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GSK announces US regulatory submissio...
GSK announces US regulatory submission for mepolizumab in Eosinophilic Granulomatosis with Polyangiitis (EGPA)
GlaxoSmithKline plc (LSE/NYSE: GSK) today announced the submission of a supplemental Biologics License Application (sBLA) to the United States Food and Drug Administration (FDA), seeking approval of mepolizumab, an interleukin-5 (IL-5) antagonist, as an add-on therapy to corticosteroids for the treatment of adult patients with Eosinophilic Granulomatosis with Polyangiitis (EGPA). EGPA is a rare disease, characterised by widespread inflammation in the walls of small blood vessels (vasculitis) which may lead to tissue and organ damage. The disease may affect multiple organ systems and be associated with symptoms of fatigue, muscle and joint pain and weight loss.
Birgitte Volck, head of rare diseases R&D at GSK, said: "The symptoms associated with EGPA are diverse and patients often experience delay in diagnosis. The burden of disease may be severe, preventing patients from carrying out everyday activities and recurrent relapses place them at risk of permanent tissue and organ damage. If approved, mepolizumab will be the first treatment in the US indicated for EGPA and has the potential to offer healthcare professionals and patients a new treatment option to help improve symptoms and disease control."
The regulatory submission is based on results from a pivotal, 52-week Phase III study which evaluated the efficacy and safety of mepolizumab vs placebo as an add-on therapy to standard of care in patients with relapsing and/or refractory EGPA.
Regulatory filings in other countries are planned during the course of 2017 and 2018. Mepolizumab is not approved anywhere in the world for EGPA.
About EGPA (previously known as Churg-Strauss Syndrome)
Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare disease that causes inflammation in the walls of small blood vessels (or vasculitis). The global incidence is generally reported to be in the range 1–4 per million, with an estimated prevalence of approximately 14–45 per million. The mean age of diagnosis is 48 years and the disease can be life-threatening for some patients.
In EGPA, patients usually develop asthma initially, before the vasculitis extends to inflammation in the walls of small blood vessels that supply tissues in the lungs, sinuses, skin, nerves and other organs. EGPA can result in damage to multiple organs in the body and the symptoms common to most include extreme fatigue, weight loss, muscle and joint pain, sinonasal symptoms and breathlessness, all of which affect patients' ability to carry out everyday activities without difficulty.
The current approach to disease management is primarily based on reduction of active inflammation and suppression of the immune response through the use of corticosteroid therapy and concomitant immunosuppressive therapy (e.g., methotrexate, azathioprine, mycophenolate mofetil) and/or cytotoxic agents (e.g., cyclophosphamide). Although the use of these treatments can be effective for establishing remission, patients remain vulnerable to either the complications of the long-term use of these therapies, or to the risk of relapse, particularly if the dose of corticosteroid is reduced.
About mepolizumab
Mepolizumab is a targeted anti-IL-5 monoclonal antibody. Mepolizumab binds to the signalling protein IL-5, preventing it from binding to its receptor on the surface of white blood cells called eosinophils. Inhibiting IL-5 binding in this manner reduces blood, tissue and sputum eosinophil levels.
Eosinophils are believed to play a role in protecting the body against infection. In some people, increased eosinophil levels can lead to inflammation and play a role in the development of some inflammatory diseases.
Mepolizumab has been developed for the treatment of diseases that are driven by inflammation caused by eosinophils. Mepolizumab is approved for use in the US, under the brand name Nucala, as the first-in-class add-on maintenance treatment for patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. Nucala has also been approved for severe eosinophilic asthma in the EU, Japan and a number of other countries worldwide although the details of the indications may vary. Trademarks are owned by or licensed to the GSK group of companies.
Mepolizumab is not approved anywhere in the world for EGPA.
Mepolizumab is also being investigated in chronic obstructive pulmonary disease (in phase III), eosinophilic granulomatosis with polyangiitis (EPGA, also referred to as Churg-Strauss syndrome, in phase III), severe hypereosinophilic syndrome (in phase III), and severe atopic dermatitis (phase II).
Important Safety Information for Nucala in Severe Asthma with an Eosinophilic Phenotype (based on US Prescribing Information)
Please consult the full Prescribing Information for all the labelled safety information for Nucala.
Nucala should not be administered to patients with a history of hypersensitivity to mepolizumab or excipients in the formulation.
Hypersensitivity reactions (e.g. anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash) have occurred following administration of Nucala. These reactions generally occur within hours of administration but in some instances can have a delayed onset (i.e. days). In the event of a hypersensitivity reaction, Nucala should be discontinued.
Acute Asthma Symptoms or Deteriorating Disease
Nucala should not be used to treat acute asthma symptoms, acute exacerbations, or acute bronchospasm.
Opportunistic Infections: Herpes Zoster
In controlled clinical trials, 2 serious adverse reactions of herpes zoster occurred in subjects treated with Nucala compared to none in placebo. Consider varicella vaccination if medically appropriate prior to starting therapy with Nucala.
Reduction of Corticosteroid Dosage
Do not discontinue systemic or inhaled corticosteroids (ICS) abruptly upon initiation of therapy with Nucala. Decreases in corticosteroid doses, if appropriate, should be gradual and under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
Parasitic (Helminth) Infection
It is unknown if Nucala will influence a patient's response against parasites. Treat patients with pre-existing helminth infections before initiating therapy with Nucala. If patients become infected while receiving treatment with Nucala and do not respond to anti-helminth treatment, discontinue treatment with Nucala until infection resolves.
The most common adverse reactions (≥3% and more common than placebo) reported in the first 24 weeks of two clinical trials with Nucala (and placebo) were: headache, 19% (18%); injection site reaction, 8% (3%); back pain, 5% (4%); fatigue, 5% (4%); influenza, 3% (2%); urinary tract infection 3% (2%); abdominal pain upper, 3% (2%); pruritus, 3% (2%); eczema, 3% (<1%); and muscle spasm, 3% (<1%).
Systemic Reactions, including Hypersensitivity Reactions: In 3 clinical trials, 3% of subjects who received Nucala experienced systemic (allergic and nonallergic) reactions compared to 5% in the placebo group. Systemic allergic/hypersensitivity reactions were reported by 1% of subjects who received Nucala compared to 2% of subjects in the placebo group. Manifestations included rash, pruritus, headache, and myalgia. Systemic nonallergic reactions were reported by 2% of subjects who received Nucala and 3% of subjects in the placebo group. Manifestations included rash, flushing, and myalgia. A majority of the systemic reactions were experienced on the day of dosing. Reports of anaphylaxis have been received postmarketing.
Injection site reactions (e.g. pain, erythema, swelling, itching, burning sensation) occurred at a rate of 8% in subjects treated with Nucala compared with 3% in subjects treated with placebo.
USE IN SPECIFIC POPULATIONS
The data on pregnancy exposures from the clinical trials are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as mepolizumab, are progressively transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential effects on a foetus are likely to be greater during the second and third trimesters of pregnancy.
GSK – one of the world's leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit www.gsk.com/about-us.
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D 'Principal risks and uncertainties' in the company's Annual Report on Form 20-F for 2016.
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Shrinking and Pinking: Two Steps Forward, One Step Back
April 9, 2013 Hilary
This time of year is always a big one for female athletes-- especially with the recent popularity of NCAA basketball superstars like Brittney Griner and Skylar Diggins. While it's so important to celebrate these victories, it's also important to remember the ways in which we still have room to grow when it comes to female athletes. So here are some steps forward, and a few steps back from the past few weeks. Step forward: Mark Cuban announces he would give Brittney Griner a shot to try out for the NBA, and is considering drafting her in the second round. It appears a woman trying out for a NBA team hasn't happened since 1979.
Step forward: Lauren Silberman, a college soccer player, became the first woman ever to participate in an NFL Regional Scouting Combine. She tried out as a kicker (apparently you pay to compete at these events, but there are a limited number of slots).
Step back: Silberman did not perform well-- at all. Neither of her two kicks went beyond 20 yards. Some even suggested this was designed to torpedo women trying out for the NFL in the future.
Step forward: Danielle Coughlin became the first female to win a state wrestling title in Massachusetts. She won in the 106-pound final in Division 2. She also served as a captain of her high school's co-ed team. I really enjoyed this quote from the article about what her victory meant to her: "After I won, a guy in the stands actually turned to me and he said, 'Smile, I have to send a picture to my daughter in Africa and tell her that in this country women can become anything.' I actually started crying when he said that."
Step forward: Caroline Pia, whose family had taken their fight to the media to ensure that their twelve-year-old daughter would be able to play on her Catholic League's football team, was given the go-ahead to play in the League.
Step back: Thirteen-year-old Ella Wood in California is the reason why her team-- which won every game in their season-- actually "lost." The Foothill Sports League decided ex post that having a girl play meant a game was forfeited. To their credit, all of Ella's male teammates said they should forfeit. But as of now she won't be able to play with her teammates next year.
But let's end on a more positive note! Former Olympic swimmer Donna de Varona, who helped establish the Women's Sports Foundation and served as its president, is now helping female athletes do even more trailblazing. She recently announced a partnership with Ernst & Young to help female athletes transition to leadership roles in their careers outside of sport.
I found this statistic especially interesting: About 4800 women took part in last year's London Games and less than 30% will return to compete in Rio. While it's somewhat discouraging that this is necessary, overall it will be a huge step forward.
To more steps forward!
In Playing to Win Blog, Shrinking and Pinking Tags Brittney Griner, Caroline Pia, Danielle Coughlin, Donna de Varona, Ella Wood, Female wrestlers, Lauren Silberman, London Olympics, NCAA basketball, Skylar Diggins, Women's Sports Foundation

