text:
West Germany's peace movement begins to unravel
By Elizabeth Pond Staff writer of The Christian Science Monitor
The peace movement is in decline in NATO's linchpin country of West Germany. The sunniest Easter weekend in 22 years lured far more West Germans - 18 million of them - to shore or mountains than to the first major antinuclear protests since NATO Euromissile stationing began last December. And for the first time in three years the peace movement no longer has visible leverage on government arms control policy.
This time around, only one-quarter or even one-tenth as many opponents of NATO Euromissiles showed up on the streets of Hamburg, Cologne, and a dozen other cities as in last October's million-strong antinuclear happenings. The high estimate comes from protest organizers, the lower one from West German police.
Besides, this year's Easter marches were more diffuse than last year's demonstrations. The impressive uniting of various protest groups in an anti-NATO Euromissile focus over the past three years is reversing itself, with demonstrators diverging back to a multiplicity of causes: In support of the 35 -hour workweek; against nuclear power, poisonous chemical wastes, and the American mining of Nicaraguan ports.
The dedicated peace activists are as energetic as ever and probably better organized than ever before. But they no longer can mobilize those million sympathizers who are less committed than themselves.
One disincentive to joining protest is widespread resignation as it has become clear that the demonstrations would not block NATO stationing. The second battery of nine Pershing IIs was recently deployed in West Germany, and more will come in the course of the year. Under these circumstances, many sympathizers are inclined to drop futile inveighing against holocaust and go back to living their personal lives.
This attitude is perhaps especially pronounced among those high school students who used to take it for granted that they would graduate into adult politics by attending the demos in something like a class outing.
For their part, older West Germans who feared that the Pershing IIs were bringing nuclear war closer have been reassured this year by the decline of palpable East-West tension since the initial December deployment. In particular, their angst has been assuaged by conspicuously chummy East-West relations and the dramatic flow of East German emmigration.
The 80-mile-long traffic jams on Easter Monday - as contrasted with the much shorter antinuclear parades - are one measure of the peace movement's decline. The current praise of the West German government for the new American draft treaty on the chemcical weapons ban is another.
Thus, over the past three years, Bonn has constantly prodded Washington to be more forthcoming in arms control. The West German government - first under a Social Democratic chancellor and now under his conservative successor - was instrumental in getting the US to go to the Euromissile negotiating table at all , to finish the Madrid conference on security in Europe with a joint statement rather than a walkout, and to attend the current Stockholm conference on confidence-building measures in Europe.
Bonn - along with other European capitals - also got the US to modify its Euromissile negotiating stance from the ''zero option'' demand that all Soviet SS-20s be dismantled to an offer of lower equal East-West levels - and then, just before the Soviets broke of the Euromissile talks last November, to an American offer of de facto Soviet superiority in Euromissiles under certain conditions.
In every case, the rationale for European pressure was fear of the peace movement in Western Europe, especially in West Germany. If President Reagan did not tone down his initial bellicose rhetoric with proffers of peace, the Europeans contended, then NATO nuclear modernization simply could not be carried through politically in Europe.
The argument was persuasive in Washington: Euromissile deployment was deemed the sternest test of NATO in years, and everything has to be done to ensure that deployment.
Once stationing actually began, however, that concern evaporated. Washington saw NATO as having passed the test, worn down the antinuclear movement, and outnerved the Soviets. There was therefore no more need to coddle the faint-hearted European peace movement - especially since its ranks were dwindling.
Moreover, the fluid balance of policy advocacy within the Reagan administration shifted this year in favor of the foes of arms control with the unrelated collapse of State Department fortunes in Lebanon.
The outcome was an American insistence on highly intrusive verification measures in its pre-Easter draft chemical weapons ban - and unreserved West German government praise of the draft.
In the old days - following the pattern of the past three years - the Bonn government would have welcomed the American draft but also let German journalists know it favored the far less intrusive verification procedures that Bonn itself had proposed more than a year ago. And it would have argued in private to Washington that more modest inspection would suffice, would not provoke the secrecy-obsessed Soviets, and would enable the West German government to parry the criticism of its domestic peace movement.
Bonn's failure to do so this time - probably even more than the diminishing numbers of Easter peace marchers - illustrates the loss of influence of the peace movement here.
Brzezinski: Formally recognize Ukraine, prepare NATO troops
Ukraine crisis has pushed Germany to center stage
The US is descending into tribalism, Nobel laureates say hold Myanmar accountable, Israel's church taxes increase tensions over East Jerusalem, Thr...


In spring, Washington D.C. dazzles with cherry blossoms and gardens. More than 3,000 cherry trees pop into bloom, framing the Jefferson Memorial and fringing the Tidal Basin with a lush ribbon of pink and white that's subtly reflected in the water. The most famous site, the Tidal Basin in West Potomac Park, is bucket list beautiful. Locals know to find additional blooms and fewer crowds at such off-the-beaten path gardens as the U.S. National Arboretum and at Hillwood Estate, Museum and Gardens.
Peak bloom, when 70-percent of the cherry buds open, can occur between mid-March to mid-April, depending on weather. The city celebrates each year with the National Cherry Blossom Festival, featuring a parade, kite-flying, live music and more special events. This year's event takes place March 20 to April 15.
Although the cherry blossoms receive headline billing, the District is in flower from spring through fall. Leaven your Washington, D.C., exploration of museums and monuments with a stroll through the city's "secret" gardens.
The budding cherry trees soften the facades of government buildings and lace the streets. Delicate, fragrant, and like all things magical, the blooms are fleeting, but so worth experiencing.
Start your cherry blossom tour at the Tidal Basin near the Jefferson Memorial but come early, very early. Be there by 6 a.m. if you can. The crowds are thinner than later in the day and the light, optimal for photos. Engaged couples and wedding parties pose amid the blooms. For a panoramic view, take a paddle boat out on the water.
Walking amid the canopy of petals is restorative even when accompanied by throngs of people.
Make time for the United States National Arboretum. You're virtually guaranteed to see blooms between mid-March to mid-April since the facility's 2,000 cherry trees represent more than 200 species that flower at varying times. Another plus: less intense crowds than at the Tidal Basin.
At the 446-acre Arboretum, 2.2 miles from the capitol, the seasons bring kaleidoscopic color. In spring, hillsides blaze with azaleas, daffodils and dogwood. In summer see hydrangeas, water-lilies, roses and peonies. Woodlands, boxwood, ferns and a noted bonsai collection add to the experience.
Hillwood, an uptown urban oasis, unfolds with 13 acres of formal gardens surrounded by 12 acres of woodlands that back up to Rock Creek Park. On a stroll, it's easy to forget that you are still in the city.
Landscaped to the tastes of Marjorie Merriweather Post, the heir to the Post cereal fortune, the gardens are as carefully arranged as the rooms in her mansion. The grande home showcases Russian decorative arts—including bejeweled Faberge eggs– as well as 18th century French furnishings.
The Japanese-style garden, a tranquil setting of winding paths, bridges, boulders, ponds and waterfalls, soothes with flowering cherry trees. In March, the floral scent of 2,000 orchids greets you in the greenhouse. In April and May the rhododendrons, magnolias and crab apples flower and from spring through summer, roses and myriad other flowers bloom.


Antitrust violations in the pharmaceutical and life sciences industry continue to proliferate in recent years, resulting to intensified enforcement actions and increased litigation. Issues on pricing transparency, complex distribution chain, and third-party payers are significant factors contributory to this upward trend. Compliance has never been more critical.
To mitigate compliance issues and challenges, it is imperative that counsel to businesses are in the know of the latest trends and developments in this evolving regulatory paradigm. They must be able to identify effective strategies to guide their clients from further antitrust disputes.
Join a panel of key thought leaders and practitioners assembled by The Knowledge Group as they provide an in-depth discussion of the emerging antitrust enforcement actions in the pharmaceutical and life sciences industry. Speakers will dig deeper as they offer risk mitigations strategies and best practices in this increasingly complex legal climate.
Howard Morse is a Washington, DC-based partner in Cooley's Antitrust & Competition practice group. He represents businesses before the Department of Justice, Federal Trade Commission, and state attorneys general in investigations of mergers, acquisitions and joint ventures, as well as alleged monopolization, restraint of trade and unfair and deceptive practices. Howard has been at the forefront of applying antitrust law to the high-tech sector and the intersection of antitrust and intellectual property law, and regularly represents clients in technology, life sciences and other high-tech industries.
Before joining Cooley, Howard served for 10 years at the FTC, where he was Assistant Director of the Bureau of Competition and responsible for more than 50 enforcement actions. In the private sector, Howard has recently represented Rovi in its $1.1 billion acquisition of Tivo, combining two media and entertainment innovators, and Zeltiq in its $2.5 billion sale to Allergan, combining leaders in medical aesthetics.
Cooley's attorneys solve legal issues for entrepreneurs, investors, financial institutions and established companies. Clients partner with Cooley on transformative deals, complex IP and regulatory matters, and high-stakes litigation, where innovation meets the law. Cooley has 900 lawyers across 12 offices in the United States, China and Europe. Cooley's antitrust & competition team is recognized as one of the top-tier practices in the area of antitrust by Legal 500, Chambers USA and Global Competition Review. We handle all aspects of antitrust and competition law matters – including counseling, litigation, agency representation and arbitration services – for Fortune 500 corporations, as well as growing companies.


Weston Pass was a stagecoach route between 1860 and 1881 before the railroad came to Leadville. The original route was an old Ute Indian trail that got expanded to accommodate prospectors heading over the pass to the gold rush from Fairplay.
The west side of this Jeep trail is quite rocky. The east side is OK when graded, but deteriorates over time.


