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Mol. Biol. Cell Table of Contents for 15 March 2010; Vol. 21, No. 6

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A new issue of Molecular Biology of the Cell is available online:: 15 March 2010; Vol. 21, No. 6
The below Table of Contents is available online at: http://www.molbiolcell.org/content/vol21/issue6/?etoc
Meeting Review
Morphogenesis in Kyoto: A Confluence of Cell and Developmental Biology Jennifer A. Zallen and Alpha S. Yap: Jennifer A. Zallen and Alpha S. Yap
Cell Cycle
Mutations in Caenorhabditis elegans him-19 Show Meiotic Defects That Worsen with Age A Highlights from MBoC Selection
Lois Tang, Thomas Machacek, Yasmine M. Mamnun, Alexandra Penkner, Jiradet Gloggnitzer, Christina Wegrostek, Robert Konrat, Michael F. Jantsch, Josef Loidl, and Verena Jantsch
Faithful meiotic chromosome segregation requires pairing, synapsis and recombination of homologous chromosomes. In mammals, chromosomal non-disjunction increases with age. A mutation in Caenorhabditis elegans him-19 mimics these age-dependent chromosome segregation defects and might therefore further our understanding of this phenomenon.: Lois Tang, Thomas Machacek, Yasmine M. Mamnun, Alexandra Penkner, Jiradet Gloggnitzer, Christina Wegrostek, Robert Konrat, Michael F. Jantsch, Josef Loidl, and Verena Jantsch
Faithful meiotic chromosome segregation requires pairing, synapsis and recombination of homologous chromosomes. In mammals, chromosomal non-disjunction increases with age. A mutation in Caenorhabditis elegans him-19 mimics these age-dependent chromosome segregation defects and might therefore further our understanding of this phenomenon.
A Specific Form of Phospho Protein Phosphatase 2 Regulates Anaphase-promoting Complex/Cyclosome Association with Spindle Poles Jorge Z. Torres, Kenneth H. Ban, and Peter K. Jackson The anaphase-promoting complex/cyclosome (APC/C) is phosphorylated in a cell cycle dependent manner. We discovered that a specific form of PPP2 is necessary for APC/C dephosphorylation in mitosis and that this dephosphorylation event regulates the association of the APC/C with mitotic spindle poles.: Jorge Z. Torres, Kenneth H. Ban, and Peter K. Jackson
The anaphase-promoting complex/cyclosome (APC/C) is phosphorylated in a cell cycle dependent manner. We discovered that a specific form of PPP2 is necessary for APC/C dephosphorylation in mitosis and that this dephosphorylation event regulates the association of the APC/C with mitotic spindle poles.
Emi2 Inhibition of the Anaphase-promoting Complex/Cyclosome Absolutely Requires Emi2 Binding via the C-Terminal RL Tail A Highlights from MBoC Selection
Munemichi Ohe, Yoshiko Kawamura, Hiroyuki Ueno, Daigo Inoue, Yoshinori Kanemori, Chiharu Senoo, Michitaka Isoda, Nobushige Nakajo, and Noriyuki Sagata
Both the D-box and the zinc-binding region (ZBR) of Emi2 are implicated in APC/C inhibition. This article shows that Emi2 binds the APC/C via the C-terminal tail, termed here the RL tail. The RL tail apparently promotes the inhibitory interactions of the D-box and the ZBR with the APC/C. The RL tail thus serves as a docking site for the APC/C.: Munemichi Ohe, Yoshiko Kawamura, Hiroyuki Ueno, Daigo Inoue, Yoshinori Kanemori, Chiharu Senoo, Michitaka Isoda, Nobushige Nakajo, and Noriyuki Sagata
Both the D-box and the zinc-binding region (ZBR) of Emi2 are implicated in APC/C inhibition. This article shows that Emi2 binds the APC/C via the C-terminal tail, termed here the RL tail. The RL tail apparently promotes the inhibitory interactions of the D-box and the ZBR with the APC/C. The RL tail thus serves as a docking site for the APC/C.
Requirements and Reasons for Effective Inhibition of the Anaphase Promoting Complex Activator Cdh1 A Highlights from MBoC Selection
Jonathan A. Robbins and Frederick R. Cross
Inhibitory phosphorylation of Cdh1 by CDK and Polo kinase has been proposed to inactivate APC-Cdh1. Through an exact gene replacement approach, we find CDK, but not Polo, phosphorylation of Cdh1 to be a critical regulatory mechanism. APC-Cdh1 inhibits multiple aspects of spindle morphogenesis, and its activity is modulated by endogenous ACM1.: Jonathan A. Robbins and Frederick R. Cross
Inhibitory phosphorylation of Cdh1 by CDK and Polo kinase has been proposed to inactivate APC-Cdh1. Through an exact gene replacement approach, we find CDK, but not Polo, phosphorylation of Cdh1 to be a critical regulatory mechanism. APC-Cdh1 inhibits multiple aspects of spindle morphogenesis, and its activity is modulated by endogenous ACM1.
Rad17 Plays a Central Role in Establishment of the Interaction between TopBP1 and the Rad9-Hus1-Rad1 Complex at Stalled Replication Forks A Highlights from MBoC Selection
Joon Lee and William G. Dunphy
This work provides novel mechanistic insights into how TopBP1 and the Rad9-Hus1-Rad1 (9-1-1) complex dock with one another at stalled replication forks. This step is necessary for the ATR-dependent activation of Chk1 during checkpoint responses.: Joon Lee and William G. Dunphy
This work provides novel mechanistic insights into how TopBP1 and the Rad9-Hus1-Rad1 (9-1-1) complex dock with one another at stalled replication forks. This step is necessary for the ATR-dependent activation of Chk1 during checkpoint responses.
Cell Motility
A Receptor-associated Protein/Phosphatidylinositol 3-Kinase Pathway Controls Pseudopod Formation Arjan Kortholt, Parvin Bolourani, Holger Rehmann, Ineke Keizer-Gunnink, Gerald Weeks, Alfred Wittinghofer, and Peter J.M. Van Haastert GbpD, a guanine exchange factor specific for Rap1, has been implicated in adhesion, cell polarity, and chemotaxis of Dictyostelium cells. Here it is shown that activated Rap1 directly binds to PI3K. The activation of PI3K by Rap1 and RasG regulates basal and chemoattractant-stimulated PIP3 levels and pseudopod formation.: Arjan Kortholt, Parvin Bolourani, Holger Rehmann, Ineke Keizer-Gunnink, Gerald Weeks, Alfred Wittinghofer, and Peter J.M. Van Haastert
GbpD, a guanine exchange factor specific for Rap1, has been implicated in adhesion, cell polarity, and chemotaxis of Dictyostelium cells. Here it is shown that activated Rap1 directly binds to PI3K. The activation of PI3K by Rap1 and RasG regulates basal and chemoattractant-stimulated PIP3 levels and pseudopod formation.
