact doesn't change. I apologize for the inconvenience I caused to the friends of the team, who are also my personal friends, several of them. I thank Olympiacos' president Mr. Michailis Kountourisfor for the very honorable proposal submitted by coach Theodoros Vlachos. Both showed understanding and treated me as if they were my parents", Vlachopoulos (26) said.
He played for Olympiacos until 2016. After leaving Greece, he played for Posillipo (2016-2017), Eger (2017-2020), and for Brescia (2020-21).
The series of rumors about Novi Beograd's high ambitions and potential reinforcements started with a piece of news that the Serbian club is interested in bringing Aleksandar Ivovic, Pro Recco captain.
The Montenegrin player confirmed that there were negotiations with Novi Beograd, but with Pro Recco, too.
But, as things stand now, he won't leave Italy.
"Yes, we called Ivovic, because his contract with Pro Recco expired. But, as soon, as Pro Recco offered him a new contract, our negotiations with him was ended. Ivovic will stay in Recco", Novi Beograd coach Vladimir Vujasinovic told Mozzart sport. Vujasinovic underlines that his club has ambitions but that Novi Beograd's budget can't be compared with Pro Recco's financial resources.
Many other players have been linked with Novi Beograd in the unofficial pieces of information in the last few days– Dusan Mandic, Nikola Jaksic, brothers Strahinja and Viktor Rasovic, etc. But all of them are focused on the current season. Most of them still don't want to talk about the new season. More information will be available when Novi Beograd reveals its plans.
Two arrivals at Novi Beograd have been confirmed a few months ago. Dusko Pijetlovic and Radomir Drasovic will play for this club, after expiring their two-year contracts with Szolnok.
Neither other clubs are not revealing their plans yet.
But a big bomb of this year's transfer market might be Denes Varga's move from Ferencvaros to Pro Recco. There are still no official confirmations regarding this piece of information.
All news about transfers you can find HERE
Photo: Total Waterpolo
LEN Challenger Cup draw: Final could be national derby
Lee Kai Yang, the goalkeeper of the national team of SIngapore, and Felipe Perrone at today's ceremony Photo: Ng Chrong Meng/World Aquatics
Three World Championships in three years in Asia: Singapore to host 2025 Worlds
Guiseppe Valentino (Trieste) Photo by Philippe Fretault / WP inside


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Soccer Perspective
RFK Stadium comes back to life for one night of old-school soccer charm
RFK Stadium welcomed back soccer Tuesday night, hosting El Salvador and Peru. (Steven Goff/The Washington Post)
By Steven Goff
Steven Goff
Reporter covering soccer (D.C. United, MLS, U.S. national teams, World Cup), plus some college basketball.
RFK Stadium, that wavy mass of chipped concrete and rusting steel stuck between East Capitol Street and the Anacostia, crackled back to life Tuesday night.
Left for dead when D.C. United bolted for Audi Field after the 2017 MLS season, an old friend reopened its crusty eyes and heavy arms to soccer for a friendly between the Peruvian and Salvadoran national teams. (El Salvador was a surprising 2-0 winner.)
Lot 8 was a swirl of Salvadoran blue and Peruvian red. Fans flowed from the Metro station again. Vendors sold horns, hats and churros. Tailgating was back in lots typically reserved these days for festivals and buses.
Ticket windows were stacked a dozen deep. Gridlocked traffic circled the gray hulk, a mix of rush-hour freedom-seekers and futbol aficionados in a fender-bending weave. In fading light, it was modern art.
The Peruvians were no match for the traffic; running late, the players and coaches exited the team bus and walked the final few hundred feet to the stadium entrance.
Inside, the sweet smell of pupusas on the grill wafted along the lower concourse.
Washington's vibrant soccer community has moved on from RFK, which for decades, was the only venue in town — and one of the best for the sport in the country.
FedEx Field came along in 1997, luring big-ticket events, such as the Real Madrid-Arsenal match this summer.
[Real Madrid to play Arsenal in International Champions Cup match at FedEx Field]
Then came Maryland SoccerPlex in Montgomery County for small acts, such as United's U.S. Open Cup dates and women's pro teams. Last summer, Audi Field, a long-awaited home for United, entered the mix and, beginning this year, is arranging soccer of all kinds (not to mention lacrosse this summer and XFL games next year).
This summer, United will open another stadium, a 5,000-seater in Leesburg for its second-division squad, Loudoun United, and various other events.
RFK is old, old school; there have never been any frills and, nearing its 58th birthday, the stadium has little left to offer, except an uncomfortable orange seat, a cacophonous setting and a two-hour journey into yesteryear.
The billboards are free advertising for companies that no longer need to pay. Most of the field was rich green, but portions were a pre-spring yellowish green.
At some point, the structure will come down, making room for perhaps a Redskins stadium. For now, a faint heartbeat pulsates.
[From 2017: Images from 56 years of sports glory at RFK Stadium]
United continues to lease space at RFK for its training base, using the same locker room as it always did and venturing to the training grounds outside the stadium on most mornings for workouts. A new center will open next year in Leesburg. The club has abandoned the upper office space for shiny digs at Buzzard Point.
RFK continues to seek clients. Last summer, South Africa and Wales played a rugby match. A few months later, three high school football games were stacked end to end one autumn afternoon.
And Tuesday, a high-powered Peruvian squad arrived from the New York metro area, where it had defeated Paraguay, 1-0, in a friendly Friday. El Salvador had beaten visiting Jamaica, 2-0, on Saturday in a Concacaf Nations League qualifier.
The Salvadoran team is a regular in Washington, where promoters have tapped into the vast immigrant community.
A Peruvian fan paraded with a replica World Cup trophy, a nod to his country ending a 36-year drought by qualifying for the Russian-hosted tournament last year. A group of Salvadorans wore "503 Nation" sweatshirts, homage to the country code. Others brought brass instruments.
The match transpired in an expected way: Peru in control of possession, El Salvador seeking to counterattack. Salvadoran goalkeeper Henry Hernandez performed well under steady duress.
Fans traded chants: "El, Sal-va-DOR!" and "Peh-roo!"
Sixteen minutes into the second half, El Salvador went ahead on an own goal by Miguel Trauco. Peru pressed for an equalizer, failed, then conceded another goal in stoppage time. On the counter, Oscar Ceren accelerated into the clear and scored on a searing shot.
Revive el tremendo contragolpe de #ElSalvador que terminó en el segundo tanto del partido.#PER 🇵🇪 0-2 🇸🇻 #SLV#PerúxMDeportes#Incondicionales ❤
Mira #EnVivo por nuestras señales ⤵
Movistar TV ► 003/703HD
Movistar Play ► https://t.co/eNEWZt1UKX pic.twitter.com/N9GXLvzs6L
— Movistar Deportes (@MovistarDeporPe) March 27, 2019
The Salvadorans on the field and in the stands celebrated as if they had qualified for the World Cup, something they have failed to do in several decades. RFK danced like the old days, the upper deck dipping and rising.
The "Ole" roar raised the volume. Organizers did not immediately announce attendance, but it was probably 15,000-20,000 — a turnout that, in the semi-enclosed facility, sounded like 50,000.
Well after the match ended, Salvadoran fans were still causing a noisy ruckus on the ramps and in the parking lots.
For sure, the place has enjoyed much better days. But on this night, perhaps one of the last to salute soccer, RFK in some ways never looked and sounded better.
Steven Goff Steven Goff has covered soccer for The Washington Post since the early 1990s. His beats include D.C. United, MLS and the U.S. national teams. He has been on assignment at every World Cup since 1994, plus five Women's World Cups. Follow