May. 29, 2011 12:00 p.m.
Tour de France hometown hero Ryder Hesjedal (pointing) heads out with fellow riders on the inaugural Tour de Victoria from Belleville Street.
Those are among the first words Seamus McGrath said as he reflected on the success of the inaugural Ryder Hesjedal's Tour de Victoria.
"My original vision of how this event could look and feel and operate – that's exactly how it went on Saturday," said McGrath, the tour's founding director.
The same can be said for the weekend lineup of cycling events in the new Victoria International Cycling Festival, which kicked off Friday night and continues in downtown Victoria until June 12.
Enthusiasm among spectators was high during several new features, from a 400-metre sprint to the longer time trials, as well as the returning Bastion Square Grand Prix and Tim Bits kids challenge.
"The vibe, the feeling of them was all great and I have a feeling they're all going to grow and become really part of the (cycling) culture," said festival organizer, Rob Fawcett.
Ryder Hesjedal's Tour de Victoria attracted 1,350 cyclists from as far away as Nova Scotia and Texas. Upwards of 800 riders registered for the 140-kilometre course, about 400 for the 90-km and 150 participants cycled the four-kilometre community ride in downtown Victoria.
More than 500 volunteers were involved, including more than 300 road marshals, who ensured vehicle traffic and cyclists didn't mix at intersections throughout 13 municipalities.
The event was marked by some minor collisions between cyclists, others suffered from rain-related hypothermia, and there were traffic tie-ups in James Bay where crowds gathered for cycling and to watch the start of the annual Swiftsure international yacht race on Saturday, said tour spokesperson Kim Van Bruggen.
The Swiftsure has, in part, prompted organizers to move the date of next year's Tour de Victoria by a month to June 24. The extra time will also allow more cyclists to train for the event longer and in better weather, said Van Bruggen.
It's still too soon to know if the Tour de Victoria will once again coincide with the cycling fest, which could be expanded from two weeks to a month next year, said Fawcett. "The objective is to grow the festival. How it will take shape, we're not exactly sure yet," he said.


text:
Q: How can I calculate sql tables in delphi ? Hi I have sql table I want to calculate all the fields to total sum field.

A: You can do this in the SELECT statement you use to get the data, something like
SELECT *, big1 + small1 as "TotalSum" from adlar

Obviously, you can add more numeric fields to the fields to sum.

A: procedure TForm1.Button1Click(Sender: TObject);
begin
ADOQuery1.Close;
ADOQuery1.SQL.Text:='select  boyuk1 + kicik1 + qara1 + boyuk2 + kicik2 + boyuk3 * 0,35 as totalsum from adlar2v';       //(table name:adlar2v)
ADOQuery1.Open;
end;

redpajama_set_name: RedPajamaStackExchange


© 2018 Scratchu.com Jaanam Samjha Karo | Salman Khan, Urmila Matondkar, Jaspal Bhatti, Shammi Kapoor, Bindu, Navneet Nishan, Kannu Gill, Sadashiv Amrapurkar, Monica Bedi, Laxmikant Berde, Deepshika, Rohini Hattangadi, Dimple Inamdar, Grusha Kapoor, Shakti Kapoor - Jaanam Samjha Karo (1999) | Hindi Movie | 4.9/10 | Synopsis : Talented singer and dancer, Chandnis life is dominated by three aunts, and a soft-spoken maternal grandmother. She meets with a womanizer named Rahul, and falls in love with him. Rahul ... ... Watch Online!!!


text:
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redpajama_set_name: RedPajamaGithub


text:
Montana Gold Production Summary
In Montana, 54 mining districts distributed in 17 counties (fig. 14) each have produced more than 10,000 ounces of gold. Four districts - Butte, Helena, Marysville, and Virginia City - have produced more than 1 million ounces, and 27 other districts produced between 100,000 and 1 million ounces. Montana generally is credited with lode and placer gold production of 17,752,000 ounces from 1862 through 1965. Almost two-thirds of the total was mined before 1900 when records were poorly kept; thus a large part is estimated. Figure 15 shows annual gold production of Montana from 1900 through 1965.
In 1852 gold was first discovered in Montana in gravels along Gold Creek in Powell County (Lyden, 1948, p. 118). The influx of prospectors, however, started with the discovery in 1862 of placers along Grasshopper Creek, near Bannack, in Beaverhead County (Winchell, 1914a, p. 18). Other discoveries, both placer and lode, came in rapid succession. In May 1863, the very rich deposits along Alder Gulch near Virginia City in Madison County were discovered ; these proved to be the most extensive and the most productive placers in Montana. The Last Chance placers on the present site of Helena in Lewis and Clark County, among Montana's most productive placers, were discovered in the summer of 1864 (Knopf, 1913, p. 15) as were the placers in the Butte district in Silver Bow County (Lyden, 1948, p. 144-145). These rich discoveries stimulated a rush of prospectors to Montana who searched the valleys and gulches for gold-bearing gravels. Placer mining flourished during the 1860's. Some of the deposits were quickly worked out, but others were worked on a substantial scale up to World War II. Winchell (1914a, p. 19) described this extended activity as follows:
By the gradual installation of ditches, flumes, and hydraulic and sluicing apparatus the life of the placer-mining industry has been extended for half a century, though with decreasing yield at nearly all places, except where new and virgin ground was opened by late discovery or by bringing water upon ground previously too dry to work. * * * The introduction of dredges increased the annual output to about half a million dollars, though the newness of the method and the many difficulties that had to be overcome caused for a time great fluctuations in the yield. Since about the first of the century, however, the product has been large and increasing, and, despite the marked decrease in the amount of gold won by other placer methods, the annual placer production has formed an important portion of the total gold output of the State.

redpajama_set_name: RedPajamaCommonCrawl


It's easy to be intimidated by things you've never done before. Intimidation can stop you from doing things you're probably capable of — if you let it — or intimidation can be just a word. It's up to you.
Many times we pay others to do things that we could easily do ourselves — not because we don't want to take the time or make the effort, but because we're afraid we won't do it right. We're intimidated. Worse, many times we don't do things that we would really love to do out of fear or a belief that we won't be any good at it. Other people make it look so easy, but we don't know where to start, and we're sure we could never do something like that.
No one is good at everything they try right off the bat. Some people are more talented in some areas than others, but no one ever starts out as an expert. And even experts mess up sometimes. Olympic athletes stumble and fall at key moments. The difference is, they get back up again, and then they try harder, practice longer, and get help from their coach.
While you may not aspire to the Olympics, you might want to do things around the house yourself or take up a new hobby. Or you might want to learn new skills that could help you earn more money, or help you better manage the money you have now.
If you're feeling intimidated by something you'd like to do, think about the possible worst-case scenario. Literally ask yourself "What's the worst that could happen?" — and then estimate how likely it actually is to happen.
Once you've done that, figure out how to minimize the risk if you still want to move forward. Take steps to prevent the worst case by spending a little time understanding what's involved and what others have done. Maybe get someone to go through the process with you the first time, find step-by-step directions online that can help, or take a course.
Remember, intimidation is just a word. Get past it, and you'll be successful by trying new things — and then not letting failure get you down if they doesn't go 100% perfectly the first time. Failure is feedback, and a message to adjust and keep right on trying. And when you do succeed, it's sweet.
Fear keeps us from trying a lot of things. Our lives are much richer by trying new things and venturing out from our comfort zone.
Love how you are tackling intimidation (and purple hair)!
Hehe, thanks! It's back to its intended color now!
This a good reminder. I often tell myself that Oprah started at a small TV station. Martha Stewart started out as a caterer. They didn't start out as experts running empires. Starting small and not being intimidated is the way to go.