Gq-coupled Purinergic Receptors Inhibit Insulin-like Growth Factor-I/Phosphoinositide 3-Kinase Pathway-dependent Keratinocyte Migration Salma Taboubi, Françoise Garrouste, Fabrice Parat, Gilbert Pommier, Emilie Faure, Sylvie Monferran, Hervé Kovacic, and Maxime Lehmann After skin wound, released growth factors and extracellular nucleotides regulate the different phases of healing, including re-epithelialization. Here, we show that, in keratinocytes, purinergic P2Y2 receptors inhibit the motogenic IGF-I/PI3K pathway. Therefore, extracellular nucleotides may play key roles during skin remodelling after wound.: Salma Taboubi, Françoise Garrouste, Fabrice Parat, Gilbert Pommier, Emilie Faure, Sylvie Monferran, Hervé Kovacic, and Maxime Lehmann
After skin wound, released growth factors and extracellular nucleotides regulate the different phases of healing, including re-epithelialization. Here, we show that, in keratinocytes, purinergic P2Y2 receptors inhibit the motogenic IGF-I/PI3K pathway. Therefore, extracellular nucleotides may play key roles during skin remodelling after wound.
Membrane Trafficking
Combinational Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Proteins VAMP8 and Vti1b Mediate Fusion of Antimicrobial and Canonical Autophagosomes with Lysosomes Nobumichi Furuta, Naonobu Fujita, Takeshi Noda, Tamotsu Yoshimori, and Atsuo Amano Autophagy (xenophagy) degrades intracellular bacteria. The cargoes are degraded after the fusion of xenophagosomes with lysosomes. However, the molecular mechanism underlying the fusion remains unclear. Here we show that combinational SNARE proteins VAMP8 and Vti1b mediate fusion of antimicrobial and canonical autophagosomes with lysosomes.: Nobumichi Furuta, Naonobu Fujita, Takeshi Noda, Tamotsu Yoshimori, and Atsuo Amano
Autophagy (xenophagy) degrades intracellular bacteria. The cargoes are degraded after the fusion of xenophagosomes with lysosomes. However, the molecular mechanism underlying the fusion remains unclear. Here we show that combinational SNARE proteins VAMP8 and Vti1b mediate fusion of antimicrobial and canonical autophagosomes with lysosomes.
Role of the Second Cysteine-rich Domain and Pro275 in Protein Kinase D2 Interaction with ADP-Ribosylation Factor 1, Trans-Golgi Network Recruitment, and Protein Transport Ganesh Varma Pusapati, Denis Krndija, Milena Armacki, Götz von Wichert, Julia von Blume, Vivek Malhotra, Guido Adler, and Thomas Seufferlein The present study provides the first link between the “classical” machinery regulating protein transport at the Golgi compartment, namely ARF proteins and PKDs, and demonstrates that the direct interaction of both is crucial for efficient protein transport from the TGN to the plasma membrane.: Ganesh Varma Pusapati, Denis Krndija, Milena Armacki, Götz von Wichert, Julia von Blume, Vivek Malhotra, Guido Adler, and Thomas Seufferlein
The present study provides the first link between the “classical” machinery regulating protein transport at the Golgi compartment, namely ARF proteins and PKDs, and demonstrates that the direct interaction of both is crucial for efficient protein transport from the TGN to the plasma membrane.
Regulators of Vps4 ATPase Activity at Endosomes Differentially Influence the Size and Rate of Formation of Intralumenal Vesicles Daniel P. Nickerson, Matthew West, Ryan Henry, and Greg Odorizzi Disassembly of ESCRT-III requires Vps4 ATPase activity under the control of regulatory proteins. Described here are distinct spatiotemporal functions for Vps4 regulators, with Did2 playing a unique role in regulating MVB lumenal vesicle size and Vtal-Vps60 promoting efficient membrane scission and delivery of vesicles into the endosome lumen.: Daniel P. Nickerson, Matthew West, Ryan Henry, and Greg Odorizzi
Disassembly of ESCRT-III requires Vps4 ATPase activity under the control of regulatory proteins. Described here are distinct spatiotemporal functions for Vps4 regulators, with Did2 playing a unique role in regulating MVB lumenal vesicle size and Vtal-Vps60 promoting efficient membrane scission and delivery of vesicles into the endosome lumen.
Vesicular Calcium Regulates Coat Retention, Fusogenicity, and Size of Pre-Golgi Intermediates Marvin Bentley, Deborah C. Nycz, Ashwini Joglekar, Ismene Fertschai, Roland Malli, Wolfgang F. Graier, and Jesse C. Hay This study establishes a role for luminal Ca²⁺ in ER/Golgi transport organelles and elucidates an effector mechanism involving the EF-hand protein ALG-2 and regulation of COPII coat retention.: Marvin Bentley, Deborah C. Nycz, Ashwini Joglekar, Ismene Fertschai, Roland Malli, Wolfgang F. Graier, and Jesse C. Hay
This study establishes a role for luminal Ca²⁺ in ER/Golgi transport organelles and elucidates an effector mechanism involving the EF-hand protein ALG-2 and regulation of COPII coat retention.
The Endoplasmic Reticulum–associated Degradation of the Epithelial Sodium Channel Requires a Unique Complement of Molecular Chaperones Teresa M. Buck, Alexander R. Kolb, Cary R. Boyd, Thomas R. Kleyman, and Jeffrey L. Brodsky This study describes new yeast expression systems for each subunit of the heterotrimeric epithelial sodium channel (ENaC). We found that a significant amount of each subunit resides in the ER and is destroyed via ERAD. We also found that the chaperone requirements for ENaC subunit degradation were unlike any other ERAD substrate examined.: Teresa M. Buck, Alexander R. Kolb, Cary R. Boyd, Thomas R. Kleyman, and Jeffrey L. Brodsky
This study describes new yeast expression systems for each subunit of the heterotrimeric epithelial sodium channel (ENaC). We found that a significant amount of each subunit resides in the ER and is destroyed via ERAD. We also found that the chaperone requirements for ENaC subunit degradation were unlike any other ERAD substrate examined.
Assembly of the AAA ATPase Vps4 on ESCRT-III Anna Shestakova, Abraham Hanono, Stacey Drosner, Matt Curtiss, Brian A. Davies, David J. Katzmann, and Markus Babst A complex network of interactions mediates the recruitment of Vps4 to ESCRT-III and its subsequent assembly, two key steps in the ESCRT-dependent vesicle formation at the endosome. A model is presented depicting the order of events that lead to active, ESCRT-III–associated Vps4.: Anna Shestakova, Abraham Hanono, Stacey Drosner, Matt Curtiss, Brian A. Davies, David J. Katzmann, and Markus Babst
