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Intraneuronal beta-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation

Holly Oakley
Oct 4, 2006; 26:10129-10140
Neurobiology of Disease




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Neuregulin1 Nuclear Signaling Influences Adult Neurogenesis and Regulates a Schizophrenia Susceptibility Gene Network within the Mouse Dentate Gyrus

Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: (1) local axonal PI3K-AKT signaling and (2) cleavage by -secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al., 2003; Hancock et al., 2008). To dissect the contribution of these alternate signaling strategies to neuronal development, we generated a transgenic mouse with a missense mutation (V321L) in the Nrg1 transmembrane domain that disrupts nuclear back signaling with minimal effects on forward signaling or local back signaling and was previously found to be associated with psychosis (Walss-Bass et al., 2006). We combined RNA sequencing, retroviral fate mapping of neural stem cells, behavioral analyses, and various network analyses of transcriptomic data to investigate the effect of disrupting Nrg1 nuclear back signaling in the dentate gyrus (DG) of male and female mice. The V321L mutation impairs nuclear translocation of the Nrg1 ICD and alters gene expression in the DG. V321L mice show reduced stem cell proliferation, altered cell cycle dynamics, fate specification defects, and dendritic dysmorphogenesis. Orthologs of known schizophrenia (SCZ)-susceptibility genes were dysregulated in the V321L DG. These genes coordinated a larger network with other dysregulated genes. Weighted gene correlation network analysis and protein interaction network analyses revealed striking similarity between DG transcriptomes of V321L mouse and humans with SCZ.




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A miR-383-5p Signaling Hub Coordinates the Axon Regeneration Response to Inflammation

Neuroinflammation can positively influence axon regeneration following injury in the central nervous system. Inflammation promotes the release of neurotrophic molecules and stimulates intrinsic proregenerative molecular machinery in neurons, but the detailed mechanisms driving this effect are not fully understood. We evaluated how microRNAs are regulated in retinal neurons in response to intraocular inflammation to identify their potential role in axon regeneration. We found that miR-383-5p is downregulated in retinal ganglion cells in response to zymosan-induced intraocular inflammation. MiR-383-5p downregulation in neurons is sufficient to promote axon growth in vitro, and the intravitreal injection of a miR-383-5p inhibitor into the eye promotes axon regeneration following optic nerve crush. MiR-383-5p directly targets ciliary neurotrophic factor (CNTF) receptor components, and miR-383-5p inhibition sensitizes adult retinal neurons to the outgrowth-promoting effects of CNTF. Interestingly, we also demonstrate that CNTF treatment is sufficient to reduce miR-383-5p levels in neurons, constituting a positive-feedback module, whereby initial CNTF treatment reduces miR-383-5p levels, which then disinhibits CNTF receptor components to sensitize neurons to the ligand. Additionally, miR-383-5p inhibition derepresses the mitochondrial antioxidant protein peroxiredoxin-3 (PRDX3) which was required for the proregenerative effects associated with miR-383-5p loss-of-function in vitro. We have thus identified a positive-feedback mechanism that facilitates neuronal CNTF sensitivity in neurons and a new molecular signaling module that promotes inflammation-induced axon regeneration.




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Retinal Input to Macaque Superior Colliculus Derives from Branching Axons Projecting to the Lateral Geniculate Nucleus

The superior colliculus receives a direct projection from retinal ganglion cells. In primates, it remains unknown if the same ganglion cells also supply the lateral geniculate nucleus. To address this issue, a double-label experiment was performed in two male macaques. The animals fixated a target while injection sites were scouted in the superior colliculus by recording and stimulating with a tetrode. Once suitable sites were identified, cholera toxin subunit B-Alexa Fluor 488 was injected via an adjacent micropipette. In a subsequent acute experiment, cholera toxin subunit B-Alexa Fluor 555 was injected into the lateral geniculate nucleus at matching retinotopic locations. After a brief survival period, ganglion cells were examined in retinal flatmounts. The percentage of double-labeled cells varied locally, depending on the relative efficiency of retrograde transport by each tracer and the precision of retinotopic overlap of injection sites in each target nucleus. In counting boxes with extensive overlap, 76–98% of ganglion cells projecting to the superior colliculus were double labeled. Cells projecting to the superior colliculus constituted 4.0–6.7% of the labeled ganglion cell population. In one particularly large zone, there were 5,746 cells labeled only by CTB-AF555, 561cells double labeled by CTB-AF555 and CTB-AF488, but no cell labeled only by CTB-AF488. These data indicate that retinal input to the macaque superior colliculus arises from a collateral axonal branch supplied by ~5% of the ganglion cells that project to the lateral geniculate nucleus. Surprisingly, there exist no ganglion cells that project exclusively to the SC.




