nikesasasassa's blog
Talkbacks Hollywood stars
disarmed populace! Genocide is what happens after people are disarmed, Hollywood! 30 miilion disarmed Russians slaughterd by Josef Stalin. 70 milliion disarmed Chinese slaughtered by Mao Tse Tung. 1.5 million disarmed Armenians slaughtered by Turks. 6 million Jews and 12 million Christians were first disarmed and then slaughtered by Adolf Hitler.
Put bracelet van cleef and arpels replica armed guards in schools with Uzi's like in Israel! And put Shatterguard plastic glue paper on the inside of windows and steel sliding bolt locks on the inside of doors in schools, for goodness sake!
When the public is disarmed, foreign nations will be more likely to attack and invade. The only reason van cleef and arpels perlee bracelet copy Japan did not attack the US West Coast in WWII was because US citizens have guns. When the Mongol invasion of California hits, US citizens need assault weapons to defend themselves. The Koreans in the Watts riots of Los Angeles kept their homes and businesses from being burned down because they had assault weapons on the roof in the hands of defenders of the properties since the police would not go into Watts to protect people or properties.
Those laws good in itself will never prevent Massacres and Massmurders.
Even only with a Pistol with only a 7 shot Magazine,
one could carry several 7 shot Magazines with oneself and extra ammo and still conduct a Massacre and Massmurder.
"The only thing that stops a bad guy with a gun is a good guy with a gun."
Millions of US citzens feel
insecure without their own modern military weapons to be ready to repel.
I personally doubt that 90% of USA gun owners
have the training , the skill or the GUTS needed to defend themselves.
TRAINED, armed school guards are the only insurance for schools in the USA.
I my mind untrained citizenry; which includes braggarts, phoney heroes, tough guys, etc.
should NOT be allowed access to high capacity, automatic and high calibre weapons.
want to scrap the 2nd amendment because the framers used muzzle loading guns, or those that consider the costs vs the good. Are you also in favor of scrapping the 13th amendment because a majority of the prison population in the US is black? What is wrong with people being checked before the enter a school, mall or building? Not only does it increase employment, it makes people feel safer because they are safer. Cost? Is that the issue or saving lives? Would you ban tire irons if a murderer uses one? Knife? pen? fire? but guns are ok to ban? liberal really must try to get their understanding straight.
Ban assault rifles, ban hi caps mags, ban this ban that.
If we look to the statistics, the guns are not mentioned by the CDC not even in the first TEN causes of death.
If we look homicide statistic, baseball bats looks like the preferred means to end the life of your dears in USA.
If we look to the stats of gun crimes by gun type, AR15s are used in a tiny fraction of the homicides in the USA.
People, including famous ones, when it comes to guns just disconnects their brains and embrace popularity.
Because burning Jews, in the past, even a recent one, was a very popular practice.
Use FACTS, not EMOTIONS, use BRAINS, not your BELLY.
You are on the right track, but need to go several steps further. Repealing the 2nd Amendment to the US Constitution is a worthy idea, but what really is needed is for the US President to declare a state of emergency and suspend all Constitutional guarantees pending the drafting and ratification of a new Constitution by a Constitutional Convention, more relevant to the 21st century. We also must recognize that times have changed much since 1789 and that individual liberty must be subordinated to the van cleef clover bracelet knock off well being of the whole.
disarmed populace! Genocide is what happens after people are disarmed, Hollywood! 30 miilion disarmed Russians slaughterd by Josef Stalin. 70 milliion disarmed Chinese slaughtered by Mao Tse Tung. 1.5 million disarmed Armenians slaughtered by Turks. 6 million Jews and 12 million Christians were first disarmed and then slaughtered by Adolf Hitler.
Put bracelet van cleef and arpels replica armed guards in schools with Uzi's like in Israel! And put Shatterguard plastic glue paper on the inside of windows and steel sliding bolt locks on the inside of doors in schools, for goodness sake!
When the public is disarmed, foreign nations will be more likely to attack and invade. The only reason van cleef and arpels perlee bracelet copy Japan did not attack the US West Coast in WWII was because US citizens have guns. When the Mongol invasion of California hits, US citizens need assault weapons to defend themselves. The Koreans in the Watts riots of Los Angeles kept their homes and businesses from being burned down because they had assault weapons on the roof in the hands of defenders of the properties since the police would not go into Watts to protect people or properties.
Those laws good in itself will never prevent Massacres and Massmurders.
Even only with a Pistol with only a 7 shot Magazine,
one could carry several 7 shot Magazines with oneself and extra ammo and still conduct a Massacre and Massmurder.
"The only thing that stops a bad guy with a gun is a good guy with a gun."
Millions of US citzens feel
insecure without their own modern military weapons to be ready to repel.
I personally doubt that 90% of USA gun owners
have the training , the skill or the GUTS needed to defend themselves.
TRAINED, armed school guards are the only insurance for schools in the USA.
I my mind untrained citizenry; which includes braggarts, phoney heroes, tough guys, etc.
should NOT be allowed access to high capacity, automatic and high calibre weapons.
want to scrap the 2nd amendment because the framers used muzzle loading guns, or those that consider the costs vs the good. Are you also in favor of scrapping the 13th amendment because a majority of the prison population in the US is black? What is wrong with people being checked before the enter a school, mall or building? Not only does it increase employment, it makes people feel safer because they are safer. Cost? Is that the issue or saving lives? Would you ban tire irons if a murderer uses one? Knife? pen? fire? but guns are ok to ban? liberal really must try to get their understanding straight.
Ban assault rifles, ban hi caps mags, ban this ban that.
If we look to the statistics, the guns are not mentioned by the CDC not even in the first TEN causes of death.
If we look homicide statistic, baseball bats looks like the preferred means to end the life of your dears in USA.
If we look to the stats of gun crimes by gun type, AR15s are used in a tiny fraction of the homicides in the USA.
People, including famous ones, when it comes to guns just disconnects their brains and embrace popularity.
Because burning Jews, in the past, even a recent one, was a very popular practice.
Use FACTS, not EMOTIONS, use BRAINS, not your BELLY.
You are on the right track, but need to go several steps further. Repealing the 2nd Amendment to the US Constitution is a worthy idea, but what really is needed is for the US President to declare a state of emergency and suspend all Constitutional guarantees pending the drafting and ratification of a new Constitution by a Constitutional Convention, more relevant to the 21st century. We also must recognize that times have changed much since 1789 and that individual liberty must be subordinated to the van cleef clover bracelet knock off well being of the whole.
- decorate van cleef arpels ring fortunate man copy give you wedding all goodliness
- spirit magic van cleef rose pendant price?
- van cleef and arpels earrings trefoil men replica give ground matrimony to a higher degree bliss
- adorn van and arpels necklace fortunate couple replica Let you marriage to a higher degree happy
- decorate van cleef and arpels bracelet fortunate couple knockoff Let you the wedding a fortiori fragrant
The beat poet
Paul Muldoon is Professor of Poetry at Oxford University. He also lectures at Princeton University. He won the T. S. Eliot Prize for poetry in 1994. He bought Alanis Morissette's latest album, Under Rug Swept, just the other week.
The line between one van cleef and arpels 10 motif necklace fake of the world's acclaimed poets and a young, pop music performer who has sold enough CDs to reach the moon is not as tenuous as at first glance. For Muldoon Oxford professor, Princeton lecturer is a fan of popular music. In his collection Hay the musicality of his muse meets the music he admires in a series of poems based on a sort of personal Top 20 albums.
He writes of Jimi Hendrix (Are You Experienced?), Cream (Disraeli Gears), The Beatles (The Beatles), The Rolling Stones (Beggar's Banquet), Van Morrison (Astral Weeks), Eric Clapton (i>461 Ocean
Boulevard), Elvis Costello and the Attractions (My Aim is True), Warren Zevon (Excitable Boy), Dire Straits (Dire Straits), Blondie (Parallel Lines), Bruce Springsteen (The River), Lloyd Cole and the Commotions (Easy Pieces), Talking Heads (True Stories), U2 (The Joshua Tree), Pink Floyd (A Momentary Lapse of Reason), Paul Simon (Negotiations and Love Songs), Leonard Cohen (I'm Your Man), Nirvana (Bleach), Bob Dylan (Oh Mercy) and REM (Automatic for the People).
Muldoon's poetry has provoked divided opinion from "a kind of acrobat, piling up strange rhymes, references and conceits" (Adam Kirsh, The New Republic) or a poet who was "an unholy amalgam of Ezra Pound and Dr Seuss" (Ben Downing, The Wall Street Journal).
What is not in dispute is his voice, his great gift, the
glissade over the surface of the English language that creates markings both
strange and yet van cleef onyx necklace replica strangely familiar. Muldoon and his wordplay are often spoken of
in the same breath as James Joyce, the ultimate fantastic confabulator. But in
matters musical, the closest Joyce came to harmony and melody was his collection
Chamber Music ("Who may this singer be whose song about my heart is
falling?"). Muldoon lives far closer to the clef and chine of its body and soul.
The cadences quaver and quake, slide and stop start. He is not afraid to mingle
the two worlds of music and literature together, nor their inhabitants. knock off van cleef red clover necklace His
poetry uses musicians and their works, such as from Quoof :
Or she would turn up The Songs of Leonard Cohen
on the rickety oldand you knew by the way she unbound her tresses
and stepped
from her William Morris dresses
you might just as well beFrom Kissing and Telling
But in recent months Muldoon has come even closer to the real thing. So close, in fact, that he can now claim co songwriting credit among his achievements. The American initiated the endeavour after receiving a fan letter from a most unlikely source.
huge fan. I've been following his career since Excitable Boy (1978). About 18 months ago I wrote a fan letter. I heard nothing for close to a year then I had a phone call from him one day. We got together and he asked me if I would consider writing something for him, which, of course, was a great thrill for me, as it would be for interested in popular songwriting.
Paul Muldoon is Professor of Poetry at Oxford University. He also lectures at Princeton University. He won the T. S. Eliot Prize for poetry in 1994. He bought Alanis Morissette's latest album, Under Rug Swept, just the other week.
The line between one van cleef and arpels 10 motif necklace fake of the world's acclaimed poets and a young, pop music performer who has sold enough CDs to reach the moon is not as tenuous as at first glance. For Muldoon Oxford professor, Princeton lecturer is a fan of popular music. In his collection Hay the musicality of his muse meets the music he admires in a series of poems based on a sort of personal Top 20 albums.
He writes of Jimi Hendrix (Are You Experienced?), Cream (Disraeli Gears), The Beatles (The Beatles), The Rolling Stones (Beggar's Banquet), Van Morrison (Astral Weeks), Eric Clapton (i>461 Ocean
Boulevard), Elvis Costello and the Attractions (My Aim is True), Warren Zevon (Excitable Boy), Dire Straits (Dire Straits), Blondie (Parallel Lines), Bruce Springsteen (The River), Lloyd Cole and the Commotions (Easy Pieces), Talking Heads (True Stories), U2 (The Joshua Tree), Pink Floyd (A Momentary Lapse of Reason), Paul Simon (Negotiations and Love Songs), Leonard Cohen (I'm Your Man), Nirvana (Bleach), Bob Dylan (Oh Mercy) and REM (Automatic for the People).
Muldoon's poetry has provoked divided opinion from "a kind of acrobat, piling up strange rhymes, references and conceits" (Adam Kirsh, The New Republic) or a poet who was "an unholy amalgam of Ezra Pound and Dr Seuss" (Ben Downing, The Wall Street Journal).
What is not in dispute is his voice, his great gift, the
glissade over the surface of the English language that creates markings both
strange and yet van cleef onyx necklace replica strangely familiar. Muldoon and his wordplay are often spoken of
in the same breath as James Joyce, the ultimate fantastic confabulator. But in
matters musical, the closest Joyce came to harmony and melody was his collection
Chamber Music ("Who may this singer be whose song about my heart is
falling?"). Muldoon lives far closer to the clef and chine of its body and soul.