A complex network of interactions mediates the recruitment of Vps4 to ESCRT-III and its subsequent assembly, two key steps in the ESCRT-dependent vesicle formation at the endosome. A model is presented depicting the order of events that lead to active, ESCRT-III–associated Vps4.
Nuclear Functions
Members of the RSC Chromatin-Remodeling Complex Are Required for Maintaining Proper Nuclear Envelope Structure and Pore Complex Localization Laura C. Titus, T. Renee Dawson, Deborah J. Rexer, Kathryn J. Ryan, and Susan R. Wente Genome-wide screening approaches were employed to identify factors required for nuclear pore complex structure and distribution in Saccharomyces cerevisiae. Roles were found for multiple components of the RSC complex, revealing a functional connection between proper chromatin remodeling and nuclear envelope/nuclear pore complex structure.: Laura C. Titus, T. Renee Dawson, Deborah J. Rexer, Kathryn J. Ryan, and Susan R. Wente
Genome-wide screening approaches were employed to identify factors required for nuclear pore complex structure and distribution in Saccharomyces cerevisiae. Roles were found for multiple components of the RSC complex, revealing a functional connection between proper chromatin remodeling and nuclear envelope/nuclear pore complex structure.
Signaling
Ras and Calcium Signaling Pathways Converge at Raf1 via the Shoc2 Scaffold Protein Sayaka Yoshiki, Rie Matsunaga-Udagawa, Kazuhiro Aoki, Yuji Kamioka, Etsuko Kiyokawa, and Michiyuki Matsuda Activation of Raf1 at the plasma membrane requires not only Ras activation but also an increase in Ca²⁺ concentration or inhibition of calmodulin. The Ca²⁺-dependent activation of Raf1 is abrogated by knockdown of Shoc2. We show that the Shoc2 scaffold protein modulates Ras-dependent Raf1 activation in a Ca²⁺- and calmodulin-dependent manner.: Sayaka Yoshiki, Rie Matsunaga-Udagawa, Kazuhiro Aoki, Yuji Kamioka, Etsuko Kiyokawa, and Michiyuki Matsuda
Activation of Raf1 at the plasma membrane requires not only Ras activation but also an increase in Ca²⁺ concentration or inhibition of calmodulin. The Ca²⁺-dependent activation of Raf1 is abrogated by knockdown of Shoc2. We show that the Shoc2 scaffold protein modulates Ras-dependent Raf1 activation in a Ca²⁺- and calmodulin-dependent manner.
Compartmentalized Cyclic Adenosine 3′,5′-Monophosphate at the Plasma Membrane Clusters PDE3A and Cystic Fibrosis Transmembrane Conductance Regulator into Microdomains A Highlights from MBoC Selection
Himabindu Penmatsa, Weiqiang Zhang, Sunitha Yarlagadda, Chunying Li, Veronica G. Conoley, Junming Yue, Suleiman W. Bahouth, Randal K. Buddington, Guangping Zhang, Deborah J. Nelson, Monal D. Sonecha, Vincent Manganiello, Jeffrey J. Wine, and Anjaparavanda P. Naren
PDE3A functionally and physically interacts with CFTR. Inhibition of PDE3A generates compartmentalized cAMP, which further clusters PDE3A and CFTR into microdomains at the plasma membrane of epithelial cells and potentiates CFTR channel function. Our findings provide insights into the important role of PDE3A in compartmentalized cAMP signaling.: Himabindu Penmatsa, Weiqiang Zhang, Sunitha Yarlagadda, Chunying Li, Veronica G. Conoley, Junming Yue, Suleiman W. Bahouth, Randal K. Buddington, Guangping Zhang, Deborah J. Nelson, Monal D. Sonecha, Vincent Manganiello, Jeffrey J. Wine, and Anjaparavanda P. Naren
PDE3A functionally and physically interacts with CFTR. Inhibition of PDE3A generates compartmentalized cAMP, which further clusters PDE3A and CFTR into microdomains at the plasma membrane of epithelial cells and potentiates CFTR channel function. Our findings provide insights into the important role of PDE3A in compartmentalized cAMP signaling.
Transforming Growth Factor-β1 Induces Transdifferentiation of Myoblasts into Myofibroblasts via Up-Regulation of Sphingosine Kinase-1/S1P₃ Axis Francesca Cencetti, Caterina Bernacchioni, Paola Nincheri, Chiara Donati, and Paola Bruni Transforming growth factor-β1 induces Smad-dependent transdifferentiation of myoblasts into myofibroblasts via up-regulation of sphingosine kinase-1/S1P₃ axis with a mechanism involving Rho/Rho kinase activation.: Francesca Cencetti, Caterina Bernacchioni, Paola Nincheri, Chiara Donati, and Paola Bruni
Transforming growth factor-β1 induces Smad-dependent transdifferentiation of myoblasts into myofibroblasts via up-regulation of sphingosine kinase-1/S1P₃ axis with a mechanism involving Rho/Rho kinase activation.
Vav3-deficient Mice Exhibit a Transient Delay in Cerebellar Development Celia Quevedo, Vincent Sauzeau, Mauricio Menacho-Márquez, Antonio Castro-Castro, and Xosé R. Bustelo Vav proteins are phosphorylation-dependent Rho/Rac exchange factors that have usually been associated with immune- and cardiovascular-related functions. In this paper, Quevedo et al. demonstrate that Vav3 plays important, although transient, pleiotropic roles during the postnatal development of the cerebellum.: Celia Quevedo, Vincent Sauzeau, Mauricio Menacho-Márquez, Antonio Castro-Castro, and Xosé R. Bustelo
Vav proteins are phosphorylation-dependent Rho/Rac exchange factors that have usually been associated with immune- and cardiovascular-related functions. In this paper, Quevedo et al. demonstrate that Vav3 plays important, although transient, pleiotropic roles during the postnatal development of the cerebellum.
Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT Amrik Singh, Min Ye, Octavian Bucur, Shudong Zhu, Maria Tanya Santos, Isaac Rabinovitz, Wenyi Wei, Daming Gao, William C. Hahn, and Roya Khosravi-Far This article describes a functional interaction between PP2A and FOXO3a in which PP2A promotes rapid dephosphorylation of FOXO3a at its conserved AKT phosphorylation sites, leading to FOXO3a dissociation from 14-3-3, nuclear translocation, and transcriptional activation in response to inhibition of PI3K signaling.: Amrik Singh, Min Ye, Octavian Bucur, Shudong Zhu, Maria Tanya Santos, Isaac Rabinovitz, Wenyi Wei, Daming Gao, William C. Hahn, and Roya Khosravi-Far
This article describes a functional interaction between PP2A and FOXO3a in which PP2A promotes rapid dephosphorylation of FOXO3a at its conserved AKT phosphorylation sites, leading to FOXO3a dissociation from 14-3-3, nuclear translocation, and transcriptional activation in response to inhibition of PI3K signaling.
Meeting Review
Morphogenesis in Kyoto: A Confluence of Cell and Developmental Biology Jennifer A. Zallen and Alpha S. Yap: Jennifer A. Zallen and Alpha S. Yap

