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Organs On Chips Will Make Drugs Safer—And More Precise
By Deborah Borfitz
November 21, 2019 | The origins of the organs-on-chips industry can be traced back more than three decades to when Cornell University biomedical engineering professor Michael Shuler set out to make a pharmacokinetic model of the human body in cell culture to expedite drug discovery and toxicology studies. In 2001, a small paper was published about the microfabrication of an animal-on-a-chip device for this process, Shuler says, followed by a series of papers on multiorgan microscale systems (aka "body-on-a-chip") that effectively marked the birth of a new industry.
But it wasn't until 2012 that the field started getting serious attention, says Vanderbilt University professor John Wikswo, a biological physicist and founding director of the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE). That's the year the Defense Advanced Research Projects Agency (DARPA), the U.S. Food and Drug Administration (FDA), and the National Institutes of Health (NIH) partnered to form a collaboration to focus on advancing the development of organ-on-a-chip technology and launch the national tissue chips programs.
The main NIH tissue chips program is run by the National Center for Advancing Translational Sciences (NCATS). The projects of Shuler and Wikswo were among the many funded during the initial NIH tissue chips program, in parallel with the DARPA-funded work at Harvard University and the Massachusetts Institute of Technology (MIT), says Wikswo. The NCATS focus includes the development of tissue chip models for rare diseases that are difficult if not impossible to study in humans and may have no realistic animal model.
The most important catalyst for federal-level attention was a breathing lung-on-a-chip system developed by Donald Ingber, an accomplished scientist at Harvard University, together with his then post-doctoral trainee Dan Huh, as an alternative to existing drug-testing models, says Wikswo. It was heralded as one of the most important research advances in biological and medical science of 2010.
The lung model was the size of a rubber eraser and fabricated out of soft and stretchy material to effectively model the alveolus, says Wikswo. "They showed that you could put epithelial cells that line the inside of an alveolus on one side of a porous membrane, and vascular endothelial cells on the other side, stretch the membrane to mimic breathing, and record beautiful movies of an immune cell crawling down the vascular side, crossing the membrane through the holes in the barrier, and tracking down a bacterium."
A significant influx of money from the NIH and DARPA gave microphysiological systems a sense of legitimacy, says Wikswo, and the rate of publishing on the subject skyrocketed from a handful of scientific papers annually to about 1,000 last year. Wikswo has been a thought leader on microphysiological systems from the beginning, and his special interest is in functional coupling of organ-on-a-chip devices involving the sequential transfer of biofluid from one to the next.
NIH Trifecta
Launch of the NCATS tissue chip program was exciting news to scientists at the University of Washington's (UW's) Kidney Research Institute, who were all too familiar with the difficulties in making new therapies for kidney diseases, says Director Jonathan Himmelfarb. "The kidney is a very complicated organ with more cell types [40-plus] and complex architecture than the brain."
Every cell in the fist-sized organ is governed to some extent by fluidics—700 liters of blood flow through the kidneys every day, making it the most vascularized organ in the human body, he adds. Its complex filtering apparatus processes about 140 liters of water daily. The tubular epithelium reabsorb 99% of the water and the rest gets excreted as urine. Sensors, receptors, and channels within the kidneys help maintain the blood in a steady state, Himmelfarb says, "so when they're not functioning well every organ in the body does not function well."
Two-dimensional in vitro assays are poorly representative of in vivo physiology for the kidneys, Himmelfarb continues, because they lack fluidics and the ability to induce important flow and shear stresses. Blood vessels account for 25% of the kidneys by volume and their vasculature system is highly complicated.
UW researchers were competitively selected to be part of the first two rounds of the NCATS tissue chip program and, earlier this year, also sent tissue chips to the International Space Station, Himmelfarb says.
Commercializing the Technology
"DARPA has been legendary for getting people past the Valley of Death [between academia and commerce]," says Wikswo, including developers of the internet, stealth aircraft, drones, and autonomous vehicles. Often, one of the DARPA program requirements is that investigators have a plan for commercializing their technology.
To that end, a Harvard group created a company called Emulate and an MIT group licensed their technology to UK-based CN Bio Innovations. Wikswo has licensed his MultiWell MicroFormulator to CN Bio Innovations, and a commercial product is expected in early 2020.
MIT succeeded in getting 10 coupled organs working together, which was DARPA's initial plan, Wikswo says, and a paper was published describing the absorption, distribution, metabolism, and excretion toxicity of pharmaceutical compounds in the different organs. Anyone interested in toxicology should be interested in the multi-organ effects of a drug that organs-on-chips make possible. "It's going to be hard to do that with organoids because they are so small."
Drug toxicity was the initial emphasis of DARPA, which appreciated the public and scientific concern over drugs like GlaxoSmithKline's antidiabetic drug Avandia, which had been implicated in over 100,000 cardiac fatalities after 10 years of clinical use, Wikswo says. As was extensively discussed in a 2017 perspective piece in Experimental Biology and Medicine (DOI: 10.1177/1535370217732765) he authored with his colleagues at Eli Lilly and the NIH, microphysiological devices can help drug developers answer a long list of questions related to pharmacology as well as efficacy.
Flurry of Activity
The emergence of organ-on-a-chip systems parallels a shift away from the study, in a plastic dish, of primary human cells or immortalized cell lines—including the cells famously taken from the cervical tumor of Henrietta Lacks nearly 70 years ago—to a "hopefully much more realistic recapitulation of 3-dimensional biology," Wikswo says. Some of the more advanced platforms incorporate blood vessel networks that ensure survival of the surrounding tissue.
An organ-on-a-chip system can be constructed in about six hours by a skilled technician, backed by a lot of infrastructure, says Wikswo. A drug company can expect to spend almost $500 per device for one experiment, but that compares to an easy $5,000 to $10,000 for each statistically sound test involving a rat and scientist.
A 2017 review (DOI: c6lc01554a) of microphysiological systems identified over 20 companies working in this general space, says Shuler, a figure that has "probably increased to well over 50 by now." Shuler is president and CEO of Hesperos, one of few companies that concentrates on multiorgan systems and the only one that operates much like a contract research organization. "Companies send us their drugs and we do the test for them."
The single-organ systems under development couldn't be more different. Among the latest in the news are an organ-on-an-electronic-chip platform that shrink-wraps sensors around heart cells to extract electrophysiological information from tissue, a cartilage-on-a-chip system the size of a coin that mimics osteoarthritis and a pancreas-on-a-chip that delivers synchronized glucose pulses to help scientists study and develop effective treatments for diabetes.