The Albanian Institute for International Studies together with the Forum for International Relations of the European Movement in Serbia, with support from the Federal Republic of Germany is implementing the project of sustaining part of the 2016 activities of the Joint Centre for Albania-Serbia relations. In this context we organized the Durres Forum, an interactive 2 days event that took place May 6-7 and which gathered speakers and participants from various walks of life.
On March 15th 2016, the Albanian Institute for International Studies and the Embassy of the Republic of Italy to Albania organized the second session of a series of Foreign Policy Forums for 2016. Keynote speaker to this event was the Italian Ambassador in Albania, His Excellency Mr. Alberto Cutillo. The topic of the Forum was "State of affairs in Europe and the potential implication on the EU and EU enlargement".
Germany contributes, granting 40 000 euros, to a project of two non-governmental organizations in Albania and in Serbia, which is perceived to support dialogue and exchange between the two countries. By founding a joint centre and through the activities and projects this center will organize, the Albanian Institute for International Studies (AIIS) and the Forum for International Relations of the European Movement Serbia (EMinS) aim to contribute in improving the relations between the two EU-candidate countries, Albania and Serbia.
Media coverage of AIIS Symposium "Albania 25 years after communism"
Albanian Institute for International Studies (AIIS) in cooperation with Friedrich Ebert Stiftung and the US Embassy in Tirana, organized on 25th of November a symposium with experts and scholars on the examination of transition and the future of the European project of Albania. The event was addressed by HE Mr. Donald Lu, HE Mrs. Romana Vlahutin, HE Mr. Florian Rauning as well as well-known scholars such as Dr. Florian Bieber (keynote speaker), Gabriel Partos, Dr. Elez Biberaj, Prof. Emer. Bernd Fischer, Dr. Franz-Lothar Altmann and many other Albanian experts.
April 13, 2015 - AIIS researcher Sashenka Lleshaj was invited at Tete a Tete talk show of A1 Report to discuss on the European Social Model, a joint initiative of several think tanks in Albania with the support of the Friedrich Ebert Stiftung Office in Tirana. As a lead researcher and author of the publication: ''Albanians and the European Social Model: Towards a redefinition of the social contract'', Ms. Lleshaj shared the findings of the publication and discussed more broadly, together with other participants, the European Social Model in Albania.


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Composed of the best management professors and authors
JP Eggers
Strategy and Decision Making in Uncertain Environment
Previously a strategy consultant, JP Eggers is now a professor at New York University Stern School of Business, where he mainly teaches strategy to MBA students.
His work and research interests focus on decision making in an uncertain environment, technological change and new product development. NYU Stern's Professor of the Year 2010 for the MBA programme, JP Eggers has also recently been named one of the Top 40 Business School Professors Under the Age of 40.
See all Faculty members


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South Lake Tahoe drops to a bone-chilling 9 degrees, over a foot of snow
Amy Graff
SF Gate
Mon, 11 Apr 2022 10:22 UTC
© UC Berkeley Central Sierra Snow Lab
Snow was falling at the UC Berkeley Central Sierra Snow Lab at Echo Summit on April 11, 2022.
A winter-like cold front swept across the Sierra Nevada on Monday, delivering a mass of cold air to the region.
On Tuesday morning, temperatures were downright freezing. In the Tahoe area, South Lake Tahoe dropped to 9 degrees and Truckee 10 degrees, the National Weather Service said.
The storm dropped several inches of snow across the basin and higher elevations got more than a foot. More snow is on the way as early as Wednesday night and into Thursday.
A winter-like cold storm smacked the West Coast on Monday, dumping several inches of snow on California's Tahoe Basin in April. More storm activity is expected through Saturday, and over the course of the week, elevations above 6,500 feet could record totals of up to 1 to 3 feet of snow, said Jim Mathews, a forecaster with the National Weather Service.
"The pattern is similar through the weekend, and we'll be getting more of these colder systems from the northeastern Pacific in coming days," Mathews, who works at the weather service's Sacramento office, said. "We'll be getting more wintry weather this week than we've had most of this winter."
The unsettled weather arrived on the West Coast on Monday morning as a storm system that originated near the Gulf of Alaska swept the region. The system was focused over the Pacific Northwest on Monday morning, dumping heavy snow over the mountain peaks and even delivering a dusting of measurable snow in Portland.
"In 82 years of record keeping, #PDX had never recorded more than a trace of snow in April," the weather service office in Portland posted on Twitter. "That ended today. Looking out the window, it appears there will be more than 0.1 inch when all is said and done."
The southern edge of the storm passed over Northern California, and the UC Berkeley Central Sierra Snow Lab at Donner Summit reported nearly 4 inches of snow at 8:49 a.m., with more falling.
The lab later shared at 12:24 p.m., "It's absolutely dumping snow out there!"
Caltrans implemented chain control on sections of Highways 50 and 80 early Monday. As of noon, chain control was still in effect on 80 and had been lifted on 50. Get the latest information from Caltrans.
Mathews said Blue Canyon in Placer County, which sits at about 5,000 feet, is expected to measure 8 inches by the end of Monday with another 10 inches in the forecast for Thursday.
Winternights3 · 2022-04-13T01:25:09Z
Much is happening due to the continuing development of cold air in the Northern hemisphere.
As for Lake Tahoe, the arrival of snow should come as no surprise, as cold air has sank down the Western side of the USA, I've been watching live feed broadcasting of violent thunderstorms and tornadoes further South East as the cold air scrambles warm air upwards.
It's April and so much cold air does not bode well.


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Q: How to Connect LiveLink Using LAPI SingleSignOn Can anyone guide me as to how can i connect to LiveLink through LAPI using Single Sign On.I need to get the connectionstring.
Regards,
Vix

A: You need to configure the config parameter in LL_SessionAllocEx. There you can configure EnableNTLM. However, SSO only works with Java.

A: Check out the Java EasyLAPI framework on the OpenText Knowledge Center.  It contains some sample code for transparently authenticating using SSO.

redpajama_set_name: RedPajamaStackExchange


This residence designed by Gálvez & Márton Arquitetura, is located on a generous site and has an extensive leisure program, such as swimming pool, games room, sauna, rest room, spa and gourmet area.
Text description provided by the architects. This residence designed by Gálvez & Márton Arquitetura, is located on a generous site and has an extensive leisure program, such as swimming pool, games room, sauna, rest room, spa and gourmet area.
The house has 6 suites, living and dining areas, gourmet area, covered porch, gym, sauna, swimming pool with spa, home theater, extensive service area, 4 car garage and caretaker's house. Approximate area of ??1200 m², including pool area and spa.