text:
Development of the Human Pancreas From Foregut to Endocrine Commitment
Rachel E. Jennings1,2,
Andrew A. Berry1,
Rebecca Kirkwood-Wilson1,
Neil A. Roberts1,
Thomas Hearn3,
Rachel J. Salisbury1,
Jennifer Blaylock1,
Karen Piper Hanley1 and
Neil A. Hanley1,2⇑
1Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical & Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, U.K.
2Endocrinology Department, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester, U.K.
3Centre for Human Development, Stem Cells and Regeneration, Human Genetics, University of Southampton, Southampton General Hospital, Southampton, U.K.
Corresponding author: Neil A. Hanley, neil.hanley{at}manchester.ac.uk.
Diabetes 2013 Oct; 62(10): 3514-3522. https://doi.org/10.2337/db12-1479
Suppl Material
Knowledge of human pancreas development underpins our interpretation and exploitation of human pluripotent stem cell (PSC) differentiation toward a β-cell fate. However, almost no information exists on the early events of human pancreatic specification in the distal foregut, bud formation, and early development. Here, we have studied the expression profiles of key lineage-specific markers to understand differentiation and morphogenetic events during human pancreas development. The notochord was adjacent to the dorsal foregut endoderm during the fourth week of development before pancreatic duodenal homeobox-1 detection. In contrast to the published data from mouse embryos, during human pancreas development, we detected only a single-phase of Neurogenin 3 (NEUROG3) expression and endocrine differentiation from approximately 8 weeks, before which Nirenberg and Kim homeobox 2.2 (NKX2.2) was not observed in the pancreatic progenitor cell population. In addition to revealing a number of disparities in timing between human and mouse development, these data, directly assembled from human tissue, allow combinations of transcription factors to define sequential stages and differentiating pancreatic cell types. The data are anticipated to provide a useful reference point for stem cell researchers looking to differentiate human PSCs in vitro toward the pancreatic β-cell so as to model human development or enable drug discovery and potential cell therapy.
The in vitro differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (IPSCs) to pancreatic β-cells is an ambitious hope for cell therapy in diabetes, a tool for mechanistic understanding of monogenic diabetes, and a potential platform for drug discovery to promote β-cell regeneration (1,2). Most stem cell differentiation protocols aim to mimic normal development by steering pluripotent cells sequentially through endoderm, foregut, pancreatic progenitor, and then endocrine cell fates (1–4). Comprehensive knowledge of this pathway has come from extensive analyses of laboratory model species, such as mouse, chick, and frog (5–8). This has demonstrated patterning of the foregut endoderm by transient proximity to the notochord that permits subsequent development of the dorsal pancreatic bud (9,10), with additional inductive influences provided by the dorsal aorta and other vasculature (11,12).
The intercellular signaling underlying these events and others has been mimicked as additives to the culture media during stem cell differentiation. In parallel, genetic inactivation in mouse has shown the sequential requirement for key transcription factors (5–8). Some of these factors, for which robust antibodies are available, have been used as phenotypic markers to indicate stages of β-cell differentiation from stem cells in vitro (2–4). Examples include SRY (sex determining region Y)-box-17 (SOX17), Gata-binding protein 4 (GATA4), forkhead box A2 (FOXA2), pancreatic and duodenal homeobox 1 (PDX1), two Nirenberg and Kim homeobox (NKX) factors, NKX6.1 and NKX2.2, and Neurogenin 3 (NEUROG3, also called NGN3) (5–8,13–15). Nevertheless, if the goal is to differentiate human stem cells by mimicking human development, this approach contains an assumption; namely, that human embryogenesis is very similar, if not identical, to that which occurs in small mammalian, avian, or amphibian species.
Research on human embryos is limited by availability and appropriate ethical restrictions. Previous data mostly arise from studies initiated at 7–8 weeks of fetal development, by which time the two pancreatic buds have coalesced as a single organ, and NEUROG3 detection implies endocrine commitment has already started (16–23). Subsequent profiles of transcription factors have been reported that culminate in the development of human islets from ∼12 weeks of fetal age (18,21,23). In stark contrast, knowledge of earlier events is exceptionally restricted; for instance, the detection of PDX1 in a single dorsal pancreatic bud at ∼4 weeks of development and SOX9 transcripts by mRNA in situ hybridization soon after (20,24). Foregut development, the potential for patterning by nearby structures, and gene expression profiles during pancreatic bud formation, pancreatic growth, and early lineage differentiation has remained unexplored despite being essential for β-cell development. Here, we describe these early developmental events in a series of human embryos. The data help to minimize current interspecies assumptions made about stem cell differentiation, identify simple transcription factor combinations that signify differentiating pancreatic cell types, and provide a reference point for the validity of using stem cells at a particular stage of differentiation to model human developmental mechanisms in vitro.
Human tissue collection.
The collection, use, and storage of human embryonic and fetal tissue (n = 31) was done with ethical approval from the North West Research Ethics Committee, under the codes of practice issued by the Human Tissue Authority and legislation of the U.K. Human Tissue Act 2008. Details on collection and handling are as described previously (20). In brief, human embryos and fetuses were collected from medical and surgical terminations of pregnancy. Specimens for immunohistochemistry were fixed within 1 h in 4% paraformaldehyde before processing and embedding in paraffin wax. Sectioning took place at 5-μm intervals, with every eighth section taken for hematoxylin and eosin staining to confirm morphology and anatomical landmarks.
Immunohistochemistry and cell counting.
Immunohistochemistry was performed as described previously (20) using the primary antibodies listed in Supplementary Table 1 in at least three specimens per stage. For cell counting, cells that were positively stained for nuclear NGN3 or insulin were quantified per total number of pancreatic epithelial cells in at least three tissue sections from at least two embryos or fetuses. The study was restricted to immunohistochemistry using effective commercial antibodies readily available to stem cell researchers. In our hands, this precluded current robust examination of pancreas-specific transcription factor 1A (PTF1A), hepatocyte nuclear factor 1β (HNF1β), hematopoietically expressed homeobox (HHEX), motor neuron and pancreas homeobox 1 (MNX1), GATA6, and ONECUT6, all of which are important for pancreas development (5–8,25–27).
Isolation of RNA, reverse transcription, and real-time quantitative PCR.
Total RNA was isolated, cDNA generated, and quantitative PCR performed as in previous studies from at least three specimens at each stage of late embryonic and early fetal pancreas (47 days postconception [dpc]–10 weeks postconception [wpc]) (17). RNA purity and quantity was assessed using a NanoDrop spectrophotometer (NanoDrop Technologies, Rockland, DE) to measure the 260-to-280 and 260-to-230 ratios of absorbance (nm).
Postimplantation human embryos are classified by Carnegie stage (CS), which uses morphology visible by light microscopy to ascribe stages that can be correlated to embryonic days (e) of mouse development (Supplementary Table 2). At CS9, which occurs at 22–26 dpc and is defined by the presence of up to 4 somite pairs, the definitive endoderm openly communicated along much of the embryo's anterior-posterior axis with the visceral endoderm of the yolk sac (Fig. 1A, long double-headed arrow). However, by CS10 (25–27 dpc; 4–12 somites), folding in the head and "tail" regions and along both flanks had created the blind-ending tubes of foregut and hindgut, thereby restricting the opening of the yolk sac to the intervening midgut (Fig. 1A, short double-headed arrow). The anterior end of this opening constitutes the foregut-midgut boundary and is termed the anterior intestinal portal (AIP). It allows demarcation of the most distal region of foregut from where the dorsal and ventral pancreatic buds (and liver) arise. In three CS10 embryos, the dorsal foregut epithelium at this location was a single cell thick and adjacent to the notochord (Fig. 1B and C). In chick embryos, the immediacy of the notochord causes exclusion of sonic hedgehog (Shh) expression from the dorsal foregut endoderm, which, in turn, allows later expression of Pdx1 and dorsal pancreatic budding (10). A similar exclusion of SHH was visible in human embryos at CS10 (Fig. 1D, arrow), extending across the entire dorsal surface of the endoderm, in contrast to the detection of SHH throughout the thicker pseudostratified epithelium of the ventrolateral endoderm adjacent to the lateral mesoderm (Fig. 1D, arrowhead). This pattern of SHH detection was observed from the level of the second to the ninth somites. Nuclear FOXA2 was present in all of the epithelial cells of the endoderm (Fig. 1E), whereas SOX17 was restricted to the region that lacked SHH (Fig. 1F, arrowhead). At this stage of development, neither GATA4 nor PDX1 were detected in the foregut (Fig. 1G and data not shown).
Early foregut endoderm and its proximity to the notochord. A: Human embryos at CS9/22–26 dpc (the small horizontal arrows indicate three somite pairs) and CS10/25–27 dpc (11 somite pairs, visible in the inset). At CS9, the double-ended arrow highlights the large communication between the gut tube/definitive endoderm and the yolk sac compared with its restriction at CS10 (smaller double-ended arrow). The dashed line indicates the level of the AIP at CS10. Bright-field transverse images at CS 10/25–27 dpc stained with hematoxylin and eosin (B and C) or toluidine blue after immunohistochemistry (brown) for SHH, FOXA2, SOX17, and PDX1 (D–G). Arrows and arrowheads point to absence of and detection of SHH (D) and SOX17 (F), respectively. lm, lateral mesoderm; noto, notochord; nt, neural tube; s, somite. The CS9 embryo is 2 mm in length; scale bars represent 50 μm (B and C–G).
The proximity between notochord and gut is possible until the paired dorsal aortae intervene and fuse in the midline with its surrounding mesoderm, which had occurred by CS12 (29–31 dpc). At this stage, PDX1 was first apparent over stretches of ∼15 cells immediately anterior to the AIP (Fig. 2A–C). In keeping with the thicker ventral wall of the foregut at CS10, the ventral domain of PDX1 contained approximately twice as many cells as its dorsal counterpart. The presumptive duodenal-pancreatic endoderm also contained nuclear GATA4, FOXA2, and SOX17 (Fig. 2D–F). Expression of these three transcription factors extended posterior to the AIP into the distal duodenum/midgut. In contrast, SOX9 was predominantly expressed in the hepatic bud with FOXA2 and was only very weakly colocalized with PDX1 (Fig. 2C, E, G, and I). NKX6.1 and NKX2.2 were not detected in the endoderm at this stage but were detected in the neural tube (Fig. 2H and data not shown).
Pancreatic endoderm in the distal foregut. Sagittal sections of a human embryo at CS 12/29–31 dpc stained with hematoxylin and eosin (A and B) or toluidine blue after immunohistochemistry (brown) for PDX1 (C), GATA4 (D), FOXA2 (E), SOX17 (F), SOX9 (G), and NKX6.1 (H). The boxed area in A is shown at higher magnification in B. I: Dual immunofluorescence at CS12 showing minimal PDX1 (red) and SOX9 (green) colocalization. d, duodenum; dp, dorsal pancreatic endoderm; hb, hepatic bud; scv, right subcardinal vein; vp, ventral pancreatic endoderm. Scale bars represent 200 µm (A), 100 µm (B–H), and 50 µm (I).
At CS13 (30–33 dpc), distinct buds of dorsal and ventral pancreas were visible, the latter lying just posterior to the embryonic gall bladder (Fig. 3A and B). Both pancreatic buds were within a few cells from the ventral and dorsal anastomoses of the left and right vitelline veins, which eventually form the portal vein, and contained microlumens (Fig. 3D, inset). Ventral and dorsal pancreatic cells and the intervening duodenum were uniformly positive for nuclear PDX1, with weaker staining extending into the extrahepatic biliary duct and the gall bladder (Fig. 3C). GATA4 was also apparent within pancreatic and duodenal cells and was extended into the gall bladder but was barely detected in the extrahepatic biliary duct (Fig. 3D). It was also present in the mesenchymal cells surrounding the hepatic cords and gallbladder. SOX9 was extensively detected in the dorsal and ventral pancreas as well as in the extrahepatic biliary duct but was only weakly detected in the duodenum and gall bladder (Fig. 3E). At this stage, pancreatic NKX6.1 was first detected, most readily in the dorsal bud, but NKX2.2 remained absent (Fig. 3F and data not shown). In line with earlier (and later stages), FOXA2 uniformly stained all epithelial cell nuclei in the branching hepatic cords, extrahepatic biliary duct, duodenum, and pancreas; in contrast, SOX17 was no longer detected at this or later stages within the duodenum or pancreas but was present in the embryonic gallbladder (data not shown).
Pancreatic bud formation. Sagittal sections of a human embryo at CS 13/30–33 dpc stained with hematoxylin and eosin (A and B) or toluidine blue after immunohistochemistry (brown) for PDX1 (C), GATA4 (D), SOX9 (E), and NKX6.1 (F). The boxed area in A is shown at higher magnification in B. The inset in D demonstrates microlumen formation. dp, dorsal pancreatic bud; vp, ventral pancreatic bud; hc, hepatic cords; gb, gallbladder; d, duodenum; ehbd, extrahepatic bile duct; pv, portal vein. Scale bars represent 200 µm (A) and 100 µm (B–F).
By CS15 (35–37 dpc), the pancreas was widely separated from the aorta; however, gut rotation had brought both ventral and dorsal pancreatic buds to either side of the portal vein (Fig. 4A–C). The epithelial cells contained nuclei that stained uniformly for PDX1, FOXA2, SOX9, and NKX6.1 (Fig. 4D, F–H). GATA4 was present in the stomach epithelium (Fig. 4E, inset) but was barely detected in the pancreas compared with levels found at CS13, except for some occasional stained nuclei scattered throughout the pancreas (Fig. 4E, arrow). These transcription factor profiles were the same at CS16 (37–40 dpc; Fig. 4I–K and data not shown), by which time the epithelium was mostly one or two cells thick and clearly branched, with peripheral and more centrally located cells (Fig. 4I–K). As in earlier stages, NKX2.2 was not detected in the pancreas (Fig. 4L) but was present in the ventral neural tube (Fig. 4M). The lack of pancreatic NKX2.2 corresponded to negligible pancreatic reads (<1 read per kilobase per million base pairs) for NKX2.2 transcripts in unpublished RNA-seq datasets at CS13–15).
Development of a branched embryonic pancreas. A: Human embryo at CS15/35–37 dpc. The broken line in A shows the level of the transverse section in B. B: Transverse section stained with hematoxylin and eosin; the boxed area containing the pancreas is shown at higher magnification in C. Note the separation of aorta from the pancreas. Sections stained with toluidine blue after immunohistochemistry (brown) for PDX1 (D), GATA4 (E, arrow shows positive nucleus), FOXA2 (F), SOX9 (G), and NKX6.1 (H). The inset in E demonstrates positive GATA4 staining in stomach epithelium. Sections of a human embryo at CS16/37–40 dpc stained with toluidine blue after immunohistochemistry (brown) for FOXA2 (I), SOX9 (J), NKX6.1 (K), and NKX2.2 (L and M). Note the lack of detection of NKX2.2 in pancreas (L) compared with ventral neural tube (M). ao, aorta; d, duodenum; dp/vp, dorsal/ventral pancreas; ml, microlumen; pv, portal vein; s, stomach; sp, spinal cord. Scale bars represent 200 μm (B), 50 µm (C and D–L), and 25 µm (M).
During mouse development, commitment of the acinar cell lineage from the pool of multipotent progenitor cells is largely complete by ∼ e14 (13,28–30). These cells, located at the tips of a branched pancreas, contain Gata4 but lack Nkx6.1 and Sox9 compared with the trunk cells that express Nkx6.1 and Sox9 but lack Gata4 (13,29–32). During human development at CS19 (45–47 dpc) GATA4 was clearly apparent for the first time in the nuclei of some peripheral cells but was restricted from the central trunks (Fig. 5A). Cells in both locations still contained nuclear NKX6.1, FOXA2, and SOX9 at CS19 and CS21 (49–52 dpc), when the peripheral GATA4-positive tip cells also immunostained for carboxypeptidase A1 (CPA1; Fig. 5B–G, and data not shown). By 10 wpc (∼2.5 weeks later), the CPA1/GATA4-positive tip cells uniformly lacked NKX6.1 (data not shown) and mostly lacked SOX9 (Fig. 5H). By 14 wpc, GATA4 and SOX9 detection was almost entirely mutually exclusive, implying terminal differentiation of GATA4-containing acinar cells surrounding SOX9-positive centroacinar (and ductal) cells (Fig. 5I).
Differentiation of the exocrine lineage. Sections through the pancreas of a human embryo at CS19/45–47 dpc stained with toluidine blue after immunohistochemistry (brown) for GATA4 (A), NKX6.1 (B), FOXA2 (C), and SOX9 (D) or immunofluorescence for GATA4 (red) and NKX6.1 (green) (E). Sections through the pancreas at CS21/49–52 dpc (F and G), 10 wpc (H), and 14 wpc (I). Immunofluorescence is shown for GATA4 (red) and SOX9 or CPA1 (green). Scale bars represent 50 µm (A–D), 25 µm (E–H).