A heart-on-a-chip system engineered by TARA Biosystems has also demonstrated its ability to replicate drug responses found in humans. Another heart-on-a-chip, developed by Wikswo's group, allows application of controlled forces to an engineered cardiac tissue and fitting of a numerical model of cardiac contraction. And Penn Engineering researchers came up with a blinking eye-on-a-chip that is expected to improve understanding and treatment of dry eye disease.
The ability of an organ-on-a-chip system to study the blood-brain barrier (BBB) is a very big deal, says Wikswo. For example, anti-epilepsy drugs and chemotherapeutics targeting cancer metastasized to the brain get met by transport proteins in the BBB that haul the drug out of the epithelial cells as fast as it enters, making the body resistant to treatment, Wikswo says.
VIIBRE researchers have had "very good luck" building brain-on-a-chip barriers, having made substantial progress over the past seven years, says Wikswo. VIIBRE's NeuroVascular Unit (NVU) seeds two chambers with four different cell types, which are grown in opposition to one another to form the BBB within the NVU. The advantage of their NVU is that it has enough cells for untargeted metabolic activity—resulting from inflammatory changes that affect the BBB—to be measured with a mass spectrometer.
A number of papers about gut-on-a-chip models, most notably one by Dan Huh and Don Ingber of Harvard, have shown that intestinal epithelial cells could serve as a barrier to microbes living in the gut. The models are becoming more realistic and will ultimately model different regions of the intestinal track, says Wikswo.
Organ Coupling
A more holistic view of drug effects is being made possible by connected organ-on-a-chip systems.
Wikswo and his collaborators at the University of Pittsburgh, the University of Washington, Johns Hopkins University and the Baylor College of Medicine have looked at the way organs interact when they are functionally coupled by transporting media from a gut-chip (Hopkins-Baylor) to a liver chip (Pittsburgh), a kidney proximal-tubule chip (Washington) and the Vanderbilt NVU.
Their study (DOI: 10.1038/srep42296) showed that the organ-specific processing of vitamin C and a withdrawn antihistamine (terfenadine) was consistent with clinical data, demonstrating the potential use of coupled organs as toxicity models, says Wikswo.
To simulate the metabolic activity of microbes in the intestinal microbiome, which convert the amino acids choline and carnitine in food to the chemical tri-methyl amine (TMA), the researchers added TMA to the lumen of the intestine chip, he explains. The media from the vascular side of the intestine chip, which contained TMA transported across the epithelial barrier, was delivered to the liver chip where the TMA was metabolized into trimethylamine N-oxide (TMAO), a predictive marker for chronic renal disease, atherosclerosis and heart failure.
The liver effluent, with both TMA and TMAO, was delivered to the vascular side of both the kidney and NVU chips, Wikswo continues. Studies of media from the organ side of these two chips showed that the kidney eliminated both TMA and TMAO, as expected from the medical literature. Whether TMAO penetrated the BBB was unknown.
"The most exciting result from this study was that the NVU predicted that TMAO would easily cross the blood-brain barrier," Wikswo says. Researchers in Italy subsequently found that TMAO was detectable in the human cerebrospinal fluid of more than 50 human subjects. This might be the first prediction made using tissue chips that was subsequently confirmed in clinical measurements on humans, he adds.
For its part of the experiment, UW's Kidney Research Institute used a microphysiology platform commercially available from Nortis that spun out of UW engineering a decade ago, says Himmelfarb. Nortis manufactures a credit card-sized chip ideal for bioengineering kidney components, including the renal tubule and microvasculature, in a space of 70 nanoliters—one-thousandths the size of a water droplet.
The tubules being created are about 120 microns across, relatively close to the 60- to 80-micron size of a normal human tubule, and flow rates mimic tubules in vivo at about half a microliter per minute, Himmelfarb says. Shear stresses are similarly well matched. "We've shown in a number of papers that we can recapitulate the function and diseases of the proximal tubule... the most metabolically active part of the kidney."
A functional rather than a physical coupling experiment was pursued as a matter of convenience, says Himmelfarb. Rather than try to assemble all the organ chips in one location, the biofluid was shuttled from university to university as it would be sequentially processed by organs in the body.
The Kidney Research Institute at Washington has on its own physically coupled a kidney and liver on the same chip to provide a mechanistic understanding of nephrotoxins and drugs that are injurious to the kidney, says Himmelfarb, noting that animal models often don't mimic results seen in humans. UW researchers were also the first to successfully isolate endothelial cells from human kidneys and propagate them in vitro to better understand their structure and function and show that their phenotypic characteristics are different from endothelial cells elsewhere in the body.
To continue the functional coupling experiment, VIIBRE researchers plan to create coupled tissue chips, linked via surrogate blood, to study the direct transfer of chemical information from one organ to another, Wikswo says. "We believe we can build a coupled gut-liver-brain system to look at the transfer and modification of opioids from the gut through the liver to the brain, as well as the under-appreciated effect of inflammatory agents generated by the gut in response to opioids on both the liver and brain. We have already shown that cytokines released by cells can open up the blood-brain barrier, which means stuff can get in that we want to keep out and vice versa."
What the Vanderbilt team wants to do, Wikswo says, is "test in vitro a hypothesis that some of the chronic pain that leads to opioid abuse is in fact due to inflammation of the gastrointestinal tract triggered by the opioids themselves." For unknown reasons, opioids more effectively treat chronic pain and cause fewer problems when given with nonsteroidal anti-inflammatory drugs.
Microbiome Studies
Literature on the microbiome is 10 times more voluminous than that on microphysiological systems and doubling every 3.3 years, surpassing environmental toxicology, says Wikswo, and "organ chips are ideal for studying the microbiome." Donald Ingber has also been a leading voice in this arena.
"I think organs-on-chips will be extremely important in studying the microbiome, and not just in the gut," Wikswo says. The vaginal microbiome is thought to play a role in premature delivery, for instance. And the skin microbiome varies from the right hand to the left—and can be passed around the office with a few handshakes, he notes.
Medicines tailored to individuals will not be possible until science untangles more of the complexities and mysteries surrounding the human microbiome, Wikswo says, which will be difficult. "The microbiome readily detected in the stool is different from the microbiome that is harder to measure in the mucus of the colon, which is different from the microbiome in the three regions of your small intestine," he cites as an example.
"The human genome has around 21,000 genes and about 3,000 of them have been deemed druggable," says Wikswo. "Of those, only 700 have FDA-approved drugs targeting them. And the microbiome, depending on how you count proteins, has at least three million genes and possibly 100 million."
Pharmaceutical companies are probably both excited by the prospects and alarmed by the complexity and expense, he adds. But given the microbial mismatch between mice and humans, organ-on-a-chip technology appears to be a potentially important tool in the moonshot goal of precision medicine.
Wikswo says he is convinced that tissue and organ chips will be keeping scientists and engineers busy for decades unraveling some of the hardest problems in medicine—contributing to a "renaissance in human physiology and systems biology."