The cadences quaver and quake, slide and stop start. He is not afraid to mingle
the two worlds of music and literature together, nor their inhabitants. knock off van cleef red clover necklace His
poetry uses musicians and their works, such as from Quoof :
Or she would turn up The Songs of Leonard Cohen
on the rickety oldand you knew by the way she unbound her tresses
and stepped
from her William Morris dresses
you might just as well beFrom Kissing and Telling
But in recent months Muldoon has come even closer to the real thing. So close, in fact, that he can now claim co songwriting credit among his achievements. The American initiated the endeavour after receiving a fan letter from a most unlikely source.
huge fan. I've been following his career since Excitable Boy (1978). About 18 months ago I wrote a fan letter. I heard nothing for close to a year then I had a phone call from him one day. We got together and he asked me if I would consider writing something for him, which, of course, was a great thrill for me, as it would be for interested in popular songwriting.
- through vac necklace lucky man fake give ground the wedding more bliss
- van cleef arpels pendant clover couple copy give ground marriage more felicity
- decorate van arpels rings fortunate men copy Make ceremony more felicity
- embellish van and arpels pendant alhambra woman copy Let you matrimony to a higher degree glorious
- spirit magic van diamond jewelry do you want it?
Returning WWI soldiers' hatred for the leaders who sent them to die
It is one of the most profound and moving books about the Great War based on previously unpublished accounts from the men who lived and died in the trenches.
In yesterday's extract from Richard van Emden's The Soldier's War, troops recalled the horror of battle. Today, we reveal how delight at the Armistice turned to resentment as survivors returned home.
It was a brutal secret no one wanted to face. But despite the flag waving that greeted Britain's returning troops 90 years ago today, many felt nothing but hatred for the leaders who'd sent them to die. and now seemed happy to forget them.
Wearing a distinctive Burberry trench coat, the young English captain was an obvious target for a German sniper. His smart uniform, plus the fact that he was openly poring over a map, marked him out as an officer. As dawn lit up the night sky, his sergeant major warned him to take cover. 'Oh, I'll be all right,' the captain said jauntily.
But he wasn't. Minutes later, he was shot in the stomach. 'He was in great pain,' recalled the sergeant major, Arthur Cook. 'I asked him if there was anything I could do and he said: "No, Sergeant Major. I'm finished."
What made this death so poignant out of all the millions on the Western Front during World War I was that it came so near the end. 'He and I had fought and suffered together so long,' Cook recorded in his diary. 'He never knew what fear was, he was the bravest officer I ever saw, and here he was lying crushed and bleeding at my feet.'
Celebrations in London on November 11, 1918: But many battle scarred soldiers found the concept of peace bewildering
It was November 1, 1918 and the fighting was as fierce as ever with Allied troops pushing the retreating German forces out of France and back towards their own border.
As Cook's battalion of the Somerset Light Infantry moved in to mop up resistance in a French village, snipers began to pick them off, starting with the captain. Then a shell burst on the hard cobbles and Cook was hit by debris and shrapnel.
'I could scarcely believe I was wounded. I had been dodging bullets for four years and I'd begun to feel I was immune. I had been with the battalion from the beginning of the war and had the misfortune to be injured in its very last action.'
Along the Front, the next few days were full of rumours that the Germans were suing for peace. It didn't seem possible. The Kaiser's armies had been fighting a tenacious rearguard action and, though many prisoners had fallen into Allied hands, the expectation was that the war would drag on into 1919.
This sudden talk of an armistice made everyone nervous. Sergeant Walter Sweet recalled how the sound of a shell sent men scurrying for shelter, while before they would have taken little notice. 'If the end was near, we were taking no chances of being pipped at the last minute.'
The morning of November 11 was extremely cold and a white frost covered the Front. Sweet marched his platoon from the Monmouthshire Regiment to the next village and was billeting them in a barn when the colonel walked in.
'He wished us good day and looked at his watch. "It is 10am. Men, I am pleased to tell you that in one hour the Armistice comes into force and you will all be able to return to your homes." '
Armistice Day 1918: Crowds in London's Tralfalgar Square celebrating the end of the first world war
But the news of the imminent German surrender was greeted with silence. 'We did not cheer,' Sweet recalled. 'But just stood, stunned and bewildered.'
He continued: 'Then, on the stroke of 11am the CO raised his hand and told us that the war was over. That time we cheered, with our tin hats on and our rifles held aloft. For old hands like me, it was funny realising that this day we had waited so long for had come at last.'
The celebrations began. Lieutenant John Godfrey was lucky: he toasted the victory with fine wines. The owner of the house in which he was billeted had retrieved vintage bottles from the garden where he had hidden them from the German occupiers.
'The bally war is over, which is the great thing and a joy,' the lieutenant noted. But the concept of peace was baffling after so many years of bloody conflict. 'To think that I shall not have to toddle among machine guns again and never hear another shell burst. It is simply unimaginable.'
Another soldier admitted that he too was apprehensive. 'What's to become of us?' he asked. 'We have lived this life for so long. Now we shall have to start all over again.'
The Royal Family, seen on the balcony at Buckingham Palace, celebrating with servicemen and civilians after the announcement of the Armistice
The actual return home was a joy. Private John McCauley of the 2nd Border Regiment remembered cheering crowds, waving flags and bands playing music everywhere. In London, he went onto the streets 'to be swallowed up in the swirling multitude'.
But being demobbed meant sad farewells 'handshakes with old comrades fine fellows with whom I had shared experiences that will live in the memory as long as life shall last.'
And many were haunted by painful memories. Pte Charles Heare, his discharge papers in his pocket, was on a train returning from the Front when he passed the Ypres battlefield, where he had fought. He saw how 'smashed up' it was and wondered to his mates how they had managed sweet alhambra necklace fake to live through it.
'A lot of luck, good hearing and a sense of danger,' one alhambra pendant necklace fake replied. Then someone asked: 'What was it for? What have we got for it, or anyone else for that matter?' No one had an answer.
The vintage alhambra necklace 10 motifs fake crowd gathered outside the Stock Exchange and the Bank of England in London after the announcement of the Armistice
As he neared his home in Wales, his friend Pte Black, who had been with him in France since the start in 1914, was sentimental about leaving his comrades.
'We have had to protect one another from danger, share our sleep and food. We have seen thousands of dead and dying. We have had romping good times and horrid bad ones together. But now we must part and start a new life. Let's hope we have lived through it all for a good purpose.'
Many men now found themselves reflecting on what had happened and asking themselves and each other the same question: Was it all worth it?
It is one of the most profound and moving books about the Great War based on previously unpublished accounts from the men who lived and died in the trenches.
In yesterday's extract from Richard van Emden's The Soldier's War, troops recalled the horror of battle. Today, we reveal how delight at the Armistice turned to resentment as survivors returned home.
It was a brutal secret no one wanted to face. But despite the flag waving that greeted Britain's returning troops 90 years ago today, many felt nothing but hatred for the leaders who'd sent them to die. and now seemed happy to forget them.
Wearing a distinctive Burberry trench coat, the young English captain was an obvious target for a German sniper. His smart uniform, plus the fact that he was openly poring over a map, marked him out as an officer. As dawn lit up the night sky, his sergeant major warned him to take cover. 'Oh, I'll be all right,' the captain said jauntily.
But he wasn't. Minutes later, he was shot in the stomach. 'He was in great pain,' recalled the sergeant major, Arthur Cook. 'I asked him if there was anything I could do and he said: "No, Sergeant Major. I'm finished."
What made this death so poignant out of all the millions on the Western Front during World War I was that it came so near the end. 'He and I had fought and suffered together so long,' Cook recorded in his diary. 'He never knew what fear was, he was the bravest officer I ever saw, and here he was lying crushed and bleeding at my feet.'
Celebrations in London on November 11, 1918: But many battle scarred soldiers found the concept of peace bewildering
It was November 1, 1918 and the fighting was as fierce as ever with Allied troops pushing the retreating German forces out of France and back towards their own border.
As Cook's battalion of the Somerset Light Infantry moved in to mop up resistance in a French village, snipers began to pick them off, starting with the captain. Then a shell burst on the hard cobbles and Cook was hit by debris and shrapnel.
'I could scarcely believe I was wounded. I had been dodging bullets for four years and I'd begun to feel I was immune. I had been with the battalion from the beginning of the war and had the misfortune to be injured in its very last action.'
Along the Front, the next few days were full of rumours that the Germans were suing for peace. It didn't seem possible. The Kaiser's armies had been fighting a tenacious rearguard action and, though many prisoners had fallen into Allied hands, the expectation was that the war would drag on into 1919.
This sudden talk of an armistice made everyone nervous. Sergeant Walter Sweet recalled how the sound of a shell sent men scurrying for shelter, while before they would have taken little notice. 'If the end was near, we were taking no chances of being pipped at the last minute.'
The morning of November 11 was extremely cold and a white frost covered the Front. Sweet marched his platoon from the Monmouthshire Regiment to the next village and was billeting them in a barn when the colonel walked in.
'He wished us good day and looked at his watch. "It is 10am. Men, I am pleased to tell you that in one hour the Armistice comes into force and you will all be able to return to your homes." '
Armistice Day 1918: Crowds in London's Tralfalgar Square celebrating the end of the first world war
But the news of the imminent German surrender was greeted with silence. 'We did not cheer,' Sweet recalled. 'But just stood, stunned and bewildered.'
He continued: 'Then, on the stroke of 11am the CO raised his hand and told us that the war was over. That time we cheered, with our tin hats on and our rifles held aloft. For old hands like me, it was funny realising that this day we had waited so long for had come at last.'
The celebrations began. Lieutenant John Godfrey was lucky: he toasted the victory with fine wines. The owner of the house in which he was billeted had retrieved vintage bottles from the garden where he had hidden them from the German occupiers.
'The bally war is over, which is the great thing and a joy,' the lieutenant noted. But the concept of peace was baffling after so many years of bloody conflict. 'To think that I shall not have to toddle among machine guns again and never hear another shell burst. It is simply unimaginable.'
Another soldier admitted that he too was apprehensive. 'What's to become of us?' he asked. 'We have lived this life for so long. Now we shall have to start all over again.'
The Royal Family, seen on the balcony at Buckingham Palace, celebrating with servicemen and civilians after the announcement of the Armistice
The actual return home was a joy. Private John McCauley of the 2nd Border Regiment remembered cheering crowds, waving flags and bands playing music everywhere. In London, he went onto the streets 'to be swallowed up in the swirling multitude'.
But being demobbed meant sad farewells 'handshakes with old comrades fine fellows with whom I had shared experiences that will live in the memory as long as life shall last.'
And many were haunted by painful memories. Pte Charles Heare, his discharge papers in his pocket, was on a train returning from the Front when he passed the Ypres battlefield, where he had fought. He saw how 'smashed up' it was and wondered to his mates how they had managed sweet alhambra necklace fake to live through it.
'A lot of luck, good hearing and a sense of danger,' one alhambra pendant necklace fake replied. Then someone asked: 'What was it for? What have we got for it, or anyone else for that matter?' No one had an answer.
The vintage alhambra necklace 10 motifs fake crowd gathered outside the Stock Exchange and the Bank of England in London after the announcement of the Armistice
As he neared his home in Wales, his friend Pte Black, who had been with him in France since the start in 1914, was sentimental about leaving his comrades.
'We have had to protect one another from danger, share our sleep and food. We have seen thousands of dead and dying. We have had romping good times and horrid bad ones together. But now we must part and start a new life. Let's hope we have lived through it all for a good purpose.'