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materials@nature contents: 11 March 2010

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Uncertainty in the Diagnosis: How Do You Want That Told to You?

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The patient comes to me

Sick with symptoms and uncertainty

Is it bad; is it fatal, can I be cured?

She sits in front of me with that look

That look asks me to tell her the answers

“Sure” I think to myself

No uncertainty on my part to myself

And I guess no uncertainty is on my face

I say to her “Tell me how you feel”

Then comes the stream of symptoms and complaints

I try to keep the stream from flooding my understanding

In my mind the diagnoses start their own stream

It could be this, it could be that, but it couldn’t be the other
Or could it?

I reassure myself. The physical exam will sort it all out

But does it? I thought it would but it doesn’t

Maybe this or that seems now unlikely but yet on the other hand…

The history and physical is over and the patient sits in front of me

She awaits my diagnosis

But, in fact, I, myself await the diagnosis

Is uncertainty now seen on my face?

I have no decision since, in fact, I am undecided.

How do I respond to her and her look for me to tell her the answers? I would like your help. Should the words “I don’t know yet” come from my mouth? Will that be therapeutic for her symptoms and her concerns? Should I say “Well, it could be this, it could be that, it could be…It could be”?
Should I say “I know it could be this, I know it could be that, I know it could be… it could be”? Should I just say “I am just uncertain as to what is wrong with you so let’s wait until the tests are back”? What is wrong for the doctor telling the patient “I just don’t know at present”? Or is it wrong for the doctor to be expressing uncertainty to a patient who has symptoms and herself uncertainty? Help me understand how you would expect the doctor to express the doctor’s uncertainty about your symptoms and concerns. ..Maurice.

#getupandmove for #sxsh – The Bed Jump Challenge Returns!!

admin — Thu, 11 Mar 2010 10:16:30 +0000

Grown-ups (I use the term loosely) – have you forgotten how much friggin’ fun it is to jump on a bed?
I highly recommend it. Find your inner silly kid. It still feels damn good…
PS – also, I like to put the ole’ bed jump on ice til I’m in a hotel. My bed deserves better .

Click on a video below to watch it:

#getupandmove for #sxsh!
Video Length 0:57
Click here to watch

To learn more about the Flip Video Camcorder, click here.

Posted via email from Jen’s Posterous

23andMe – Oprah discount

admin — Thu, 11 Mar 2010 10:16:28 +0000

As a result of the several recent genealogy TV shows (Faces of America and Who Do You Think You Are) and a segment on a recent Oprah show, 23andMe is offering a $200 discount on either their Ancestry Edition or their Complete Edition. This brings these prices down to $199 and $299, respectively.

If anyone is interested in either of these, email me here and I’ll tell you how to do it.

This offer is only good until March 31, 2010.

Have an article you want to share?

admin — Thu, 11 Mar 2010 10:16:27 +0000

If you would like to be able to post articles to this blog, please let me know.

A New Finding Clarifies the Cause of Spinal Muscular Atrophy

admin — Thu, 11 Mar 2010 10:16:26 +0000

MARCH 09, 2010
A New Finding Clarifies the Cause of Spinal Muscular Atrophy

Howard Hughes Medical Institute (HHMI) researchers have made a surprising discovery about the molecular basis underlying spinal muscular atrophy (SMA), an often fatal neurodegenerative disease and the most common genetic cause of childhood mortality. The findings suggest that there may be a way to promote survival of neurons by helping a beneficial protein linger a little longer inside nerve cells.

“With these results we can develop more targeted screens for compounds that stabilize SMNΔ7.”
Gideon Dreyfuss

Patients with SMA gradually lose the motor neurons in the spine that control most of their muscles. Researchers have known since the 1990s that the disease is nearly always linked to the absence or disruption of a gene known asSMN1 (Survival of Motor Neuron 1). A nearby gene, SMN2, is virtually identical to SMN1, and in principle could produce enough SMN protein to keep neurons healthy — yet somehow fails to do so.

In the March 2010, issue of the journal Genes & Development, HHMI investigator Gideon Dreyfuss and Sungchan Cho, a postdoctoral researcher in his lab at the University of Pennsylvania School of Medicine, report on their work solving this mystery.

Dreyfuss and Cho found that most of the SMN protein produced from SMN2 is flagged for rapid degradation by a cellular waste-disposal system. Thus, the protein is cleared before it accumulates sufficiently to sustain the health of motor neurons. Blocking this degradation signal could therefore, in theory, be a way to treat SMA, Dreyfuss says.

Dreyfuss first identified the SMN protein in 1995. The subsequent discovery of a link between SMN and SMA led him to focus a considerable amount of his lab’s work on the disease. In recent years, one aspect of that work has been concerned with uncovering the function of the somewhat mysterious SMN2 gene.

The SMN2 gene differs from SMN1 by a single letter of DNA, or nucleotide. This slight change appears to confound the cellular systems that turn gene sequences into RNA-based templates for the production of proteins. As a result, about 80 percent of the SMN protein copies produced from SMN2are missing a segment encoded by part of the gene known as exon 7.

This shorter version of SMN protein, termed SMNΔ, is almost undetectable in the cells of patients with SMA. But the shorter protein does seem to work: SMA patients who have more copies of the SMN2 gene have milder signs of disease, and animal studies also suggest that increased levels of SMNΔ can be beneficial. This suggests to scientists that if the level of SMNΔ could be boosted therapeutically, patients might benefit.

To find out why SMNΔ levels are so low in patients’ cells, Cho and Dreyfuss created cells that produce SMNΔ that is linked to luciferase, a light-producing enzyme found in the tails of fireflies. After shutting down new protein synthesis, they could observe how quickly the existing SMNΔ was cleared from cells by observing the rate at which luciferase’s glow faded.

Using this system, Cho and Dreyfuss confirmed that SMNΔ disappeared much faster than normal-length SMN. The researchers then tinkered with SMNΔ, deleting certain segments at the malformed end to see whether this could restore the protein’s stability.