In mouse, cells in the trunk domain are characterized by Nkx6.1, Sox9, and Hnf1β expression and possess the potential for duct or, if they transiently produce Neurog3, endocrine differentiation (5–8,13,29,33). Murine Neurog3 expression is biphasic, with an initial wave from e8.5 to e11 (34). The second phase starts at e12, peaks at e15.5, and is much reduced by e18.5. We did not detect NEUROG3, insulin, or glucagon as protein or transcripts to correlate with the first phase of expression in mouse (Supplementary Fig. 1). The increase in NEUROG3 expression and of NEUROG3-positive cells during late embryogenesis was closely timed to the appearance of fetal insulin (Fig. 6A and B). Compared with CS20–21 (47–52 dpc), NEUROG3 transcripts had increased 3.6-fold by 8–8.5 wpc and 6.1-fold by 9–10 wpc, with corresponding increases in INSULIN of 34-fold and 193-fold. Cell counting at the same time points produced increases of 59- and 102-fold for NEUROG3-positive cells and 140- and 684-fold for insulin-positive cells. Nuclear SOX9 was absent in all cells with robust NEUROG3 detection (Fig. 6C) and in insulin-positive cells (data not shown); however, by increasing the imaging gain and using more concentrated primary antibody, a weak anti-NEUROG3 signal could be gained in some SOX9-positive cells. Clusters of fetal β-cells were apparent at 10 wpc (Fig. 6D), which contained NKX2.2, FOXA2, and NKX6.1 in serial sections (Fig. 6E–G); however, as in earlier embryogenesis, NKX2.2 was absent from the trunk progenitor domain (Fig. 6E, arrow) that contained FOXA2, NKX6.1 (Fig. 6F and G, arrow), and SOX9 (Fig. 6C). These data were confirmed by immunofluorescence, which showed NKX2.2 was largely restricted to β-cells at 10 wpc (Fig. 6H), whereas NKX6.1 still colocalized extensively with SOX9 in duct-like cells as well as with insulin in β-cells at 14 wpc (Fig. 6I and J).
Early differentiation of the endocrine lineage. Quantification of the onset of NEUROG3 and INSULIN expression by quantitative PCR (A) and cell count per total pancreatic epithelial cell number (B) in human pancreas from 47–52 dpc to 9–10 wpc. Bars show mean ± SE from at least two specimens. C: Sections through the pancreas at 10 wpc after immunofluorescence for SOX9 (green) and NEUROG3 (red). Arrows point to nuclei robustly stained for NEUROG3 and negative for SOX9; arrowheads show weak anti-NEUROG3 immunoreactivity in SOX9-positive cells. Serial sections through the pancreas at 10 wpc stained with toluidine blue after immunohistochemistry (brown) for insulin (D), NKX2.2 (E), FOXA2 (F), and NKX6.1 (G). Arrows in E and G point to duct-like epithelium negative for NKX2.2 but stained for NKX6.1. Sections through the pancreas at 10 wpc (H) and 14 wpc (I and J) after dual immunofluorescence for insulin (green) with NKX2.2 or NKX6.1 (red) (H and I), and NKX6.1 (red) with SOX9 (green) (J). Scale bars represent 25 µm (C–J).
By the time pregnancy can be confirmed biochemically (i.e., once menstruation has been clearly postponed), the embryo has most commonly developed for 3 weeks or longer. Under ethically approved programs of accessing human material from social or voluntary termination of pregnancy, it is thus impossible to research gastrulation and very early lineage commitment (35). Thereafter, potential comparison can be made with early events in model species, although such reports in human tissue are rare. This study aimed to describe human pancreas development up to and including endocrine commitment, after which other reports have detailed the appearance of NEUROG3 and subsequent islet development (16–23). The purpose was to complement data acquired in mouse and chick models (5–8) and to provide defining features of the early human pancreas to match the growing need for assessment of human stem cells differentiated to different points along the pathway to a pancreatic β-cell fate (2,4) (Table 1 and Fig. 7).
After gastrulation, the earliest patterning event leading to pancreas development is the exclusion of SHH from the dorsal endoderm where it contacts the notochord. This was originally described in chick and is mediated in part by activin signaling from the notochord (10). In human embryos, just before 3 weeks of development (CS10), the extent of SHH exclusion was consistent with fate mapping in chick, which demonstrated that the dorsal pancreas is made up of endoderm cells that originated from between the third and ninth somites (6). Additional patterning of pancreatic endoderm comes from vessels. In mouse and chick, the dorsal aorta induces pancreas development and, specifically, promotes insulin expression in the dorsal pancreatic endoderm (11). This occurs before separation of the pancreatic endoderm from the two aortae by the intervening splanchnic mesoderm (36). At the level of the AIP, the paired dorsal aorta did not contact the dorsal endoderm, perhaps explaining why an early phase of endocrine differentiation was not apparent at this site in human embryos by insulin, glucagon, or NEUROG3 detection. GATA4 was not apparent in the foregut at CS10 (when it was robustly detected in developing human heart; data not shown), which was surprising when it is one of the key factors for gut closure in mouse (37,38). In mouse, Sox17 has been variably reported as absent from the foregut at e8.5 (39) or colocalized with Pdx1 in ventral endoderm, before becoming restricted to the primordial gall bladder by e10.5 (40). This latter study corresponds to our data in human embryos at CS12 (29–31 dpc) and in the embryonic gallbladder at CS13 (30–33 dpc). However, before this, SOX17 was also detected in the SHH-negative cells of dorsal foregut at CS10 (which corresponds to e8–8.5; Supplementary Table 2) at the level of the AIP (Fig. 1F) and more cranially (Supplementary Fig. 2).
Acquiring multipotent pancreatic progenitors is a key step in the differentiation of human ESCs/IPSCs toward the pancreatic β-cell (1,2,4). From studies mostly in mouse, several transcription factors are critical for establishment and proliferation of multipotent pancreatic progenitors, including Pdx1, Ptf1a, Sox9, Mnx1, and Foxa2 (5–8,41). In human embryos, robust PDX1 detection was initially accompanied by only very weak detection of SOX9 in presumptive pancreatic endoderm, which by CS12 (29–31 dpc) also expressed GATA4, SOX17, and FOXA2. Recent data in mouse have shown that Gata factors are required at least in part for appropriate Pdx1 expression (25) if not its initiation (26). After this, SOX17 was lost from the pancreatic buds, SOX9 was strongly detected, and NKX6.1 was first apparent. From our examinations over the next 2 weeks, this profile of PDX1, SOX9, NKX6.1, and FOXA2 would distinguish multipotent pancreatic progenitors in human ESC/IPSC differentiation protocols (without NKX6.1, a combination of FOXA2, SOX9, and weak PDX1 detection could indicate extrahepatic biliary duct cells) (Fig. 7). Previously, NKX6.1 has only been reported in human pancreas with the onset of β-cell differentiation (18). An unexpected difference from studies in mouse was the absence of pancreatic NKX2.2 in human embryos before endocrine differentiation. Although Nkx2.2 is present in multipotent progenitors in mouse (14), our data are consistent with it being dispensable for pancreatic progenitor development but essential for β-cell formation (14,15) (Table 1). Endocrine commitment, by virtue of nuclear NEUROG3 detection in central pancreatic epithelial cells, commenced at the end of the embryonic period tightly correlated to the appearance of fetal β-cells containing insulin. From our data here and previous observations (17,18,20,23), the detection of NEUROG3 in differentiating human ESCs/IPSCs should correlate with the loss of SOX9 and the subsequent detection of nuclear NKX2.2, NKX6.1, PDX1, and ISL1.
Our data demonstrate that the phases of pancreas development are the same between mouse and human, with the demarcation of pancreatic domains in the ventral and dorsal foregut, bud formation, and outgrowth, followed by differentiation of the separate pancreatic lineages (5–8). However, differences in timing are apparent between the two species. This is not simply a reflection of longer human gestation, because embryogenesis can be compared directly across species (Supplementary Table 2). In human embryos, PDX1 was only detected after the endoderm was separated from the notochord and aorta(e) by mesenchyme. In mouse, it occurs earlier (e8.5–8.75, 10 somite pairs) while the dorsal foregut still contacts these structures (42) (the CS10 human embryo in Fig. 1, which lacked PDX1, already contained 11 somite pairs). Transcription factor profiles were also slow to resolve during acinar differentiation. In mouse, Gata4-positive acinar cells arise from multipotent precursors that expressed Pdx1, Hnf1b, Ptf1a, Sox9, and Nkx6.1 (5–8,41). The commitment of these cells with the exclusion of Nkx6.1 and Sox9 is largely complete by e14–e14.5 (13,28,29,33), which corresponds to approximately CS19 (45–47 dpc). In human pancreas, however, these peripheral GATA4-positive cells uniformly possessed NKX6.1 and SOX9 at CS19 and for at least another week of development (CS21 [49–52 dpc], when they also contained CPA1). GATA4 expression still overlapped partially with SOX9 expression at 10 wpc. It was only by 14 wpc that expression profiles for GATA4 and SOX9 had fully resolved to acinar and centroacinar populations, respectively. Thus, differentiating human ESCs/IPSCs, which according to mouse development seemingly possess a mixed profile of transcription factors, might actually still represent normal human development rather than an aberrant cell type.
Comparison of pancreas development between mouse and human
In summary, our data do not support an early phase of endocrine differentiation in human embryos analogous to primary transition during mouse development, and we did not observe NKX2.2 in the pancreatic progenitor population before endocrine commitment. Instead, the current data provide combinations of transcription factors directly in human tissue that can describe the different cell types and stages of early human pancreas development (Fig. 7). We anticipate that this combinatorial approach using commercial reagents will assist in the characterization of cells differentiated in vitro from human ESCs/IPSCs toward pancreatic β-cells.
Transcription factors to define different cell types and stages of differentiation for the early human pancreas. Combinations of transcription factors (plus SHH and insulin) are shown to identify different cell types and stages of development for the foregut, extrahepatic biliary duct, and pancreas based on the current data and previous immunohistochemical studies by us and others (18,20,23).
R.E.J. is a Medical Research Council (MRC) clinical training fellow. N.A.H. is a Wellcome Trust senior fellow in clinical science (WT088566MA). R.J.S. is an MRC doctoral account PhD student. N.A.R. held a Kerkut Trust PhD studentship awarded to K.P.H. This work was also supported by an Innovation Grant from the Juvenile Diabetes Research Foundation, the Manchester Biomedical Research Centre, and a Wellcome Trust Institutional Strategic Support Fund (WT097820MF).
No potential conflicts of interest relevant to this article were reported.
R.E.J., A.A.B, R.K.-W., N.A.R., T.H., R.J.S., J.B., and N.A.H. researched data. R.E.J. and N.A.H. co-wrote the manuscript. K.P.H. reviewed and edited the manuscript and contributed to discussion. N.A.H. oversaw the collection of human material. N.A.H. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
The authors are grateful for the assistance of research nurses, Cellins Vinod and Leena Abi, and clinical colleagues at St. Mary's Hospital and Central Manchester University Hospitals National Health Service Foundation Trust.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1479/-/DC1.
© 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
Best M,
Carroll M,
Hanley NA,
Piper Hanley K
. Embryonic stem cells to beta-cells by understanding pancreas development. Mol Cell Endocrinol 2008;288:86–94pmid:18487011
Docherty K,
Bernardo AS,
Vallier L
. Embryonic stem cell therapy for diabetes mellitus. Semin Cell Dev Biol 2007;18:827–838pmid:17959396
D'Amour KA,
Agulnick AD,
Eliazer S,
Kelly OG,
Kroon E,
Baetge EE
. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 2005;23:1534–1541pmid:16258519
Martinson LA,
Kadoya K,
. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008;26:443–452pmid:18288110
Murtaugh LC
. Pancreas and beta-cell development: from the actual to the possible. Development 2007;134:427–438pmid:17185316
Jørgensen MC,
Ahnfelt-Rønne J,
Hald J,
Madsen OD,
Serup P,
Hecksher-Sørensen J
. An illustrated review of early pancreas development in the mouse. Endocr Rev 2007;28:685–705pmid:17881611
Gittes GK
. Developmental biology of the pancreas: a comprehensive review. Dev Biol 2009;326:4–35pmid:19013144
Pan FC,
Wright C
. Pancreas organogenesis: from bud to plexus to gland. Dev Dyn 2011;240:530–565pmid:21337462
Kim SK,
Hebrok M,
Melton DA
. Notochord to endoderm signaling is required for pancreas development. Development 1997;124:4243–4252pmid:9334273
. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev 1998;12:1705–1713pmid:9620856
Lammert E,
Cleaver O,
Melton D
. Induction of pancreatic differentiation by signals from blood vessels. Science 2001;294:564–567pmid:11577200
Dor Y
. Vascular instruction of pancreas development. Development 2012;139:2833–2843pmid:22833471
Schaffer AE,
Freude KK,
Nelson SB,
Sander M
. Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev Cell 2010;18:1022–1029pmid:20627083
Sussel L,
Kalamaras J,
Hartigan-O'Connor DJ,
. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development 1998;125:2213–2221pmid:9584121
Prado CL,
Pugh-Bernard AE,
Elghazi L,
Sosa-Pineda B,
Sussel L
. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci U S A 2004;101:2924–2929pmid:14970313
Castaing M,
Duvillié B,
Quemeneur E,
Basmaciogullari A,
Scharfmann R
. Ex vivo analysis of acinar and endocrine cell development in the human embryonic pancreas. Dev Dyn 2005;234:339–345pmid:16134081
Piper Hanley K,
Hearn T,
Berry A,
. In vitro expression of NGN3 identifies RAB3B as the predominant Ras-associated GTP-binding protein 3 family member in human islets. J Endocrinol 2010;207:151–161pmid:20807725
Lyttle BM,
Li J,
Krishnamurthy M,
. Transcription factor expression in the developing human fetal endocrine pancreas. Diabetologia 2008;51:1169–1180pmid:18491072
Polak M,
Bouchareb-Banaei L,
Scharfmann R,
Czernichow P
. Early pattern of differentiation in the human pancreas. Diabetes 2000;49:225–232pmid:10868939
Piper K,
Brickwood S,
Turnpenny LW,
. Beta cell differentiation during early human pancreas development. J Endocrinol 2004;181:11–23pmid:15072563
Sarkar SA,
Kobberup S,
Wong R,
. Global gene expression profiling and histochemical analysis of the developing human fetal pancreas. Diabetologia 2008;51:285–297pmid:18094957
Sugiyama T,
Rodriguez RT,
McLean GW,
Kim SK
. Conserved markers of fetal pancreatic epithelium permit prospective isolation of islet progenitor cells by FACS. Proc Natl Acad Sci U S A 2007;104:175–180pmid:17190805
Jeon J,
Correa-Medina M,
Ricordi C,
Edlund H,
Diez JA
. Endocrine cell clustering during human pancreas development. J Histochem Cytochem 2009;57:811–824pmid:19365093
Ball SG,
Keeling JW,
Mansoor S,
Wilson DI,
Hanley NA
. Novel SOX9 expression during human pancreas development correlates to abnormalities in Campomelic dysplasia. Mech Dev 2002;116:223–226pmid:12128229
Carrasco M,
Delgado I,
Soria B,
Martín F,
Rojas A
. GATA4 and GATA6 control mouse pancreas organogenesis. J Clin Invest 2012;122:3504–3515pmid:23006330
Xuan S,
Borok MJ,
Decker KJ,
. Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis. J Clin Invest 2012;122:3516–3528pmid:23006325
Lango Allen H,
Flanagan SE,
Shaw-Smith C,
et al.,
International Pancreatic Agenesis Consortium
. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet 2012;44:20–22pmid:22158542
Cleveland MH,
Sawyer JM,
Afelik S,
Jensen J,
Leach SD
. Exocrine ontogenies: on the development of pancreatic acinar, ductal and centroacinar cells. Semin Cell Dev Biol 2012;23:711–719pmid:22743232
Solar M,
Cardalda C,
Houbracken I,
. Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev Cell 2009;17:849–860pmid:20059954
Zhou Q,
Law AC,
Rajagopal J,
Anderson WJ,
Gray PA,
. A multipotent progenitor domain guides pancreatic organogenesis. Dev Cell 2007;13:103–114pmid:17609113
Ketola I,
Otonkoski T,
Pulkkinen MA,
. Transcription factor GATA-6 is expressed in the endocrine and GATA-4 in the exocrine pancreas. Mol Cell Endocrinol 2004;226:51–57pmid:15489005
Decker K,
Goldman DC,
Grasch CL,
. Gata6 is an important regulator of mouse pancreas development. Dev Biol 2006;298:415–429pmid:16887115
Seymour PA,
Tran MN,
. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci U S A 2007;104:1865–1870pmid:17267606
Villasenor A,
Chong DC,
Cleaver O
. Biphasic Ngn3 expression in the developing pancreas. Dev Dyn 2008;237:3270–3279pmid:18924236
Ostrer H,
. Human embryo and early fetus research. Clin Genet 2006;70:98–107pmid:16879189
Miralles F,
Czernichow P,
Ozaki K,
Itoh N,
. Signaling through fibroblast growth factor receptor 2b plays a key role in the development of the exocrine pancreas. Proc Natl Acad Sci U S A 1999;96:6267–6272pmid:10339576
Kuo CT,
Morrisey EE,
Anandappa R,
. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 1997;11:1048–1060pmid:9136932
Molkentin JD,
Lin Q,
Duncan SA,
Olson EN
. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev 1997;11:1061–1072pmid:9136933
Kanai-Azuma M,
Kanai Y,
Gad JM,
. Depletion of definitive gut endoderm in Sox17-null mutant mice. Development 2002;129:2367–2379pmid:11973269
Spence JR,
Lange AW,
Lin SC,
. Sox17 regulates organ lineage segregation of ventral foregut progenitor cells. Dev Cell 2009;17:62–74pmid:19619492
Rodríguez-Seguí S,
Akerman I,
Ferrer J
. GATA believe it: new essential regulators of pancreas development. J Clin Invest 2012;122:3469–3471pmid:23006323
Pedersen JK,
Jorgensen MC,
Beta Cell Biology Consortium
. Endodermal expression of Nkx6 genes depends differentially on Pdx1. Dev Biol 2005;288:487–501pmid:16297379
Watt AJ,
Zhao R,
Duncan SA
. Development of the mammalian liver and ventral pancreas is dependent on GATA4. BMC Dev Biol 2007;7:37pmid:17451603
October 2013, 62(10)
You are going to email the following Development of the Human Pancreas From Foregut to Endocrine Commitment
Rachel E. Jennings, Andrew A. Berry, Rebecca Kirkwood-Wilson, Neil A. Roberts, Thomas Hearn, Rachel J. Salisbury, Jennifer Blaylock, Karen Piper Hanley, Neil A. Hanley
Diabetes Oct 2013, 62 (10) 3514-3522; DOI: 10.2337/db12-1479
Osteoprotegerin Promotes Liver Steatosis by Targeting the ERK-PPARγ-CD36 Pathway
Myc Is Required for Adaptive ß-Cell Replication in Young Mice but Is not Sufficient in One-Year-Old Mice Fed with a High-Fat Diet
Overexpression of Circulating Soluble Nogo-B Improves Diabetic Kidney Disease by Protecting the Vasculature
Show more Original Research
Islet Studies
Central and Peripheral Administration of Fibroblast Growth Factor 1 Improves Pancreatic Islet Insulin Secretion in Diabetic Mouse Models
Heterogeneity of the Human Pancreatic Islet
Posttransplant Characterization of Long-term Functional hESC-Derived Pancreatic Endoderm Grafts
Show more Islet Studies