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Sexting and Kenny Loggins: Lennon Parham and Jessica St. Clair talk Playing House
Kyle Ryan
"Just think about something sad," says Jessica St. Clair to Lennon Parham. The creators, producers, writers, and stars of Playing House are in a remote part of Malibu shooting a scene for the sixth episode of the show's second season in a hot tub with guest stars Randy and Jason Sklar. Parham keeps breaking after a line from one of the Sklars, and everyone's eager to get out of the hot tub, which has a bunch of dead bugs and a gross film on the water. ("There so much knee-to-soft-thigh touching," St. Clair said as they settled into the tub earlier.) Adding to the urgency to get a good take: It's a hot day, an errant air hose that's providing the bubbles keeps popping up out of the water next to Jason Sklar's nipple, and St. Clair and Parham are uncomfortably positioned on underwater crates so they're framed correctly in the shot. It's not one of the more glamorous days on the Playing House set, but Parham and St. Clair are clearly enjoying themselves. That they're even filming a second season counts as a victory; after low-rated premiere season (balanced somewhat by solid VOD numbers) and no word from USA for months about a second season pickup, it seemed like Playing House would go the way of Best Friends Forever, Parham and St. Clair's short-lived NBC show. Sustained demand for a second season on social media helped move the needle, and the duo was given a shorter second season last December. It returns with the first of eight episodes August 4 on USA (with an earlier viewing option for Comcast subscribers). A few weeks after that day in Malibu, The A.V. Club talked to Parham and St. Clair about the upcoming season, how doing their own show has helped their careers, and the bizarre world of their podcast, Womp It Up!
The A.V. Club: Where are you in production right now?
Jessica St. Clair: We're in editing right now.
Lennon Parham: We started last week, and we're on episode two currently.
JSC: So it's a lot of being in a dark room together, side by side, asking ourselves or each other over and over again, "Does my neck look weirder than last year?" That kind of thing.
LP: Yeah.
JSC: And the answer is always yes, Kyle. The answer is always yes.
AVC: How did the shorter run of episodes affect how you wrote?
LP: I don't really think it affected much at all, to be honest. I mean, we had 10 the first season, which also feels kind of truncated compared to the classic network sitcom. So anywhere from six to 10 for me feels like a really good number to tell a nice, satisfying story arc.
JSC: Yeah. For a couple reasons, we felt like we wanted to put all of our best hits into these eight. We probably had, like, 15 episode ideas, and then, because there were only eight slots, I feel like the best got done. I think with a longer order you might think, "Oh, we have to come up with 20 episodes, so I guess this will have to be in it." But, for us, we actually had to throw away five big ones.
What we also do sometimes is like, if we have a physical bit that we love, that Lennon and I want to do, sometimes we put it aside and then we find, "Oh, it'll actually fit in this episode we decided to do." So sometimes we'll harvest—that sounds like we're harvesting body parts—the best stuff from a thrown-away episode and put it into one that we're actually doing.
LP: I've asked her not to use farmer's terms in this interview, and she refuses.
JSC: Harvest! Harvest an organ, Lennon, is what I was thinking.
LP: I know, but let's think of harvest like, the time of the year all the wheat is given, and people are nourished by the comedy we're providing, instead of, like, we have to go to the side of the road and someone's had an accident and take their kidney.
AVC: Are there any ideas you weren't able to do this season that you can talk about?
LP: Well, we really wanted to get Queenetta in there. Daija [Owens], our sweet babysitter from Best Friends Forever, and like—what do they call it when you hide little nuggets?
AVC: Easter eggs.
LP: Easter eggs. Yeah, kind of like an Easter egg, but also because she's stone-cold just the funniest girl in the world. We had her for a hot second in episode eight, but, when you watch episode eight, you'll understand why we couldn't have another new character. [Laughs.] Because it is jam-packed with amazing personalities. And Kenny Loggins.
JSC: But we have a pledge to make to our fans. I made a pledge in season one to have baby raccoons in season two, and I did not deliver on that promise, so—
LP: You did? Why did you promise that? I wasn't there for that. You've got to check with me on this shit. [Laughs.]
JSC: It's in writing somewhere.
LP: In the Twittersphere? No, we tweet enough. I think it's gotten swallowed now.
JSC: Yeah. But we pledged for this season, for the diehard BFF fans, that Queenetta will be our babysitter/Girl Scout that hates my guts. She will be that.
LP: What if we just say we'll use Daija? [Laughs.]
JSC: Okay.
LP: What if we don't promise a specific storyline? [Laughs.]
JSC: I want her in a sash. I want her in that green outfit and a sash, and I will die on that sword.
We didn't know if we were even going to get a second season. When we got one, we felt like we were just going to go for the gold. Everyone in the writers' room went around and we said, "Who is your dream actor to write for or somebody that you just want to meet?" Like, in terms of Kenny Loggins, Lennon just needed to meet him, so we put him on the board, and we made a pledge, like, "We are going to make everybody's dreams come true this year." Then we did! Somebody in our writers' room had an obsession with the Property Brothers—
LP: That was me.
JSC: We wrote them sexting with Lennon in a dream, and they said yes to it. We wrote these almost, like, stalkerish letters to people that, if I read one, I would feel unsafe.
LP: But then you would say yes because you can't say no.
JSC: You can't say no because you're afraid! So we did that. Pamela Adlon was a good example. We've been obsessed with her forever, and then we saw her at the WGA Awards, and we were like, "Oh, my God, she's so beautiful and so funny and so kickass." So we wrote her a scene, basically, with Zach Woods in the finale, and we were like, "There's no way she's going to have time, writing for Louie or whatever." But we wrote her this insane letter, and she was like, "You complimented me in the letter. I'm going to do the part." She came and did it, and we had the best time of our lives.
AVC: It seems like she would eat Zach Woods' character alive.
LP: It's interesting, because you would think that, and you can tell that's what they both want to have happen, but they really go toe-to-toe with each other. He is in his wheelhouse with music, so when they meet up, she's like, "Oh, you are a musical genius."
JSC: Let's just say sparks fly between the tallest man in Hollywood and Pamela Adlon.
AVC: The second season is airing earlier on demand, right?
LP: The first week, episode one and two will air back-to-back at 10 and 10:30, August 4th, and then right after that, episode three will become available for Comcast Xfinity subscribers. So if you have Comcast, you can watch all three; otherwise, you've got to wait until the second week to watch episode three. Then episode four will be released that week for Comcast Xfinity, and then that'll go through September to the day after Labor Day, when the last two episodes will air. The finale will not be released early, so everyone will have to watch it when it airs or right after it airs.
AVC: Did the budget change much on a per-episode basis compared to season one?
LP: Yeah, we did go down some. I mean, we were already kind of doing it for a discount, and it did go down some more.
JSC: It was basically, like, we had to be really creative. You saw the hot-tub scene with the Sklar Brothers, but we had another insane dream—we have no idea why—of a paddleboat race, like a regatta, on a lake. Our production line producer was like, "If you do this, you have to give up your week off." And we were like, "That's fine."
We become obsessed with these things. Then we were baking under the hot Malibu sun and, like, literally almost died out there, and I was like, "Oh, this better be worth it." [Laughs.] But the moment I saw the Sklar Brothers have to jump in that dirty lake, I was like, "This is 100 percent worth it." [Laughs.]
You know what else I think is really fun about this? Because it's for the love of the game, obviously, and that's how the UCB always was for us. For us to even get paid at all is always kind of a shock.
LP: We don't like to put that in writing, though, because of our families.
JSC: I know, that's true.
LP: We have families and mortgages and stuff.
JSC: We wrote those episodes for all of our best friends, like Rob Riggle, Jack McBrayer, Keegan [Michael Key], Zach, and they come on, and nobody—because it's all for the love of comedy—[it's] almost like a summer-camp vibe about it. It's like, "Yeah, I'll fucking do that!" We had Riggle in a welding mask he couldn't see out of, and he was like, "Guys, I can't see where I'm welding. But if it's funny, I'll still take the risk." We were like, "You're a father of two. We probably shouldn't do that." But the UCB mentality is you do anything for each other to make each other's projects better. That is very touching for Lennon and I, that every week, we would have another one of our best friends show up and say, "What can I do? Do you need anything else?" That's the most special part of the show for us.
AVC: You're both newish mothers. Does that inform what's going on through this season, now that Maggie has had her baby?
LP: One hundred percent. In season one, when I started the writers' room, I had a 10-week-old, and Jess was super-pregnant, and then we took a little break. We started shooting when Jess had a 10-week-old, and I had a 6-month-old. This whole motherhood thing has really been, like, back to work from the get-go. It's sort of a balance. We've been trying to figure out how to balance being a great mom and being present and having our girls know what we do and see where we're going every day. A lot of times they come with us to work. They did for sure first season. Second season, they're a little bit more rambunctious. They need their space.
JSC: Also both of our daughters had to become comfortable with Lennon in that Bosephus beard.
JSC: My daughter kept going, "Aunt Lala? Where's Aunt Lala?" "I don't know what to tell you, but that's your Aunt Lala in that beard. You're just going to have to accept this as part of our reality now."
LP: Yeah, and my daughter met Bosephus when she was still breastfeeding. I brought her into the trailer with me while I got the mustache put on, so when she would see me later, she would not reject my mother's milk. [Laughs.] Then there's some weird video of her talking to Bosephus and getting used to that. But then she learned how to say "Gimme dem crawdads" and everything was okay.
But I mean, as far as it informing the show, for me, I guess it affects both of them because, in effect, Emma also is a new mom. But it was a real balance for us of, like, how much baby, and having a baby inform the decisions, but not feeling like we were bound to baby storylines or bound to the house because when you're a new mom, you do less. We didn't do that; we didn't do less. We didn't stay close to home because we literally couldn't do that with deadlines. Maybe I would have stayed home longer if I had the choice, but we were like, "Just hit the ground running and find the comedy in that," and we did. This season is pretty reflective of that, like new parents trying to get back into the world, but, at the same time, you're a new mom, and what does that mean, and how does that make your choices more important or different?