Many men now found themselves reflecting on what had happened and asking themselves and each other the same question: Was it all worth it?
specific structural variation across 1000 medulloblastoma genomes
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson disease, which is exquisitely restricted to Group 4 Recurrent translocations of PVT1, including PVT1 MYC and PVT1 NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF signalling in Group 3, and NF signalling in Group 4, suggest future avenues for rational, targeted therapy.
a, The medulloblastoma genome classified by subgroup. c, Significant regions of focal SCNA identified by GISTIC2 in either pan cohort or subgroup specific analyses. The number of genes mapping to the GISTIC2 peak region (where applicable) is listed in brackets after the suspected driver gene, as is the frequency of each event.
a, GISTIC2 significance plot of amplifications (red) and deletions (blue) observed in SHH. The number of genes mapping to each significant region are included in brackets and regions enriched in SHH are shaded red. b, c, Recurrent amplifications of PPM1D (b) and PIK3C2B/MDM4 (c) are restricted to SHH. d, Fluorescence in situ hybridization (FISH) validation of MDM4 amplification. e, SHH signalling, TP53 signalling and RTK/PI3K signalling represent the core pathways genomically targeted in van cleef arpel alhambra necklace fake SHH. P values indicate the prevalence with which the respective pathway is targeted in SHH versus non SHH cases (Fisher exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. f, Mutual exclusivity analysis of focal SCNAs in SHH. g, Clinical implications of SCNAs affecting MYCN, GLI2 or PTCH1 in SHH (log rank tests).
a, b, GISTIC2 plots depicting significant SCNAs in Group 3 (a) and Group 4 (b) with subgroup enriched regions shaded in yellow and green, respectively. c, Recurrent amplifications targeting type II (ACVR2A and ACVR2B) and type I (TGFBR1) activin receptors in Group 3. Frequencies of focal and broad (parentheses) SCNAs are listed. e, Enrichment map of gene sets affected by SCNAs in Group 3 versus Group 4.
a, Highly recurrent, focal, single copy gain of SNCAIP in Group 4. b, Paired end mapping verifies recurrent tandem duplication of SNCAIP in Group 4. c, Schematic representation of SNCAIP tandem duplication. d, SNCAIP is a Group 4 signature gene. Upper panel, SNCAIP expression across subgroups in a published series of 103 primary medulloblastomas. Error bars depict the minimum and maximum values, excluding outliers. Lower panel, SNCAIP ranks among the top 1% (rank, 39th out of 16,758) of highly expressed genes in Group 4. e, NMF consensus clustering of 188 expression profiled Group 4 tumours supports two transcriptionally distinct subtypes designated 4 and 4 (cophenetic coefficient = 0.9956). g, Group 4 cases harbouring SNCAIP duplication exhibit a 1.5 fold increase in SNCAIP expression. f, g, Error bars depict the minimum and maximum values, excluding outliers.
a, b, RNA Seq identifies multiple fusion transcripts driven by PVT1 in Group 3. Schematics depict the structures of verified PVT1 MYC (a) and PVT1 NDRG1 (b) fusion genes. c, Heat map of the MYC/PVT1 locus showing a subset of 13 MYC amplified Group 3 cases subsequently verified to exhibit PVT1 gene fusions (shown in d). Yellow box highlights the common breakpoint affecting the first exon/intron of PVT1, including miR 1204. d, Summary of PVT1 fusion transcripts identified in Group 3. e, f, WGS confirms complex patterns of rearrangement on chr8q24 in PVT1 fusion (+) Group 3.
a, Quantitative RT of PVT1 encoded microRNAs confirms upregulation of miR 1204 in PVT1 MYC fusion (+) Group 3 tumours. MYC balanced/fusion ( n = 4; MYC amplified/fusion ( n = 6; MYC amplified/fusion (+), n = 8. b, c, Knockdown of miR 1204 attenuates the proliferative capacity of PVT1 MYC fusion (+) MED8A medulloblastoma cells (b) but has no effect on fusion ( ONS76 cells (c). Four principal subgroups of medulloblastoma have been identified: WNT, SHH, Group 3 and Group 4 (ref. 7), and there is preliminary evidence for clinically significant subdivisions of the subgroups3, 7, 8. Rational, targeted therapies based on genetics are not currently in use for medulloblastoma, although inhibitors of the Sonic Hedgehog pathway protein Smoothened have shown early promise9. Actionable targets for WNT, Group 3 and Group 4 tumours have not been identified4, 10. Sanger sequencing of 22 medulloblastoma exomes revealed on average only 8 single nucleotide variants (SNVs) per tumour11. Some SNVs were subgroup restricted (PTCH1, CTNNB1), whereas others occurred across subgroups (TP53, MLL2). We proposed that the observed intertumoural heterogeneity might have underpowered prior attempts to discover targets for rational therapy.
The Medulloblastoma Advanced Genomics International Consortium (MAGIC) consisting of scientists and physicians from 46 cities across the globe gathered more than 1,200 medulloblastomas which were studied by SNP arrays (n = 1,239; Fig. 1a, Supplementary Fig. 1 and Supplementary Tables 1 Medulloblastoma subgroup affiliation of 827 cases was determined using a custom nanoString based RNA assay (Supplementary Fig. 2)12. Disparate patterns of broad cytogenetic gain and loss were observed across the subgroups (Fig. 1b and Supplementary Figs 3, 7, 8, 10 and 11). Analysis of the entire cohort using GISTIC2 (ref. 13) to discover significant events delineated 62 regions of recurrent SCNA (Fig. 1c, Supplementary Fig. 4 and Supplementary Tables 4 and 5); analysis by subgroup increased sensitivity such that 110 candidate SCNAs were identified, most of which are subgroup enriched (Fig. 1c and Supplementary Table 6).
a, The medulloblastoma genome classified by subgroup. c, Significant regions of focal SCNA identified by GISTIC2 in either pan cohort or subgroup specific analyses. The number of genes mapping to the GISTIC2 peak region (where applicable) is listed in brackets after the suspected driver gene, as is the frequency of each event. 1d and Supplementary Table 7). The most prevalent amplifications affected members of the MYC family with MYCN predominantly amplified in SHH and Group 4, MYC in Group 3, and MYCL1 in SHH medulloblastomas. Multiple genes/regions were exclusively amplified in SHH, including GLI2, MYCL1, PPM1D, YAP1 and MDM4 (Fig. 1d). Recurrent homozygous deletions were exceedingly rare, with only 15 detected across 1,087 tumours (Fig. 1e). Homozygous deletions targeting known tumour suppressors PTEN, PTCH1 and CDKN2A/B were the most common, all enriched in SHH cases (Fig. 1e and Supplementary Table 7). Novel homozygous deletions included KDM6A, a histone lysine demethylase deleted in Group 4. A custom nanoString CodeSet was used to verify 24 significant regions of gain across 192 MAGIC cases, resulting in a verification rate of 90.9% (Supplementary Fig. 5). We conclude that SCNAs in medulloblastoma are common, and are predominantly subgroup enriched.
WNT medulloblastoma genomes are impoverished of recurrent focal regions of SCNA, exhibiting no significant regions of deletion and only a small subset of focal gains found at comparable frequencies in non WNT tumours (Supplementary Figs 4, 6 and Supplementary Table 8). CTNNB1 mutational screening confirmed canonical exon 3 mutations in 63 out of 71 (88.7%) WNT tumours, whereas monosomy 6 was detected in 58 out of 76 (76.3%) (Supplementary Fig. 6; Supplementary Table 9). Four knock off black van cleef necklace WNT tumours (4/71; 5.6%) had neither CTNNB1 mutation nor monosomy 6, but maintained typical WNT expression signatures. Given the size of our cohort and the resolution of the platform, we conclude that there are no frequent, targetable SCNAs for WNT medulloblastoma.
SHH tumours exhibit multiple significant focal SCNAs (Fig. 2a, Supplementary Figs 12, 15, 16 and Supplementary Tables 10 and 11). SHH enriched/restricted SCNAs included amplification of GLI2 and deletion of PTCH1 (Fig. 2a, e, f)10. MYCN and CCND2 were among the most frequently amplified genes in SHH (Supplementary Table 6), but were also altered in non SHH cases. Genes upregulated in SHH tumours (that is, SHH signature genes) are significantly over represented among the genes focally amplified in SHH tumours (P = 0.001 permutation tests; Supplementary Fig. 9). Recurrent amplification of SHH signature genes has clinical implications, as amplification of downstream transcriptional targets could mediate resistance to upstream SHH pathway inhibitors14.
a, GISTIC2 significance plot of amplifications (red) and deletions (blue) observed in SHH. The number of genes mapping to each significant region are included in brackets and regions enriched in SHH are shaded red. b, c, Recurrent amplifications of PPM1D (b) and PIK3C2B/MDM4 (c) are restricted to SHH. d, Fluorescence in situ hybridization (FISH) validation of MDM4 amplification. e, SHH signalling, TP53 signalling and RTK/PI3K signalling represent the core pathways genomically targeted in SHH. P values indicate the prevalence with which the respective pathway is targeted in SHH versus non SHH cases (Fisher exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. f, Mutual exclusivity analysis of focal SCNAs in SHH. g, Clinical implications of SCNAs affecting MYCN, GLI2 or PTCH1 in SHH (log rank tests).
Novel, SHH enriched SCNAs included components of TP53 signalling, including amplifications of MDM4 and PPM1D, and focal deletions of TP53 (Fig. 2a Targetable events, including amplifications of IGF signalling genes IGF1R and IRS2, PI3K genes PIK3C2G and PIK3C2B, and deletion of PTEN were restricted to SHH tumours (Fig. 2a, c, e). Importantly, focal events affecting genes in the SHH pathway were largely mutually exclusive and prognostically significant (Fig. 2f, g). Many of the recurrent, targetable SCNAs identified in SHH medulloblastoma (IGF1R, KIT, MDM4, PDGFRA, PIK3C2G, PIK2C2B and PTEN) have already been targeted with small molecules for treatment of other malignancies, which might allow rapid translation for targeted therapy of subsets of SHH patients (Supplementary Table 16). Novel SHH targets identified here are excellent candidates for combinatorial therapy with Smoothened inhibitors, to avoid the resistance encountered in both humans and mice9, 14, 15.
Group 3 and Group 4 medulloblastomas have generic names as comparatively little is known about their genetic basis, and no targets for rational therapy have been identified7. MYC amplicons are largely restricted to Group 3, whereas MYCN amplicons are seen in Group 4 and SHH tumours (Fig. 1d)3, 4. Indeed, MYC and MYCN loci comprise the most significant regions of amplification observed in Group 3 and Group 4, respectively (Fig. 3a, b, Supplementary Figs 13, 14, 17 and Supplementary Tables 12 Group 3 MYC amplicons were mutually exclusive from those affecting the known medulloblastoma oncogene OTX2 (ref. 16) and were highly prognostic (Supplementary Fig. 21)3, 16. Type II activin receptors, ACVR2A and ACVR2B and family member TGFBR1 are highly amplified in Group 3 tumours, indicating deregulation of TGF signalling as a driver event in Group 3 (Fig. 3c and Supplementary Fig. 22). The Group 3 enriched medulloblastoma oncogene OTX2 is a prominent target of TGF signalling in the developing nervous system17 and TGF pathway inhibitors CD109 (ref. 18), FKBP1A (refs 19 and 20) and SNX6 (ref. 20) are recurrently deleted in Group 3 (Fig. 3a, d). 3d). Similarly, novel deletions affecting regulators of the NF pathway, including NFKBIA (ref. 21) and USP4 (ref. 22) were identified in Group 4 (Supplementary Fig. 23), proposing that NF signalling may represent a rational Group 4 therapeutic target.
a, b, GISTIC2 plots depicting significant SCNAs in Group 3 (a) and Group 4 (b) with subgroup enriched regions shaded in yellow and green, respectively. c, Recurrent amplifications targeting type II (ACVR2A and ACVR2B) and type I (TGFBR1) activin receptors in Group 3. Frequencies of focal and broad (parentheses) SCNAs are listed. e, Enrichment map of gene sets affected by SCNAs in Group 3 versus Group 4.
Network analysis of Group 3 and Group 4 SCNAs illustrates the different pathways over represented in each subgroup. Only TGF signalling is unique to Group 3 (Fig. 3e). In contrast, cell cycle control, chromatin modification and neuronal development are all Group 4 enriched. Cumulatively, the dismal prognosis of Group 3 patients, the lack of published targets for rational therapy, and the prior targeting of TGF signalling in other diseases suggest that van cleef gold necklace copy TGF may represent an appealing target for Group 3 rational therapies (Supplementary Table 16).