redpajama_set_name: RedPajamaCommonCrawl


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Daily Ratings & News for Imperial Oil Limited (IMO.TO)
Complete the form below to receive the latest headlines and analysts' recommendations for Imperial Oil Limited (IMO.TO) with our free daily email newsletter:
Albertsons Companies (NYSE:ACI) Issues Earnings Results, Beats Estimates By $0.24 EPS
Imperial Oil Limited (IMO.TO) Announces Quarterly Dividend of $0.22 (TSE:IMO)
Imperial Oil Limited (IMO.TO) (TSE:IMO) (NYSEMKT:IMO) announced a quarterly dividend on Friday, October 30th, Zacks reports. Shareholders of record on Thursday, December 3rd will be given a dividend of 0.22 per share on Friday, January 1st. This represents a $0.88 annualized dividend and a yield of 3.63%. The ex-dividend date is Wednesday, December 2nd.
TSE IMO opened at C$24.23 on Monday. The company has a current ratio of 1.27, a quick ratio of 0.74 and a debt-to-equity ratio of 23.60. Imperial Oil Limited has a 12-month low of C$10.27 and a 12-month high of C$35.80. The stock has a market capitalization of $17.79 billion and a price-to-earnings ratio of -40.38. The business's 50 day moving average is C$19.15 and its two-hundred day moving average is C$20.57.
Get Imperial Oil Limited (IMO.TO) alerts:
A number of brokerages have commented on IMO. CIBC increased their target price on Imperial Oil Limited (IMO.TO) from C$25.00 to C$26.00 in a report on Monday, November 23rd. Royal Bank of Canada set a C$24.00 target price on Imperial Oil Limited (IMO.TO) and gave the company a "sector perform" rating in a report on Friday, November 20th. Morgan Stanley decreased their price target on Imperial Oil Limited (IMO.TO) from C$27.00 to C$19.00 in a report on Tuesday, October 20th. National Bank Financial lifted their price objective on shares of Imperial Oil Limited (IMO.TO) from C$21.00 to C$22.00 and gave the company a "sector perform" rating in a research note on Thursday. Finally, Raymond James boosted their target price on shares of Imperial Oil Limited (IMO.TO) from C$17.00 to C$22.00 and gave the stock a "market perform" rating in a research report on Friday, November 20th. Four equities research analysts have rated the stock with a sell rating and nine have assigned a hold rating to the company. The stock has a consensus rating of "Hold" and an average target price of C$22.71.
Imperial Oil Limited (IMO.TO) Company Profile
Imperial Oil Limited explores for, produces, and sells crude oil and natural gas in Canada. It operates through three segments: Upstream, Downstream, and Chemical. The Upstream segment explores for and produces crude oil, natural gas, synthetic oil, and bitumen. As of December 31, 2019, this segment had 397 million oil-equivalent barrels of proved undeveloped reserves.
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Canopy Growth (CGC) & Its Rivals Critical Analysis
Imperial Oil Limited Plans Quarterly Dividend of $0.17 (NYSE:IMO)
Loop Industries Issues Quarterly Earnings Results


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Symposium Integration between Modeling and Experiments for Crystalline Metals: From Atomistic to Macroscopic Scales IV
TMS Materials Characterization Committee
TMS: Nanomaterials Committee
Organizer(s) Mariyappan Arul Kumar, Los Alamos National Laboratory
Irene J. Beyerlein, University of California, Santa Barbara
Levente Balogh, Queen's University
Caizhi Zhou, University of South Carolina
Lei Cao, University of Nevada
Josh Kacher, Georgia Institute of Technology
Scope This symposium will provide a platform for researchers working on the state-of-the-art of multiscale modeling of materials, microstructural characterization, and small-scale mechanical testing to understand the mechanical behavior of crystalline metals.
Background and Rationale: The mechanical behavior of crystalline metals strongly depends on microstructure and the evolution of microstructure at different length scales. Examples include changes in crystallography, defect content and distribution, grain morphology, interfaces, and texture. The success behind the development of multiscale predictive model relies on finding and exploiting the synergies between modeling and experiments. In recent years intense efforts have been dedicated to advancing atomistic, micro, meso and macro-scale simulations tools and bridging them to understand the structure-property relationship. Achieving this goal requires a strong connection between models and experimental characterization techniques at different length scales. This symposium aims to encourage scientists/researchers from diverse areas of materials science and engineering to present recent achievements, identify challenges in developing multiscale material models from the atomic scale to the macro scale, and discuss connections with advanced experimental techniques.
The subject areas of the symposium include, but are not limited to:
1.	Structural, functional and nuclear materials
2.	Dislocations, deformation twins, phase transformation and recrystallization
3.	Atomistic modeling
4.	Dislocation dynamics and phase field modeling
5.	Crystal plasticity models
6.	Advanced X-ray and neutron diffraction techniques
7.	Advanced microscopy techniques including HR-(S)TEM, HR-EBSD, PED and in-situ TEM and SEM
8.	Emphasis on integrating experiments with modeling for guidance/validation
9.	Experimentally aided Multi-scale Material Modeling
Proceedings Plan Planned: At-meeting proceedings


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How long do people spend at Prague Castle?
Is Prague Castle worth seeing?
Can you walk around Prague Castle?
Do people live in Prague Castle?
How much does it cost to get into Prague Castle?
Can you go inside Prague Castle?
Why is the Prague Castle popular?
Does the orloj clock work?
What time is changing of the guard at Prague Castle?
Where can I buy tickets for Prague Castle?
Is the Prague Castle the biggest in the world?
Is Prague Castle in Old Town?
Does Prague have a royal family?
Where is the biggest castle in the world?
Can you use the euro in Prague?
You should allow 2-3 hours at minimum for visiting Prague Castle. However, if you find that you want to follow the audio tour, seeing the Prague Castle Complex may take longer. Make sure you've eaten breakfast before you go.
The castle is wonderful. We just walked around the grounds since it was a sunny day. The views from the grounds across Prague are amazing. We were lucky enough the see the changing of the guards which was a great experience.
It's important to note that the castle grounds are entirely free to visit. There are some areas you need a ticket to enter, but most of the castle grounds are free to visit. These areas include multiple courtyards, gardens, the Deer Moat, the entrance of St. Vitus Cathedral, and more.
The castle is among the most visited tourist attractions in Prague attracting over 1.8 million visitors annually.
IT IS INTERESTING: How much can international students earn in Czech Republic?
Current tenants Miloš Zeman (2013–present)
Construction started 870
Architect Matthias of Arras, Peter Parler
Full admission
Family admission
Prague Castle – Short Tour (Old Royal Palace, St. George's Basilica, Golden Lane & Daliborka Tower, St. Wenceslas Vineyard, Powder Tower) 250 CZK 300 CZK
'The Story of Prague Castle' Exhibition 140 CZK 200 CZK
Prague Castle Picture Gallery 150 CZK 200 CZK
Powder Tower 70 CZK 110 CZK
The Prague Castle grounds are open daily from 6 AM to 10 PM, however the monuments don't open until 9 AM. To avoid the overwhelming crowds of tourists and long security lines, we highly recommend getting there about 15 to 20 minutes before it opens (around 8:40 AM). You can enter the castle through the main entrance.
Today Prague Castle, besides being the seat of the head of state, is also an important cultural and historical monument. The Crown Jewels are kept at Prague Castle, as are the relics of Bohemian kings, precious Christian relics, art treasures and historical documents.
The clock stopped working many times in the centuries after 1552, and was repaired many times. … The last renovation of the astronomical clock was carried out from January to September 2018, following a reconstruction of the Old Town Tower.
The ceremonial Changing of the Guard including a fanfare and the flag ceremony happens daily at 12.00 noon in the first courtyard of the Castle. The sentries at the gates of the medival castle change on the hour from 07.00 to 20.00 in the summer season and from 07.00 to 18.00 in the winter season.
IT IS INTERESTING: Best answer: Is Czech Republic safe to study?
Tickets can only be purchased at the Information Centres of Prague Castle located in the second and in the third courtyards, in the Prague Castle Picture Gallery, in the Old Royal Palace, and at two ticket offices in the Golden Lane.
According to the Guinness Book of World Records, Prague Castle is the largest coherent castle complex in the world, with an area of almost 70,000 m². … Since the Velvet Revolution, Prague Castle has undergone significant and ongoing repairs and reconstructions.
You see, Prague has all the elements of great fairytale- cobblestone streets, alluring architecture, enchanting spires, and of course, a monumental castle. The tower at Old Town City Hall with Týn Cathedral in the background. Prague is indeed, a real life fairytale.
Following the dissolution of the monarchy, the Bohemian lands, now also referred to as Czech lands, became part of Czechoslovakia, and they have formed today's Czech Republic since 1993.
List of Bohemian monarchs.
Monarchy of Bohemia
Residence Prague Castle, Prague
Appointer Hereditary
The Castle of the Teutonic Order in Malbork (Polish: Zamek w Malborku; German: Ordensburg Marienburg) is a 13th-century Teutonic castle and fortress located near the town of Malbork, Poland. It is the largest castle in the world measured by land area and a UNESCO World Heritage Site.
IT IS INTERESTING: What is inside Prague Castle?
The currency in Prague is the Czech Crown (CZK). … Some hotels, shops and restaurants accept Euros as well, but many only take Czech Crowns.