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Phaedra: Blackwinged Night
Phaedra is a project led by Ingvild Langg�rd who is a graduate of the Oslo Academy of Fine Arts and has been involved in many different art forms before music became center stage. She released her first CD The Sea in 2011 and is back with her latest disc Blackwinged Night.
On the album Langg�rd adds vocals, harmonium, zither, korg delta and bass and is joined by eight guest musicians playing a variety of instruments like violin, viola, clarinet, drums and flute. There is a nice blending of acoustic and electric instruments and the sound is lush and dreamy and the pace is very slow and luxurious. The first track "Lightbeam" is representative of what you will find here; lush vocals and gently flowing multi-layered soundscapes giving the track an extremely dreamy vive with equal elements of pop and folk. In "Too Much Sugar" Langg�rd's vocals are particularly dreamy over a dense backdrop of synths, glockenspiel, percussion, voice samples and a heavy drum beat. "Half Human" has a darker vibe with dense synthesizer layers and a gorgeous vocal arrangement. The title track is along a similar vein as many of the other tracks, very slow, lush and dense due in large part to the heavy use of violin and viola. "The Void" is another mellow offering with sparse and subtle instrumentation and jazzy lead vocals.
My one complaint is that many of these songs are quite similar and are hard to separate from each other after listening to the album. That said, Phaedra certainly has as its own style and doesn't stray very far from that sound. If dream pop is to your liking Blackwinged Night might be an album worth exploring.
1.	Lightbeam
2.	Too Much Sugar
3.	Half Human
4.	Blackwinged Night
5.	The Void
6.	Mend Me
7.	Finally Unfolding
Added: November 30th 2015
Reviewer: Jon Neudorf
Related Link: Label's Official Site