Although Group 4 is the most prevalent medulloblastoma subgroup, its pathogenesis remains poorly understood. The most frequent SCNA observed in Group 4 (33/317; 10.4%) is a recurrent region of single copy gain on chr5q23.2 targeting a single gene, SNCAIP (synuclein, alpha interacting protein) (Fig. 4a and Supplementary Fig. 24). SNCAIP, encodes synphilin 1, which binds to to promote the formation of Lewy bodies in the brains of patients with Parkinson disease23, 24. Additionally, rare germline mutations of SNCAIP have been described in Parkinson families25. Large insert, mate pair, whole genome sequencing (WGS) demonstrates that SNCAIP copy number gains arise from tandem duplication of a truncated SNCAIP (lacking non coding exon 1), inserted telomeric to the germline SNCAIP allele (Fig. 4b, c and Supplementary Fig. 25). Affymetrix SNP6 array profiling of patient matched germline material confirmed that SNCAIP duplications are somatic (Supplementary Fig. 26), and subsequent whole transcriptome sequencing (RNA Seq) of select Group 4 cases (n = 5) verified that SNCAIP is the only gene expressed in the duplicated region (Supplementary Fig. 27). Analysis of published copy number profiles for 3,131 primary tumours26 and 947 cancer cell lines27 (total of 4,078 cases) revealed only four cases with apparent duplication of SNCAIP, all of which were inferred as Group 4 medulloblastomas (data not shown). We conclude that SNCAIP duplication is a somatic event highly specific to Group 4 medulloblastoma.
a, Highly recurrent, focal, single copy gain of SNCAIP in Group 4. b, Paired end mapping verifies recurrent tandem duplication of SNCAIP in Group 4. c, Schematic representation of SNCAIP tandem duplication. d, SNCAIP is a Group 4 signature gene. Upper panel, SNCAIP expression across subgroups in a published series of 103 primary medulloblastomas. Error bars depict the minimum and maximum values, excluding outliers. Lower panel, SNCAIP ranks among the top 1% (rank, 39th out of 16,758) of highly expressed genes in Group 4. e, NMF consensus clustering of 188 expression profiled Group 4 tumours supports two transcriptionally distinct subtypes designated 4 and 4 (cophenetic coefficient = 0.9956). g, Group 4 cases harbouring SNCAIP duplication exhibit a 1.5 fold increase in SNCAIP expression. f, g, Error bars depict the minimum and maximum values, excluding outliers.
Re analysis of 499 published medulloblastoma expression profiles confirmed that SNCAIP is one of the most highly upregulated Group 4 signature genes (Fig. 4d and Supplementary Fig. 28). Profiling of 188 Group 4 tumours on expression microarrays followed by consensus non negative matrix factorization (NMF) clustering delineates two subtypes of Group 4 (4 and 4 Fig. 4e and Supplementary Fig. 29). SNCAIP is more highly expressed in Group 4 than 4 (Fig. 4f), and 4 samples with tandem duplication showed approximately 1.5 fold increased expression, consistent with gene dosage (Fig. 4g and Supplementary Figs 35 and 36). Group 4 exhibits a relatively balanced genome compared to 4 (Supplementary Figs 30 and several 4 cases harbour SNCAIP duplication in conjunction with i17q and no other SCNAs (Supplementary Fig. 33). Importantly, SNCAIP duplications are mutually exclusive from other prominent SCNAs in Group 4, including MYCN and CDK6 amplifications (Supplementary Fig. 34).
Although recurrent gene fusions have recently been discovered in solid tumours, none have been reported in medulloblastoma. RNA Seq of Group 3 tumours (n = 13) identified two independent gene fusions in two different tumours (MB 182 and MB 586), both involving the 5 end of PVT1, a non coding gene frequently co amplified with MYC in Group 3 (Fig. 5a, b, Supplementary Fig. 37 and Supplementary Tables 17 and 18). Sanger sequencing confirmed a fusion transcript consisting of exons 1 and 3 of PVT1 fused to the coding sequence of MYC (exons 2 and 3) in MB 182, and a fusion involving PVT1 exon 1 fused to the 3 end of NDRG1 in MB 586 (Fig. 5a, b).
a, b, RNA Seq identifies multiple fusion transcripts driven by PVT1 in Group 3. Schematics depict the structures of verified PVT1 MYC (a) and PVT1 NDRG1 (b) fusion genes. c, Heat map of the MYC/PVT1 locus showing a subset of 13 MYC amplified Group 3 cases subsequently verified to exhibit PVT1 gene fusions (shown in d). Yellow box highlights the common breakpoint affecting the first exon/intron of PVT1, including miR 1204. d, Summary of PVT1 fusion transcripts identified in Group 3. e, f, WGS confirms complex patterns of rearrangement on chr8q24 in PVT1 fusion (+) Group 3.
Group 3 copy number data at the MYC/PVT1 locus indicated that additional samples might harbour PVT1 gene fusions (Fig. 5c). PCR with reverse transcription (RT profiling of select Group 3 cases confirmed PVT1 MYC fusions in at least 60% (12/20) of MYC amplified cases (Fig. 5d and Supplementary Table 19). Fusion transcripts included many other portions of chr8q, with up to four different genomic loci mapping to a single transcript, a pattern reminiscent of chromothripsis28, 29 (Fig. 5d). WGS performed on four MYC amplified Group 3 tumours harbouring PVT1 fusion transcripts identified a series of complex genomic rearrangements on chr8q (Fig. 5e, f, Supplementary Fig. 38 and Supplementary Tables 20 and 21). Chromosome 8 copy number profile for MB 586 (PVT1 NDRG1) derived from WGS showed that PVT1 and NDRG1 are structurally linked, as predicted by RNA Seq, and several adjacent regions of 8q24 were extensively rearranged (Fig. 5e, f and Supplementary Table 21). Monte Carlo simulation suggests that this fragmented 8q amplicon arose through chromothripsis, a process of erroneous DNA repair following a single catastrophic event in which a chromosome is shattered into many pieces (Supplementary Fig. 39). Further examination of our copy number data set revealed rare examples of chromothripsis across subgroups (Supplementary Fig. 40), with only chr8 in Group 3 demonstrating statistically significant, region specific chromothripsis (Q = 0.0004, false discovery rate (FDR) corrected Fisher exact test). Among Group 3 tumours, the occurrence of chr8q chromothripsis is correlated with deletion of chr17p (location of TP53; data not shown), in keeping with the association of loss of TP53 and chromothripsis recently described in medulloblastoma (P = 0.0199, Fisher exact test)28. Whereas the PVT1 locus has been suggested to be a genomically fragile site, we observe that the majority of MYC amplified Group 3 tumours harbour PVT1 fusions that arise through a process consistent with chromothripsis.
PVT1 is a non coding host gene for four microRNAs, miR 1204 Previous studies have implicated miR 1204 as a candidate oncogene that enhances oncogenesis in combination with MYC30, 31. PVT1 fus
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson disease, which is exquisitely restricted to Group 4 Recurrent translocations of PVT1, including PVT1 MYC and PVT1 NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF signalling in Group 3, and NF signalling in Group 4, suggest future avenues for rational, targeted therapy.
a, The medulloblastoma genome classified by subgroup. c, Significant regions of focal SCNA identified by GISTIC2 in either pan cohort or subgroup specific analyses. The number of genes mapping to the GISTIC2 peak region (where applicable) is listed in brackets after the suspected driver gene, as is the frequency of each event.
a, GISTIC2 significance plot of amplifications (red) and deletions (blue) observed in SHH. The number of genes mapping to each significant region are included in brackets and regions enriched in SHH are shaded red. b, c, Recurrent amplifications of PPM1D (b) and PIK3C2B/MDM4 (c) are restricted to SHH. d, Fluorescence in situ hybridization (FISH) validation of MDM4 amplification. e, SHH signalling, TP53 signalling and RTK/PI3K signalling represent the core pathways genomically targeted in van cleef arpel alhambra necklace fake SHH. P values indicate the prevalence with which the respective pathway is targeted in SHH versus non SHH cases (Fisher exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. f, Mutual exclusivity analysis of focal SCNAs in SHH. g, Clinical implications of SCNAs affecting MYCN, GLI2 or PTCH1 in SHH (log rank tests).
a, b, GISTIC2 plots depicting significant SCNAs in Group 3 (a) and Group 4 (b) with subgroup enriched regions shaded in yellow and green, respectively. c, Recurrent amplifications targeting type II (ACVR2A and ACVR2B) and type I (TGFBR1) activin receptors in Group 3. Frequencies of focal and broad (parentheses) SCNAs are listed. e, Enrichment map of gene sets affected by SCNAs in Group 3 versus Group 4.
a, Highly recurrent, focal, single copy gain of SNCAIP in Group 4. b, Paired end mapping verifies recurrent tandem duplication of SNCAIP in Group 4. c, Schematic representation of SNCAIP tandem duplication. d, SNCAIP is a Group 4 signature gene. Upper panel, SNCAIP expression across subgroups in a published series of 103 primary medulloblastomas. Error bars depict the minimum and maximum values, excluding outliers. Lower panel, SNCAIP ranks among the top 1% (rank, 39th out of 16,758) of highly expressed genes in Group 4. e, NMF consensus clustering of 188 expression profiled Group 4 tumours supports two transcriptionally distinct subtypes designated 4 and 4 (cophenetic coefficient = 0.9956). g, Group 4 cases harbouring SNCAIP duplication exhibit a 1.5 fold increase in SNCAIP expression. f, g, Error bars depict the minimum and maximum values, excluding outliers.
a, b, RNA Seq identifies multiple fusion transcripts driven by PVT1 in Group 3. Schematics depict the structures of verified PVT1 MYC (a) and PVT1 NDRG1 (b) fusion genes. c, Heat map of the MYC/PVT1 locus showing a subset of 13 MYC amplified Group 3 cases subsequently verified to exhibit PVT1 gene fusions (shown in d). Yellow box highlights the common breakpoint affecting the first exon/intron of PVT1, including miR 1204. d, Summary of PVT1 fusion transcripts identified in Group 3. e, f, WGS confirms complex patterns of rearrangement on chr8q24 in PVT1 fusion (+) Group 3.
a, Quantitative RT of PVT1 encoded microRNAs confirms upregulation of miR 1204 in PVT1 MYC fusion (+) Group 3 tumours. MYC balanced/fusion ( n = 4; MYC amplified/fusion ( n = 6; MYC amplified/fusion (+), n = 8. b, c, Knockdown of miR 1204 attenuates the proliferative capacity of PVT1 MYC fusion (+) MED8A medulloblastoma cells (b) but has no effect on fusion ( ONS76 cells (c). Four principal subgroups of medulloblastoma have been identified: WNT, SHH, Group 3 and Group 4 (ref. 7), and there is preliminary evidence for clinically significant subdivisions of the subgroups3, 7, 8. Rational, targeted therapies based on genetics are not currently in use for medulloblastoma, although inhibitors of the Sonic Hedgehog pathway protein Smoothened have shown early promise9. Actionable targets for WNT, Group 3 and Group 4 tumours have not been identified4, 10. Sanger sequencing of 22 medulloblastoma exomes revealed on average only 8 single nucleotide variants (SNVs) per tumour11. Some SNVs were subgroup restricted (PTCH1, CTNNB1), whereas others occurred across subgroups (TP53, MLL2). We proposed that the observed intertumoural heterogeneity might have underpowered prior attempts to discover targets for rational therapy.