They found that the improper junction between the segments that normally flank exon 7 had, by chance, created a signal that caused the entire protein to be degraded quickly. Removing this signal from SMNΔ restored the protein to near-normal stability.

How does this signal cause the mutant protein to disappear so quickly? Cho and Dreyfuss found strong evidence implicating the proteasome system, a set of protein-crunching machines that roam through cells, destroying malformed or otherwise unwanted proteins. By suppressing proteasome activity, they restored SMNΔ to normal stability, whereas suppressing other protein-clearance mechanisms had no effect.

“So ultimately SMNΔ meets a proteasome and that is where it gets degraded,” said Dreyfuss.

Proteasomes normally degrade only proteins that have been marked for destruction with special tagging molecules. These tags, in turn, bind to target proteins only after detecting certain molecular signatures they interpret as degradation signals, or degrons. “A degron is like a flag that says ‘take me out,’” said Dreyfuss.

In this case, the experiments showed that the mutated end of SMNΔ happens to form a degron. “Thus we found the cause of the extreme instability of SMNΔ,” Dreyfuss said. “That’s important, because it wasn’t clear why this protein simply vanishes.”

Further molecular tinkering by Cho and Dreyfuss revealed that, surprisingly, changing a single amino acid removed the degradation signal, allowing SMNΔ levels to rise. This more stable version of SMNΔ was enough to keep alive cultured cells, which quickly die without SMN.

“We don’t know yet whether the same approach will work in mammalian organisms,” said Dreyfuss. “But there are other reasons to believe that SMNΔ contributes a similar function to that of normal-length SMN.”

Dreyfuss and his colleagues want to find out more about the cellular mechanisms that trigger SMNΔ destruction. But they are already thinking about the development of therapies based on their findings. The fact that a single amino-acid substitution stabilizes SMNΔ is encouraging, Dreyfuss says, suggesting that a drug compound might produce a similar effect.

Dreyfuss’s lab has been working on very broad drug screening efforts, including a large-scale collaboration with the pharmaceutical company Merck. “With these results we can develop more targeted screens for compounds that stabilize SMNΔ,” Dreyfuss said, “and we are pursuing this vigorously.”

Mol. Biol. Cell MBoC In Press for 10 Mar 2010

admin — Thu, 11 Mar 2010 10:16:24 +0000

QUICK SEARCH:

[advanced]

	Author:		Keyword(s):
Year:		Vol:		Page:

New Molecular Biology of the Cell MBoC In Press articles have been made available (for the period 3 Mar 2010 to 10 Mar 2010):
Retrospective
Divest Yourself of a Preconceived Idea: Transcription Factor ATF6 Is Not a Soluble Protein! Kazutoshi Mori: Kazutoshi Mori
Articles
Analysis of Human Nucleolar snoRNAs and the Development of snoRNA Modulator of Gene Expression (snoMEN) Vectors Motoharu Ono, Kayo Yamada, Fabio Avolio, Michelle S. Scott, Silvana van Koningsbruggen, Geoffrey J. Barton, and Angus I. Lamond: Motoharu Ono, Kayo Yamada, Fabio Avolio, Michelle S. Scott, Silvana van Koningsbruggen, Geoffrey J. Barton, and Angus I. Lamond
LRPPRC and SLIRP Interact in a Ribonucleoprotein Complex that Regulates Posttranscriptional Gene Expression in Mitochondria Florin Sasarman, Catherine Brunel-Guitton, Hana Antonicka, Timothy Wai, Eric A. Shoubridge, and LSFC Consortium: Florin Sasarman, Catherine Brunel-Guitton, Hana Antonicka, Timothy Wai, Eric A. Shoubridge, and LSFC Consortium
Src-dependent TrkA Transactivation Is Required for PACAP38-mediated Rit Activation and Neuronal Differentiation Geng-Xian Shi, Ling Jin, and Douglas A. Andres: Geng-Xian Shi, Ling Jin, and Douglas A. Andres
Stepwise Assembly of Dimeric F₁F_o-ATP Synthase in Mitochondria Involves the Small F_o-subunits k and i Karina Wagner, Inge Perschil, Christiane D. Fichter, and Martin van der Laan: Karina Wagner, Inge Perschil, Christiane D. Fichter, and Martin van der Laan
Analyzing the Birth and Propagation of Two Distinct Prions in Yeast Vidhu Mathur, Vibha Taneja, Yidi Sun, and Susan W. Liebman: Vidhu Mathur, Vibha Taneja, Yidi Sun, and Susan W. Liebman
Yeast Mpk1 Cell Wall Integrity MAPK Regulates Nucleocytoplasmic Shuttling of the Swi6 Transcriptional Regulator Ki-Young Kim, Andrew W. Truman, Stefanie Caesar, Gabriel Schlenstedt, and David E. Levin: Ki-Young Kim, Andrew W. Truman, Stefanie Caesar, Gabriel Schlenstedt, and David E. Levin
Interaction of the Double-Strand Break Repair Kinase DNA-PK and Estrogen Receptor- Senad Medunjanin, Sönke Weinert, Alexander Schmeisser, Doris Mayer, and Ruediger C. Braun-Dullaeus: Senad Medunjanin, Sönke Weinert, Alexander Schmeisser, Doris Mayer, and Ruediger C. Braun-Dullaeus
Dissecting the M Phase-specific Phosphorylation of S/T-P Motifs Chuan Fen Wu, Ruoning Wang, Qianjin Liang, Jianjiao Liang, Wenke Li, Sung Yun Jung, Jun Qin, Sue-Hwa Lin, and Jian Kuang: Chuan Fen Wu, Ruoning Wang, Qianjin Liang, Jianjiao Liang, Wenke Li, Sung Yun Jung, Jun Qin, Sue-Hwa Lin, and Jian Kuang
Retrospective
Divest Yourself of a Preconceived Idea: Transcription Factor ATF6 Is Not a Soluble Protein! Kazutoshi Mori: Kazutoshi Mori

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Nature 11 March 2010 Volume 464 Number 7286 pp141-316

admin — Thu, 11 Mar 2010 10:16:18 +0000

NATURE

11 March 2010 Volume 464 Number 7286, pp 141 – 316

Visit Nature online to browse the journal.