redpajama_set_name: RedPajamaCommonCrawl


Police closed a road in Peterborough after being called to concerns for a person holding a knife.
Units were called to Lawson Avenue in Stanground at 2.40pm this afternoon.
Officers cordoned off the road with buses not serving the Lawson Avenue stop.
The woman was sat in the road but has now been arrested.


Published: Dec 14, 2018 at 11:07 a.m.
The Canadian Council of Fisheries and Aquaculture Ministers (CCFAM) has decided to advance the legislative development process for an Aquaculture Act in Canada.
The province's aquaculture industry association is lauding the decision of the Canadian Council of Fisheries and Aquaculture Ministers to make the push for a specific act governing the industry, which is currently operating under the 150-year-old Fisheries Act that doesn't define aquaculture.
The Newfoundland Aquaculture Industry Association (NAIA), which represents more than 120 members from around the world, was pleased to see the federal and provincial ministers for recognizing the industry's importance to the Canadian economy, particularly in rural coastal communities.
A federal regulatory regime focused on innovation, economic growth and sustainability, NAIA says, will allow for new business opportunities and jobs in rural areas of Newfoundland and Labrador.
"We look forward to collaborating with Indigenous, federal, provincial, and non-government partners to draft and modernize Canada's legislation and regulations with the goal of keeping our seafood farming business competitive, innovative and growing sustainably," NAIA executive director Mark Lane stated in a release.


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Tag: Rolling Stones
Prince and The Rolling Stones, 1981
By A Pop Life (Erwin Barendregt) in Commemoration, Concert, Prince
In 1981 Prince played two shows as support act to The Rolling Stones. How did the crowd react to the crossing of new wave and funk?
Prince, Rolling Stones
In memoriam: Charlie Watts 1941-2021
By A Pop Life (Erwin Barendregt) in In memoriam
Charlie Watts, Rolling Stones
Emotional Rescue, the forgotten Rolling Stones album
By A Pop Life (Erwin Barendregt) in Review
In 1980 The Rolling Stones released the album (and single) Emotional Rescue. The album tends to be overlooked. Unjustly so. The story of a forgotten album.
The best Rolling Stones singles
By A Pop Life (Erwin Barendregt) in List, Tribute
The World's Greatest Rock and Roll Band: The Rolling Stones. So much great music. A selection of the 10 best singles. A tribute to The Rolling Stones
How Devo made a classic its own
How Devo made a classic its own and received Mick Jagger's blessing. (I Can't Get No) Satisfaction the way Devo does it, is a completely new song.
Devo, Rolling Stones
The ugliest albumcovers
By A Pop Life (Erwin Barendregt) in List, Music
After the greatest, now the ugliest albumcovers, including on not in my possession, expanded with visitors' covers. Great watching!
Andre Hazes, Beach Boys, Beck, Malcolm McLaren, Michael Jackson, R.E.M., Rolling Stones, Smashing Pumpkins, Sufjan Stevens, Van Halen
Strongest & best-known band & artist logos
By A Pop Life (Erwin Barendregt) in Music
Music and branding go together, more and more. Logos are a part of that. An inventory of the strongest & best known band & artist logos.
ABBA, Bauhaus, Crass, Dead Kennedys, Deadmau5, Kraftwerk, Motörhead, Nine Inch Nails, Nirvana, Pixies, Prince, Public Enemy, Public Image Ltd, Queen, Radiohead, Rammstein, Ramones, Rolling Stones, Simple Minds, Smashing Pumpkins, Van Halen, Weezer
Concerts, top 50
By A Pop Life (Erwin Barendregt) in Concert, Top 50
Coming after the album top 50, I present the 50 best concerts I witnessed before my 50th birthday!
Arcade Fire, Bruce Springsteen, Concert, Cure, D'Angelo, David Sylvian, Eels, Family Stand, George Clinton, Iggy Pop, Kraftwerk, Lauryn Hill, LCD Soundsystem, Lenny Kravitz, Morrissey, Nick Cave, Outkast, Paul McCartney, Prince, Public Enemy, Radiohead, Ramones, Rolling Stones, Roxy Music, Sezen Aksu, Smashing Pumpkins, Specials, Sufjan St, Top 50, U2, Underworld, Waterboys, Wendy & Lisa
Album decade list 1960-1969
By A Pop Life (Erwin Barendregt) in List
Beach Boys, Beatles, Bob Dylan, Crosby Stills & Nash, Doors, Jimi Hendrix, Led Zeppelin, Rolling Stones, Velvet Undergound, Who
Best albums of the 20th century
Beatles, Bob Marley, Clash, Marvin Gaye, Neil Young, Nirvana, Prince, Rolling Stones, Sly & The Family Stone, Van Halen
Album yearlist 1972
David Bowie, Isaac Hayes, Lou Reed, Neil Young, Rolling Stones
Beatles, Jimi Hendrix, Rolling Stones, Sly & The Family Stone, Velvet Underground
Beach Boys, Beatles, Bob Dylan, Frank Sinatra, Rolling Stones
The Rolling Stones, 09/05/1998
2/5: Bad show by the Stones.
4½/5: The first time I would see The Rolling Stones. The audience was immensely annoying and agressive, but the show was impressive!
Prince – Crystal Ball / The Truth / Kamasutra
Advertising 1967, 1987 & 2017: The Beatles – Sgt. Pepper's Lonely Hearts Club Band
The Cure surprises with the sublime Seventeen Seconds