The Medulloblastoma Advanced Genomics International Consortium (MAGIC) consisting of scientists and physicians from 46 cities across the globe gathered more than 1,200 medulloblastomas which were studied by SNP arrays (n = 1,239; Fig. 1a, Supplementary Fig. 1 and Supplementary Tables 1 Medulloblastoma subgroup affiliation of 827 cases was determined using a custom nanoString based RNA assay (Supplementary Fig. 2)12. Disparate patterns of broad cytogenetic gain and loss were observed across the subgroups (Fig. 1b and Supplementary Figs 3, 7, 8, 10 and 11). Analysis of the entire cohort using GISTIC2 (ref. 13) to discover significant events delineated 62 regions of recurrent SCNA (Fig. 1c, Supplementary Fig. 4 and Supplementary Tables 4 and 5); analysis by subgroup increased sensitivity such that 110 candidate SCNAs were identified, most of which are subgroup enriched (Fig. 1c and Supplementary Table 6).
a, The medulloblastoma genome classified by subgroup. c, Significant regions of focal SCNA identified by GISTIC2 in either pan cohort or subgroup specific analyses. The number of genes mapping to the GISTIC2 peak region (where applicable) is listed in brackets after the suspected driver gene, as is the frequency of each event. 1d and Supplementary Table 7). The most prevalent amplifications affected members of the MYC family with MYCN predominantly amplified in SHH and Group 4, MYC in Group 3, and MYCL1 in SHH medulloblastomas. Multiple genes/regions were exclusively amplified in SHH, including GLI2, MYCL1, PPM1D, YAP1 and MDM4 (Fig. 1d). Recurrent homozygous deletions were exceedingly rare, with only 15 detected across 1,087 tumours (Fig. 1e). Homozygous deletions targeting known tumour suppressors PTEN, PTCH1 and CDKN2A/B were the most common, all enriched in SHH cases (Fig. 1e and Supplementary Table 7). Novel homozygous deletions included KDM6A, a histone lysine demethylase deleted in Group 4. A custom nanoString CodeSet was used to verify 24 significant regions of gain across 192 MAGIC cases, resulting in a verification rate of 90.9% (Supplementary Fig. 5). We conclude that SCNAs in medulloblastoma are common, and are predominantly subgroup enriched.
WNT medulloblastoma genomes are impoverished of recurrent focal regions of SCNA, exhibiting no significant regions of deletion and only a small subset of focal gains found at comparable frequencies in non WNT tumours (Supplementary Figs 4, 6 and Supplementary Table 8). CTNNB1 mutational screening confirmed canonical exon 3 mutations in 63 out of 71 (88.7%) WNT tumours, whereas monosomy 6 was detected in 58 out of 76 (76.3%) (Supplementary Fig. 6; Supplementary Table 9). Four knock off black van cleef necklace WNT tumours (4/71; 5.6%) had neither CTNNB1 mutation nor monosomy 6, but maintained typical WNT expression signatures. Given the size of our cohort and the resolution of the platform, we conclude that there are no frequent, targetable SCNAs for WNT medulloblastoma.
SHH tumours exhibit multiple significant focal SCNAs (Fig. 2a, Supplementary Figs 12, 15, 16 and Supplementary Tables 10 and 11). SHH enriched/restricted SCNAs included amplification of GLI2 and deletion of PTCH1 (Fig. 2a, e, f)10. MYCN and CCND2 were among the most frequently amplified genes in SHH (Supplementary Table 6), but were also altered in non SHH cases. Genes upregulated in SHH tumours (that is, SHH signature genes) are significantly over represented among the genes focally amplified in SHH tumours (P = 0.001 permutation tests; Supplementary Fig. 9). Recurrent amplification of SHH signature genes has clinical implications, as amplification of downstream transcriptional targets could mediate resistance to upstream SHH pathway inhibitors14.
a, GISTIC2 significance plot of amplifications (red) and deletions (blue) observed in SHH. The number of genes mapping to each significant region are included in brackets and regions enriched in SHH are shaded red. b, c, Recurrent amplifications of PPM1D (b) and PIK3C2B/MDM4 (c) are restricted to SHH. d, Fluorescence in situ hybridization (FISH) validation of MDM4 amplification. e, SHH signalling, TP53 signalling and RTK/PI3K signalling represent the core pathways genomically targeted in SHH. P values indicate the prevalence with which the respective pathway is targeted in SHH versus non SHH cases (Fisher exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. f, Mutual exclusivity analysis of focal SCNAs in SHH. g, Clinical implications of SCNAs affecting MYCN, GLI2 or PTCH1 in SHH (log rank tests).
Novel, SHH enriched SCNAs included components of TP53 signalling, including amplifications of MDM4 and PPM1D, and focal deletions of TP53 (Fig. 2a Targetable events, including amplifications of IGF signalling genes IGF1R and IRS2, PI3K genes PIK3C2G and PIK3C2B, and deletion of PTEN were restricted to SHH tumours (Fig. 2a, c, e). Importantly, focal events affecting genes in the SHH pathway were largely mutually exclusive and prognostically significant (Fig. 2f, g). Many of the recurrent, targetable SCNAs identified in SHH medulloblastoma (IGF1R, KIT, MDM4, PDGFRA, PIK3C2G, PIK2C2B and PTEN) have already been targeted with small molecules for treatment of other malignancies, which might allow rapid translation for targeted therapy of subsets of SHH patients (Supplementary Table 16). Novel SHH targets identified here are excellent candidates for combinatorial therapy with Smoothened inhibitors, to avoid the resistance encountered in both humans and mice9, 14, 15.
Group 3 and Group 4 medulloblastomas have generic names as comparatively little is known about their genetic basis, and no targets for rational therapy have been identified7. MYC amplicons are largely restricted to Group 3, whereas MYCN amplicons are seen in Group 4 and SHH tumours (Fig. 1d)3, 4. Indeed, MYC and MYCN loci comprise the most significant regions of amplification observed in Group 3 and Group 4, respectively (Fig. 3a, b, Supplementary Figs 13, 14, 17 and Supplementary Tables 12 Group 3 MYC amplicons were mutually exclusive from those affecting the known medulloblastoma oncogene OTX2 (ref. 16) and were highly prognostic (Supplementary Fig. 21)3, 16. Type II activin receptors, ACVR2A and ACVR2B and family member TGFBR1 are highly amplified in Group 3 tumours, indicating deregulation of TGF signalling as a driver event in Group 3 (Fig. 3c and Supplementary Fig. 22). The Group 3 enriched medulloblastoma oncogene OTX2 is a prominent target of TGF signalling in the developing nervous system17 and TGF pathway inhibitors CD109 (ref. 18), FKBP1A (refs 19 and 20) and SNX6 (ref. 20) are recurrently deleted in Group 3 (Fig. 3a, d). 3d). Similarly, novel deletions affecting regulators of the NF pathway, including NFKBIA (ref. 21) and USP4 (ref. 22) were identified in Group 4 (Supplementary Fig. 23), proposing that NF signalling may represent a rational Group 4 therapeutic target.
a, b, GISTIC2 plots depicting significant SCNAs in Group 3 (a) and Group 4 (b) with subgroup enriched regions shaded in yellow and green, respectively. c, Recurrent amplifications targeting type II (ACVR2A and ACVR2B) and type I (TGFBR1) activin receptors in Group 3. Frequencies of focal and broad (parentheses) SCNAs are listed. e, Enrichment map of gene sets affected by SCNAs in Group 3 versus Group 4.
Network analysis of Group 3 and Group 4 SCNAs illustrates the different pathways over represented in each subgroup. Only TGF signalling is unique to Group 3 (Fig. 3e). In contrast, cell cycle control, chromatin modification and neuronal development are all Group 4 enriched. Cumulatively, the dismal prognosis of Group 3 patients, the lack of published targets for rational therapy, and the prior targeting of TGF signalling in other diseases suggest that van cleef gold necklace copy TGF may represent an appealing target for Group 3 rational therapies (Supplementary Table 16).
Although Group 4 is the most prevalent medulloblastoma subgroup, its pathogenesis remains poorly understood. The most frequent SCNA observed in Group 4 (33/317; 10.4%) is a recurrent region of single copy gain on chr5q23.2 targeting a single gene, SNCAIP (synuclein, alpha interacting protein) (Fig. 4a and Supplementary Fig. 24). SNCAIP, encodes synphilin 1, which binds to to promote the formation of Lewy bodies in the brains of patients with Parkinson disease23, 24. Additionally, rare germline mutations of SNCAIP have been described in Parkinson families25. Large insert, mate pair, whole genome sequencing (WGS) demonstrates that SNCAIP copy number gains arise from tandem duplication of a truncated SNCAIP (lacking non coding exon 1), inserted telomeric to the germline SNCAIP allele (Fig. 4b, c and Supplementary Fig. 25). Affymetrix SNP6 array profiling of patient matched germline material confirmed that SNCAIP duplications are somatic (Supplementary Fig. 26), and subsequent whole transcriptome sequencing (RNA Seq) of select Group 4 cases (n = 5) verified that SNCAIP is the only gene expressed in the duplicated region (Supplementary Fig. 27). Analysis of published copy number profiles for 3,131 primary tumours26 and 947 cancer cell lines27 (total of 4,078 cases) revealed only four cases with apparent duplication of SNCAIP, all of which were inferred as Group 4 medulloblastomas (data not shown). We conclude that SNCAIP duplication is a somatic event highly specific to Group 4 medulloblastoma.
a, Highly recurrent, focal, single copy gain of SNCAIP in Group 4. b, Paired end mapping verifies recurrent tandem duplication of SNCAIP in Group 4. c, Schematic representation of SNCAIP tandem duplication. d, SNCAIP is a Group 4 signature gene. Upper panel, SNCAIP expression across subgroups in a published series of 103 primary medulloblastomas. Error bars depict the minimum and maximum values, excluding outliers. Lower panel, SNCAIP ranks among the top 1% (rank, 39th out of 16,758) of highly expressed genes in Group 4. e, NMF consensus clustering of 188 expression profiled Group 4 tumours supports two transcriptionally distinct subtypes designated 4 and 4 (cophenetic coefficient = 0.9956). g, Group 4 cases harbouring SNCAIP duplication exhibit a 1.5 fold increase in SNCAIP expression. f, g, Error bars depict the minimum and maximum values, excluding outliers.
Re analysis of 499 published medulloblastoma expression profiles confirmed that SNCAIP is one of the most highly upregulated Group 4 signature genes (Fig. 4d and Supplementary Fig. 28). Profiling of 188 Group 4 tumours on expression microarrays followed by consensus non negative matrix factorization (NMF) clustering delineates two subtypes of Group 4 (4 and 4 Fig. 4e and Supplementary Fig. 29). SNCAIP is more highly expressed in Group 4 than 4 (Fig. 4f), and 4 samples with tandem duplication showed approximately 1.5 fold increased expression, consistent with gene dosage (Fig. 4g and Supplementary Figs 35 and 36). Group 4 exhibits a relatively balanced genome compared to 4 (Supplementary Figs 30 and several 4 cases harbour SNCAIP duplication in conjunction with i17q and no other SCNAs (Supplementary Fig. 33). Importantly, SNCAIP duplications are mutually exclusive from other prominent SCNAs in Group 4, including MYCN and CDK6 amplifications (Supplementary Fig. 34).
Although recurrent gene fusions have recently been discovered in solid tumours, none have been reported in medulloblastoma. RNA Seq of Group 3 tumours (n = 13) identified two independent gene fusions in two different tumours (MB 182 and MB 586), both involving the 5 end of PVT1, a non coding gene frequently co amplified with MYC in Group 3 (Fig. 5a, b, Supplementary Fig. 37 and Supplementary Tables 17 and 18). Sanger sequencing confirmed a fusion transcript consisting of exons 1 and 3 of PVT1 fused to the coding sequence of MYC (exons 2 and 3) in MB 182, and a fusion involving PVT1 exon 1 fused to the 3 end of NDRG1 in MB 586 (Fig. 5a, b).
a, b, RNA Seq identifies multiple fusion transcripts driven by PVT1 in Group 3. Schematics depict the structures of verified PVT1 MYC (a) and PVT1 NDRG1 (b) fusion genes. c, Heat map of the MYC/PVT1 locus showing a subset of 13 MYC amplified Group 3 cases subsequently verified to exhibit PVT1 gene fusions (shown in d). Yellow box highlights the common breakpoint affecting the first exon/intron of PVT1, including miR 1204. d, Summary of PVT1 fusion transcripts identified in Group 3. e, f, WGS confirms complex patterns of rearrangement on chr8q24 in PVT1 fusion (+) Group 3.