Now available at http://links.ealert.nature.com/ctt?kn=229&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Please note that you need to be a subscriber to enjoy full text
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———————-
EDITORIALS
———————-
Climate of fear p141
The integrity of climate research has taken a very public battering
in recent months. Scientists must now emphasize the science, while
acknowledging that they are in a street fight.
doi:10.1038/464141a
http://links.ealert.nature.com/ctt?kn=96&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Scientific glasnost pp141-142
Russia's scientific reputation will continue to dwindle unless it
embraces international research.
doi:10.1038/464141b
http://links.ealert.nature.com/ctt?kn=110&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Europe's research future p142
The region's member states must follow through on their political
and scientific commitments.
doi:10.1038/464142a
http://links.ealert.nature.com/ctt?kn=107&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
RESEARCH HIGHLIGHTS
———————-
Palaeontology: The long and the short p144
doi:10.1038/464144a
http://links.ealert.nature.com/ctt?kn=65&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Metabolism: Warm milk p144
doi:10.1038/464144b
http://links.ealert.nature.com/ctt?kn=70&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Chemistry: Cellulose busters p144
doi:10.1038/464144c
http://links.ealert.nature.com/ctt?kn=76&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Neuroscience: Nerve cell talk p144
doi:10.1038/464144d
http://links.ealert.nature.com/ctt?kn=81&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Biomaterials: Squishy particles p144
doi:10.1038/464144e
http://links.ealert.nature.com/ctt?kn=136&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Cancer biology: Arsenic activation pp144-145
doi:10.1038/464144f
http://links.ealert.nature.com/ctt?kn=104&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Physics: Photon storage for telecoms p145
doi:10.1038/464145a
http://links.ealert.nature.com/ctt?kn=120&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Cancer genomics: Melanoma's mutations p145
doi:10.1038/464145b
http://links.ealert.nature.com/ctt?kn=112&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Nanotechnology: Harvesting heat p145
doi:10.1038/464145c
http://links.ealert.nature.com/ctt?kn=131&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Evolution: Creating cooperation p145
doi:10.1038/464145d
http://links.ealert.nature.com/ctt?kn=126&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
JOURNAL CLUB
———————-
Journal club p145
Markus Reichstein
doi:10.1038/464145e
http://links.ealert.nature.com/ctt?kn=39&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
NEWS
———————-
News briefing: 11 March 2010 pp146-147
The week in science.
doi:10.1038/464146a
http://links.ealert.nature.com/ctt?kn=192&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Outcry over scientists' dismissal pp148-149
Following years of acrimony, two high-profile researchers in
Mexico have been expelled from their institute.
Rex Dalton
doi:10.1038/464148a
http://links.ealert.nature.com/ctt?kn=284&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Climate e-mail rerun p149
Attack sparks memories of McCarthy witch-hunt.
Jeff Tollefson
doi:10.1038/464149a
http://links.ealert.nature.com/ctt?kn=293&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Old rocks drown dry Moon theory pp150-151
Samples collected during Apollo missions suggest a wet interior,
raising questions about lunar origins.
Eric Hand
doi:10.1038/464150a
http://links.ealert.nature.com/ctt?kn=290&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Biology thinks big to stay cuts p151
Intercontinental programme sets vision for frontier projects.
Alison Abbott
doi:10.1038/464151a
http://links.ealert.nature.com/ctt?kn=282&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Science survives Canadian budget p153
Spending plans aim to battle national deficit yet still invest
in research.
Nicola Jones
doi:10.1038/464153a
http://links.ealert.nature.com/ctt?kn=299&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Plant biologists fear for cress project p154
Is enthusiasm withering for funding studies into Arabidopsis thaliana?
Heidi Ledford
doi:10.1038/464154a
http://links.ealert.nature.com/ctt?kn=280&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Graphic detail: Securing UK science p155
Royal Society sets out case for investment in research.
Richard Van Noorden
doi:10.1038/464155a
http://links.ealert.nature.com/ctt?kn=278&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

A rescue plan for UK physics funding p155
Research council faces restructuring to resolve financial woes.
Geoff Brumfiel
doi:10.1038/464155b
http://links.ealert.nature.com/ctt?kn=316&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
NEWS FEATURES
———————-
Nuclear weapons physics: Welcome to the Atomic Weapons Establishment
pp156-157
With the launch of a powerful laser facility, Britain's most
secretive lab is opening up to academics.
Geoff Brumfiel secures a preview.
doi:10.1038/464156a
http://links.ealert.nature.com/ctt?kn=314&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Bioengineering: What to make with DNA origami pp158-159
Chemists looking to create complex self-assembling nanostructures
are turning to DNA.
Katharine Sanderson looks at the science beneath the fold.
doi:10.1038/464158a
http://links.ealert.nature.com/ctt?kn=311&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
CORRESPONDENCE
———————-
Science and Mexico are the losers in institute politics p160
Harold W. Kroto et al.
doi:10.1038/464160a
http://links.ealert.nature.com/ctt?kn=33&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Colour-coded targets would help clarify biodiversity priorities p160
Anne Larigauderie, Georgina M. Mace and Harold A. Mooney
doi:10.1038/464160b
http://links.ealert.nature.com/ctt?kn=35&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Barriers to carbon capture and storage may not be obvious p160
Frances Bowen
doi:10.1038/464160c
http://links.ealert.nature.com/ctt?kn=28&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
OPINION
———————-
Accelerating HIV vaccine development pp161-162
Translational-research programmes supported by flexible, long-term,
large-scale grants are needed to turn advances in basic science
into successful vaccines to halt the AIDS epidemic,
says Wayne C. Koff.
doi:10.1038/464161a
http://links.ealert.nature.com/ctt?kn=30&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
BOOKS AND ARTS
———————-
Evolution of the motor car p163
A proposed reinvention for urban motoring based on ultra-small
electric vehicles does not address the bigger environmental or
social challenges, finds Daniel Sperling.
Daniel Sperling reviews Reinventing the Automobile: Personal
Urban Mobility for the 21st Century by William J. Mitchell,
Christopher E. Borroni-Bird and Lawrence D. Burns
doi:10.1038/464163a
http://links.ealert.nature.com/ctt?kn=56&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Space to contemplate pp164-165
Joanne Baker reviews The Edge of Physics: A Journey to Earth's
Extremes to Unlock the Secrets of the Universe/Dispatches from
the Frontiers of Cosmology by Anil Ananthaswamy
doi:10.1038/464164a
http://links.ealert.nature.com/ctt?kn=54&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Genius who shuns the limelight p165
George Szpiro reviews Perfect Rigor: A Genius and the Mathematical
Breakthrough of the Century by Masha Gessen
doi:10.1038/464165a
http://links.ealert.nature.com/ctt?kn=52&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Q&A: Peter Hessler on urbanization in China p166
In Country Driving, the final book in his China trilogy, Peter Hessler
recounts his 11,000-kilometre drive across China to see at first hand
the effects of rapid industrialization. The New Yorker journalist
explains how mass migration to cities brings out people's
resourcefulness, but also how the speed of social and environmental
change leads them to seek meaning in their lives.
Jane Qiu reviews Country Driving: A Journey Through China from Farm
to Factory by Peter Hessler
doi:10.1038/464166a
http://links.ealert.nature.com/ctt?kn=50&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
NEWS AND VIEWS
———————-
Structural biology: When four become one pp167-168
Every machine is made of parts. But, as the new structure of the HIV
integrase enzyme in complex with viral DNA shows, one could not have
predicted from the individual parts just how this machine works.
Robert Craigie
doi:10.1038/464167a
http://links.ealert.nature.com/ctt?kn=48&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