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Please visit http://socialecology.uci.edu/newsletters/2011/summer.html to view the e-newsletter in your browser.
"Glacier Melt, Early Snowmelt and Sea Ice Melt"
Examining the implications for human security and ecosystem sustainability
UCI Medal
Honoring Social Ecology alum Manuel Gomez
Mentor Program Kick-Off Social
SE Alumni interested in becoming a mentor for 2011-12 can meet your student mentee.
For up-to-date information on all upcoming Social Ecology events, please visit: socialecology.uci.edu/events
The School of Social Ecology is on Facebook! Become a fan and keep up-to-date on the latest Social Ecology news and events.
The School of Social Ecology has just joined Twitter!
MFI Gift
We are pleased to announce a gift from Heritage Fields El Toro, LLC on behalf of Great Park Neighborhoods, Irvine's newest master planned community. This gift will launch the Metropolitan Futures Initiative (MFI), a research-based approach to analyzing key regional patterns, trends and challenges facing Orange County and the broader Southern California area. Learn More...
Building Better Communities
Professor Marlon Boarnet, Department of Planning, Policy and Design, is a nationally recognized authority on planning and policy issues at the intersection of economics, land use, and urban planning. He brings this valuable expertise to the Metropolitan Futures Initiative (MFI). View Social Ecology's latest video featuring Boarnet...
Loneliness: A Dilemma in Later Life
Karen Rook, Associate Dean of Research, School of Social Ecology and Professor of Psychology and Social Behavior, was featured in a recent edition of ZotZine. Professor Rook studies relationships and how they affect one's health and happiness. Her research has shed light on the psychological toll of loneliness on the elderly. Learn More...
Inspiration and Spirit
City of Irvine Mayor Sukhee Kang delivered the commencement address at the School of Social Ecology's Commencement Ceremony on June 11, 2011. Family members and friends filled the Bren Events Center, which included 715 students graduating with Social Ecology degrees. Dean Valerie Jenness and special guest Peter the Anteater led the students in a rousing "ZOT! ZOT! ZOT!" cheer. Learn More...
Faculty, Student and Alumni Accolades
Elizabeth Cauffman, Professor of Psychology and Social Behavior, was recognized as the School of Social Ecology's honoree for Excellence in Undergraduate Teaching. She was recognized at the annual Celebration of Teaching awards event in May. Learn More...
Henry Pontell, Professor of Criminology, Law and Society, received the Herbert Bloch Award for his outstanding contributions to the American Society of Criminology and to the professional interests in criminology. Learn More...
Roxane Cohen Silver, Professor of Psychology and Social Behavior, has been selected by the UC Irvine Institute for Clinical and Translational Science (ICTS) as one of the recipients of the inaugural Faculty Mentor-Mentee Awards for 2011. Learn More...
View More Faculty and Student Accolades
Student Awards Ceremonies:
Social Ecology students gave us many reasons to celebrate the 2010-11 school year, including their accomplishments in research, community service and academic achievement.
PPD Lecture by Larry Webb:
Larry Webb, Partner and CEO of The New Home Company, was the featured speaker on April 29, 2011. This event was co-hosted by the Department of Planning, Policy and Design Advisory Board and the Center for Real Estate at the Paul Merage School of Business. Webb spoke about his 30 years of homebuilding experience along with his philosophy on urban planning.
Human Security Award:
On May 4, 2011 Alexandra Cousteau, founder of the nonprofit Blue Legacy, was the recipient of the 2011 Human Security Award from the Center for Unconventional Security Affairs. She was honored for her efforts to use new technology to raise awareness of watershed issues.
Building Resilient Neighborhoods
Dan Immergluck, Professor of City and Regional Planning at Georgia Tech University, was the featured speaker on May 4, 2011. This event was part of the Metropolitan Futures Initiative and was co-sponsored by MFI, School of Social Ecology, Community Outreach Partnership Center and the Center for Community Development Studies. Immergluck presented on the policies and systems for responding to foreclosures and the housing market stress.
TEDx-Richard Matthew
Richard Matthew, Professor of Planning, Policy and Design and Director of the Center of Unconventional Security Affairs, spoke at a sold-out Orange County TEDx conference at the Segerstrom Concert Hall on May 19, 2011. TED's mission is "ideas worth spreading." The TEDx program is designed to stimulate dialogue through TED-like experiences at the local level. Orange County's theme was "Innovation Without Borders."
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The 34th Annual Buddy Holly Dance February 9th at the Dubuque County Fairgrounds.
Dance to your favorite hits of the 50's from 7pm till 11pm.
Peggy Sue look-a-like contest to win a wood rocker from Banworth and Udelhoven Furniture. The best dressed couple in the 50's style contest wins a summer midweek sneak away from Chestnut Mountain.
Tickets available at the fairgrounds and from any East Dubuque VFW member.