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Doom with a view
Waldemar on the Art from Russia show, at the Saatchi Gallery
For some of the most shocking, moving, disquieting and powerful imagery you will ever see in an art exhibition, I recommend a visit to the new Russian show at the Saatchi Gallery. Some people will believe you should not take your children to this display, and I leave that up to you, but I would certainly take my children. The sights on offer here are as vivid a warning as they will ever receive of the terrible things that collapsing societies are capable of doing to their citizens; and the even worse things those citizens go on to do to themselves.
Was there ever a harsher place to live than the remnants of the old Soviet Union? I suppose there must have been, but, right now, after a roomful of Boris Mikhailov's gripping photographs, I cannot imagine where or when. Taken in Kharkov, Ukraine, in 1997-8, his snapshots of street kids and tramps, prostitutes and drunks, drug addicts and rag-pickers, soaked in Chernobyl radiation and pickled in home-made vodka, slap you about the face and force you to pay attention in the manner popularised by East German border guards in the 1980s. (I speak from personal experience, but it's a long story.)
The Saatchi Gallery has given Mikhailov two big rooms in which to scare us. Both are full of startling imagery. A beaten-up woman with a black eye gulps a beer with the cross-eyed partner who hit her. A prepubescent street kid, puffing on a fag, lifts up the shirt of his prepubescent sister and gives her boobies a squeeze for the lads. A naked 40-year-old prostitute and her naked 60-year-old mother jointly show off the most intimate scars of their profession. We are watching a society reversing out of the process we call civilisation: slithering underground, turning feral. To make it all even worse, most of the photographs are taken in the snow, so not only do you feel the extra-cold of the post-Soviet winter deep-freezing the bones of Mikhailov's unfortunates, the snow itself seems to frame their predicament in white, making it even clearer.
As I stumbled past these unhappy sights, trying not to cry, the artist who kept popping into my mind was Goya. He, too, refused to avert his gaze from the deepest darkness of his times, trying instead to make that darkness so obvious that missing it required a deliberate act of avoidance. To my eyes, Mikhailov's Kharkov photographs rank alongside the Chapman brothers' masterpiece, Hell, as the most important political art of recent years.
Perversely, the Saatchi show they appear in takes its title from a notorious quote by Stalin, who said, in 1935, that "Gaiety is the most outstanding feature of the Soviet Union". It was a ludicrous claim, and it's been chosen for the title here precisely because it was so flagrantly untrue. On the catalogue, Stalin's words are displayed beneath a Mikhailov close-up of a tramp's mouth with one rotten tooth left in it, ringed by a rainforest of slimy beard. Thus, the photo says one thing, the quote says another, and together they set the show's agenda, in a sneaky, sarky, occluded and typically Russian fashion.
Although Mikhailov is the outstanding artist here, the show actually includes work by 18 artists, and presents itself as a survey of new Russian art. The exhibitors come from Russia itself, or from the surrounding ring of post-Soviet states. All the usual Saatchi suspects are present, by which I mean all the different kinds of artist you invariably find in a Saatchi show. There's a doomy painter who lets black do most of the work (Janis Avotins); a punkish, cartoon-loving slacker, obsessed with sex (Tamuna Sirbiladze); a minimalist, so modest you can easily miss her (Liudmila Konstantinova); and a sculptor whose work looks as if it has been pulled out of a fire, and who seeks, therefore, to pinch the instant depth that charring always brings (Nika Neelova).
All the above may perhaps have appeared more substantial in another display, but here they are made to look like makeweights by the urgency and power of Mikhailov and of two other outstanding exhibitors. All three are photographers working mainly in black and white. All three highlight the misery of the post-Soviet world. All three, including Mikhailov, throw something unexpected into their mix: humour.
If you look up from the rotten mouth of the tramp on the cover of the catalogue, you'll see that his eyes are actually bursting with merriment. It's partly due to drunkenness, for sure. And it's certainly not gaiety. But it is hilarity, of a particularly fierce and nihilistic Russian variety. Mooning at the devil? Laughing in the face of death? The urge to guffaw does indeed seem to be chained up in the basement of these scary Russian psyches. It's as if Russian mothers pass on to their offspring in their milk a psychic defence that no evil despot, no national tragedy, no wicked social legislation, will ever fully breach — the mocking laugh.
Thus, Vikenti Nilin photographs people sitting nonchalantly on window ledges, high up on the edges of run-of-the-mill Soviet apartment blocks, legs dangling, eyes down. At first, you assume they are all suicides waiting for their moment, and that this, too, is a comment on the grimness of post-Soviet life. One slip and they'd all be dead. But something un-tragic about the mood of the pictures causes you to examine the victims more closely. And you begin to notice unexpected things about them. All the men appear to be wearing the same suit. And the same shoes. And the same shirt, rolled over their jacket sleeves in the same way. The fatter ones stretch the suit. The thinner ones are engulfed by it. These are supposed to be tragic situations, but it is the drolleries and the absurdities that are being enjoyed here.
There is also something weirdly comic about Sergei Vasiliev's exciting portraits of tattooed criminals in Russian jails. If you want to see bad tattooing at its worst, peer at the overcrowded skins of these preening Soviet delinquents. Apparently, each tattoo has a secret meaning that only the criminal gangs understand, but there are enough swastikas and crosses and religious icons scattered among the messy nudes to make the final effect unmistakeably fascistic.
Like all sporters of tattoos, the Russian prisoners are trying desperately to look tough. But most are so skinny, they are little more than tattooed skeletons. On all their faces, I could sense a powerful unseriousness tugging at the corners of their lips.
As if Gaiety didn't offer enough hardcore Russian experience for any viewer, the Saatchi Gallery has simultaneously opened a second show, devoted to the art made in Moscow in the years 1960-89. This is art made illegally, under the nose of the government. There's a lot of it, the display is busy and rambling, and I advise you to think carefully about where you pause. Just because it's dissident art, that doesn't mean it's any good. I remember being sent to Russia to write about this stuff when Brezhnev was alive, and discovering that most of it consisted of crucified nudes wearing Wrangler jeans. It was some of the worst art I have ever seen.
So I advise you to head straight for Komar and Melamid's work, and particularly their hilarious send-ups of socialist-realist painting. See that dark and sumptuous religious image of a bare-footed old man praying in front of a mirror, based on Caravaggio's gorgeous portrait of Mary Magdalene? That's not any old man. That's Stalin.
« Serving a glorious life sentence as prisoner of their satanic majesties
Seduced by the city »