JSC: I think a lot of times for a show, having a baby can actually ruin it. Like, "Oh, God, now they have a baby and now they'll have to do episodes about going to Mommy And Me." I don't feel like that's really reflective of people's lives necessarily. It was actually a positive for us when the baby was out and about for the show, because all the stakes were raised.
What Maggie decides to do with her life career-wise—we have a whole episode about that she's very concerned about the fact that, if she's going to be away from home and her daughter, it'd better be something important. The beautiful thing about raising a baby with your best friend is that you're both there to help achieve each other's dreams. If anything, it just gave us higher stakes, which is always good for comedy, and the drama part of it. There's really no episodes that revolve around the baby. The baby is just part of our lives; she's with us on adventures, and sometimes she's not, but we want to be better people for the baby. That's something true for Lennon and I: We're always trying to get our shit together, and sometimes succeeding and failing. [Laughs.]
AVC: In an old interview, you said that with Best Friends Forever, the episodes that aired were exactly what you wanted them to be. At the end of the day, does it feel the same way going forward with Playing House?
JSC: Yes.
LP: It does, honestly. We're lucky in that we came to USA at a time when they were just figuring out what they wanted to be for comedy, and then the demand for the show is what brought us back. Jeff Wachtel, who was the main reason our show came back, and also got picked up to begin with, is from the New York theater. He believes in the artist's voice, and I feel like he's said at some point, "Let's let them do their thing." Which I think is what you're seeing with a Broad City, or with an [Inside] Amy Schumer, or with any of the shows on AMC, or you're getting with FX. You're getting a pure version of the artist's voice, and for comedy, that's essential. That's also what we learned at the UCB. It's like, "What do you think is funny? Put that up." Because nobody knows how to make you funny better than you.
JSC: Yeah, and I would say USA, if anything, people on the production side and development, they're trying to make it work. We come to them with crazy things, like, "We're going to have Kenny Loggins, a tour bus, a concert hall. Let's see how we can do this." That feels really good, you know?
LP: Yeah, and they also look out for us. It's like a family at this point, like a lot of the guys on the studio side, too, are like looking out for us. Like in season one, when we were like, "We want to do it all on location," they were like, "You have a 10-week-old. Let's have a stage." And we were like, "Okay, that makes sense." We were so thankful they were looking out for us in that way. There's just a real nurturing thing that is happening from a lot of the support there.
AVC: Have you allowed yourselves to think beyond this season? Like you said, when you came over to USA, it was part of this comedy wave the network was doing, and now Playing House is the last lady standing of those shows.
JSC: I think for Lennon and I, we always are. I mean, the characters that we play are so close to ourselves, and I feel like we always have 24 more episodes to do. If we had to sit down tomorrow and write those, it would be no problem. But I also feel like we've definitely been in the business long enough to go, "We're going to enjoy this moment and this season, and not necessarily obsess over what the next one will be or when the next one will be." Right now, we're really enjoying putting together this season. We always leave our seasons on a cliffhanger, and this season, there's a pretty good one in this finale. So we're excited, really excited, to come back. We almost set up a problem for ourselves that then we have to solve in the next season. We did that with Bird Bones and Mark—you'll see what happens with our relationship and their relationship and everything. We've definitely done that; we've cut our work out for us for season three, if we're lucky enough to have one.
LP: Yeah, and we've still got a bunch of names on that board that we want to get in going into season three. We have a bunch of ideas that didn't get into season two that we could do as well.
AVC: You've said in the past that your shared awful pilot experiences pushed you two to do your own show, whether it was Playing House or Best Friends Forever, as a way to show Hollywood what to do with you. Do you feel like your work on the shows has helped accomplish that?
JSC: Oh, yeah. I feel like that the guest stars we do now in our off time are so much more well suited to what we can do because people have just seen it. I think that what's nice about the show, the comedy community has been really supportive of the show and just watched it.
I love our show because it's so specific, and I feel like, in answer to your question about USA and being the last lady standing, it's like we're in a new part of television where it actually doesn't matter where you air. What matters is that you've connected with an audience. It feels like that audience seems to keep growing. So I'm interested to see how season two goes, because it's almost like we could be airing anywhere and people will find it, hopefully. But that's how I feel about all the shows that have broken out. Even Key & Peele took a while to build, and then they got this core audience that was so passionate, and that carried them.
LP: For me, I was in New York, getting my chops or whatever. I did my one-woman show in order to show people what to do with me. But I was dressed as a man, which, eventually, made it into [Playing House]. I was dancing around to a Michael Jackson song with a ribbon. [Laughs.] It wasn't exactly like, "Take that and put that on television."
When we got to do our own show, it was like we were just trying to figure out the story that we wanted to tell, which, to us, was the story of these two women—almost a romantic relationship between two best friends and what happens and how that happens. I definitely feel like having a couple of seasons of that out there, people see pieces of it or whatever and are like, "Okay, I kind of get better what to do with you." But, to be honest, even if they haven't seen it, they're like, "You've been the star of your show for two years and you write and produce it? Let's see what you have to offer." It just gets us in different rooms or something, even if they haven't seen it.
JSC: Or a show like Veep, which we both did, they loved to bring people on that are writer-performers because there's a lot of improv that goes into it, so that's nice. Something like that was a dream job for both of us.
LP: Yeah, and Review is the same way. We know Andy Daly, obviously, and have loved him for a thousand years, and he's like one of the best actor-comedians in the whole world—
AVC: He's a national treasure.
JSC: He is a national treasure, truly, and in the podcast world, he's next-level.
LP: Jess was on season one with him, and then we brought him onto our show, and then I was on season two and Jess was on season two. The director, Jeff Blitz, directed our pilot and the birth episode, so it's just a conversation that was already happening. When they thought of this character, they thought, "Oh, you know, Lennon would be good as this algebra teacher that he seduces or whatever."
JSC: We found our director because I had done Review, and Jeff Blitz was directing that. I was like, "This guy is amazing."
LP: On BFF, we had sat down with him and felt really good with him, and then he couldn't do it. I think that's how we originally met him. Then you did Review with him.
JSC: And I totally fell in love.
LP: And then there was no escaping.
LP: We harvested him.
JSC: We harvested him.
AVC: You mentioned podcasts, so we have to talk about Womp It Up!
LP: Yes, please.
AVC: How did that come together?
JSC: Marissa [Wompler] was a little reluctant. I never do characters, ever on anything; I only play somewhat close to myself, so I was so uncomfortable when he asked me to do Comedy Bang! Bang! I'm like, "This is going to be terrible. I'm going to ruin your show." Then Marissa had a bit of a—I don't know, she just fit in with the world or whatever, and they kept having us back. Then Lennon joined, and then that became its own thing. I mean, really Marissa didn't become who she was until [Marissa's teacher/best friend, Charlotte] Listler came on the scene.
LP: Not true. Maybe she wasn't, like, a sellable commodity or something [Laughs.] until it was an unlikely duo. Marissa is one of the fan favorites of Comedy Bang! Bang! for everyone throughout the years.
JSC: Well, that's nice. The point is, Scott had been suggesting, "You guys should do your own podcast."
LP: And Jeff Ullrich, who used to run Earwolf as well, was always like, "Can you do it? How can you do it?" We had been doing the Womptacular specials, where we would just get, like, every single person, and everyone would play, like, four different characters, and it was insanity from the get-go. Those were doing really well, and so then we thought, "Well, we could just do it the way we do our show," which is, every week we have another of our incredibly funny friends play something that they think would fit into the world.
JSC: For Andy Daly's [episode], we were like, "Come in and do whatever you want." Most people are playing something close to a teacher they knew in their public high school. Joe Bongo is, I guess, very close to a teacher he had once. Then you know what's funny is I saw Daly yesterday, and he's like, "Oh, Joe Bongo came on Comedy Bang! Bang!" So I feel like now we're cross-pollinating both shows, like people who are doing characters on our show then cross over. Then we had a—it's not a finale, but the eighth episode of Womp It Up! We did a live spot. Scott came on as a guest. And I think Marissa was downright rude to him!
LP: She was always rude to him.
JSC: She was like, "I got my own show now." I actually felt like I had to apologize to Scott after the show for the rude things I said.
LP: You always feel that way.
JSC: Then we had a—somebody who I won't name—somebody found out about the show and crashed the live performance, and it was very revealing, let's say. A lot of spoilers. We haven't done an episode since then, so I really don't know how we're going to bounce back from some of the information that was brought to light.
LP: I always forget everything that has happened after we do it. Because we kind of like go into this vortex when we record it, and I hear it back and I'm like, "Whoa, that's a weird thing we just said." [Laughs.] Then, especially when we were in the writers' room and we would just go and record two back-to-back, we would just say the craziest stuff, or set up some storyline.
AVC: When did you record the episodes?
LP: Last fall and into the early winter.
AVC: Were you writing the show at the time?
LP: We started writing in January. We were both shooting Review and Veep and a bunch of other stuff, I think.
JSC: I usually have a headache after I do one of those because I'm screaming so much more than I scream in my normal life, which is already a lot.
AVC: Do you think you'll be able to record a second season soon?
JSC: Yeah.
LP: Yeah, we said we're going to start recording again soon. There will be no gaps, hopefully.
JSC: For Womptacular Birthday we're going to go on Comedy Bang! Bang! too. Apparently, the money that was spent at Six Flags was because there was damage done to a log flume, which meant that Seth has no money to spend on her birthday this year, so it's at an American Legion and they're going to be sharing space with a bunch of Korean veterans. So it'll be an interesting group.
LP: Wait a minute, like from the Korean War? Or for actual Korean men who are also veterans?
JSC: Well, it will be for Korean men, but they're from the Korean War. Yeah.
LP: What? Let's talk about this.
JSC: [Laughs.] But that's the only space that was available for her! But there are going to be a lot of speeches, it has a bar downstairs, it's going to be great. Joe Bongo said he's going to come.