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2N3904 * MMBT3904 * * PZT3904 PD Total Device Dissipation Derate above 25° C 625 5. 0 mW mW/ ° C RθJC Thermal Resistance, Junction to Case 83. 3 ° C/ W RθJA Thermal Resistance, Junction to Ambient° C/ W * Device mounted on FR- 4 PCB 1. Request Motorola MC2830P: Voice Activated Switch online from Elcodis, view and download MC2830P pdf datasheet, Transistors ( BJT) - Single specifications. 2N3904 NPN Silicon Transistor Descriptions • General small signal application • Switching application.
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The characterization of induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) routinely includes analyses of chromosomal integrity. The belief is that pluripotent stem cells best suited to the generation of differentiated derivatives should display a euploid karyotype; although, this does not appear to have been formally tested. While aneuploidy is commonly associated with cell transformation, several types of somatic cells, including hepatocytes, are frequently aneuploid and variation in chromosomal content does not contribute to a transformed phenotype. This insight has led to the proposal that dynamic changes in the chromosomal environment may be important to establish genetic diversity within the hepatocyte population and such diversity may facilitate an adaptive response by the liver to various insults. Such a positive contribution of aneuploidy to liver function raises the possibility that, in contrast to existing dogma, aneuploid iPSCs may be capable of generating hepatocyte-like cells that display hepatic activities.
We examined whether a human iPSC line that had multiple chromosomal aberrations was competent to differentiate into hepatocytes and found that loss of normal chromosomal content had little impact on the production of hepatocyte-like cells from iPSCs.
iPSCs that harbor an abnormal chromosomal content retain the capacity to generate hepatocyte–like cells with high efficiency.
The availability of human pluripotent stem cells has provided a cell culture platform for study of human disease and development. Pluripotent cells could also potentially be used therapeutically as a source of cells for transplant or drug discovery. Moreover, the finding that patient–specific pluripotent cells can be relatively easily generated by molecular reprogramming raises the prospect of using personalized regenerative medicine to treat a variety of diseases, arguably without fear of immune rejection[2, 3]. While the biomedical potential of pluripotent stem cells is irrefutable, to realize such potential requires an in depth understanding of the fundamental properties and complications that are associated with genomic changes that accompany the reprogramming process. Many studies have revealed that, as a consequence of reprogramming and stem cell culture, genetic instability commonly occurs. The genetic variations that have been observed are diverse and include copy number variations (CNVs), chromosomal rearrangements, and several sub-chromosomal mutations including deletions and point mutations[5–10]. For pluripotent cells to be used safely in regenerative medicine, substantial characterization would therefore be necessary to ensure the genomic integrity of transplantable cells.
Although it is clear that iPSC–derived cells used for cell therapy should be euploid due to the need for safety, how chromosomal variation affects the production of differentiated cells in culture remains ill defined. Cell differentiation is an orchestrated process that relies on complex extracellular signals coupled with epigenetic and genetic responses, which establish transcription factor networks that drive cell fate. With this in mind it would seem intuitive that aneuploid genomes would be detrimental to the differentiation of a specific cell type. However, analyses in both mice and humans have shown that, unlike most somatic cells, the chromosomal content of proliferating hepatocytes is diverse and that aneuploidy is commonly observed[11, 12]. In liver damage models it has been established that changes in chromosomal content are dynamic with cells constantly gaining and losing chromosomes. This dynamic nature of chromosomal imbalances found in hepatocytes has been referred to as the 'ploidy conveyer' and it has been hypothesized that the conveyer may facilitate an adaptive response of hepatocytes to noxious environments. With this model in mind, it is formally possible that hepatic function may best be recapitulated if hepatocytes are generated from iPSCs that display genomic variation. The generation of polyploidy in rodent hepatocytes begins after weaning and increases as the animals age; however, the impact of aneuploidy on hepatocyte differentiation is unknown. We, therefore, addressed whether hepatocyte-like cells could be generated from iPSCs that are karyotypically abnormal.
We have previously described the generation of a human iPSC line, referred to as iPSC-K3, which was produced by reprogramming foreskin fibroblasts using transient transfection of plasmids that express OCT4, NANOG, LIN28, and KLF4. These iPSCs are free of integrated exogenous DNA and have a high capacity to differentiate into cells that display characteristics of hepatocytes. The iPSC-K3 cells maintain a stable karyotype; however, as with all human pluripotent stem cells, colonies spontaneously arise that contain chromosomal variations that presumably support their efficient proliferation in culture.
During routine analyses of a subculture of iPSC-K3 cells we identified a cell line that was extensively aneuploid (Figure 1 and Table 1). In this culture, the majority of the cells approached a tetraploid state, but included both gain and loss of discrete chromosomes as well as chromosomal rearrangements. The composite karyotype of the line, determined by examination of 19 cells with consistent abnormalities, is XXYY,-3,-6,-7,-8,-11,+12,-13,-14,-15,-16,-17,dup(17)(q11.2q25)ins(17)(q25;q25q11.2),-18,-19,-22. These 19 cells contained 79 ~ 87 chromosomes per cell and the frequency of a given chromosomal imbalance is indicated within the square brackets ([n]). The major chromosomal imbalances observed were a gain of chromosome 12 and loss of chromosomes 3, 6, 7, 8, 11, 13, 14, 15, 16, 17, 18, 19 and 22. In addition, in all 19 cells we observed an unbalanced structural abnormality of chromosome 17 that represented a gain of long (q) sequences from chromosome 17 (dup(17)(q11.2q25)ins(17)(q25;q25q11.2)). Rearrangements of chromosome 17 have been commonly found in both human ESCs and iPSCs and are believed to confer advantageous growth in culture. Although all cells examined were abnormal not all cells contained every observed rearrangement. Chromosomal imbalances found in a minority of cells included loss of chromosomes 7, 13, 14, 18, and 22, raising the possibility that the culture arose from a mixed population. However, given that all cells approached tetraploidy, we favor an alternative explanation in which the cells originated clonally from a single tetraploid event and subsequently diverged in culture. Figure 1 shows karyograms of the parental iPSC-K3 line and a single cell from the aneuploid iPSC-K3 (iPSC-K3aneuploid) derivative that contains the majority of the chromosomal abnormalities that were identified and Table 1 describes the frequency of each abnormality. In addition to the majority of the cells that displayed a shared karyotype, a single non-clonal cell was identified with the karyotype 66,XXY,+1,+2,-3,+4,+5,+9 + 12,-14,-15,-16, dup(17)(q11.2q25)ins(17)(q25;q25q11.2),-19,-19,-21,-21,-22.
Characterization of iPS cells with abnormal karyotype. A) Control iPSC-K3 cells were generated from human foreskin fibroblasts and have a normal diploid male (46, XY) karyotype. B) A sub-line of iPSC-K3 cells, referred to as iPSC-K3aneuploid, have an abnormal near-tetraploid karyotype as well as rearrangements in chromosome 17 (red arrow). The karyogram presented here is representative of the cells analyzed. C) Left panel shows a phase contrast micrograph of iPSC-K3aneuploid cells in culture. Immunocytochemistry revealed the presence of OCT4 (middle panel) and DAPI was used to identify cell nuclei. Scale bar = 100 μm. D) FACS analysis reveals that iPSC-K3aneuploid cells do not express a marker of differentiated cells, CD13 (left panel); however, pluripotent markers SSEA-4 (middle panel) and Tra-1-81 (right panel) are expressed on the surface of 99% and 96% of the cells, respectively. Isotype controls for each antibody are indicated by the red line, antibodies by the blue line.
Despite the abnormal karyotype, the iPSC-K3aneuploid cells formed colonies that displayed a morphology that is characteristic of human pluripotent stem cells and immunocytochemistry revealed that the majority of cells within the colonies expressed the pluripotency marker OCT4 (Figure 1C). In addition, FACS analyses revealed that close to all of the cells in the culture expressed the pluripotent cell surface markers SSEA-4 (99%) and Tra-1-81 (96%), but not the fibroblast marker CD13 (Figure 1D).
To determine whether iPSCs harboring chromosomal variation could form hepatocyte–like cells in culture, we subjected iPSC-K3aneuploid cells to culture conditions that we have previously demonstrated generates iPSC–derived cells with hepatocyte characteristics (http://www.stembook.org/node/721). The differentiation process was observed by following the expression of markers that reflect specific stages of hepatocyte differentiation by immunocytochemistry. Figure 2 shows that prior to the initiation of differentiation the cells expressed proteins associated with pluripotency including OCT4, whereas markers expressed in differentiated cells, such as SOX17 were not detected (Figure 2, Day 0). To generate definitive endoderm, Activin A, BMP4, and FGF2 were added to the culture during the first two days of differentiation, then Activin A alone was included for a subsequent 3 days. At this stage nearly all the cells expressed FOXA2 and SOX17, both of which are robustly expressed in the definitive endoderm (Figure 2, day 5). To generate hepatic progenitor cells, Activin A was removed from the medium and replaced with BMP4 and FGF2. After 5 days in culture nearly all of the cells expressed HNF4a, which is a transcription factor that is expressed in hepatic progenitor cells and is essential for their differentiation to hepatocytes (Figure 2, day 10). At this stage, some cells also began to express low levels of alpha-fetoprotein (AFP), which is another marker of the early hepatic lineage. After the addition of HGF for a further 5 days, which induces the hepatic progenitors to differentiate into fetal hepatocytes, the cells continued to express HNF4a and the cells increased expression of AFP, which became easily detected in nearly all of the cells in the culture (Figure 2, day 15). These fetal hepatocyte–like cells were then cultured for a further 5 days in Hepatocyte Culture Media supplemented with Oncostatin M. By completion of the protocol, nearly all of the cells expressed Albumin (Figure 2, day 20). During the differentiation process the morphology of the cells changed to eventually adopt a cuboidal appearance, with a high cytoplasmic to nuclear ratio, and evidence of glycogen granules and lipid vesicles observed in the cytoplasm (Figure 2). We confirmed that the differentiated cells retained an aneuploid phenotype by performing karyotype analyses after the completion of the differentiation protocol. As expected, the differentiated cells exhibited a low mitotic index, and very few cells were in metaphase at the time of cell harvest. A total of four metaphase cells were recovered; however, the chromosome morphology was poor and so we were unable to perform a thorough g-band analysis. Nevertheless, the chromosomal content of these cells was polyploid and the cells appeared to have a structural abnormality tentatively associated with chromosome 17.
Generation of hepatocyte–like cells from iPSC-K3 aneuploid iPSCs. The top row of panels shows phase contrast microscopy revealing the changes in morphology that accompany each stage of differentiation. Remaining panels document the result of immunocytochemistry performed on the cells to detect proteins that are characteristically expressed at specific stages of development. At day 0, prior to adding differentiation media or growth factors, the cells express OCT4, a marker of pluripotent cells, but do not express SOX17. At day 5, the cells have formed definitive endoderm, as seen by expression of the endodermal transcription factors FOXA2 and SOX17. At day 10, HNF4a, which is highly expressed in hepatic progenitor cells, can be identified in the majority of cells in the culture. At the same stage, low levels of AFP, a fetal hepatocyte marker, can be identified in a subset of cells. By day 15, almost all cells robustly express AFP indicating that they are forming immature hepatocytes. By the end of the protocol most cells express Albumin, which is highly expressed in adult hepatocytes. Scale bar = 100 μm.
To gain a better understanding of the efficiency of differentiation we used qRT-PCR to determine the relative levels of several hepatic mRNAs in primary human hepatocytes and hepatocyte-like cells derived from either control iPSC-K3 or from iPSC-K3aneuploid cells in independent differentiations (n = 5). As shown in Figure 3, the levels of APOA1, APOB, CPS1, CYP1A1, FGA, FGG, GSTA1, HGD, HNF1A, HNF4A, LXR, RXR, SERPINA1, SLC10A1, TF, and TTR mRNAs could be detected in all cell types. Although significant differences (p ≤ 0.05) in the levels of a subset of hepatic mRNAs were observed between the different lines, the hepatocyte–like cells derived from iPSC-K3aneuploid cells exhibited an overall expression profile that was very similar to the parental cells. As we have described previously all iPSC–derived hepatocytes also retained expression of some fetal mRNAs including AFP and a number of mRNAs that are normally expressed in mature hepatocytes, including CYP3A4, were undetected in both control and iPSC-K3aneuploid hepatocyte–like cells (data not shown).
Expression of hepatic mRNAs following differentiation iPSC-K3 aneuploid cells. Bar graph showing the relative levels of characteristic hepatic mRNAs identified by qRT-PCR in fresh human hepatocytes and in hepatocyte–like cells derived from iPSC-K3aneuploid (red bars) and control iPSC-K3 (parental; blue bars) cells. The level of mRNAs detected in primary human hepatocytes was set to 1 (black dashed line). Specific mRNA levels in all other samples are presented relative to primary human hepatocytes. Error bars represent the standard deviation recorded from five (n = 5) independent differentiation experiments and p ≤ 0.05 was considered significant (*).
The identification of proteins and mRNAs that are normally expressed during normal hepatocyte differentiation suggested that aneuploidy did not have a substantial impact on formation of hepatocytes from iPSCs. However, we recognized that this was a limited set of markers and so felt that it was important to determine whether the differentiated cells displayed activities that are normally associated with both primary hepatocytes and hepatocyte–like cells derived from euploid iPSCs[14, 13]. The ability to store glycogen was assessed by Periodic Acid Schiff staining of cells (Figure 4A), oil red O staining revealed the presence of lipid droplets within the differentiated cells (Figure 4B), the cells were capable of the uptake of Indocyanine Green (Figure 4C), and incubation with fluorescently labeled low-density lipoprotein demonstrated the ability of the differentiated cells to uptake LDL (Figure 4D). Finally, we analyzed the supernatant in which the differentiated cells were cultured and observed that the iPSC-K3aneuploid derived cells effeciently secreted Albumin (Figure 4E) at levels that were statistically indistinguishable from the iPSC-K3 derived cells. From these data, we conclude that the aneuploid status of the iPSC-K3 cells does not hinder their ability to differentiate into hepatocyte-like cells.
Identification of basic hepatocyte functions in cells derived from iPSC-K3 aneuploid cells. Top panels show bright-field images with their corresponding phase contrast images below; scale bar = 100 μm. (A, A') iPSC-K3 derived hepatocytes are capable of storing glycogen as shown by periodic acid-Schiff staining. (B, B') Oil Red O staining demonstrates the cells' ability to store lipids. (C, C') Cells can take up indocyanine green. D) Differentiated cells were incubated with fluoresceinated low-density lipoprotein to demonstrate their ability to internalize LDL. The corresponding DAPI image is seen in the right panel. E) Bar graph showing levels, measured by ELISA, of human Albumin secreted into the culture medium from hepatocyte–like cells derived from either parental iPSC-K3 or iPSC-K3aneuploid cells. Error bars represent the standard deviation recorded from three (n = 3) independent differentiations and no statistically significant difference in Albumin levels (p = 0.45) was observed.
In the current study we have shown that cells with hepatocyte characteristics can be generated from iPSCs that harbor a severely abnormal chromosomal state. Although from a developmental perspective the successful directed differentiation of aneuploid iPSCs may seem surprising, the cells used in the current study retained representative loci from all chromosomes, albeit in an unbalanced state. It is likely that as regulatory networks are established during differentiation they stabilize through cross-regulation and so chromosomal imbalances may have little impact when cells are differentiated in culture. The iPSC-K3aneuploid line also has a heterogeneous karyotype and the observed chromosomal abnormalities likely reflect the selective pressure of the culture environment. If a specific chromosomal arrangement were detrimental to cell viability or proliferation it would be lost during the culture of the pluripotent cells and if it were detrimental for hepatocyte formation it potentially could be selected against during the 20–day differentiation process.
Although in general it would be deemed prudent to ensure pluripotent stem cells retain a normal karyotype, it is possible that for some applications aneuploid cells could offer advantages. Indeed cancer cells with abnormal karyotypes have been used extensively for the study of cell function and activity because they can be easily grown in culture. Since iPSCs with abnormal karyotypes often grow robustly in culture they could be useful for applications that require large numbers of cells, such as drug screening and biochemical applications, especially if sub-lines can be identified that differentiate particularly well as a consequence of the chromosomal environment. In addition, comparative analyses between parental cells and aneuploid derivatives may be useful for the identification of loci that confer specific functional phenotypes, especially as they relate to cell growth. In the case of hepatocytes this may be particularly relevant given the variation in ploidy that is observed in adult hepatocytes and the potential contribution of ploidy to hepatocyte function.
To conclude we have demonstrated that a human iPSC line that has extensive chromosomal abnormalities retains the ability to differentiate into cells that display hepatocyte characteristics. These data demonstrate that there exists considerable flexibility in the chromosomal content that is compatible with differentiation of pluripotent cells to the hepatocyte lineage.
Human iPSCs (iPSC-K3) were routinely cultured under low oxygen conditions (4% O2/5% CO2) in hES cell media (DMEM/F12 medium supplemented with 20% knockout serum replacement (Invitrogen), non essential amino acids (Invitrogen), glutamine (Invitrogen), penicillin/streptomycin (Invitrogen) and zbFGF (4 ng/ml)) on mitotically inactivated mouse embryonic fibroblasts (MEFs). Alternatively, cells were cultured on a recombinant E-cadherin-IgG Fc fusion protein matrix (StemAdhere, Primorigen Biosciences, Inc) in MEF-conditioned hES medium or mTeSR. When cultured on E-cadherin-IgG Fc, cells were passaged every 4–5 days by non-enzymatic methods using Versene/EDTA. All work carried out using human pluripotent stem cells was approved by the MCW Human Stem Cell Research Oversight Committee (hSCRO approval# 09–005) and all work performed using animals was approved by the MCW IACUC.
Pluripotent cells were differentiated as discussed previously[14, 18]. Briefly, pluripotent cells cultured on E-cadherin-IgG Fc were harvested using Accutase (Millipore) and plated onto 6-well tissue culture-treated plates pre-coated with 2 mg/ml Matrigel (Geltrex; Invitrogen). Typically, one 100 mm dish of cells cultured on E-cadherin-IgG Fc provided enough cells for 2 wells of a 6-well plate. Approximately 24 hours after seeding the cells onto Matrigel, when the cells were 85-95% confluent, differentiation was initiated by culture for 5 days with 50 ng/ml Activin A (R&D Systems) in RPMI/B27 (without Insulin) supplement (Invitrogen) under ambient oxygen/5%CO2. In addition, we included 10 ng/ml BMP4 (Peprotech) and 20 ng/ml FGF-2 (Invitrogen) for the first 2 days. This resulted in reproducible differentiation into definitive endoderm at efficiencies of greater than 80%. Cells were cultured for 5 days with 20 ng/ml BMP4 (Peprotech)/10 ng/ml FGF-2 (Invitrogen) in RPMI/B27 (containing Insulin) under 4%O2/5%CO2, then 5 days with 20 ng/ml HGF (Peprotech) in RPMI/B27 (containing Insulin) under 4%O2/5%CO2, and finally for 5 days with 20 ng/ml Oncostatin-M (R&D Systems) in Hepatocyte Culture Media (Lonza) supplemented with SingleQuots (without EGF) in ambient oxygen/5% CO2.
Pluripotent cells were cultured in T25 flasks coated with Matrigel in MEF-conditioned media for 2–3 days. Cells were transported to WiCell Research Institute (Madison, WI), who performed cell harvest and karyotype analysis of metaphase chromosomes using G-banding. For karyotype analysis of iPS cell-derived hepatocytes, cells were differentiated on 6-well tissue culture dishes coated with Matrigel. After three days of culture in Hepatocyte Culture Medium and Oncostatin M, cells were sent to WiCell Research Institute (Madision, WI) for cell harvest and analysis.
Total RNA was collected from cells at each stage of the differentiation using the RNeasy Mini Kit (Qiagen). Contaminating genomic DNA was removed using 1 μl of RNase-free DNaseI per 5 μg RNA. First strand cDNA was synthesized using MMLV-RT with dNTPs and random hexamer primers. Taqman-based qRT-PCR assays (PrimeTime) were obtained from IDT (Table 2) and PCR performed using an Applied Biosystems StepOnePlus™ Real-Time PCR System. All data were collected from reactions performed in triplicate.
Concentration of human albumin in cell culture supernatant was measured using the Human Albumin ELISA Quantitation Set (Bethyl; E80-129) according to the manufacturer's instructions. Absorbance (OD) was read on a plate reader within 15 minutes at 450 nm. Raw values were converted to concentration based on the standard curve for each experimental run using ReaderFit (http://www.readerfit.com).
For glycogen detection, differentiated cells were fume-fixed by adding 1 ml PBS with calcium and magnesium to each well and 4% paraformaldehyde in the spaces between the wells. Fixation occurred by incubation at 37°C for 1 hour. Cells were permeabilized with 0.4% Triton X-100 in PBS for 20 minutes at room temperature. Control cells were incubated with Diastase (1 mg/ml in PBS; Sigma) for 1 hour 37°C. Cells were then incubated with Periodic acid (0.5 g dissolved in 100 ml nano-pure water) for 5 min at room temperature, washed with distilled water and incubated with fresh prepared Schiff's reagent for 15 min.
LDL uptake assays were performed as previously described, based on published protocols[20, 21]. At the end of the differentiation protocol, cells were washed 3 times with ice-cold PBS, then incubated in ice-cold Hepatocyte Culture Media containing 5 μg/ml BODIPY® FL LDL (Invitrogen) for 3.5 hours at 37°C. Unbound LDL was rinsed away with 5 mg/ml heparin in PBS before imaging.
Cellular uptake of indocyanine green (Cardiogreen; Sigma) was performed using indocyanine green at 1 mg/ml diluted in Hepatocyte Culture Medium (stock is 5 mg/ml reconstituted in water, stable for up to 8 hours). Differentiated cells were incubated for 1 hour at 37°C and rinsed three times with PBS before imaging.
For the detection of lipid accumulation, differentiated cells were fixed with 4% paraformaldehyde in PBS for 20 minutes at room temperature, washed twice with nano-pure water for 5 minutes, then washed with 60% 2-propanol for 5 minutes. Cells were then incubated for 20 min at room temperature with a freshly prepared working solution. A 0.5% stock solution of Oil Red O was prepared by dissolving 0.05 g in 100 ml 2-propanol and incubating at room temperature overnight. The working solution contained 60% Oil Red O stock solution and 40% water, which was allowed to stand for 20 minutes at room temperature and then passed through a 0.20 μm filter before using. Cell nuclei were then counterstained with hematoxylin.
Cultured cells were fixed with 4% paraformaldehyde for 20 min at room temperature, made permeable with 0.4% Triton X-100 in PBS for 15 min and blocked with 3% BSA in PBS for 1 hour. Cells were incubated overnight at 4°C with primary antibodies diluted in 1% BSA in PBS. Primary antibodies used were Oct3/4 (Santa Cruz; rabbit, 1:500), Sox17 (R&D Systems; goat, 1:250), FoxA2 (Novus Biologicals; Mouse, 1:1000), HNF4a (Santa Cruz; goat, 1:250), AFP (Sigma; mouse, 1:1000), and Albumin (DAKO; rabbit, 1:500). Primary antibodies were probed with respective secondary antibodies conjugated to Alexa Fluor 488 or 594 (Molecular Probes; 1:1000) and nuclei were visualized with DAPI.
Pluripotent iPS cells grown on E-cadherin-IgG Fc were removed from the plate by incubating with Accutase (Millipore) for 3 minutes at room temperature. Cells were blocked with 10% FBS (Gibco) in 1XPBS on ice for 15 minutes, then labeled with antibodies conjugated to fluorophores diluted 1:20 in 1% FBS (100 μl total) on ice for 20 minutes. Cells were washed with 1% FBS and resuspended in 1% FBS for analysis. Antibodies used were mouse anti-human CD13-488 (AbD Serotec), mouse anti-human SSEA-4-PE (Millipore FlowCellect), and mouse anti-human Tra-1-81-PE (Millipore FlowCellect). Unstained cells and cells stained with the appropriate fluorophore-conjugated isotype were used as controls.
Fallon K Noto, Megan R Determan contributed equally to this work.
This work was supported by gifts from the Marcus Family, the Phoebe R. and John D. Lewis Foundation, the Sophia Wolf Quadracci Memorial Fund, the Dr. James Guhl Memorial Fund, the Advancing a Healthier Wisconsin Fund, and by NIH grants DK55743, HG006398 and HL094857 (to SAD), DK091994 (to MAC), AA019874 (to FKN), DK098926 (to MRD) and a JDRF Fellowship 3-2010-497 (to JC).
FKN: Contributed to experimental design, performed the majority of experiments and wrote draft of manuscript. MRD: Performed cell differentiations, qRT-PCR analyses, contributed to FACS studies and generated figures. JC: Contributed to qRT-PCR experiments. MAC: Performed LDL uptake assays. SKM: Performed albumin ELISAs. SAD: Contributed to experimental design, oversight of experiments performed, data interpretation, and wrote final version of manuscript. All authors read and approved the final manuscript.