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How Century-Old Paintings Reveal the Indigenous Roots and Natural History of New England Landscapes

Seven guest collaborators bring new eyes to a Smithsonian museum founder’s collection of American art




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How an Indigenous Weaver’s Mastery of Color Infuses Her Tapestries With a Life Force

The work of Diné artist DY Begay, now on view at the National Museum of the American Indian, blends tradition and modernity




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FAO Director-General applauds UN Secretary-General's stance on hunger

FAO Director-General José Graziano da Silva today praised UN Secretary-General Ban Ki Moon for his support in the fight against hunger at a meeting with FAO member countries, the Committee [...]




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FAO Director-General to visit 7 countries and to attend 3 multilateral conferences in the next seven weeks

FAO Director-General José Graziano da Silva will be away from Rome during the next few weeks. During this period he will be involved in a range of [...]




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Food security tops agenda of FAO Director-General's meeting with India's Prime Minister Modi

The [...]




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Rome Based Agencies making an impact in Burkina Faso

FAO, IFAD and WFP/Burkina [...]




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FAO Director-General appoints Jacques Diouf as FAO Special Envoy for the Sahel and the Horn of Africa

FAO Director-General José Graziano da Silva today appointed Jacques Diouf as Special Envoy for the Horn of Africa and the Sahel.

In his new role, the former Director-General Jacques Diouf will [...]




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Director General opens FAO Council meeting

FAO Director-General Graziano da Silva today opened the 150th session of the FAO Council, highlighting the successful conclusion of the Second International Conference on Nutrition (ICN2), held last month in [...]




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FAO Council closure: Director-General urges Members to focus on implementation early in 2015

5 December 2014, Rome – At the closure of the FAO Council held today, the [...]




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FAO Director-General highlights International Year of Soils to Agriculture Ministers in Berlin

Berlin- FAO Director-General José Graziano da Silva has highlighted some of the most important events on the organization’s 2015 calendar during meetings with agriculture ministers who attended the Global Forum [...]




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GRULAC endorses FAO Director-General's candidature for a second term

Just announced by the Group of Latin America and the Caribbean Countries (GRULAC)

The Group of Latin American and Caribbean Countries (GRULAC) of FAO in Rome is pleased to endorse the [...]




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Incumbent Director-General only candidate for election

Rome - José Graziano da Silva, the [...]




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Africa Regional Group endorses FAO Director-General's candidature for a second term

Rome, The Africa Regional Group of Ambassadors and Permanent Representatives accredited  to the Rome based UN Agencies have announced the endorsement of the candidature of Dr. José Graziano da Silva [...]




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Near East Group endorses FAO Director-General's candidature for a second term

Rome, 02 March 2015 - In a letter addressed to the Director-General, the Chairperson of the Near East Regional Group has announced their endorsement of the candidature [...]




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Asia Regional Group endorses FAO Director-General's candidature for a second term

In a letter addressed to the Director-General, the Ambassador of Malaysia to FAO, on behalf of the Chair of the Asia Group, has announced the endorsement of the [...]




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Statement of the FAO Secretariat under agenda item 12 “Proposal of the Republic of Korea for the establishment of an FAO World Fisheries University”

Mr Chairman,

I wish to convey, through you, to the Committee on Fisheries, the considered views of the FAO Secretariat on the item on the proposed Fisheries University.  

So far, the [...]




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FAO Director-General listed among the most influential Latin Americans

FAO Director-General José Graziano da Silva has been selected as one of the world's most influential Latin Americans for his work against hunger and malnutrition in the world. In its [...]




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Follow the Director-General's meetings at the Pre-Summit

The Pre-Summit will bring together the global efforts to shape the transformation of agri-food systems.




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FAO Director-General addresses G7 Agriculture Ministers on Global Food Markets and Prices

Click here to access the presentation by QU Dongyu.

 




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171st Session of the FAO Council Statement By Dr QU Dongyu, FAO Director-General

A statement by FAO Director-General QU Dongyu




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FAO in review: The first fully digital United Nations agency

Read the series on how FAO increased efficiency, effectiveness and transparency to better support its Members in the transformation of agrifood systems.