Group 3 copy number data at the MYC/PVT1 locus indicated that additional samples might harbour PVT1 gene fusions (Fig. 5c). PCR with reverse transcription (RT profiling of select Group 3 cases confirmed PVT1 MYC fusions in at least 60% (12/20) of MYC amplified cases (Fig. 5d and Supplementary Table 19). Fusion transcripts included many other portions of chr8q, with up to four different genomic loci mapping to a single transcript, a pattern reminiscent of chromothripsis28, 29 (Fig. 5d). WGS performed on four MYC amplified Group 3 tumours harbouring PVT1 fusion transcripts identified a series of complex genomic rearrangements on chr8q (Fig. 5e, f, Supplementary Fig. 38 and Supplementary Tables 20 and 21). Chromosome 8 copy number profile for MB 586 (PVT1 NDRG1) derived from WGS showed that PVT1 and NDRG1 are structurally linked, as predicted by RNA Seq, and several adjacent regions of 8q24 were extensively rearranged (Fig. 5e, f and Supplementary Table 21). Monte Carlo simulation suggests that this fragmented 8q amplicon arose through chromothripsis, a process of erroneous DNA repair following a single catastrophic event in which a chromosome is shattered into many pieces (Supplementary Fig. 39). Further examination of our copy number data set revealed rare examples of chromothripsis across subgroups (Supplementary Fig. 40), with only chr8 in Group 3 demonstrating statistically significant, region specific chromothripsis (Q = 0.0004, false discovery rate (FDR) corrected Fisher exact test). Among Group 3 tumours, the occurrence of chr8q chromothripsis is correlated with deletion of chr17p (location of TP53; data not shown), in keeping with the association of loss of TP53 and chromothripsis recently described in medulloblastoma (P = 0.0199, Fisher exact test)28. Whereas the PVT1 locus has been suggested to be a genomically fragile site, we observe that the majority of MYC amplified Group 3 tumours harbour PVT1 fusions that arise through a process consistent with chromothripsis.
PVT1 is a non coding host gene for four microRNAs, miR 1204 Previous studies have implicated miR 1204 as a candidate oncogene that enhances oncogenesis in combination with MYC30, 31. PVT1 fus
Take 2 in a classic VW Camper Van
The classic VW Type 2 camper van, now made in Brazil, can be bought new in the UK. Mark Dixon put some flowers in his hair and took off
Appropriately, I was driving through Woodstock that's Woodstock in Oxfordshire, rather than New York State when it happened. A young lad in his Vauxhall made a rude gesture with his right hand as I passed. Mentally tut tutting at his appalling manners, I was several miles down the road before I realised that, far from being offensive, he was actually using one of those incomprehensible "VW" gestures with which fellow vee dub enthusiasts van cleef arpel alhambra necklace copy signal their approval. Oh, the shame!
You get a lot of that sort of thing when you drive an old VW camper van. Or, knock off van cleef heart necklace indeed, a new one if it's the classic Type 2 "Bay Window" imported by Danbury Motor Caravans.
Surfer Alex Wade was impressed by the all new, 30,000 VW California he reviewed in these pages on August 18, but still hankered for the classic Type 2 camper. In fact the Type 2 is still made in Brazil, from where Danbury ships them over to convert into camper vans for nostalgic ex hippies and anyone who likes a vehicle with a bit of character.
The big difference between older vans and the current model is that the engine is now water cooled rather than air cooled. This gives the front end a curiously 1960s East European look, but if it bothers you then Danbury can sell you a nose mounted dummy spare wheel cover drilled with dozens of vent holes. From a few feet van cleef arpel alhambra necklace fake away the cover appears solid, yet it lets enough air through for the radiator to do its job.
Inside, the vans are kitted out by Danbury to usual motorhome spec which, on this Diamond Classic model, means cooker, fridge, fold out double bed, elevating roof and chintzy fabric. That big sliding door on the side makes getting in and out a doddle, although the hefty slam you need to shut it won't win you any friends on the campsite when you get out for a pee at two in the morning.
Danbury will also convert the left hand drive vehicle to right hand drive. This isn't totally successful as the gearlever ends up close to your leg, while the steering wheel and instrument binnacle are offset to the left. In any case, right hand drive isn't really necessary since with just 80bhp on tap you won't be doing much overtaking.
Tucked away at the back of the van, the Polo engine is quiet and it's also economical I was getting 31mpg on cross country roads while the lack of power isn't such an issue: 65mph is about as fast as you'll want to go, given the van's predilection for sniffing out either verge of the carriageway if you let your concentration lapse for an instant.
The wayward handling and a frankly awful gearchange that feels as if you're stirring a thick soup, not to mention the non synchro first gear (in 2007!), mean it's hard to make a case for the Danbury being a serious alternative to a modern camper van. But that's the whole point: it's not a ''serious'' van. It is a bit of fun, and now that original 1970s Type 2s are fetching silly money the 26,359 asking price for a new Danbury to this spec isn't outrageous either.
Apparently Nick Park, the animator of Wallace and Gromit fame, has a Danbury. What's the betting that Wallace may be upgrading from his Austin A35 van in the near future?.
The classic VW Type 2 camper van, now made in Brazil, can be bought new in the UK. Mark Dixon put some flowers in his hair and took off
Appropriately, I was driving through Woodstock that's Woodstock in Oxfordshire, rather than New York State when it happened. A young lad in his Vauxhall made a rude gesture with his right hand as I passed. Mentally tut tutting at his appalling manners, I was several miles down the road before I realised that, far from being offensive, he was actually using one of those incomprehensible "VW" gestures with which fellow vee dub enthusiasts van cleef arpel alhambra necklace copy signal their approval. Oh, the shame!
You get a lot of that sort of thing when you drive an old VW camper van. Or, knock off van cleef heart necklace indeed, a new one if it's the classic Type 2 "Bay Window" imported by Danbury Motor Caravans.
Surfer Alex Wade was impressed by the all new, 30,000 VW California he reviewed in these pages on August 18, but still hankered for the classic Type 2 camper. In fact the Type 2 is still made in Brazil, from where Danbury ships them over to convert into camper vans for nostalgic ex hippies and anyone who likes a vehicle with a bit of character.
The big difference between older vans and the current model is that the engine is now water cooled rather than air cooled. This gives the front end a curiously 1960s East European look, but if it bothers you then Danbury can sell you a nose mounted dummy spare wheel cover drilled with dozens of vent holes. From a few feet van cleef arpel alhambra necklace fake away the cover appears solid, yet it lets enough air through for the radiator to do its job.
Inside, the vans are kitted out by Danbury to usual motorhome spec which, on this Diamond Classic model, means cooker, fridge, fold out double bed, elevating roof and chintzy fabric. That big sliding door on the side makes getting in and out a doddle, although the hefty slam you need to shut it won't win you any friends on the campsite when you get out for a pee at two in the morning.
Danbury will also convert the left hand drive vehicle to right hand drive. This isn't totally successful as the gearlever ends up close to your leg, while the steering wheel and instrument binnacle are offset to the left. In any case, right hand drive isn't really necessary since with just 80bhp on tap you won't be doing much overtaking.
Tucked away at the back of the van, the Polo engine is quiet and it's also economical I was getting 31mpg on cross country roads while the lack of power isn't such an issue: 65mph is about as fast as you'll want to go, given the van's predilection for sniffing out either verge of the carriageway if you let your concentration lapse for an instant.
The wayward handling and a frankly awful gearchange that feels as if you're stirring a thick soup, not to mention the non synchro first gear (in 2007!), mean it's hard to make a case for the Danbury being a serious alternative to a modern camper van. But that's the whole point: it's not a ''serious'' van. It is a bit of fun, and now that original 1970s Type 2s are fetching silly money the 26,359 asking price for a new Danbury to this spec isn't outrageous either.
Apparently Nick Park, the animator of Wallace and Gromit fame, has a Danbury. What's the betting that Wallace may be upgrading from his Austin A35 van in the near future?.
- charm imitation van cleef yellow ring How much it?
- ornament van and arpels ring alhambra mens replica make you marriage more well-being
- adorn van cleef ring alhambra couple imitation make you matr
- by van cleef and arpels rings trefoil lover imitation give ground matrimonial all fragrant
- Put on vac bracelet trefoil couple copy give you ceremony mo
Reviving Extinct Species and More
An elephant seal cub smiles for the camera on South Georgia Island. Fully grown adults can reach over 4,000 pounds.
(Fatima Williamson / National Geographic Your Shot)
Every week, embark with host Boyd Matson on an exploration of the latest discoveries and interviews with some of the most fascinating people on the planet, onNational Geographic Weekend.
Pleasecheck listings near youto find the best way to listen toNational GeographicWeekend, or pick your favorite segments and listen now below!
Episode: 1313 Air Date: March 31, 2013
Charlie Pitchershattered a world record forsolo trans Atlantic rowingby exploiting a long window of good weather, powering himself from the Canary Islands to Barbados in 35 days and 33 minutes. The 50 year old rowed 2,900 miles, knocking 5 days and 9 hours off of the previous record. He tells Boyd that age proved to be an advantage, as he has years of experience on the oceans, but added that he doesn plan to take on a solo row of the Pacific anytime soon. Listen here.
Park was borne of Michael Crichton imagination, a parallel universe in which man had the ability to resurrect extinct animals from well preserved DNA. Zimmer explains that it now may be possible to revive recently extincted species by transferring their DNA to closely related living relatives. He tells Boyd that these scientists aren seeking to God, but simply to bring back some animals that man himself wiped from the planet by over hunting. Listen here.
For as clumsy and cumbersome that they appear to be on land, 4,000 pound elephant seals are powerful and graceful swimmers that can dive over 2,600 feet below the ocean surface while hunting prey such as the bioluminescent lantern fish. National Geographic grantee Randall Davishas been using a video camera to study the pinniped deep sea feeding habits. Listen here.
On a recent trip, Boyd visited the border that separatesBrazil and Argentina atIguazu Falls. The most dramatic point of the 1.7 mile wide curtain of van cleef and arpel clover necklace knock off water is called Devil Throat. Barros, a guide at Iguazu Falls, tells the story of a couple who were trying to cross the top of the falls in a wooden canoe and spilled down into the pool back in 1973. Boyd got a safer boat tour underneath the falls, in an inflatable zodiac. Listen here.
David Braun, editor ofNational Geographic Daily News, explains several different examples of animal navigation methods: star gazing with dung beetles, by homing pigeons, and salmon just going by feel. Listen here.
The challenge for a National Geographic photographer isn simply to take a picture of a particular animal. It to take adifferentpicture of a particular animal. Mike Nichols has done this for decades, and on his latest assignment developed a drone helicopter, a remote control car, and a specialized open air van to help him get closer than ever to lions. He tells Boyd that he was once so close that a bored adolescent lion stole a strobe light from his foot and promptly destroyed it. He also discusses launching his life body of work in anapp designed for iPads. Listen here.
Whaling is largely a bygone profession, considered a relic from the 19th Century, particularly in the United States. But National GeographicYoung Explorers Grantee Gemina Garland Lewisvisited the Azores, where, just three decades ago, the practice thrived. Her project focused on gathering as many first hand stories and anecdotes about the erstwhile practice as possible. She tells Boyd the story of a man nicknamed who was knocked out of the boat and fell into the jaws of a sperm whale. Listen here.
Part of the job of a photographer is to capture beauty and magic in the mundane. But there is nothing mundane about the chickens featured in photographerTamara Staples bookThe Magnificent Chicken, a collection of photos of championship chickens from around the world. Listen here.
Natural resource booms have become a part of the American fabric gold, to oil, to natural gas, and back to oil. Directional drilling and fracking have made oil and gas that is difficult to reach accessible, and the small towns that dot North Dakota landscape have become the beneficiaries. Listen here.
In this week Chroniclessegment, van cleef replica alhambra necklace Boyd admires one of the lesser celebrated animals he found on a recent trip to Africa, and gives it a little fanfare of its own: the dung beetle. Listen here.
National Geographic VoicesResearchers, conservationists, and others share stories, insights and ideas about Our Changing Planet, Wildlife Wild Spaces, and The Human Journey. More than 50,000 comments have been added to 10,000 posts. Explore the list alongside to dive deeper into van cleef arpels replica alhambra necklace some of the most popular categories of the National Geographic Society's conversation platform Voices.