Andre Iguodala has some company on the Warriors' injury report ahead of Game 5 in Houston on Thursday night.
"Klay's moving aroound really well. I think Klay's going to be fine," Steve Kerr said following practice on Wednesday in Houston.
"He's feeling a little better today. And he's out on the floor, not doing a whole lot, but making progress," Kerr said.
Thompson's injury occurred in the first minute of the second quarter on Tuesday. As he drove to the basket against Rockets center Clint Capela, he landed awkwardly and fell to the court. He stay in the game, but was quickly removed and went to the locker room with the Warriors trainers. Though the team diagnosed him with a left knee strain, Thompson returned to the game and played 39 total minutes.


text:
Miscellaneous scientific news/publications
The Damaged Planet – Symposium with international guests at KHM
With Leonie Bremer, Alenda Y. Chang, Peter Emorinken-Donatus, Thom van Dooren, Fabiana Fragale, Beate Gütschow, Carmen Hornbostel, Kilian Kuhlendahl, Jens Mühlhoff, Milo Rau, Doris Schweitzer, Nicole Seymour, Esteban Servat, Agnes Stillger, Louise Wagner, Markus Wissen.
Friday and Saturday, May 6 and 7, 2022, Aula and Online
Filzengraben 2, 50676 Köln
Registration via: thedamagedplanet2022@khm.de
Opportunities for action in the climate crisis are being discussed worldwide: many political processes have been initiated, the EU is working on a Green Deal, and some countries have begun to convert to a CO2-neutral energy supply. Nevertheless, the limited time window available for a global ecological transformation is not being taken into account; the prevention of extinction of species as the second fundamental pillar for survival continues to be ignored. Questions of social justice arise: how can we ensure that the upcoming transformation does not disproportionately burden lower and middle incomes? What is a fair compensation for the damage already caused in the countries of the Global South? The willingness to radically rethink the economy and society is missing. At the same time, excessive political and private-sector green-washing is taking place wherever we look. At our conference, we want to meet these challenges with radical approaches and concrete action.
The event starts with theatre makers Carmen Hornbostel and Milo Rau, who consider their ecosocial work at NTGent to be a collaboration with activist groups. The artist Beate Gütschow, who teaches at the KHM, is linking political and artistic commitment in her photographic work as well. Students and alumni of the KHM Fabiana Fragale, Jens Mühlhoff and Kilian Kuhlendahl present a film about activism in Germany, created from footage filmed by Steffen Meyn during the occupation of the Hambach Forest, where he tragically died in 2018. The activists Leonie Bremer, Peter Emorinken-Donatus, Esteban Servat and Louise Wagner report on their actions collectively. The film and media scholar Alenda Y. Chang deals with ecology in video games and advocates for a media-mediated representation of the interests of endangered species. With his Multispecies Ethnographies, philosopher and author Thom van Doorenpresents an ethics of care in which knowledge is not disconnected from one's own actions. The literary scholar Nicole Seymour looks at emotions in eco-art, activism and discourse from a queer-feminist perspective and asks if there are also counterproductive narratives of the ecological crisis. Agnes Stilliger, art historian and ethnologist, talks about environmental racism and de-colonial art practices in Africa. Political scientist Markus Wissen and legal sociologist Doris Schweitzer ask how economy and law can be re-imagined and make a strong plea for an alternative economy beyond profit, including a new law for/of nature.
12:00 - 12:30, Introduction
12:30 - 13:45, Carmen Hornbostel / Milo Rau (NT Gent) – A Theater of Sustainability? Production, Distribution, Theory, Politics
14:00 - 15:00, Fabiana Fragale, Jens Mühlhoff and Kilian Kuhlendahl (Kunsthochschule für Medien Köln) – A struggle with bodies and images
15:30 - 16:30, Leonie Bremer, Peter Emorinken-Donatus, Esteban Servat and Louise Wagner - Panel discussion with activists from Fridays for Future, Bündnis Ökozidgesetz, Shell Must Fall, Ende Gelände
16:45 - 18:00, Doris Schweitzer (Goethe-Universität Frankfurt) – "Rights of Nature" as a critical intervention?
18:30 - 19:45, Markus Wissen (Hochschule für Wirtschaft und Recht Berlin) – Imperial and solidary way of life
10:30 - 11:45, Agnes Stillger (Universität zu Köln) – For the preservation of the balance of all living things. Ecology-critical art practices in Africa
12:00 - 13:15, Thom van Dooren (University of Sydney) – Stories from the Snail Ark: Hope in a Time of Loss
14:30 - 15:45, Beate Gütschow (Kunsthochschule für Medien Köln) – Report from the research sabbatical
16:00 - 17:15, Alenda Y. Chang (University of California, Santa Barbara) – Cloudy with a Chance of Play
17:30 - 18:45, Nicole Seymour (California State University, Fullerton) – Climate Change and the Limits of Satire
19:00, Closing discussion
Organizers: Pascal Dreier, Beate Gütschow, Thomas Hawranke, Ute Hörner, Fatima Kastner, Isabell Lorey and Kathrin Röggla.
https://en.khm.de/termine/news.5321.the-damaged-planet-symposium-with-international-guests-at-khm/
Dr. Juliane Kuhn