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FAO in Review: Emergency and humanitarian response

Read the series on how FAO increased efficiency, effectiveness and transparency to better support its Members in the transformation of agrifood systems




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Candidates for the post of FAO Director-General announced

FAO member nations to choose head of the UN specialized agency in July during the 43rd session of the FAO Conference




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Weird Science: Gender Bending Fish

Sometimes, in fact, nature is stranger than fiction




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Ask Smithsonian: Can Chimps Be Genetically Engineered to Be Like Humans?

Human beings and chimps share as much as 98 percent of their DNA. If our species are so similar, can chimps be genetically engineered to be more like us?




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Gene Therapy Experts Look Ahead in Treating Blindness

Two of the preeminent researchers of gene therapy hope to improve their patients' sight in an experimental operation (Stephen Voss/WPN)




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These Gentle Giants Would Rather Be Left Alone

Historically feared by humans, brown bears were once aggressively hunted in the contiguous U.S. Because of this, 95% of these majestic creatures live in Alaska.




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Constructing the Guggenheim

Videos from the 1950s show architect Frank Lloyd Wright at the site of the Guggenheim Museum




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World Science Festival: Misunderstood Geniuses—William Harvey




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Stephen Colbert Congratulates OK Go | Smithsonian American Ingenuity Awards

"OK Go made music videos relevant again." – Stephen Colbert OK Go​, Damian Kulash Jr. and Trish Sie​ won the Smithsonian magazine​ American Ingenuity Award for Visual Arts for pushing the music-video envelope with their zero-gravity video for "Upside Down & Inside Out." Read more about their work and see the video here: http://smithmag.co/HZ8vzr The Smithsonian has been celebrating innovation in American culture for more than 150 years, and following in this tradition, Smithsonian magazine presents the American Ingenuity Awards, honoring revolutionary breakthroughs in the arts and sciences, education and social progress. http://smithmag.co/R7hyRO




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How Many Beads Can You Glue to the Outside of a Volkswagen Beetle?

The Huichol people of west-central Mexico have designed the Vochol—a car turned work of art




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What 'Bridgerton' Gets Right About the Regency Era

From gender roles to etiquette to fashion, step back in time to learn more about the real lives of the Regency women who inspired 'Bridgerton.' --- To read more about the Regency era - and 'Bridgerton' - check out these articles from Smithsonian Magazine: What 'Bridgerton' Gets Wrong About Corsets: https://www.smithsonianmag.com/history/what-bridgerton-gets-wrong-about-corsets-180976691/ The Real History Behind 'Queen Charlotte: A Bridgerton Story' https://www.smithsonianmag.com/smart-news/the-real-history-behind-queen-charlotte-a-bridgerton-story-180982130/ Digital Editorial Director: Brian Wolly Supervising Producer & Scriptwriter: Michelle Mehrtens Producer: Nicki Marko Video Editor: Sierra Theobald




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The Story Behind Gene Kranz's Vest

Listen to a short lecture given by curator Margaret Weitekamp on Gene Kranz career with NASA and how his vest ended up at the Smithsonian




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How Artificial Intelligence Is Making 2,000-Year-Old Scrolls Readable Again

When Mount Vesuvius erupted in 79 C.E., it covered the ancient cities of Pompeii and Herculaneum under tons of ash. Millennia later, in the mid-18th century, archeologists began to unearth the city, including its famed libraries, but the scrolls they found were too fragile to be unrolled and read; their contents were thought to be lost forever. Only now, thanks to the advent of artificial intelligence and machine learning, scholars of the ancient world have partnered with computer programmers to unlock the contents of these priceless documents. In this episode of “There’s More to That,” science journalist and Smithsonian contributor Jo Marchant tells us about the yearslong campaign to read these scrolls. And Youssef Nader—one of the three winners of last year’s “Vesuvius Challenge” to make these clumps of vulcanized ash readable—tells us how he and his teammates achieved their historic breakthrough. Read Smithsonian’s coverage of the Vesuvius Challenge and the Herculaneum scrolls here (https://www.smithsonianmag.com/smart-news/three-students-decipher-first-passages-2000-year-old-scroll-burned-vesuvius-eruption-180983738/) , here (https://www.smithsonianmag.com/history/buried-ash-vesuvius-scrolls-are-being-read-new-xray-technique-180969358/) , and here (https://www.smithsonianmag.com/history/archaeologoists-only-just-beginning-reveal-secrets-hidden-ancient-manuscripts-180967455/) . Find prior episodes of our show here (https://www.smithsonianmag.com/podcast/) . There’s More to That is a production of Smithsonian magazine and PRX Productions. From the magazine, our team is Chris Klimek, Debra Rosenberg and Brian Wolly. From PRX, our team is Jessica Miller, Adriana Rosas Rivera, Genevieve Sponsler, Rye Dorsey, and Edwin Ochoa. The Executive Producer of PRX Productions is Jocelyn Gonzales. Fact-checking by Stephanie Abramson. Episode artwork by Emily Lankiewicz. Music by APM Music.