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Europe Politics
Republicans Poised to Flip 6 California Districts, Primary Results Indicate
Republicans are on a path to flip six congressional seats in California in November based on the pri..
By Sunday Herald Team , in US Politics , at March 6, 2020
Republicans are on a path to flip six congressional seats in California in November based on the primary results. Four additional seats are enough to make GOP candidates competitive. Democrats, on the other hand, dont seem to have an easy path open to even one seat currently held by a Republican.
California as a whole leans left, with Democrats holding 45 of the 53 congressional districts (two are vacant). The March 3 primary results, however, suggest the GOP may heal its losses from the 2018 midterms, where Democrats flipped seven seats.
The state holds "jungle primaries," which means both Democrats and Republicans show up on the same ballot, and the two candidates with the most votes face each other in the general election.
Voters who didnt get their primary pick could still be generally expected to go for the winning candidate of their party. Thus, by adding up the votes for all Democrats and all Republicans on the ballot, one can get a rough idea how many voters may show up for the candidate of each party in the general election.
In addition, there was only one state-wide measure on the ballot this time—one for bonds to fund public school facilities (voted down). That means Democrats may have had a stronger motivation to show up, since they were deciding on their presidential candidate, while the Republican presidential primary was a largely symbolic exercise of confirming President Donald Trump as the nominee of choice. Trump received 92.5 percent of the vote.
The 10th district, spanning northern San Joaquin Valley east of San Jose, flipped blue in 2018, but seems ready to swing back. The incumbent, Josh Harder, won the primary with 39.8 percent, while the GOP frontrunner, Ted Howze, finished with 37.5 percent. However, when adding the votes for all the Democrats on the ballot, they garnered less than 45 percent of the vote. Republicans claimed the majority with 55.
The 21st district, just south of the 10th, is a similar story. Democrat T.J. Cox unseated incumbent Republican David Valadao in 2018. But Valadao came back and won the March 3 primary with 53.1 percent. Cox only scored 36.1 percent while 8.3 percent went to the other Democrat on the ticket, Ricardo De La Fuente. There was a second Republican in the race as well, Roque "Rocky" De La Fuente, who scored 2.5 percent.
A bit further south lies the 25th district, offering a crowded primary of six Democrats, six Republicans, and one independent competing for the seat emptied by Katie Hill—the Democrat who flipped the seat in 2018, but resigned in November amid an ethics probe after photos were leaked to the media of her intimate relations with a former campaign staffer.
Some names of media prominence also joined the race: George Papadopoulos, the former Trump campaign aide implicated in the Russia investigation, and Cenk Uygur, co-founder of progressive news and opinion show "The Young Turks."
In the end, Democrat Christy Smith finished first with 29.8 pRead More – Source
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Argentina vs. Germany: Quick team facts
by Liezl Grobler · July 10, 2014
So we are almost at the end of what's been one of the most action-packed (and might I say, controversial) FIFA World Cup tournaments to date. On Sunday (21:00) we will see Finalists, Argentina and Germany battle it out for the coveted Cup at Maracanã Stadium in Rio de Janeiro.
Here are some "Quick facts" about the competing teams that you need to know:
Argentina's head coach is Alejandro Sabella (since 2011)
The first match ever recorded by Argentina was against Uruguay
Argentina has appeared in four World Cup finals, and won twice (1978 and 1986)
The national team is also known as the Albicelestes (sky blue and whites)
The team's home stadium is the Estadio Monumental Antonio Vespucio Liberti in Buenos Aires
Argentina's Captain is Lionel Messi (also the second highest goal scorer (42) for the team to date)
Most goals for Argentina were scored by Gabriel Batistuta (56) in 1991-2002
Javier Zanetti is the most capped player in the history of Argentina with 145 caps
Argentina reached the top of the FIFA World Rankings for the first time in March 2007
Argentina has won the Copa América fourteen times
Germany's head coach is Joachim Löw
Germany has won three FIFA World Cups (1954, 1974, and 1990)
During the FIFA World Cup 2014 semi-final against Brazil, Germany became the first team ever to score 5 goals in only 18 minutes during one half
Germany has won the European Championship three times
The nicknames for the team are Nationalelf (National Eleven), DFB-Elf (DFB Eleven), Die Adler (The Eagles), Die Mannschaft (The Team)
Germany played their first official match against Switzerland in 1908
The team does not have a national stadium, but home matches are rotated among various stadiums across the country
Miroslav Klose is the national team's top goal scorer with 71 goals (2001 to date)
Lothar Matthäus is Germany's most capped player (1980-2000)
Adidas has been the long-standing sponsor of Germany's kit, since 1954 and contracted to continue until 2018
So who are you rooting for? Will the Cup be staying on South American turf, or be heading to Europe? Make your prediction for the FIFA World Cup 2014 Finals below.
Tags: FIFA Quick factsFIFA World Cup 2014 Finals
Liezl Grobler
Digital Copy Editor, Blogger, SEO Writer and Online Marketing...
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Q: Difference in user endpoints In my Azure AD tenant, I have few users which I get using https://graph.microsoft.com/beta/users and I get Education users for a school using https://graph.microsoft.com/beta/education/schools/<id>/users or https://graph.microsoft.com/beta/education/users
What is the difference here and how do we differentiate them in the portal panel?
Can we make a general user an education user under a specific school?
I actually am not an admin on the portal.