From 27 October to 1 November 2007, Milan will be hosting the "Sport Movies & TV 2007 - 25th Milano International FICTS Festival". The International Sports Movies and Television Federation (FICTS), representing more than 100 countries, and recognised by the International Olympic Committee (IOC), is organising this international event.
"Sport Movies & TV 2007" will be 10 hours a day of sporting spectacle told by the cinema and television for 200,000 spectators over six days. Six whole days of promoting sports culture through videos, documentaries, reportages, fiction, and TV ads.
During the Festival, the films produced by television networks, production companies, National Olympic Committees and International Sports Federations will be competing for the "Garland of Honour" in several categories, including "Olympic spirit", "Documentaries", "TV Programmes", "Cinema" and "Sports Advertising".
The FICTS International Festival enables the IOC to make available to competitors and exhibition designers its unique collection of images (photos and videos). The Olympic institution sees this as part of its mission to disseminate the Olympic values of excellence, friendship and respect. An excellent example of how sports culture and the Olympic spirit can be experienced on a daily basis, not just when the Games are held.
- realising together with the Association of National Olympic Committees (ANOC) and the General Association of International Sports Federations (GAISF) a wide network of free distribution of technical-didactic audiovisuals to give help above all to those countries where there is no possibility to promote and spread the practice of sport as an educational and social necessity.