Home Lifestyle How much Screen Time is too much?
The measure of screen media 'addiction' in children.
Young children nowadays bent over a screen for hours, texting or gaming, lost in a digital world. Many parents are concerned because of it.
They generally tend to ask, how much screen time is too much?
According to a new study by the social problems connected with screen addiction.
There are many studies that suggest screen use. But this is the first tool that measures screen media addiction in children ages 4-11.
A portion of the notice signs includes: if screen time meddles with day to day exercises, causes strife for the youngster or in the family, or is the main action that brings the kid satisfaction.


Not only cultural contents, in Cascina Triulza you can also use the ATM of Banca Etica, one of the services of the first Italian bank entirely inspired by the principles of ethical finance. The ATM, located in the market, is available to those who want to withdraw cash or carry out other operations and it representes an opportunity to become better acquainted with Banca Etica. Around the ATM are located some pictures of reality funded by the institute, which, with the savings collected, extending credit only to individuals and member organizations for sustainable projects in social and environmental. And it is the only bank in Italy to publish funding provided to organizations on its website.
The Banca Etica Group is working to bring in Cascina Triulza a series of cultural insights that will help to give the point of view of business ethics on issues of the World Exhibition. The path promoted by the members is realized in the organization of several visits "accompanied" inside and outside the Exhibition. All information available on www.bancaetica.it/dentro-expo.