A: At the AAD level (which is what you're surfacing in the Azure Portal), there isn't a difference between the objects.
What is different is how the User resource is rendered. When you query Users via /education/users, you get some additional metadata. For example, if the User is a Student you will get the educationStudent properties. If they're a Teacher, you'll see the educationTeacher properties.
The educationUser resources also have additional navigation properties for educationClass and educationScool.  For example, you can call v1.0/education/users/{id}/classes but not v1.0/users/{id}/classes because the standard User resource lacks the classes navigational property.
This same model carries over to other areas:

*

*educationUser extends the user resource

*educationClass extends the group resource

*educationSchool extends the administrativeUnit resource

You can add an educationUser to an educationSchool like this:
POST https://graph.microsoft.com/v1.0/education/schools/{schoolId}/users/$ref
Content-type: application/json
{
  "@odata.id":"https://graph.microsoft.com/v1.0/education/users/{userId}"
}

As an aside, I strongly caution against using the /beta version. The Beta version can and will break from time to time. Breaking changes happen without warning and, as such, is simply not reliable enough to use in a production application.

redpajama_set_name: RedPajamaStackExchange


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Die Liste der Naturdenkmäler in Heuchelheim an der Lahn nennt die auf dem Gebiet der Gemeinde Heuchelheim an der Lahn gelegenen Naturdenkmäler. Sie sind nach dem Hessischen Gesetz über Naturschutz und Landschaftspflege ( – HAGBNatSchG) § 12 geschützt und bei der unteren Naturschutzbehörde des Landkreises Gießen (Fachdienst 72 Naturschutz) eingetragen.

|}

Siehe auch
 Liste der Naturschutzgebiete im Landkreis Gießen

Weblinks
 Schutzgebiete, Landkreis Gießen
 Geographisches Informationssystem GIS, Landkreis Gießen