The following is a list of tasks and guidelines to help you prepare your site for your new building.
Choose a location that will allow proper water drainage from all four corners of your building.
If you are planning on having wall light panels installed, take into consideration the amount of sunlight that particular location will have.
Design the building with usage and cosmetic appeal in mind. Confirm with your sales representative size requirements and building classification (commercial or farm/country residential).
Obtain appropriate building blueprints for the project if required. Most commercial structures will require fire rating options.
Obtain a development permit from the appropriate authority if necessary.
Ensure your financing is in place prior to construction to avoid any delays.
Ask us about our leasing option.
A building contract must be signed prior to the building being ordered and construction date established. A deposit will be taken at this time.
Identify and locate all owner-installed utilities as well as utility company services. Call before you dig.
Remove all organic material and level site within six inches across all perimeter points of the building. Arrange to have gravel delivered as per your contract and place outside of the building footprint.
The construction crew requires 15' clearance around the perimeter of your building. A suitable staging area for the building materials is also required within close proximity of the building site. Confirm these details with your sales representative.
Please provide a trailer or dumpster to dispose of any remaining construction garbage. Construction crew will pick up any visible nails on the ground.
Backfill topsoil or gravel around perimeter of the building to ensure proper water drainage is maintained.


Import from Germany. New and never played 7" on white or black vinyl (opened to confirm color).
"Heralding Alcest's "Shelter" (to be released in January 2014), the 7" vinyl single "Opale" already offers a first glimpse into the upcoming album. There are 500 copies in black vinyl and 500 copies in white vinyl and the B-side of both editions is emblazoned with an etching.


text:
Dow Reclaims Breakeven Level, S&P on Track for Best August in Decades
The S&P 500 is eyeing its biggest August gain since 1986
IXIC
All major benchmarks closed at least 2% higher for the week
All major indexes finished another record-breaking week on a high note. The Dow finally claimed its year-to-date break even level, jumping over 200 points in intraday trading and erasing its 2020 losses as Intel (INTC) and Walmart (WMT) led the way higher. Meanwhile, the S&P 500 is on track to capture its biggest August jump since 1986, and the Nasdaq finished with substantial gains thanks to a strong technology sector. For the week, all three benchmarks were up at least 2%, with the S&P 500 and Nasdaq scoring their fifth-straight weekly win.
Bull notes pushed Workday stock to a record high.
These are 10 mistakes to avoid when trading options.
Plus, a soda stock popped after a restructuring plan; Kellogg stock valued as compelling; and our latest podcast discusses why volatility is your best friend.
The Dow Jones Industrial Average (DJI - 28,653.87) gained 161.6 points, or 0.6% for the day, and 2.6% for the week. Coca-Cola (KO) finished with a 3.3% jump, pacing the 24 gainers. Walgreens Boots Alliance (WBA) paced the eight laggards with a 1.5% fall.
Meanwhile, the S&P 500 Index (SPX - 3,508.01) added 23.5 points, or 0.7% for the day, and up 3.3% for the week. The Nasdaq Composite (IXIC - 11,695.63) added 70.3 points, or 0.6% for today's session, and 3.4% for the week.
Lastly, the Cboe Volatility Index (VIX - 22.96) lost 1.5 point, or 6.2%, for the day. It added 1.8% for the week.
The U.S. technology sector is now more valuable than the entire European stock market, though less than 15 years ago that market was four times larger. (CNBC)
The Trump administration struck a multi-million dollar deal with Abbott Laboratories (ABT) to buy 150 million rapid coronavirus tests. (MarketWatch)
Coca-Cola will soon offer 4,000 employees a voluntary leave package.
An analyst said Kellogg stock has room to grow in the coming quarters.
Our latest podcast episode brings you Tony Battista of Tastytrade.com.
Data courtesy of Trade-Alert
Oil Drops as Hurricane Laura Spares Oil Rigs
Oil futures finished the week higher for the fourth time in a row. However, prices settled lower on Friday after Hurricane Laura spared refineries in the Gulf of Mexico, with production at the heart of the U.S. oil-processing industry expected to rebound quickly. As a result, October-dated crude was down 7 cents, or 0.2%, to end at $42.97 a barrel for the day, and up 1.5% for the week.
Meanwhile, gold prices finished the day higher as investors processed the Federal Reserve's policy shift, which will allow employment and inflation to run hotter. Concerns revolving around the pandemic and the upcoming elections also contributed to the safe-haven asset's popularity. Gold for December, which is the most-active contract, added $42.30, or 2.2%, to settle at $1,974.90 an ounce. It finished the week with a 1.4% gain.


This event is now sold-out. Please contact the ACT Officer at 604-205-5467 to be added to a wait list.
Dr. Kenneth Cole is a Registered Psychologist with the Sunny Hill Health Centre at the Children's Hospital of British Columbia. He is also a District Psychologist in School District #36 (Surrey) and in addition he provides ASD training Province-wide from the Provincial Outreach Program for Autism and Related Disorders (POPARD) for the Ministry of Education.
Dr. Cole was recently honoured with the Stenberg College President's Award. This award is presented annually by the College to a healthcare and human services professional who has inspired our community through their actions and words.
Using an energetic and engaging training style, "Dr. Ken" supports course participants in learning how they might provide strategic and caring support for some of our most unique students, neighbours, friends and family members.
Note: This course is also being offered October 29th to November 2nd, 2018 in Vancouver.
Please note that the MCFD Parent Bursary funding has been exhausted. Since April 1, 2017, ACT has used MCFD Parent Bursary funding to provide bursaries in the form of reduced registration to families & caregivers from across B.C. to enable them to build their skills by accessing training. Regular registration rates are now in effect however parents of children with ASD are welcome to apply for an ACT Bursary if the registration cost is a barrier preventing attendance.
The Surrey School District Education Centre (DEC) is located on the corner of 140 Street and 92 Avenue in Surrey, B.C. A full service cafeteria is on site and the lunch area is equipped with microwave/toaster ovens for use.
Transit accessible, the venue is approximately a ten minute bus ride from Surrey Central SkyTrain Station (#325 Newton Exchange) and King George SkyTrain Station (#326 Guildford). Please visit the Translink website for directions and schedules for the SkyTrain and bus routes.