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Cover letters come in various shapes and sizes, and they might be designed according to the nature of the letter and the position or rank of the addressee. Thus, a graphic design cover letter is used to aesthetically appeal to the reader and allowing them to immerse themselves into the contents of the cover letter so that they would be able to have a look at the job application. Here is a list of Sample Cover Letters.
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If you are an applicant who is looking for a job, then these sample graphic design cover letters are for you. The most important step for being successfully recruited is to catch the recruiter's attention towards your application and creating a favorable first impression in their minds. And for that, it becomes necessary to know how well you should be able to design and embellish the cover letter you are going to send. As much as the content, the design and aesthetics of the Cover Letter equally matter as far as impressing the recruiter is concerned. A good cover letter thus should look attractive.
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Just One Damned Thing After Another by Jodi Taylor
By Doug Merrill in Alternate History, Doug, Science Fiction
Here's a cure for excessively serious or positively ponderous. In Just One Damned Thing After Another, Jodi Taylor took a premise that's been used numerous times before — history as a practical academic discipline, aided and abetted by time travel — and simply wrote the hell out of it. St. Mary's Institute of Historical Research is an out of the way annex of Thirsk University, somewhere in the UK, and they definitely do not do time travel. As the director puts it, "We investigate major historical events in contemporary time." (p. 11, emphasis in the original) And the first-person narrator, Dr. Madeleine Maxwell, thinks to herself, "Put like that, of course, it all made perfect sense."
That handwaving is as close as Taylor gets to explaining how the historians' traveling machines work, which is to say not at all. She doesn't care, because this isn't the kind of book that looks at physics too closely, or carefully examines the implications of a technology that allows transportation through time and space, or that charts in exquisite detail the consequences of undertaking numerous hazardous missions with high casualty rates. This is the kind of book that in just over three hundred pages sends its major characters to the Western Front of World War I, to an unknown but predator-filled location in the Mesozoic, and to the very flames of the Library at Alexandria.
Maxwell has an unhappy family history that is never explained, but which leaves her unattached in the present; she has advanced training in history and archeology, which give her the skills and mindset for a hands-on approach to history. Together, they produce a devil-may-care approach that suits the book's madcap pace. Then there's her penchant for risk-taking or, as she puts it in her internal narration of a most unusual job interview, "Thinking carefully is something that happens to other people." (p. 10)
While many laws of physics are waved away for the sake of the story, there is something of a law of conservation of history. Or History, as the director of St. Mary's puts it.
"Think of History as a living organism, with its own defence mechanisms. History will not permit anything to change events that have already taken place. If History thinks, even for one moment, then it will, without hesitation, eliminate the threatening virus. Or historian, as we like to call them." (p. 12)
So there's dangerous but exciting work. Naturally there's a team of people eager to do it, and a supporting cast that's also full of quirks and striking personalities. The security team is particularly striking, but usually give fair warning when they are about to do it.
The new historians are put through rigorous training before they can be trusted to accompany more senior members on any missions.
"Wednesday was [the] Self-Defence [examination]. I made no headway at all with Weasel as he none too gently chucked me around all over the place, grinning his stupid head off all the time. I waited until a particularly heavy fall then placed my hand on my lower stomach, curled into a ball and uttered, 'Oh God, the baby!'
"Weasel stopped dead, saying 'What …?' and I hacked his legs out from underneath him, leaped to my feet, ran across his chest, and rang the bell, which was the whole point of the exercise. Weasel shot me a filthy look and, at this point, there was no scribbling [on the examiners' clipboards] at all. Major Guthrie threw down his clipboard and walked off.
"'Oh dear,' said to a watching Murdoch.
"'No, you're OK. He's gone round the corner where no one can see him laugh.'" (pp. 32–33)
The pace isn't much slower anywhere in the book, and it's so full of life that it's a joy to read from start to finish. Plus it's a cracking good adventure story because not only does History itself resent intruders from one part in another, the Institute has enemies within the University (disproving the old adage about stakes being low in academic politics), and not everyone within the Institute is a reliable as they first appear. Taylor pulled out all the stops, but, improbably, there are now at least six sequels in the chronicles of St. Mary's. One damned thing after another.
Alternate History, Doug, History Has Its Eyes On You, Jodi Taylor, Science Fiction, Sufficiently Advanced Technology
Writer, editor, translator, project manager, reformed bookseller. Currently based in Berlin, following stints in Moscow, Tbilisi, Munich, Washington, Warsaw, Budapest and Atlanta. Also blogs at A Fistful of Euros, though less frequently than here these days.
Permanent link to this article: http://www.thefrumiousconsortium.net/2019/06/13/just-one-damned-thing-after-another-by-jodi-taylor/