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Stephen Hawking Congratulates the LIGO Team | Smithsonian American Ingenuity Awards

"They have given mankind a completely new way of looking at the universe." – Stephen Hawking, congratulates Kip Thorne, Rainer Weiss, Barry Barish and Ronald Drever, the first scientists to detect gravitational waves. | Smithsonian magazine #IngenuityAwards The Smithsonian has been celebrating innovation in American culture for more than 150 years, and following in this tradition, Smithsonian magazine presents the American Ingenuity Awards, honoring revolutionary breakthroughs in the arts and sciences, education and social progress.




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Erin Brockovich Congratulates Marc Edwards & LeeAnne Walters | Smithsonian American Ingenuity Awards

“Superman isn’t coming. It is a moment in our time when we must look to ourselves, and not take for granted or wait for something from the top to come down, but rather…pick up the torch, carry the torch, to find information and the truth…” – Erin Brockovich applauds Marc Edwards and LeeAnne Walters for their work exposing the Flint water crisis | Smithsonian Magazine American #IngenuityAwards Read more about Edwards and Walters’ work: http://smithmag.co/D4dIHy The Smithsonian has been celebrating innovation in American culture for more than 150 years, and following in this tradition, Smithsonian magazine presents the American Ingenuity Awards, honoring revolutionary breakthroughs in the arts and sciences, education and social progress. http://smithmag.co/R7hyRO




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In Case Humans Go Extinct, This Memory Crystal Will Store Our Genome for Billions of Years

Scientists have created "a form of information immortality" meant to instruct future species on how to recreate humans. But who, or what, will find it?




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Rare and Elusive Australian Bird, Once Thought Extinct for 100 Years, Discovered by Indigenous Rangers and Scientists

Using sound recordings, the team identified the largest known population of the night parrot, a secretive species known as the "Holy Grail of birdwatching"




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American Scientists Win Nobel Prize in Medicine for 'Groundbreaking' Gene Discovery Made by Studying Worms

Victor Ambros and Gary Ruvkun discovered microRNA, tiny molecules that play a crucial role in how cells develop, paving the way for new treatments for diseases




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Scientists Who Developed the Building Blocks of Artificial Intelligence Win Nobel Prize in Physics

John Hopfield and Geoffrey Hinton shared the award for their work on artificial neural networks and machine learning




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A New Marine Sanctuary Off California Will Be Co-Managed by Indigenous Peoples

NOAA designated the Chumash Heritage National Marine Sanctuary this month, following a decade of advocacy by supporters. The protected site will be finalized after a 45-day review period




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A 110-Year-Old Pickled Thylacine Head Helped Build the Most Complete Ancient Genome to Date, Says 'De-Extinction' Company

Colossal Biosciences reports it extracted DNA and RNA from the Tasmanian tiger specimen, a key step forward in its effort to create a modern proxy of the extinct species. Other scientists are calling for data to back up the claim




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Land & Sea: The legacy of Nellie Winters, a much-loved Inuit crafts legend

Nellie Winters is 87. From the time she was a child, her hands and mind have been busy pursuing her love of Inuit art and craft.



  • News/Canada/Nfld. & Labrador

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Indigenous children in foster care should stay in home communities, says head of roundtable

A Labrador foster parent and head of a group working to better the Labrador foster care system is stressing the importance of keeping Indigenous children with Indigenous parents in their Indigenous communities.



  • News/Canada/Nfld. & Labrador

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School in Sipekne'katik First Nation commemorates Indigenous Veterans Day

The L'nu Sipuk Kina'muokuom school observed Indigenous Veterans Day with an event on Friday. Students, faculty and staff got together to honour Mi’kmaw military veterans and RCMP members.




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Video game shines light on Indigenous history and voices

Two Falls (Nishu Takuatshina) was developed in Montreal by a local studio that collaborated closely with Indigenous designers and consultants.