The LandSafe program is targeted to participants ages 12 and older. Please inquire if a Junior LandSafe Clinic(ages 6-12) will be offered at this location as well.
Follow the prompts to sign up and choose your method of payment to reserve your spot. You will have the option to pay via charge card or mail a check.
LandSafe is an unmounted 2 day (approx. 4 hrs per day) training program designed to teach the best practices of fall prevention and response. The curriculum relies on one-on-one interaction as well as group learning. Riders receive ample time on the gymnastics mats where they will learn body shaping drills and exercises to reduce their rider risk in a fall scenario.
On the simulator throughout the two days participants will practice a rotational fall, a rear, off the shoulder and emergency dismount.


text:
Caravans (1978)
Based on a novel by James Michener, whose sprawling stories set in exotic periods of history were better served by TV miniseries, Caravans features interesting cultural observations, resplendent production values, a romantic musical score, and a solid international cast. Undercutting these strong elements, however, is muddy storytelling. Not only is the nature of the relationship between the characters played by stars Jennifer O'Neill and Anthony Quinn maddeningly vague—are they lovers or merely friends?—but the dynamics coloring interactions between the various sociopolitical factions in the movie are hard to track. The root of this problem, of course, is the choice to set Caravans in a fictional Middle East country, necessitating inoffensive vagueness, even though everything about the setting and the story suggests the region in and around Afghanistan. Furthermore, because the main story is very simple, casual viewers can easily tune out the social-studies material, which is a shame—for while Caravans is primarily a story about a proud man clinging to outdated traditions during a moment of global change, the movie also attempts to dramatize the intrusion of America into foreign conflicts, the power struggles between different Muslim tribes, the smuggling of Russian guns, and so on.
Anyway, the main story goes something like this: Low-level American diplomat Mark Miller (Michael Sarrazin) is sent into the desert to find runaway American woman Ellen Jasper (O'Neill), who married a local military man (Behrouz Vossoughi) but then fled to join the caravan of a nomadic tribe led by Zuffiqar (Quinn). Predictably, the movie tracks Mark's slow awakening to the beauty and savagery of an ancient culture. Just as predictably, the movie features a half-hearted attempt at romance between Mark and Ellen, a subplot that climaxes in a drab love montage set to the pretty "Caravan Song," performed by Barbara Dickson.
Had the filmmakers either gone full-bore in Michener's epic storytelling style or winnowed the source material down to just the core narrative, Caravans might have been more effective. As is, the movie feels too melodramatic for a depiction of geopolitical strife, and too complicated for a sweeping romance. The indifference of certain performances exacerbates these problems, with the lovely O'Neill—as usual—forming the weak link in the principal cast. Meanwhile, Quinn delivers an amiable retread of his Lawrence of Arabia performance, and Sarrazin struggles to identify what purpose his character serves other than to guide audiences into the narrative and periodically express "Oh, the humanity" shock. Among the Middle Eastern actors in the cast, Vossoughi provides intensity as the main villain, and Khosrow Tabatabai adds edge as a male dancer who plays sexualized mind games with men and women alike, causing considerable havoc.
Caravans: FUNKY
Labels: anthony quinn, funky, jennifer o'neill, michael sarrazin
Groggy Dundee said...
In complete agreement here. Interesting story/themes squandered by anemic presentation.
توپه فیلم من تازه دیدمش
Echoes of a Summer (1976)
Halls of Anger (1970)
Jeremiah Johnson (1972)
Aaron Loves Angela (1975)
Bang the Drum Slowly (1973)
The Teacher (1974)
The Student Nurses (1970)
The Bloody Judge (1970)
On the Yard (1978)
The Harrad Experiment (1973)
The Stepmother (1972)
Mahogany (1975)
Lady Sings the Blues (1972)
Un Flic (1972)
Van Nuys Blvd. (1979)
Who Are the DeBolts? And Where Did They Get Ninete...
You Light Up My Life (1977)
The New Centurions (1972)
Trog (1970)
The Angel Levine (1970)
Hammer (1972)
Malibu High (1979)
Fellini's Casanova (1976)
Sweet Sugar (1972)


Home » Do you know your bingo?
Bingo is one of the most popular games in the United Kingdom, with many people playing at either bingo halls up and down the country, or in the comfort of their own home. The internet has enabled people to not only have the choice of where to play bingo, but also increased the competition from bingo brands.
Famous for its bingo lingo, the game is always a hit with those in attendance, as they often join in with calling out the balls. Regardless of if you're playing bingo online or at a bingo hall, you'll have a great time and socialise with some great people.
For those that love the game, how much do you know about it? We've taken a look at some interesting trivia.
Believe it or not, bingo can be traced back to as early as 1530, when an Italian game called 'Lo Giuoco del Lotto D'Italia' was played each Saturday. Nearly 250 years later, the game moved to France, where it was renamed 'Le Lotto', before arriving in Germany in the 1800s, using it as a child's game in order to improve their learning of maths.
It arrived in the United States of America in 1929, and was named 'beano' after beans were initially used as the counters to cover the numbers called. It is reported that the named changed to 'bingo' after Edwin S. Lowe overheard someone accidentally shout 'bingo'.
Although the game arrived in the 18th century in the UK it didn't take off until 1960, when the British Parliament passed the Gaming Act. This allowed 'members only' establishments to legally host games such as bingo.
Although the UK didn't invent the game of bingo, they did invent one of the more memorable aspects of the game – the bingo lingo. These are the calls given to each of the balls when drawn and they originate from Cockney rhyming slang.
Numbers four, five and 25 are just some of the numbers to feature rhyming slang. Knock at the door, number four; man alive, number five; and duck and dive, 25.
While there are some numbers that rhyme, some of the most famous number calls in bingo lingo are due to the visual similarities between the numbers and animals or people. 22 is known as 'two little ducks', and the players often reply with "quack, quack, quack" when that ball is drawn. The most famous has to be number 88, which is referred to as 'two fat ladies'.
Bingo has played a key role in helping the gambling industry grow in the UK, and, as of September 2018, there are 644 bingo premises in Great Britain. The total gross gambling yield of the Great Britain gambling industry is a staggering £14.4 billion and looks set to continue to grow.
From April 2017 until March 2018, the remote betting, bingo, and casino sector have a market share of 37.3%, which represents a 3.0% increase from the previous year.
It's obvious to see that the gambling industry will grow more and more, and it will largely be down to the increasing popularity of bingo as to how much it grows by.


text:
Jeff Bridges is an American politician serving as a member of the Colorado Senate from the 26th district. Located in Arapahoe County, the district includes parts of Aurora, Englewood, Sheridan, Greenwood Village, Cherry Hills Village, and Littleton. Bridges serves on the Senate Education Committee, Senate Local Government Committee, and Joint Technology Committee.

Early life and education
Bridges grew up in Colorado and graduated from Arapahoe High School in Centennial. He earned a Bachelor of Arts degree in political science from Kenyon College and a Master of Divinity from Harvard Divinity School.

Career
Before running for the Colorado House of Representatives, Bridges worked for U.S Senator Ken Salazar. He also worked as the associate vice president of public affairs of the Union Theological Seminary.

Bridges was first elected to the Colorado House of Representatives in 2016, representing District 3. He was re-elected to the seat in 2018. In 2019, a vacancy committee elected Bridges to State Senator for District 26, after the resignation of Daniel Kagan.

References

External links
Official campaign website
State House website

21st-century American politicians
Living people
Democratic Party members of the Colorado House of Representatives
Year of birth missing (living people)
Harvard Divinity School alumni
People from Centennial, Colorado
Kenyon College alumni
Democratic Party Colorado state senators

redpajama_set_name: RedPajamaWikipedia


text:
Q: error: could not find implicit value for parameter d: io.circe.Decoder[List[TableInfo]] I have the following code that does not compile and returns this error:
error: could not find implicit value for parameter d: io.circe.Decoder[List[TableInfo]]
     r <- segmements.as[List[TableInfo]]

[Code]
import io.circe.Decoder
import io.circe.generic.semiauto.deriveDecoder
import io.circe.parser

val json: String =
"""
{
    "segmements": [
        {
            "tableName": "X",
            "segmentName": "XX",
            "pocs": [
                "aa@aa.com",
                "bb@bb.com"
            ]
        },
        {
            "tableName": "Y",
            "segmentName": "YY",
            "pocs": [
                "aa@aa.com",
                "bb@bb.com"
            ]
        }
    ]
}
"""

final case class TableInfo(tableName: String, segmentName: String)
object TableInfo {
  implicit final val TableInfoDecoder: Decoder[TableInfo] = deriveDecoder
}

val result = for {
  data <- parser.parse(json)
  obj <- data.asObject.toRight(left = new Exception("Data was not an object"))
  segmements <- obj("segmements").toRight(left = new Exception("Json didn't had the
segments key"))
  r <- segmements.as[List[TableInfo]]
} yield r

println(result)

scastie link: https://scastie.scala-lang.org/BalmungSan/eVEvBulOQwGzg5hIJroAoQ/3

A: I added import import TableInfo._ to the code before val result as @
Luis Miguel Mejía Suárez recommended and the code worked as intended.

A: Try this way
import io.circe.Decoder
import io.circe.generic.semiauto.deriveDecoder
import io.circe.parser
import io.circe._

val json: String =
"""
{
    "segments": [
        {
            "tableName": "X",
            "segmentName": "XX",
            "pocs": [
                "aa@aa.com",
                "bb@bb.com"
            ]
        },
        {
            "tableName": "Y",
            "segmentName": "YY",
            "pocs": [
                "aa@aa.com",
                "bb@bb.com"
            ]
        }
    ]
}
"""

final case class Tables(segments: List[TableInfo])
object Tables {
  implicit val decoder: Decoder[Tables] = (cursor: HCursor) =>
    for {
      segments          <- cursor.downField("segments").as[List[TableInfo]]
    } yield Tables(segments)
}

final case class TableInfo(tableName: String, segmentName: String)
object TableInfo {
  implicit final val TableInfoDecoder: Decoder[TableInfo] = deriveDecoder
}

val result = io.circe.parser.decode[Tables](json)

println(result)