The characean internode has been established as a valuable experimental system for investigating local wound responses. The cells readily react to injury by exocytosis of wall material. The structure, chemical composition and the function of the wound wall vary according to the type of wounding (light, chemicals or mechanical injury) and to the extent of damage. We are especially interested in the reorganization of the cytoskeleton, in actin-microtubule interactions, and in visualizing exocytotic stages in living cells. The results obtained with characean algae are compared with wound responses and defence mechanisms in other plant cells.
Cortical and subcortical endoplasmic reticulum (ER) in internodal cells are separated from each other by a layer of stationary chloroplasts. The inner ER tubes are coated with myosin molecules which generate cytoplasmic streaming by interaction with subcortical actin filament bundles. In contrast to this fast moving system the cortical ER forms a more stable meshwork close to the plasma membrane. We showed recently that the morphology and dynamics of this cortical ER depends on interaction with microtubules during early stages of cell elongation. We currently investigate how the microtubule-dependent dynamics of the cortical ER affects the deposition of cellulose microfibrils.
The surface of internodal cells is characterized by alternating bands of acid and alkaline pH which differ in photosynthetic activity in spite of a homogenous distribution of chloroplasts. The pH banding pattern is reflected by spatiotemporal variations in the number and density of cortical mitochondria required for recycling and detoxification of photosynthetic metabolites. The uneven distribution of mitochondria is controlled by interaction with cortical actin filaments and microtubules. Dual interaction with both fibrillar systems also determines the dynamic morphology of giant mitochondria formed in thalli grown under low light conditions. Current research focuses on the identification of signalling pathways between chloroplasts, cortical cytoskeleton and mitochondria.
The plasma membrane of characean internodes contains discrete plasma membrane domains, up to 3 µm in diametre, which can be stained with FM-dyes and with filipin suggesting that they are enriched in sterols. These plasma membrane domains are heterogeneously distributed over the cell surface and are especially abundant in internodal cells of the genus Chara. We investigate their possible involvement in the pH-banding pattern and in endocytosis.
We combine light and electron microscopical techniques with immunocytochemistry, perfusion and microinjection.