Take action today to make a difference in your community.
Your support of United Way helps our community all year long.
You can fuel community solutions, volunteer time, or lend a voice to a cause.
We go beyond temporary fixes to create lasting change in your community.


text:
Q: Коллекции моделей в Laravel 5 Привет. Меня интересует вопрос по моделях. На моих моделях висит бизнес-логика, и в самих объектах есть состояния, то есть есть поля с данными и методы и когда я создаю модель, мне нужно провести инициализацию. Я думал делать их через конструктор, но почему то у меня были ошибки, уже не помню какие, это было давно, я решил сделать метод init(), и получается где то так $user = User(); $user->init($id). И теперь вопрос,  когда я хочу использовать коллекции, например  $users = User::all(), есть ли способ, как нибудь их проинициализировать, более красиво, чем просто через цикл?

A: Проблемы с конструктором были скорее всего потому, что вы не добавили в него
parent::_construct()

И все должно работать. Модель прекрасно экстендиться. В данном случае, $user->init($id) - это костыль, а практически любое решение с костылем - будет костыль костыля)) Так что настраивайте инициализацию класса.
Но я бы лично посоветовал использовать $casts или если не устраивает $casts, можно использовать произвольный класс коллекции со своими свойствами и методами.


text:
using System.Collections.Generic;
using Azure.Core;

namespace Azure.ResourceManager.DeviceUpdate.Models
{
    /// <summary> Private link service connection details. </summary>
    public partial class PrivateLinkServiceConnection
    {
        /// <summary> Initializes a new instance of PrivateLinkServiceConnection. </summary>
        public PrivateLinkServiceConnection()
        {
            GroupIds = new ChangeTrackingList<string>();
        }

        /// <summary> Initializes a new instance of PrivateLinkServiceConnection. </summary>
        /// <param name="name"> Private link service connection name. </param>
        /// <param name="groupIds"> List of group IDs. </param>
        /// <param name="requestMessage"> Request message. </param>
        internal PrivateLinkServiceConnection(string name, IList<string> groupIds, string requestMessage)
        {
            Name = name;
            GroupIds = groupIds;
            RequestMessage = requestMessage;
        }

        /// <summary> Private link service connection name. </summary>
        public string Name { get; set; }
        /// <summary> List of group IDs. </summary>
        public IList<string> GroupIds { get; }
        /// <summary> Request message. </summary>
        public string RequestMessage { get; set; }
    }
}

redpajama_set_name: RedPajamaGithub


Have you heard people saying, "oh, she had the most gorgeous smile" It is usually said in a tone which conveys deep respect. This should not come as a surprise because many people admire a beautiful, bright smile. Use the advice in this article to have a whiter, brighter smile.
Stay away from tobacco, coffee, and wine. These products contain dark chemicals that will stain your teeth. If you don't want to quit your coffee and cigarette habits, brush your teeth every time you finish smoking or drinking. Or, you can buy a mini toothbrush that you can carry around with you to brush more conveniently. The brush's roughness is what gets your teeth clean.
If you have untreated cavities or gum problems, you really ought to see a dentist before starting a whitening of the teeth treatment. You have to take extra precautions when you whiten your teeth. Your dentist can advise you on the proper whitening techniques and whether or not they are appropriate for you.
Strips that whiten your teeth are inexpensive and can be found nearly anywhere. Just place the strips on your teeth for a specific time period so they can work their magic. Whitening strips enjoyed a brief surge in popularity, but their lack of results mean that less and less people are buying them.
It is possible that your dentist can recommend home whitening kits that are effective but will not damage your gums or teeth. Some products are superior to others, and your dentist is an excellent resource to help you make the best choice.
When you use teeth whitening products, read the directions carefully and follow them exactly. Whitening of the teeth products can have side effects like harming or inflaming gums, which can be worsened by leaving them on too long. After you have whitened your teeth, do not consume any drinks that can erode enamel like sports drinks or soda pop, they contain acids.
Once you have used any whitening program for you teeth, you must avoid any dark liquids. Your teeth absorb color more easily during this time so coffee, tea, and fruits are not a good idea.
Put strawberry juice on a toothbrush and brush as normal to whiten your teeth. The acid from the juice softens your tooth enamel, thus enabling you to clean away much of the discoloration from your teeth. This is a less expensive way to get those pearly whites you always dreamed about.
Don't start any teeth whitening systems without knowing that teeth whiteners will only provide results on real teeth. If you have had dental work, like crowns, fillings, implants or veeners, whitening will not work on them and they will stay the color they are. Whitening teeth could make make your teeth look worse because it will emphasize your dental work.
If you feel pain from teeth whitening at home, stop. When you use products to whiten your teeth, you may cause sensitivity. Additionally, your gums may become inflamed. If you experience these symptoms after using a product, stop and don't continue until you have gotten advice from a dentist. He may suggest other products to use that won't make your teeth sensitive.
Give the appearance of whiter teeth by changing the color you wear on your lips. Consider a blue-based lipstick or lip gloss. Colors such as blue-tinted reds and berries help make your teeth appear whiter. Avoid red or yellow-based matte lipstick shades, which will only bring out the yellow in your teeth.
Twice a day, be sure to brush your teeth, floss, and massage your gums. After every meal, you should brush and floss as a means of keeping your teeth as white as possible. By doing this, you remove any loose debris or plaque that would have stained your teeth.
Rubbing the insides of orange peels on your teeth can help to remove surface stains. Alternatively, create a toothpaste out of dried orange peels and ground up bay leaves. Make sure to rinse your mouth thoroughly afterwords to remove the fruit sugar.
Avoid off the shelf mouthwash, especially if there is color added. It is possible that your teeth may be discolored as a result of long-term use. They have alcohol in them which can harm your gums while also soaking through under your tongue and getting in the bloodstream.
Know what you can expect from whitening of the teeth techniques. If you expect miracles, disappointment may be inevitable. Many factors play into the results you get, including your age and the extent to which your teeth are discolored. Ask your dentist what to expect.
If you plan on getting wire braces in the near future, one recommendation is that you whiten your teeth before the process begins. If you do that you will have straight teeth that are much whiter once they are removed. Your new, improved, beautiful smile will be a source of constant delight and satisfaction!
Now that you've read these tips, are you ready to hear people say that YOUR smile is perfect? When you've whitened your teeth, people will respect you as a different person than you were before. Apply the tips you read in this article today to start on the road to respect!
Make Friends With The Scale – Follow These Tips!