50 & 100 years ago p168
doi:10.1038/464168b
http://links.ealert.nature.com/ctt?kn=9&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Atmospheric chemistry: Wider role for airborne chlorine pp168-169
Unexpected chlorine chemistry in the lowest part of the atmosphere
can affect the cycling of nitrogen oxides and the production of
ozone, and reduce the lifetime of the greenhouse gas methane.
Roland von Glasow
doi:10.1038/464168a
http://links.ealert.nature.com/ctt?kn=11&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Supramolecular chemistry: Sticking to sugars pp169-170
If evolution has had trouble making effective carbohydrate receptors,
what hope do humans have of creating synthetic versions? A method for
preparing libraries of such receptors boosts the chances of success.
Anthony P. Davis
doi:10.1038/464169a
http://links.ealert.nature.com/ctt?kn=4&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Sex determination: An avian sexual revolution pp171-172
Hormones are not all-powerful in determining whether birds develop
with male or female features. Chickens that are genetic sexual
mosaics reveal that individual cells also have a say in the matter.
Lindsey A. Barske and Blanche Capel
doi:10.1038/464171a
http://links.ealert.nature.com/ctt?kn=6&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Applied ecology: Grass and the X factor p172
Tim Lincoln
doi:10.1038/464172b
http://links.ealert.nature.com/ctt?kn=25&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Cosmology: Gravity tested on cosmic scales pp172-173
Einstein's theory of general relativity has been tested
– and confirmed — on scales far beyond those of our Solar System.
But the results don't exclude all alternative theories of gravity.
J. Anthony Tyson
doi:10.1038/464172a
http://links.ealert.nature.com/ctt?kn=23&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
INSIGHT
———————-
EDITORIAL
Exotic matter p175
Dan Csontos
doi:10.1038/464175a
http://links.ealert.nature.com/ctt?kn=19&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

REVIEW ARTICLE
The enigma of supersolidity pp176-182
Sebastien Balibar
doi:10.1038/nature08913
Abstract: http://links.ealert.nature.com/ctt?kn=230&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=20&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

PERSPECTIVE ARTICLE
Superconductivity gets an iron boost pp183-186
Igor I. Mazin
doi:10.1038/nature08914
Abstract: http://links.ealert.nature.com/ctt?kn=231&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=331&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

REVIEW ARTICLE
Non-Abelian states of matter pp187-193
Ady Stern
doi:10.1038/nature08915
Abstract: http://links.ealert.nature.com/ctt?kn=232&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=325&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

PERSPECTIVE ARTICLE
The birth of topological insulators pp194-198
Joel E. Moore
doi:10.1038/nature08916
Abstract: http://links.ealert.nature.com/ctt?kn=233&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=334&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

REVIEW ARTICLE
Spin liquids in frustrated magnets pp199-208
Leon Balents
doi:10.1038/nature08917
Abstract: http://links.ealert.nature.com/ctt?kn=240&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=289&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Electron liquids and solids in one dimension pp209-216
Vikram V. Deshpande, Marc Bockrath, Leonid I. Glazman and Amir Yacoby
doi:10.1038/nature08918
Abstract: http://links.ealert.nature.com/ctt?kn=241&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=292&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
REVIEW
———————-
Targeting early infection to prevent HIV-1 mucosal transmission
pp217-223
Ashley T. Haase
doi:10.1038/nature08757
Abstract: http://links.ealert.nature.com/ctt?kn=243&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=306&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
PERSPECTIVES
———————-
Immunology and the elusive AIDS vaccine pp224-231
Herbert W. Virgin and Bruce D. Walker
doi:10.1038/nature08898
Abstract: http://links.ealert.nature.com/ctt?kn=262&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=263&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
ARTICLES
———————-
Retroviral intasome assembly and inhibition of DNA strand transfer
pp232-236
The integrase protein of retroviruses such as HIV-1 catalyses
insertion of the viral genome into that of the host. Here, the
long-awaited structure of the full-length integrase complex is
predicted, revealing not only details of the biochemistry of
the integration reaction, but also the means by which current
inhibitors affect this process.
Stephen Hare et al.
doi:10.1038/nature08784
Abstract: http://links.ealert.nature.com/ctt?kn=264&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=254&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Somatic sex identity is cell autonomous in the chicken pp237-242
In mammals, embryos are considered to be sexually indifferent until
the action of a sex-determining gene initiates gonadal differentiation.
Here it is demonstrated that this situation is different for birds.
Using rare, naturally occurring chimaeric chickens where one side of
the animal appears male and the other female, it is shown that avian
somatic cells possess an inherent sex identity and that, in birds,
sexual differentiation is cell autonomous.
D. Zhao et al.
doi:10.1038/nature08852
Abstract: http://links.ealert.nature.com/ctt?kn=257&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=275&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Systems survey of endocytosis by multiparametric image analysis pp243-249
A new strategy is presented to accurately profile the activity of
human genes in endocytosis by combining genome-wide RNAi, automated
high-resolution confocal microscopy and quantitative multi-parametric
image analysis. Several novel components of endocytosis and endosome
trafficking were uncovered; a systems analysis further revealed that
the cell regulates the number, size and concentration of cargo
within endosomes.
Claudio Collinet et al.
doi:10.1038/nature08779
Abstract: http://links.ealert.nature.com/ctt?kn=259&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=121&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

The primary transcriptome of the major human pathogen Helicobacter
pylori pp250-255
The transcriptome of Helicobacter pylori, an important human pathogen
involved in gastric ulcers and cancer, is presented. The approach
establishes a model for mapping and annotating the primary
transcriptomes of many living species.
Cynthia M. Sharma et al.
doi:10.1038/nature08756
Abstract: http://links.ealert.nature.com/ctt?kn=253&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=133&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

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http://links.ealert.nature.com/ctt?kn=45&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