text:
A weekend celebrating the 75th anniversary of St. Joseph's House. And remembering Tanny in Washington Square Park.
Posted by [email protected] | Sep 23, 2016 | Events of the Day, Social Issues | 0 |
Washington Square Park, 9/23/16
On the Homeless March, 9/23/16
This weekend will be a joyous one for St. Joseph's House of Hospitality. Celebrating its 75th anniversary, St. Joe's will be alive with fellowship, meals, memories, gospel music and dancing. Martha Hennessy, the granddaughter Dorothy Day, co-founder of the Catholic Worker, will be in town from Vermont. Along with Father Larry Tracy, Father Bob Wirth — who I am told is quite a hoot — will be celebrating Mass in the parking lot under the tent.
Today, the weekend began on a somber note reminding us of the challenges faced when serving the homeless. From about 9-10:30am, about 50 people — a mix of homeless people, providers and church activists — joined in a Homeless March from the St. Joe's Parking lot to a protest rally in Washington Square Park.
Passing a few places where people experiencing homelessness sleep, the march and rally raised awareness about both the plight of the homeless and what is being done to help.
The event was also the occasion to remember a man only known as Tanny — and the other Tanny's still living as Tanny once did.
The notice ends that no foul play was suspected and police are investigating. Rochester Democrat and Chronicle, June 18th, 2015
As explained to me by Andrew Carey (who you've met before) and Nicholas Coulter (who you've met before), a few years ago a man evicted from his apartment took up refugee in the wooded area behind the Rochester Psychiatric Center on Elwood Avenue. Living in a small tent, the man remained hidden for perhaps two years. People in the human services community had heard vague rumors about Tanny's existence, but next to nothing was known beyond his name.
Nick Coulter in front
Tanny's belongings. 9/23/16 [Photo provided by James Murphy]
In June 2015, Tanny was found dead, much of his life still a mystery. After his death, Tanny's meager belongings were left in his encampment. This morning before the march, James Murphy and a few others retrieved what was left of Tanny's possessions. The items were placed in a coffin, carried from St. Joe's to Washington Square Park.
At the rally Tanny was remembered as speakers discussed homelessness in general, protesting against social conditions like poverty and discrimination that leave a sizable proportion of our population always at risk for homelessness.
As Nick and I talked, he noted the irony that Tanny lived in his isolated tent right in an area surrounded by social service organizations like the RPC, the Veteran's Administration and Department of Human Services offices on Westfall, and the Al Sigl Center just down the road on Elmwood.
Nick emphasized the point of the ceremony was not to say that social services should be necessarily seen as inadequate or ineffective.
Instead, for Nick, Tanny represents some of the most challenging cases of homelessness, of which Tanny was one of many in the Rochester area. The message is that people like Tanny need to be actively sought out. We — providers like Nick and Andy and the whole community — can't sit back waiting for people like Tanny to find help. We need to find them.
Activist Emily Good was also at the rally.
Nick knows that Tanny faced severe obstacles, like many homeless who have fallen through the cracks in the system. Remembering Tanny reminds us that reaching out to those most alone is both our hardest duty and highest reward.
I also spoke with Pastor Jeannine Zona, a lay leader at The Pillar church across the from St. Joes. Jeannine says one of her church's missions is to build friendships and provide spiritual care to people living at St. Joe's. Jeannine praised St. Joe's for its shelter-first model. Along with offering meals and services, St. Joe's goals is for clients to make St. Joe's their official address, their actual home. For example, without an address, homeless people can't get jobs. As Jeannine says, having a home — not a tent in the woods off Elmwood Ave — is the first step to getting back on one's feet.
View of the rally from the Soldier's and Sailor's Monument
On the march, I met Thomas and Crystal. They had seen the marchers on South Avenue. When they heard what the event was all about, Thomas, Crystal and new family member joined in. Near Washington Square Park, some construction workers wondered who the marchers were. When I explained, they nodded in approval, saying at some point in their lives, everybody needs some help.
Below is a video Nick took recently of Tanny's possessions that had lain in the woods for over a year.
https://talkerofthetown.com/wp-content/uploads/2016/09/My-Movie2.mp4
Cheese, pepperoni and hope in Nathaniel Rochester Square.
The Cobb's Hill tragedy of an "invisible man" ten years later
Love and Hope in the Rochester Subway
Why did the Faith Temple in Brighton give away free stuff?
PreviousFDR's first visit to Rochester as a national candidate, September 23rd, 1920 and the League of Nations.
NextA Rochester that I Know
Assault on Capitol is not about Black Lives Matter
Choosing Love Over Hate: Radical Acceptance in the Age of Trump
School Resource Officers do more than protect
Rethreading the Web: Catherine Keller and the Theology of Entangled Difference: A Report from the Hickey Center's Annual Sacred Texts and Human Contexts Conference at Nazareth College by George Payne


Beautiful little vintage coffee or side table.
Fully restored with a laser etched design featuring white lillies set against a golden amber.
Etched laminate surface is durable and hardwearing.
Orders will be based on appropriate furniture available for upcycling and designs may need to be modified slightly to suit.
Lead time 4-5 weeks from order.
Please Note: This item is now made to order only.


Blog Post: Is there only one Romeo?
Blog Post: Middle Names: Are two better than one?
Blog Post: Unisex Names: Would you use one?
Blog Post: Names from Books: Have a lifelong love affair with one?
Blog Post: The Best Popular Names--and why to pick one!


text:
Arab Fashion Council announces the first men's fashion week
DUBAI, January 5, 2021
The Dubai-based Arab Fashion Council has pioneered the first men's fashion week in the Middle East.
Presented by Arab Fashion Week in partnership with Facebook, Arab Fashion Week- Men's will run from January 28-30. Thereafter, it will take place twice a year each January and June in line with the menswear fashion week calendar.
Reinforcing the Arab Fashion Council's goal to establish a sustainable platform through which to champion fashion design talent from across the region, both established and emerging menswear designers from the UAE, Lebanon, Qatar, and Iran, have confirmed their participation in Arab Fashion Week- Men's.
Furthermore, as part of a strategic partnership between The Arab Fashion Council and The Fédération de la Haute Couture et de la Mode, four emerging menswear designers from Paris Fashion Week Men's, have been selected to participate in the first Arab Fashion Week- Men's.
"Emerging brands express a fashion forward view on the world. We are pleased to present some of these talented designers from the Paris Fashion Week calendar in Dubai at Arab Fashion Week-Men's, to allow them to increase their global reach," said Serge Carreira, Head of Emerging Brands Initiative, The Fédération de la Haute Couture et de la Mode.
Arab Fashion Week- Men's will commence on January 28 with designers premiering their collections through their individual expressions of digital creativity on Facebook Live and Instagram Live, allowing 2 billion users all around the world to view and pre-order the designer's collections direct through Instagram Shopping and the ByTribute luxury marketplace.
"Facebook, Inc is pleased to partner with the Arab Fashion Council to present the first Arab Fashion Week- Men's on Facebook Live and Instagram Live, as part of our combined mission to empower the creative community in the Middle East," said Joana Jamil, Strategic Partner Manager, MENA, Public Figures & Social Influencers at Facebook.
Arab Fashion Week- Men's is powered by the Arab Fashion Council's commitment to the principles of equality and progress across the region.
"As the only official fashion week established within the region, The Arab Fashion Council is thrilled to launch Arab Fashion Week- Men's and to begin a new journey to shape the future of the emerging menswear market across the Arab world both by nurturing the creativity of regional designers and, through our continued support to international designers wishing to explore opportunities within the region," said Jacob Abrian, Founder & CEO, The Arab Fashion Council.
The official schedule will be announced two weeks prior to the event. - TradeArabia News Service
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text:
Q: Hide relationship on Laravel Eloquent query I need your suggestion about better way to hide information from relationship array.
$members = User::with('profile')->paginate(9);

$members->makeHidden([
    'slug', 'profile.avatar'
]);

dd($members->toArray());

This code doesn't hide information from profile array.
Thanks

A: makeHidden isn't supported for relationship properties, only the entire relationship. Instead, take what you want:
$member = User::with(['profile' => $function($query) {
    $query->select('id', 'user_id', 'about');
}])->paginate(9);

The above would only give you the id, user_id, and about fields explicitly, for example.
Edit
If you're using 5.6 you can define the columns as a comma separated string, too:
$member = User:with('profile:id,user_id,about')->paginate(9);

A: Add them to your model itself.
*When hiding relationships, use the relationship's method name.
<?php

namespace App;

use Illuminate\Database\Eloquent\Model;

class User extends Model
{
/**
 * The attributes that should be hidden for arrays.
 *
 * @var array
 */
protected $hidden = ['password'];
}