Einzelnachweise

!Naturdenkmaler
Heuchelheim
!Heuchelheim an der Lahn

redpajama_set_name: RedPajamaWikipedia


Win Admission For Two to the Festival of Trees! 24 Hour Flash Giveaway!
Are you ready for our second holiday experience giveaway?
I've got admission for two to the Mary Bridge Festival of Trees in Tacoma.
I've honestly never been to this, but I know many readers have gone and enjoyed it. You'll see close to 70 amazingly decorated trees, enjoy live entertainment, and more. There are also Lots of great photo ops!
This year's public days are December 7th and 8th, with Hello Kitty! making an appearance on the 7th (kids' day).
This giveaway is for one pass that will admit two adults for Free! Kids 12 and under are always free, and students 13-18 are just 2.00, so this will make for an inexpensive day of fun! It is a fundraiser for Mary Bridge, so if you do have the means to donate a little something while you're there, it's a nice idea.
We're going to keep this one quick and simple because I have bunches more great giveaways to fit in. It's getting fun around here, isn't it?
Just leave a comment here and let me know!
For a second, optional entry, subscribe to my emails. Note that after you get the first one, you need to verify you want to receive them to actually become a subscriber. They're just a once-a-day digest of the day's posts. If you already get 'em, just say so!
Do remember to leave each comment as a separate entry, and remember that only comments left on this site count as entries. Good Luck! I'm choosing a winner for this one Sunday nigh! Remember to leave an email you check regularly!
We would LOVE to have the opportunity to take our 2 cuties to something so magical. We're having a very tight, small, Christmas this year (as are a lot of people I'm sure!) but it would be so nice to surprise them with this!
We would love to take our six year old to this!
Would love to attend this year with the kids!
We would love love to go.
We would love to go with our boys and our exchange student!
This would be such a great experience to enjoy as a family!
And have it kick off my holiday season. It really brings the magic of Christmas to life.
My kids love Christmas lights!
This would be great! Thanks for giving us an opportunity!
Would love to take my kids to see the trees! Sounds so fun!
Just moved to Tacoma and this would be fun!
I wanna go with my girls!!
New to WA and we are excited for winter and it actually feeling like winter, moved here from TX ! Would love to take my daughter here!
I would love to go to this, it would be the best kick off to my holiday season. This festival truly does bring the magic of Christmas to life.
We just love your blog 🙂 You have become a family go to for activities, thanks! It would be awesome to go check out this event!
This would be great 🙂 Thanks for the chance!
Our kids would love this!!
Would love to go this year. Enjoyed it last year.
Finally subscribed after following for a couple years!
This sounds like a lot of fun! I've never been!
On a super-tight budget and looking for inexpensive holiday fun for my kiddos. This would be awesome!
Subscribed to your blog, and to your FB page!
We love ANYTHING with the name Mary Bridge in the name….our 9 year old spent the much of her newborn life there & we learned to trust them like no other!
I'd love to take my 3 year old!
Would love to take my boyfriend's two kiddos here! Subscribing also! Thank you for this site, it's been a life-saver in our weekend plans so the kids can get out more.
What a cool idea! I would live to win these tickets! My husband just got Saturdays off and we are looking for some fun family Christmas events to take our daughter too! I also subscribe to your emails all ready! Thanks!
I signed up for e-mails. Hopefully that will be helpful when going back to a post you've posted. I find myself searching Facebook posts a lot. Thanks!
Please enter our family. This would be so much fun for all 4 of us. Thank you!
I have to accompany my hubby to all kinds of punk shows and would love to take him to this…. Or have him watch the kids so I and a friend could go.. :).
We have never been and would love to start a new family tradition.
We would love to take our 5 yr old and 2 yr old to this! They adore Christmas trees and seeing Hello Kitty would be a dream!
I am already a subscriber of your emails!!
We have never been to this. It would be great to surprise my kiddos.
We live in the Olympia area, and have had this on our Christmas 'to-see' list for the last couple of years…but have never gone! Would love to go this year!
I haven't been for 20 years. Sounds like fun!
I would love to take my family to this! What a great giveaway!
I subscribed via email. Can't wait to start getting all of your ideas/events.
I haven't been for years and would love to take my grandkids.
This sounds like so much fun. I'd love to win!
Count me in to win!!!
Oh. And I just signed up for your emails. I've been checking out your website for months and didn't realize that you had an email blast.
Great event! Thanks for the chance to win.
Lots of Fun! Would love to go again!


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andrew bynum net worth 2020
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MLB Beat the Streak Contest
How would you like a chance to win $5.6 Million in cash? Enter the MLB Beat the Streak Contest now through final game of the 2018 MLB regular season at Mlb.com/bts or Mlb.com/fantasy and Be the first to reach 57 games for your chance to win $5.6 Million prizes or other exciting prizes.
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Prizes You Could Win: (Grand Prize) The first eligible participant, if any, to achieve at least a fifty-seven (57) game hitting streak, as determined by MLBAM in its sole discretion, will win five million, six hundred thousand U.S. dollars (US$5,600,000) (the "Grand Prize"). For the avoidance of doubt, a maximum of one (1) Grand Prize will be awarded for the entire Contest.
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News> World> Content
Thursday, February 25, 2021, 14:03
Biden revokes Trump's visa ban on green card applicants
Thursday, February 25, 2021, 14:03 By Xinhua
US President Joe Biden speaks during a meeting with labor leaders in the Oval Office of the White House, in Washington, Feb 17, 2021. (EVAN VUCCI / AP)
WASHINGTON - US President Joe Biden on Wednesday revoked an executive action by his predecessor banning legal immigration for family members of US citizens and residents, and diversity visa lottery recipients.
To the contrary, it harms the United States, including by preventing certain family members of United States citizens and lawful permanent residents from joining their families here.
Joe Biden, US President
Biden said in a statement that former President Donald Trump's order blocking green card applicants and temporary foreign workers "does not advance the interests of the United States."
"To the contrary, it harms the United States, including by preventing certain family members of United States citizens and lawful permanent residents from joining their families here," Biden said.
ALSO READ: Biden treads carefully in unwinding Trump immigration policies
"It also harms industries in the United States that utilize talent from around the world. And it harms individuals who were selected to receive the opportunity to apply for, and those who have likewise received, immigrant visas through the Fiscal Year 2020 Diversity Visa Lottery," he added.
The Trump administrationu, which twice extended the suspension that is set to expire on March 31, insisted that the ban was necessary to protect American workers and the US labor market during the coronavirus pandemic.
READ MORE: White House: Biden plans to 'recalibrate' Saudi relations
"The admission of workers within several nonimmigrant visa categories also posed a risk of displacing and disadvantaging United States workers during the economic recovery following the COVID-19 outbreak," Trump said in a proclamation issued last year.