However there are an incredible lot of international pupils within the last calendar year, so they really need to have passed the documents and tests. The pupils now have the ability to obtain GRE analytical writing essays from utilizing this page. Question papers on the web free of charge. Examination, but these issues and few assessments. Enormous queries are accessible for training that may assist the students to obtain knowledgeable about the types of questions being questioned in a few competitive examinations. While this guidebook is intended to work with you to streamline your examining, let's discuss the way in which you are able to best employ these books to prep for the SAT and attain your goal results. Homework is an essential part of securing a greater rating for the majority of pupils, which School Table is eventually admitting with its endeavors to furnish free net training material. The same as with his really last show, David Warner delivers all-inclusive and crystal clear content review and instruction.
Younger grandmothers may be adept and rather active.
This means you need to return and examine the sentence you've simply composed before you begin the following one. It truly is my hope that this short article may enable you to prepare to your own forthcoming evaluations jointly with creating a great composition in all respect. So you must supply chief concentrate on Article writing as good as other sections. It's tremendously significant your composition is really a complete that each among the parts fit together. No guidebooks can become a fantastic article author. Get these pieces right and the remainder of the composition has a tendency to be mindful of itself. The writing must be in to the stage manner with distinct points in support of your own essay subject. In the event you happen to be experiencing a specific my essay for money subject or matter, don't be frightened to request help. Keep reading to find out more about writing software given in the California, DC region and notice whether any will fit the bill.
The chief tips to compose a powerful article written down task 2. Sit back with your assessment timetable, and make certain that you just simply spend adequate time for revision to every subject, paying special interest to all these areas you can be fighting with. This might be a professional as well as a con, according to what type of math student you're There'll be choice offered from various fields of study. You can buy individual essay lessons. Composing an essay might be straightforward, but not everybody finds it the very same way. Just how to Write it is going to make life easier for you. Language composition is about exercise. Composition is the initial papers. Rivals should compose an essay on a certain place.
Ask what type of credentials they try to find or should they have government or beginner – .
Many of quite a couple of other documents on the. The GRE analytical writing is among the important places of the assessment. Plus, they are able to be much easier to approach compared to tremendous complete test prep books. Language area is among the most crucial part in almost any community and private sector assessment. While Kallis is among the top books obtainable right today for SAT preparation, there are plenty of others that provide complete evaluation for the SAT. In an assessment you're under pressure. We do not actually have any notion of how to actually write answers within the test, don't worry. It's an assessment designed for nonnative Language speakers. I'll let you know about the usual errors my buddies and I Have created and we are going to warn you regarding hidden snares in the IELTS test.


text:
package com.smarttested.qa.smartassert.junit;

import com.google.common.base.Optional;
import com.google.common.base.Supplier;
import com.google.common.base.Suppliers;
import com.smarttested.qa.smartassert.SmartAssert;
import com.smarttested.qa.smartassert.SoftAssertException;
import org.junit.internal.runners.statements.ExpectException;
import org.junit.rules.TestRule;
import org.junit.runner.Description;
import org.junit.runners.model.Statement;

import static com.smarttested.qa.smartassert.SmartAssert.validateSoftAsserts;

/**
 * JUnit Verifier for SmartAssert's soft assertions.
 * Will verify and clear soft asserts after each test method
 * <p/>
 * Create instance with double checked locking, but leave
 * constructor public to give a chance to use inheritance if needed
 *
 * @author Andrei Varabyeu
 */
public class SoftAssertVerifier implements TestRule {

    private static Supplier<SoftAssertVerifier> instance = Suppliers.memoize(new Supplier<SoftAssertVerifier>() {
        @Override
        public SoftAssertVerifier get() {
            return new SoftAssertVerifier();
        }
    });

    public static SoftAssertVerifier instance() {
        return instance.get();
    }

    @Override
    public Statement apply(final Statement base, final Description description) {
        return new VerifierStatement(base);

    }

    private class VerifierStatement extends Statement {

        private Statement base;

        private boolean expectsException;

        private VerifierStatement(Statement base) {
            this.base = base;
            this.expectsException = ExpectException.class.isAssignableFrom(base.getClass());
        }

        @Override
        public void evaluate() throws Throwable {
            try {
                base.evaluate();
            } catch (AssertionError e) {
                if (expectsException) {
                    Optional<SoftAssertException> softException = SmartAssert.getSoftFailures().getException();
                    if (softException.isPresent() && e.getMessage().contains(softException.get().getClass().getCanonicalName())) {
                        /* everything is OK, we expect this exception. Leave without error */
                        return;
                    }
                    throw e;
                }
            }
            validateSoftAsserts();
        }
    }
}


text:
Produktvariation (oder Produktmodifikation) ist in der Betriebswirtschaftslehre die Produktstrategie, von einem Produkt oder einer Dienstleistung Varianten herzustellen, die das bisherige Produkt oder die bisherige Dienstleistung ersetzen.

Allgemeines
Die Produktvariation ist in der Produktpolitik eine Diversifikation in der Weise, dass ein bereits bestehendes Produkt durch ein Nachfolgeprodukt ersetzt wird, wobei eine Trennschärfe zur Produktinnovation nicht vorhanden ist. Das bereits bestehende Produkt wird nicht mehr hergestellt. Dadurch entfällt das Güterangebot für dieses Produkt auf dem Gütermarkt. Eine diesbezügliche Güternachfrage kann nur durch gebrauchte Produkte (wie Gebrauchtwagen) befriedigt werden.

Arten
Eine typische Produktvariation ist das Revival, das in Form des Relaunch oder Facelifting durchgeführt werden kann. Beim Relaunch wird ein bereits aus dem Markt genommenes Produkt nach längerer Zeit mit Produktmodifizierungen wieder eingeführt, beim Facelifting erfährt ein Produkt bloße optische Veränderungen.

Auch die Änderung des Produkt- oder Markenimage wird häufig als Produktvariation angesehen.

Typische Produktvariationen
Automobilherstellung
Unter einer Produktvariation versteht man die bewusste Veränderung einer im Markt befindlichen Baureihe unter Beibehaltung ihrer grundlegenden Konstruktionsmerkmale. Sie wird in der Automobilwirtschaft üblicherweise als "Facelifting" bezeichnet. In der Automobilherstellung liegt eine Produktvariation erst vor, wenn ein bestimmtes Fahrzeugmodell nicht mehr hergestellt wird. Beispiel ist der VW Käfer, dessen Produktion am 30. Juli 2003 eingestellt wurde. Sein "Nachfolger" wurde der bereits im Mai 1974 präsentierte VW Golf. Dessen Modelle wie der VW Golf I, VW Golf II usw. waren Produktdifferenzierungen. Die nicht mehr hergestellten Modelle können jedoch weiterhin genutzt werden, solange Ersatzteile vorhanden sind.

Computerprogramme/Software
Eine neue Version von Computerprogrammen und Software ist eine Produktvariation, sofern eine neue Version die alte ersetzt wie beim Acrobat Reader. Alte Versionen können nicht oder nur fehlerhaft genutzt werden. Kann jedoch mit der alten Version noch weitergearbeitet werden, liegt eine Produktdifferenzierung vor (wie beispielsweise bei Microsoft Word). Bei vorhandener Aufwärts- oder Abwärtskompatibilität handelt es sich stets um Produktdifferenzierungen.

Wirtschaftliche Aspekte
Die Produktvariation ist als absatzpolitisches Instrument auf Oligopolmärkten weit verbreitet, weil die oligopolistische Interdependenz aus der Sicht der Unternehmen den Einsatz solcher Aktionsparameter erfordert, die keine unmittelbar wahrnehmbare Reaktion der Konkurrenten zur Folge haben. Deshalb sind im Qualitätswettbewerb die Produktvariation und -differenzierung wichtige Komponenten.

Anlass für Produktvariation können Veränderungen des Konsumverhaltens, Erscheinen von Konkurrenzprodukten, gesetzliche Auflagen oder technischer Fortschritt sein. Die Produktvariation zielt darauf ab, den Produktlebenszyklus zu stabilisieren. Durch Produktvariation können neue Teilmärkte erschlossen werden.