Opinions are those of the blogger and/or the blogger's organization, and not necessarily those of the National Geographic Society. Posters of blogs and comments are required to observe National Geographic's community rules and other terms of service. May 21, 2017 Stuart PimmVatuvara Island: A Haven for Threatened Species May 21, 2017 Wildlife Conservation SocietyFor the Love of Honey May 19, 2017 Zach FullerAscension Island: Pristine Seas Heads to the Mountains! May 19, 2017 Paul RoseMeet the North: Hockey Love in Arctic Style May 19, 2017 Jennifer Kingsley
Blog SearchFollow the links on the sidebar of any of the blog's pages for details and tips on how to apply for a Fellowship.
Photo of the 2016/2017 class of Fellows by Randall Scott.
Featured Research: Mushara Elephant Project
Caitlin O'Connell and her husband, Tim Rodwell, started theMushara Elephant Projectin Namibia 24 years ago to better understand elephant social structure, communication and health in order to apply this knowledge to improved care in captivity and ultimately to elephant conservation in the wild. O'Connell is on thefaculty at Stanford University School of Medicineand CEO of the elephant focused nonprofit,Utopia Scientific.
Nat Geo Expedition: Rising Star
Two years after being discovered deep in a South African cave, the 1,500 fossils excavated during the Rising Star Expedition have been identified as belonging to a previously unknown early human relative that National Geographic Explorer in Residence Lee Berger and team have named Homo naledi.
With at least 15 individuals of all ages and both sexes represented, the find adds an unprecedented amount of information to our understanding of early human evolution in Africa.
In addition, the absence of any other animal remains or large debris in the fossil chamber strongly suggests that these non human beings intentionally deposited their dead within this cave.
An elephant seal cub smiles for the camera on South Georgia Island. Fully grown adults can reach over 4,000 pounds.
(Fatima Williamson / National Geographic Your Shot)
Every week, embark with host Boyd Matson on an exploration of the latest discoveries and interviews with some of the most fascinating people on the planet, onNational Geographic Weekend.
Pleasecheck listings near youto find the best way to listen toNational GeographicWeekend, or pick your favorite segments and listen now below!
Episode: 1313 Air Date: March 31, 2013
Charlie Pitchershattered a world record forsolo trans Atlantic rowingby exploiting a long window of good weather, powering himself from the Canary Islands to Barbados in 35 days and 33 minutes. The 50 year old rowed 2,900 miles, knocking 5 days and 9 hours off of the previous record. He tells Boyd that age proved to be an advantage, as he has years of experience on the oceans, but added that he doesn plan to take on a solo row of the Pacific anytime soon. Listen here.
Park was borne of Michael Crichton imagination, a parallel universe in which man had the ability to resurrect extinct animals from well preserved DNA. Zimmer explains that it now may be possible to revive recently extincted species by transferring their DNA to closely related living relatives. He tells Boyd that these scientists aren seeking to God, but simply to bring back some animals that man himself wiped from the planet by over hunting. Listen here.
For as clumsy and cumbersome that they appear to be on land, 4,000 pound elephant seals are powerful and graceful swimmers that can dive over 2,600 feet below the ocean surface while hunting prey such as the bioluminescent lantern fish. National Geographic grantee Randall Davishas been using a video camera to study the pinniped deep sea feeding habits. Listen here.
On a recent trip, Boyd visited the border that separatesBrazil and Argentina atIguazu Falls. The most dramatic point of the 1.7 mile wide curtain of van cleef and arpel clover necklace knock off water is called Devil Throat. Barros, a guide at Iguazu Falls, tells the story of a couple who were trying to cross the top of the falls in a wooden canoe and spilled down into the pool back in 1973. Boyd got a safer boat tour underneath the falls, in an inflatable zodiac. Listen here.
David Braun, editor ofNational Geographic Daily News, explains several different examples of animal navigation methods: star gazing with dung beetles, by homing pigeons, and salmon just going by feel. Listen here.
The challenge for a National Geographic photographer isn simply to take a picture of a particular animal. It to take adifferentpicture of a particular animal. Mike Nichols has done this for decades, and on his latest assignment developed a drone helicopter, a remote control car, and a specialized open air van to help him get closer than ever to lions. He tells Boyd that he was once so close that a bored adolescent lion stole a strobe light from his foot and promptly destroyed it. He also discusses launching his life body of work in anapp designed for iPads. Listen here.
Whaling is largely a bygone profession, considered a relic from the 19th Century, particularly in the United States. But National GeographicYoung Explorers Grantee Gemina Garland Lewisvisited the Azores, where, just three decades ago, the practice thrived. Her project focused on gathering as many first hand stories and anecdotes about the erstwhile practice as possible. She tells Boyd the story of a man nicknamed who was knocked out of the boat and fell into the jaws of a sperm whale. Listen here.
Part of the job of a photographer is to capture beauty and magic in the mundane. But there is nothing mundane about the chickens featured in photographerTamara Staples bookThe Magnificent Chicken, a collection of photos of championship chickens from around the world. Listen here.
Natural resource booms have become a part of the American fabric gold, to oil, to natural gas, and back to oil. Directional drilling and fracking have made oil and gas that is difficult to reach accessible, and the small towns that dot North Dakota landscape have become the beneficiaries. Listen here.
In this week Chroniclessegment, van cleef replica alhambra necklace Boyd admires one of the lesser celebrated animals he found on a recent trip to Africa, and gives it a little fanfare of its own: the dung beetle. Listen here.
National Geographic VoicesResearchers, conservationists, and others share stories, insights and ideas about Our Changing Planet, Wildlife Wild Spaces, and The Human Journey. More than 50,000 comments have been added to 10,000 posts. Explore the list alongside to dive deeper into van cleef arpels replica alhambra necklace some of the most popular categories of the National Geographic Society's conversation platform Voices.
Opinions are those of the blogger and/or the blogger's organization, and not necessarily those of the National Geographic Society. Posters of blogs and comments are required to observe National Geographic's community rules and other terms of service. May 21, 2017 Stuart PimmVatuvara Island: A Haven for Threatened Species May 21, 2017 Wildlife Conservation SocietyFor the Love of Honey May 19, 2017 Zach FullerAscension Island: Pristine Seas Heads to the Mountains! May 19, 2017 Paul RoseMeet the North: Hockey Love in Arctic Style May 19, 2017 Jennifer Kingsley
Blog SearchFollow the links on the sidebar of any of the blog's pages for details and tips on how to apply for a Fellowship.
Photo of the 2016/2017 class of Fellows by Randall Scott.
Featured Research: Mushara Elephant Project
Caitlin O'Connell and her husband, Tim Rodwell, started theMushara Elephant Projectin Namibia 24 years ago to better understand elephant social structure, communication and health in order to apply this knowledge to improved care in captivity and ultimately to elephant conservation in the wild. O'Connell is on thefaculty at Stanford University School of Medicineand CEO of the elephant focused nonprofit,Utopia Scientific.
Nat Geo Expedition: Rising Star
Two years after being discovered deep in a South African cave, the 1,500 fossils excavated during the Rising Star Expedition have been identified as belonging to a previously unknown early human relative that National Geographic Explorer in Residence Lee Berger and team have named Homo naledi.
With at least 15 individuals of all ages and both sexes represented, the find adds an unprecedented amount of information to our understanding of early human evolution in Africa.
In addition, the absence of any other animal remains or large debris in the fossil chamber strongly suggests that these non human beings intentionally deposited their dead within this cave.
- ornament van cleef & arpels rings alhambra mens co
- wear vac earrings clover mens imitation give you wedding more happiness
- Put on van cleef bracelets trefoil mens imitation offer matrimony all happy
- through arpels van cleef rings trefoil women knockoff give you matrimonial all g
- by van and arpels necklace trefoil lover knockoff give ground matrimony all fine
South van cleef and arpel clover necklace knock off Africa vs England second cricket Test
Stokes eventually went out in something of an anti climax as he skied a shot to AB de Villiers, who dropped a simple looking catch only to sweep up the ball and hit the stumps to run out the batsman as he ambled back to the crease.
South Africa's horror day did not end after the declaration with Stiaan van Zyl run out for four in the third over of their first innings, setting off for a quick run but being sent back by opening partner Dean Elgar.
Ben Stokes and Jonny Bairstow set a world record sixth wicket partnership with 399 runs, beating the previous best of 365 set by New Zealand's Kane Williamson and BJ Watling against Sri Lanka last year.
Stokes' 258 was the most runs by a batsmen at number six, beating the previous best of 250 set by Australia's Doug Walters against New Zealand in 1977.
Stokes made the fastest 250 in Test history, reaching the landmark off 196 balls.
Stokes hit 11 sixes, the most in a Test innings by an England imitation van arpels and cleef necklace cricketer. imitation van cleef and arpels necklace clover It was one short of Wasim Akram's world record of 12 set against Zimbabwe in 1996.
Stokes eventually went out in something of an anti climax as he skied a shot to AB de Villiers, who dropped a simple looking catch only to sweep up the ball and hit the stumps to run out the batsman as he ambled back to the crease.
South Africa's horror day did not end after the declaration with Stiaan van Zyl run out for four in the third over of their first innings, setting off for a quick run but being sent back by opening partner Dean Elgar.
Ben Stokes and Jonny Bairstow set a world record sixth wicket partnership with 399 runs, beating the previous best of 365 set by New Zealand's Kane Williamson and BJ Watling against Sri Lanka last year.
Stokes' 258 was the most runs by a batsmen at number six, beating the previous best of 250 set by Australia's Doug Walters against New Zealand in 1977.
Stokes made the fastest 250 in Test history, reaching the landmark off 196 balls.
Stokes hit 11 sixes, the most in a Test innings by an England imitation van arpels and cleef necklace cricketer. imitation van cleef and arpels necklace clover It was one short of Wasim Akram's world record of 12 set against Zimbabwe in 1996.
- arpels van cleef earrings clover men knockoff make you espousal a fortiori fine
- popular magic van diamonds necklace How much it?
- love magic van diamonds bracelet do you want it?
- wear van cleef earrings trefoil couple imitation Let you matrimony still further
- by van cleef and arpels bracelets fortunate woman replica Let you wedding more fine
Il detective Dade della polizia ha rubato i monili durante il mandato di ricerca di DEA
Det. Karel Rosario si trova ad affrontare le accuse di furto e tratta di proprietà rubate, secondo l'ufficio dell'avvocato dello Stato di Miami Dade.
Det. Karel Rosario si trova ad affrontare accuse di furto e di occuparsi di proprietà rubate, secondo l'ufficio dell'avvocato dello Stato di Miami Dade, non era noto se avesse un avvocato, ha dichiarato Patterson in un'affermazione: 'Questa integrità e la necessità di mantenere la La fiducia assoluta della comunità, richiede che ogni volta che uno dei nostri ufficiali rompe la legge, consideriamo quell'ufficiale responsabile '.
Rosario è un veterano di 9 anni del dipartimento. Il suo status con il dipartimento era sconosciuto.
L'uomo accusato di sparare agli ufficiali di MDPD si arrende
I funzionari hanno detto che il furto è accaduto il 20 maggio, in quanto agenti hanno eseguito il mandato di ricerca presso la casa di Yulia Martinez, che è stato preso in custodia federale e successivamente legato da prigione.
Det. Karel Rosario si trova ad affrontare le accuse di furto e tratta di proprietà rubate, secondo l'ufficio dell'avvocato dello Stato di Miami Dade.
Det. Karel Rosario si trova ad affrontare accuse di furto e di occuparsi di proprietà rubate, secondo l'ufficio dell'avvocato dello Stato di Miami Dade, non era noto se avesse un avvocato, ha dichiarato Patterson in un'affermazione: 'Questa integrità e la necessità di mantenere la La fiducia assoluta della comunità, richiede che ogni volta che uno dei nostri ufficiali rompe la legge, consideriamo quell'ufficiale responsabile '.
Rosario è un veterano di 9 anni del dipartimento. Il suo status con il dipartimento era sconosciuto.
L'uomo accusato di sparare agli ufficiali di MDPD si arrende
I funzionari hanno detto che il furto è accaduto il 20 maggio, in quanto agenti hanno eseguito il mandato di ricerca presso la casa di Yulia Martinez, che è stato preso in custodia federale e successivamente legato da prigione.