This will fix you up
https://laravel.com/docs/5.6/eloquent-serialization#hiding-attributes-from-json

redpajama_set_name: RedPajamaStackExchange


text:
Columns / Insights
Between Creativity and Luck
By Jim Haven
If you have a degree in what field is it? I have an English degree with an emphasis in professional writing.
If you could choose one person to work with (outside your own agency), who would it be? This one is easy: Banksy. His wit and the potency of his messages are inspiring and funny.
Who was the client for your first advertising project? Our first client was a brand relaunch for the Professional Bowlers Association.
If you were to change professions, what would you choose to do? I think it would be fun to be a winemaker.
What do you consider to be the greatest headline of all time? My friend Josh Denberg wrote a line for Keystone that simply read, "Poof, you're insignificant." I've always loved it.
From where do your best ideas originate? Good ideas, for me, are a non-linear process. I can think hard about solving a problem, but more often than not, the answer comes to me once I stop thinking about it directly.
How do you overcome a creative block? I go for a long run if possible.
If you could choose any product to create an ad for, what would it be? As a car guy, I would love to work in that world again. But I'm also super interested in energy and its future so that's on my list as well.
Do you have creative outlets other than advertising? I like to fly fish; it takes a great deal of creativity and a perfect presentation to convince a wise trout that your fly is legit. I also enjoy cooking with my wife; it's a cross between creativity and luck.
What's your approach to balancing work and life? I think you have to live your life and find a comfortable way of merging the two. That way it's not an on or off button. You can't create work that inspires living if you're not doing so yourself. Every once in a while you just need to have a shutdown or you'll be worthless.
What product/gadget can you not live without? Coffee is the most amazing gadget I know of.
What's your favorite quote? "The multitude was kept quiet by the morsels of meat which were flung to it..." —James Anthony Froude, Caesar; a sketch
Do you have any advice for people just entering the profession? You can't always outsmart someone, but you can often outwork them.
What's one thing you wish you knew when you started your career? The Internet.
Jim Haven co-founded Creature in 2002 and serves as co-executive creative director of the agency. His role is not just to keep the Creature perspective on the work, but to energize and enable the agency to think in new ways. Before founding Creature with Matt Peterson, he had years of copywriting experience that took him from Portland to San Francisco on to Amsterdam and, finally, Seattle. He still likes to write whenever possible and is searching the world to find the perfect pizza.
Columns / Typography
A Retail Shop That Sells—Digital Typefaces?
Stephanie Orma speaks to eTypes about setting up its brick-and-mortar retail shop.
Looming, Unfinished Problems
Josh Fehr discusses how design can take technology beyond its original intention, having a life outside of work, and the things he's managed to store in the back of his brain.
Columns / Advertising
Technopocalypse
Ernie Schenck imagines the technopocalypse.
Playlist: Advertising


text:
The Adventures of Jimmy Neutron Boy Genius: Attack of the Twonkies, är ett datorspel från 2004 publicerat av THQ. Spelet är baserat på den amerikanska animerade serien The Adventures of Jimmy Neutron: Boy Genius, i sin tur baserat på 2001-filmen, Jimmy Neutron: Boy Genius. Spelet utvecklades av THQ Studio Australia för GameCube och PlayStation 2. En Game Boy Advance-version utvecklades av Tantalus.

Referenser

Nintendo Gamecube-spel
Sportspel
Datorspel 2002

redpajama_set_name: RedPajamaWikipedia


text:
Centre de Recherche sur la Paléobiodiversité et les Paléoenvironnements (CR2P)
The table to the right includes counts of all research outputs for Centre de Recherche sur la Paléobiodiversité et les Paléoenvironnements (CR2P) published between 1 February 2018 - 31 January 2019 which are tracked by the Nature Index.
Research collaboration: Centre de Recherche sur la Paléobiodiversité et les Paléoenvironnements (CR2P) is a research collaboration whose article contributions are accrued to its participating partner institutions.
Oldest skeleton of a fossil flying squirrel casts new light on the phylogeny of the group.
Evolutionary adaptation to aquatic lifestyle in extinct sloths can lead to systemic alteration of bone structure.
Proceedings of the Royal Society B
Calcium isotopes offer clues on resource partitioning among Cretaceous predatory dinosaurs.
Euryhaline ecology of early tetrapods revealed by stable isotopes
Early African Fossils Elucidate the Origin of Embrithopod Mammals
Current Biology
Centre de Recherche sur la Paléobiodiversité et les Paléoenvironnements (CR2P), France
Laboratoire de Géologié de Lyon : Terre, Planète, Environnement (LGLTPE), France (1.38)
University of Lyon, France (0.68)
École Normale Supérieure de Lyon (ENS de Lyon), France (0.61)
Laboratoire d'Ecologie des Hydrosystèmes Naturels Anthropisés (LEHNA), France (0.23)
Institute of Light and Matter (ILM), France (0.15)
Zoo de Lyon, France (0.15)
Institut de Systématique, Évolution, Biodiversité (ISYEB), France (0.13)
De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie (PACEA), France (0.12)
French National Institute for Agricultural Research (INRA), France (0.12)
University Institute of France (IUF), France (0.12)
Leibniz Association, Germany (1.07)
University of Brunei Darussalam (UBD), Brunei (1)
Autonomous University of Barcelona (UAB), Spain (0.60)
University of Lausanne (UNIL), Switzerland (0.22)
University of Zurich (UZH), Switzerland (0.22)
Princeton University, United States of America (USA) (0.22)
Centre de Recherche sur la Paléobiodiversité et les Paléoenvironnements (CR2P) is a research collaboration whose article contributions are accrued to its participating partner institutions below.
French National Centre for Scientific Research (CNRS), France
Research Unit of Living Earth and Environment, Paris 6, France
Département Histoire de la Terre, MNHN, France
Smoke signals on the breath
The University of South Australia (UniSA)
New imaging technique gets safely to the heart of the matter
Technical University of Munich (TUM)
How to measure ultrafast processes


text:
Q: Codeigniter: updating multiple rows I'm using Codeigniter 2 and I wanted to update multiple rows.
Model
Here is my model, but, the problem is, the first row only is updated.
 foreach ($this->input->post('qty') as $key => $value) {
            $data = array(
                   'item_quantity' => $value,
                   'discount' => $this->input->post('discount')[$key],
                   'senior' => $this->input->post('qty')[$key]
            );

            $this->db->where('item_id', $this->input->post('item_id')[$key]);
            $this->db->where('request_id', $this->input->post('request_id'));
            return $this->db->update('medical_request_items', $data);
        }

On the other side, I managed to do this.
foreach ($query->result() as $row)
                                    {

                                       echo '
';
                                       echo '<input type="hidden" name="item_id[]" value="' . $row->item_id . '">';
                                       echo '' . $x++ . '	';
                                       echo '' . $row->item_id . '	';
                                       echo '' . $row->item_name . '	';
                                       echo '<input type="text" size="1" name="qty[]" value="' . $row->item_quantity . '">	';
                                       echo '' . $row->item_retailprice . '	';
                                       echo '<input type="text" size="2" name="discount[]" value="' . $row->discount . '">	';
                                       echo '<input type="text" size="2" name="senior[]" value="' . $row->senior . '">	';
                                       echo '' . ($row->item_quantity * $row->item_retailprice) . '	';
                                       echo '' . (($row->item_quantity * $row->item_retailprice)-($row->item_quantity * $row->discount)-($row->item_quantity * $row->senior)) . '	';
                                       echo '
';
                                    }

I tried to echo/print, and it is working fine. But it doesn't work on multiple update.
EDIT
So I manage to look out the update_batch yet, I have an error.
$data = array(
                    foreach ($this->input->post('qty') as $key => $value) {
                           array(
                              'request_id'      =>  $this->input->post('request_id'),
                              'item_id'         =>  $this->input->post('item_id')[$key],
                              'item_quantity'   =>  $value,
                              'discount'        =>  $this->input->post('discount')[$key],
                              'senior'          =>  $this->input->post('senior')[$key]
                           )
                    }
                );

        $this->db->update_batch('medical_request_items', $data, 'item_id, request_id');

A: You are posting multiple arrays, but in your model you are only looping through one, so your where clauses will always be the same.

A: you can definitely foreach and update them one record at a time. but i think should also be able to use update batch to do all of them at once.
$this->db->update_batch('yourTableName', $updateData, 'field_to_use_for_key');

info for ci 2
http://www.codeigniter.com/userguide2/database/active_record.html
====
ok lets dig into the code
    // define an array
    $requests = array() ;

     foreach ($this->input->post('qty') as $key => $value) {

     // notice the brackets, very important $requests[]
     // this will add to the same array in each loop

         $requests[] =      array(
             'request_id'      =>  $this->input->post('request_id'),
              'item_id'         =>  $this->input->post('item_id')[$key],
              'item_quantity'   =>  $value,
              'discount'        =>  $this->input->post('discount')[$key],
              'senior'          =>  $this->input->post('senior')[$key]
                           ) ;

                    }

   // for testing only -- echo out your array so you can confirm its all good
   echo 'here is requests array:

' ;

   print_r($requests) ;

    echo '
' ;

// use one field to act as the key
 $this->db->update_batch('medical_request_items', $requests, 'request_id');

so thats using one key. if you need more then one key or where conditions to do the update - then just update in the foreach loop. Also you are of course validating any user data before updating.