Die Definition aller Produktvariationen einschließlich der Produktdifferenzierungen sollte aus Kundensicht möglichst einheitlich insbesondere durch die technischen Daten des Kraftfahrzeuges erfolgen. Durch eine Definition der Produktvariationen, die den Anforderungen an eine ideale Boolesche Algebra entspricht, kann eine einheitliche und konsistente Produktdefinition gewährleistet werden. Dies schließt auch die Definition der Fahrzeugklassen, -baureihen und -typen mit ein, die der Produktdifferenzierung zuzuordnen sind. Um eine eindeutige und korrekte Produktdefinition zu erreichen, ist der Einsatz eines Produktkonfigurators sinnvoll, der den Kunden bei der Auswahl der Ausstattungen unterstützt.

Abgrenzung
Streng zu trennen ist die Produktvariation von der Produktdifferenzierung, bei der kein Nachfolgeprodukt geschaffen wird. Vielmehr werden an bestehenden Produkten – die auch weiterhin hergestellt werden – Produkteigenschaften, Größe, Farbe oder Aussehen verändert oder sogar stoffliche-technische Änderungen vorgenommen bis hin zur geänderten Verpackung.

Literatur

Einzelnachweise

Betriebswirtschaftslehre
Marketing
Marktpsychologie
Produktmanagement

redpajama_set_name: RedPajamaWikipedia


text:
Western Desert Campaign 1940-41
Glenn Wahlert
There has been little study of Wavell's campaign against Italian forces in 1940- 41, nor of the role of the Australian 6th Division in the Italian defeat. Today's aspiring military commanders need look no further than the early Western Desert campaign for historical examples of brilliant leadership, deception and surprise against overwhelming odds.
This book is available
While the North African campaign has been studied in detail over the years, much of this study has been dedicated to the battles between the British 8th Army and Rommel's Afrika Korps. There has been little serious study of Wavell's campaign against Italian forces in 1940- 41, nor of the role played by the Australian 6th Division in the eventual Italian defeat. Part of this can be attributed to wartime propaganda that labelled the Italian Army dilettantes and mocked their courage. The truth is much different. Many Italian units showed incredible bravery, and the Australian assaults on fortress towns such as Bardia were far from a walkover. Today's aspiring military commanders need look no further than the early Western Desert campaign for historical examples of brilliant leadership, detailed planning, deception, surprise, manoeuvre warfare and relentless pursuit, all against overwhelming odds.
Overall, an attractive medium-detail guide to a major formation in a significant campaign, at a very fair price.
Shadows of ANZAC
Captain Moonlite
Michael Tyquin
One Shot Kills
Frank Gardiner
Our Friend the Enemy
David W. Cameron
My Vietnam War
Anzac Sons
Allison Paterson


text:
UNC System
UNC Online
Institutions and Affiliates
WCU, Blue Ridge Community College approve admission agreement
Home | News | News Story
Graduates of Blue Ridge Community College will have an easier time transferring to Western Carolina University after leaders of the two institutions of higher education endorsed a direct-entry admission program Thursday, Oct. 10.
WCU Chancellor Kelli R. Brown and Blue Ridge President Laura Leatherwood signed a memorandum of understanding establishing the Catamount Blue Ridge Program during a ceremony on the campus of Blue Ridge Community College in Flat Rock.
The signing took place just prior to the Henderson County stop on the WCU "Chancellor's Welcome Tour," a series of receptions with alumni, friends of the university and community members across North Carolina designed to introduce the university's new chief executive officer to the region and state.
Originally published Oct. 11, 2019.
910 Raleigh Road
UNC Policy Manual and Code
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The UNC System is a treasured public institution dedicated to serving the people of North Carolina through world-class teaching, research, and community engagement. Today, nearly 250,000 students are enrolled in our 16 universities across the state and at the NC School of Science and Mathematics.
Copyright © 2020 University of North Carolina. All rights reserved.
The university is committed to providing services that are accessible to everyone. We continually update our website and review it with the aim of meeting users' accessibility needs. If you or someone you know encounters a barrier to the information you need, click here to request assistance.


USDA explores feasibility of alternative energy production at airports.
A recent study conducted by researchers from the USDA's Animal and Plant Health Inspection Service highlights the potential for alternative energy production at airports. The study findings were published in an article titled "Airports Offer Unrealized Potential for Alternative Energy Production" in Environmental Management and indicates that airports may want to consider converting to alternative fuels where it is both economically and environmentally beneficial.
Federal Aviation Administration is committed to working with airports interested in pursuing the potential for changes in land use to support alternative energy production.
"Some available grasslands at airports have the potential to spur the type of innovation we need to build American-made, homegrown biofuels and biobased products that will help to break our dependence on foreign oil and move our nation toward a clean energy economy," said Agriculture Secretary Tom Vilsack. "Converting airport grasslands to biofuel, solar or wind production not only provides more environmentally-sound alternative energy sources for our country, but may also increase revenue for airports and reduce the local abundance of potentially hazardous wildlife to aircraft. Such efforts may be particularly beneficial for rural economic development, as many rural airport properties contain expansive grasslands that potentially could be converted to biofuel crops or other renewable energy sources."
While federally obligated airports have restrictions on how land may be used, the Federal Aviation Administration is committed to working with airports interested in pursuing the potential for changes in land use to support alternative energy production.
Researchers at the USDA-APHIS National Wildlife Research Center note that many airport properties are already managed to reduce wildlife abundance and habitat quality as part of efforts to avoid wildlife collisions with aircraft. Once biofuel crops are identified for airport use that have low wildlife-strike risks compared to existing airport landcovers, converting grasslands to these land uses could produce renewable energy and also provide airports with an additional source of revenue.
Ongoing and future NWRC research hopes to identify renewable energy practices, including specific types of biofuel crops, which limit use by wildlife hazardous to aircraft and are compatible with safe airport operations. NWRC researchers and collaborators are currently studying wildlife use of solar arrays and adjacent airport grasslands in Arizona, Colorado and Ohio, as well as wildlife use of experimental plots containing switchgrass and mixed warm-season native grasses in Mississippi. Researchers note the economic profitability of biofuel, solar or wind production will vary markedly, but will depend primarily on yield, establishment and maintenance costs, opportunity costs of land (i.e., land rental or revenue from other commodities), and processing or utilization costs. For many airports where land is currently available, the benefits may outweigh the costs.
For additional information concerning wildlife and aviation research, please visit www.aphis.usda.gov/wildlife_damage/nwrc/research/aviation.


text:
namespace Azure.Management.Network.Models
{
    /// <summary> The virtual network connection reset shared key. </summary>
    public partial class ConnectionResetSharedKey
    {
        /// <summary> Initializes a new instance of ConnectionResetSharedKey. </summary>
        /// <param name="keyLength"> The virtual network connection reset shared key length, should between 1 and 128. </param>
        public ConnectionResetSharedKey(int keyLength)
        {
            KeyLength = keyLength;
        }

        /// <summary> The virtual network connection reset shared key length, should between 1 and 128. </summary>
        public int KeyLength { get; set; }
    }
}