Apprendere le ispirazioni
Sapevo che ho imparato meglio parlando le mie idee ad alta voce con qualcuno. Era fantastico avere un gruppo di studio e ci siamo incontrati settimanalmente. Cambierò lo schermo anche per la stagione e posso mettere informazioni importanti al centro dello schermo e file la cartella una volta terminata l'operazione. Significa che sono riuscito a raggiungere rapidamente le mie cartelle di lavoro senza guardare ovunque per loro.
Utilizza immagini come grafici, diagrammi o foto per ancorare idee e concetti in memoria e per la comprensione.
Utilizza le note 'Post It' colorate per posizionare le tue idee in copia cartacea.
Inserisci i riepiloghi multitxtuali (sia testo che immagine) per catturare le idee.
Utilizzare diagrammi di flusso per mappare informazioni e passi procedurali, ad esempio una sequenza di laboratorio e così via.
Utilizza schede flash (scrivendo piccoli pezzi di informazioni pertinenti sulle piccole schede) per la memoria e trasportali con te e passate attraverso di esse.
Organizza visivamente le informazioni sul tuo computer utilizzando un modello che soddisfa.
Utilizzare oggetti visivi e spaziali per ancorare le informazioni. Ad esempio, è possibile utilizzare l'idea di un armadio di archiviazione per organizzare informazioni per un rapporto o assegnazione dove ciascun cassetto rappresenta una sezione e quindi all'interno di ciascun cassetto, ci sono punti e prove principali.
Utilizza i calendari visivi e gli elenchi visualizzati a priorità visiva 'da fare' come promemoria.
Collegare le informazioni ai suoni e alla musica. Ad esempio, collegare le idee alle tue canzoni preferite e memorabili. Quante volte troverai che tu possa guidare alla tua canzone preferita e puoi ricordare le parole anche senza rendervi conto di sapere loro? Quanti jingle pubblicitari rimangono nella tua memoria?
Utilizzare le mnemoniche del ritmo per ricordare le informazioni e utilizzare anche l'intonazione pitch.
Ascoltare musica in background per aiutare con lo studio. Ciò consente alle onde cerebrali di entrare negli stati di onde rilassati alfa per assorbire le informazioni. Si dice che la musica barocca sia favorevole, come la musica di Handel e Vivaldi, anche provare Mozart. Andare con quello che funziona per te, ma non scegliere qualcosa che ti metta a dormire!
Sapevo che ho imparato meglio parlando le mie idee ad alta voce con qualcuno. Era fantastico avere un gruppo di studio e ci siamo incontrati settimanalmente. Cambierò lo schermo anche per la stagione e posso mettere informazioni importanti al centro dello schermo e file la cartella una volta terminata l'operazione. Significa che sono riuscito a raggiungere rapidamente le mie cartelle di lavoro senza guardare ovunque per loro.
Utilizza immagini come grafici, diagrammi o foto per ancorare idee e concetti in memoria e per la comprensione.
Utilizza le note 'Post It' colorate per posizionare le tue idee in copia cartacea.
Inserisci i riepiloghi multitxtuali (sia testo che immagine) per catturare le idee.
Utilizzare diagrammi di flusso per mappare informazioni e passi procedurali, ad esempio una sequenza di laboratorio e così via.
Utilizza schede flash (scrivendo piccoli pezzi di informazioni pertinenti sulle piccole schede) per la memoria e trasportali con te e passate attraverso di esse.
Organizza visivamente le informazioni sul tuo computer utilizzando un modello che soddisfa.
Utilizzare oggetti visivi e spaziali per ancorare le informazioni. Ad esempio, è possibile utilizzare l'idea di un armadio di archiviazione per organizzare informazioni per un rapporto o assegnazione dove ciascun cassetto rappresenta una sezione e quindi all'interno di ciascun cassetto, ci sono punti e prove principali.
Utilizza i calendari visivi e gli elenchi visualizzati a priorità visiva 'da fare' come promemoria.
Collegare le informazioni ai suoni e alla musica. Ad esempio, collegare le idee alle tue canzoni preferite e memorabili. Quante volte troverai che tu possa guidare alla tua canzone preferita e puoi ricordare le parole anche senza rendervi conto di sapere loro? Quanti jingle pubblicitari rimangono nella tua memoria?
Utilizzare le mnemoniche del ritmo per ricordare le informazioni e utilizzare anche l'intonazione pitch.
Ascoltare musica in background per aiutare con lo studio. Ciò consente alle onde cerebrali di entrare negli stati di onde rilassati alfa per assorbire le informazioni. Si dice che la musica barocca sia favorevole, come la musica di Handel e Vivaldi, anche provare Mozart. Andare con quello che funziona per te, ma non scegliere qualcosa che ti metta a dormire!
Felice di lasciarli farlo
L'ultima relazione britannica sui rapporti sociali offre un'occasione annuale per i commentatori a saltare a conclusioni circa le modalità precise in cui il paese sta andando a pentola, perché è sempre come vengono interpretate le sue scoperte. Quest'anno, il tema del titolo è l'individualismo egoista.
La gente accetta che ci sono carenze nelle abitazioni ma si oppongono ai nuovi sviluppi nella loro zona. La percentuale di persone che sostengono aumentare le tasse per migliorare la salute e l'istruzione è dimezzata in nove anni braccialetto d'amore cartier mens. Il numero di persone disposte a pagare prezzi molto più alti per proteggere l'ambiente è sceso dal 43 al 26%. Se i ricchi vogliono pagare per una migliore salute privata e l'istruzione amore replica braccialetto, sempre più di noi sono lieti di far loro farlo, qualunque ne siano le conseguenze per l'uguaglianza sociale. E così continua.
C'è una spiegazione facile per questo. In tempi difficili, la gente vede preoccuparsi degli altri come un lusso che non possono permettersi. Possiamo tutti essere in questo insieme, ma stiamo pensando di uscire da sola. Tuttavia, c'è qualcosa di pesante su questo, dato che l'ultima volta che avremmo dovuto avere una 'generazione di me' era nel boom degli anni ottanta , Non è un busto. 'Sono giusto Jack' è diventato 'io non sono bene, Jack, quindi non aspetti che ti aiuti'. Poor Jack si sbatte su quello che succede.
La verità più complessa è che molte cose modellano le nostre scelte e ciò che alcuni vecchi marxisti scolastici potrebbero ancora insistere per i braccialetti d'amore, l'economia è solo un autista, non un potente determinatore.
Naturalmente, le circostanze svolgono un ruolo importante nella definizione dei valori. Gli esperimenti hanno dimostrato che anche i banalizzatori momentanei, come ad essere in fretta o alla ricerca di una moneta, possono influenzare le disposizioni delle persone per aiutare gli sconosciuti in difficoltà. Dovrebbe essere straordinario se si sentiva sotto pressione a lungo termine o come Anche se il vostro lavoro era a rischio, non ha alterato il modo in cui abbiamo risposto alle esigenze degli altri.
Ma i valori sono anche modellati da norme sociali, e negli ultimi anni è stata diffusa molto diffusa la diffidenza del governo e degli affari. Quello, accoppiato ad una crescente convinzione che l'affidamento allo Stato ha un effetto deleterio sulla società, potrebbe andare molto a spiegare la crescente riluttanza a pagare più in materia fiscale o di prezzi sulla promessa che sia tutto per il bene comune, piuttosto Che il beneficio dei politici e dei direttori aziendali.
Tuttavia, quello che trovo più allarmante non è come gli atteggiamenti specifici siano cambiati, ma che si muovono così tanto. Ciò suggerisce che molti principi della gente hanno radici molto basse e non sono in grado di sopportare persino la minima pressione economica o sociale.
Non c'è abbastanza dell'alfabetizzazione filosofica necessaria per pensare attraverso giudizi sui valori, né l'alfabetizzazione psicologica necessaria per contrastare molte delle distorsioni cognitive e serventi che ci permettono di giustificare la nostra egoismo ei nostri pregiudizi. Senza queste basi forti, i valori sonori saranno sempre vulnerabili quando i tempi difficili forniscono un incentivo a spingere fuori dalla finestra.
Fai clic sull'icona Adblock / Adblock Plus, alla destra della barra degli indirizzi.
Su Adblock fare clic su 'Non eseguire pagine su questo dominio'.
Se sei un browser privato in Firefox, la 'Protezione del monitoraggio' può causare la visualizzazione dell'avviso adblock. Può essere disattivato temporaneamente facendo clic sull'icona 'scudo' nella barra degli indirizzi.
L'ultima relazione britannica sui rapporti sociali offre un'occasione annuale per i commentatori a saltare a conclusioni circa le modalità precise in cui il paese sta andando a pentola, perché è sempre come vengono interpretate le sue scoperte. Quest'anno, il tema del titolo è l'individualismo egoista.
La gente accetta che ci sono carenze nelle abitazioni ma si oppongono ai nuovi sviluppi nella loro zona. La percentuale di persone che sostengono aumentare le tasse per migliorare la salute e l'istruzione è dimezzata in nove anni braccialetto d'amore cartier mens. Il numero di persone disposte a pagare prezzi molto più alti per proteggere l'ambiente è sceso dal 43 al 26%. Se i ricchi vogliono pagare per una migliore salute privata e l'istruzione amore replica braccialetto, sempre più di noi sono lieti di far loro farlo, qualunque ne siano le conseguenze per l'uguaglianza sociale. E così continua.
C'è una spiegazione facile per questo. In tempi difficili, la gente vede preoccuparsi degli altri come un lusso che non possono permettersi. Possiamo tutti essere in questo insieme, ma stiamo pensando di uscire da sola. Tuttavia, c'è qualcosa di pesante su questo, dato che l'ultima volta che avremmo dovuto avere una 'generazione di me' era nel boom degli anni ottanta , Non è un busto. 'Sono giusto Jack' è diventato 'io non sono bene, Jack, quindi non aspetti che ti aiuti'. Poor Jack si sbatte su quello che succede.
La verità più complessa è che molte cose modellano le nostre scelte e ciò che alcuni vecchi marxisti scolastici potrebbero ancora insistere per i braccialetti d'amore, l'economia è solo un autista, non un potente determinatore.
Naturalmente, le circostanze svolgono un ruolo importante nella definizione dei valori. Gli esperimenti hanno dimostrato che anche i banalizzatori momentanei, come ad essere in fretta o alla ricerca di una moneta, possono influenzare le disposizioni delle persone per aiutare gli sconosciuti in difficoltà. Dovrebbe essere straordinario se si sentiva sotto pressione a lungo termine o come Anche se il vostro lavoro era a rischio, non ha alterato il modo in cui abbiamo risposto alle esigenze degli altri.
Ma i valori sono anche modellati da norme sociali, e negli ultimi anni è stata diffusa molto diffusa la diffidenza del governo e degli affari. Quello, accoppiato ad una crescente convinzione che l'affidamento allo Stato ha un effetto deleterio sulla società, potrebbe andare molto a spiegare la crescente riluttanza a pagare più in materia fiscale o di prezzi sulla promessa che sia tutto per il bene comune, piuttosto Che il beneficio dei politici e dei direttori aziendali.
Tuttavia, quello che trovo più allarmante non è come gli atteggiamenti specifici siano cambiati, ma che si muovono così tanto. Ciò suggerisce che molti principi della gente hanno radici molto basse e non sono in grado di sopportare persino la minima pressione economica o sociale.
Non c'è abbastanza dell'alfabetizzazione filosofica necessaria per pensare attraverso giudizi sui valori, né l'alfabetizzazione psicologica necessaria per contrastare molte delle distorsioni cognitive e serventi che ci permettono di giustificare la nostra egoismo ei nostri pregiudizi. Senza queste basi forti, i valori sonori saranno sempre vulnerabili quando i tempi difficili forniscono un incentivo a spingere fuori dalla finestra.
Fai clic sull'icona Adblock / Adblock Plus, alla destra della barra degli indirizzi.
Su Adblock fare clic su 'Non eseguire pagine su questo dominio'.
Se sei un browser privato in Firefox, la 'Protezione del monitoraggio' può causare la visualizzazione dell'avviso adblock. Può essere disattivato temporaneamente facendo clic sull'icona 'scudo' nella barra degli indirizzi.