=====================================================================

———————-
LETTERS
———————-
Confirmation of general relativity on large scales from weak lensing
and galaxy velocities pp256-258
Although general relativity underlies modern cosmology, its applicability
on cosmological length scales has yet to be stringently tested. Now, at
a length scale of tens of megaparsecs, the quantity EG, which combines
measures of large-scale gravitational lensing, galaxy clustering, and
the growth rate of structure, has been measured to be 0.39[plusmn]0.06,
in agreement with the general relativistic prediction of about 0.4.
Reinabelle Reyes et al.
doi:10.1038/nature08857
Abstract: http://links.ealert.nature.com/ctt?kn=255&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=82&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Deviations from a uniform period spacing of gravity modes in a massive
star pp259-261
Measuring the oscillations of a star can allow the various mixing
processes in its interior to be disentangled, through the signature
they leave on period spacings in the gravity mode spectrum. Here
numerous gravity modes in a young star of about seven solar masses
are reported: the mean period spacing enables the extent of the
convective core to be determined, and the clear periodic deviation
from the mean constrains the location of the chemical transition
zone — at about 10 per cent of the radius.
Pieter Degroote et al.
doi:10.1038/nature08864
Abstract: http://links.ealert.nature.com/ctt?kn=249&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=64&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Transmission of electrical signals by spin-wave interconversion in a
magnetic insulator pp262-266
An insulator does not conduct electricity, and so cannot in general
be used to transmit an electrical signal. But an insulator's electrons
possess spin in addition to charge, and so can transmit a signal in
the form of a spin wave. Here a hybrid metal-insulator-metal structure
is reported, in which an electrical signal in one metal layer is
directly converted to a spin wave in the insulating layer; this wave
is then transmitted to the second metal layer, where the signal can
be directly recovered as an electrical voltage.
Y. Kajiwara et al.
doi:10.1038/nature08876
Abstract: http://links.ealert.nature.com/ctt?kn=251&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=75&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Tunable polymer multi-shape memory effect pp267-270
When a shape memory polymer is deformed at a temperature defined by
a specific phase transition, the deformed shape is fixed upon cooling,
but the original shape can be recovered on reheating. Here the
perfluorosulphonic acid ionomer Nafion is shown to exhibit at least four
different shapes as a result of its broad reversible phase transition.
Tao Xie
doi:10.1038/nature08863
Abstract: http://links.ealert.nature.com/ctt?kn=271&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=195&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

A large atomic chlorine source inferred from mid-continental reactive
nitrogen chemistry pp271-274
The presence of gaseous chlorine atom precursors within the troposphere
was thought only to occur in marine areas but now nitryl chloride has
been found at a distance of 1,400 km from the nearest coastline.
A model study shows that the amount of nitryl chloride production in
the continental USA alone is similar to previous global estimates for
marine regions. A significant fraction of tropospheric chlorine atoms
may arise directly from anthropogenic pollutants.
Joel A. Thornton et al.
doi:10.1038/nature08905
Abstract: http://links.ealert.nature.com/ctt?kn=109&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=187&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Antagonistic coevolution accelerates molecular evolution pp275-278
The Red Queen hypothesis predicts that coevolution should increase
the rate of evolution at the molecular level. Here, genome sequencing
in an experimental phage-bacteria system is used to show that this
is true, but the effect is concentrated on specific loci, and also
that coevolution drives greater diversification of phage populations.
Steve Paterson et al.
doi:10.1038/nature08798
Abstract: http://links.ealert.nature.com/ctt?kn=103&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=188&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Compensatory evolution in mitochondrial tRNAs navigates valleys of
low fitness pp279-282
Evolution from one fitness peak to another must involve either
transitions through intermediates of low fitness or skirting round
the fitness valley through compensatory mutations elsewhere. Here,
the base pairs in mitochondrial tRNA stems is used as a model to show
that deep fitness valleys can be traversed. Transitions between AU
and GC pairs have occurred during mammalian evolution without help
from genetic drift or mutations elsewhere.
Margarita V. Meer, Alexey S. Kondrashov, Yael Artzy-Randrup and
Fyodor A. Kondrashov
doi:10.1038/nature08691
Abstract: http://links.ealert.nature.com/ctt?kn=106&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=223&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Sister chromosome pairing maintains heterozygosity in parthenogenetic
lizards pp283-286
The existence of all-female species of whiptail lizard, formed as a
hybrid between sexual species, has been known since 1962; however,
how the meiotic program is altered to produce diploid eggs while
maintaining heterozygosity has remained unclear. Here it is shown in
parthenogenetic species that meiosis initiates with twice the number
of chromosomes compared to sexual species, and that pairing and
recombination takes place between genetically identical sister
chromosomes instead of between homologues.
Aracely A. Lutes et al.
doi:10.1038/nature08818
Abstract: http://links.ealert.nature.com/ctt?kn=97&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=209&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Systematic genetic analysis of muscle morphogenesis and function
in Drosophila pp287-291
A genome-wide RNA interference screen to systematically test the
genetic basis for formation and function of the Drosophila muscle
is described. A role in muscle for 2,785 genes is identified;
many of these genes are phylogenetically conserved.
Frank Schnorrer et al.
doi:10.1038/nature08799
Abstract: http://links.ealert.nature.com/ctt?kn=99&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=215&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Telomere elongation in induced pluripotent stem cells from dyskeratosis
congenita patients pp292-296
Here, iPS cell technology is used to study the mechanisms underlying
dyskeratosis congenita in humans. Reprogramming restores telomere
elongation in dyskeratosis congenita cells despite genetic lesions
affecting telomerase. The reprogrammed cells were able to overcome
a critical limitation in telomerase RNA component (TERC) levels to
restore telomere maintenance and self-renewal, and multiple telomerase
components are targeted by pluripotency-associated transcription factors.
Suneet Agarwal et al.
doi:10.1038/nature08792
Abstract: http://links.ealert.nature.com/ctt?kn=93&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=168&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

The cells and peripheral representation of sodium taste in mice pp297-301
Mammals are repelled by large concentrations of salts but attracted to
low concentrations of sodium. In mice, the latter behaviour can be
blocked by the ion channel inhibitor amiloride. Here, mice have been
produced lacking the drug's target sodium channel, ENaC, specifically
in taste receptor neurons. It is confirmed that sodium sensing, like
the four other taste modalities (sweet, sour, bitter and umami), is
mediated by a dedicated 'labelled line'.
Jayaram Chandrashekar et al.
doi:10.1038/nature08783
Abstract: http://links.ealert.nature.com/ctt?kn=95&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=164&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

B-cell-derived lymphotoxin promotes castration-resistant prostate
cancer pp302-305
In a mouse model of prostate cancer it is shown that infiltrating
B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin
accelerates the emergence of castration-resistant prostate tumours
in this model. Interfering with this pathway may offer therapeutic
strategies for androgen-independent prostate cancer.
Massimo Ammirante et al.
doi:10.1038/nature08782
Abstract: http://links.ealert.nature.com/ctt?kn=90&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=179&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

JARID2 regulates binding of the Polycomb repressive complex 2 to
target genes in ES cells pp306-310
Polycomb proteins have a key role in regulating the expression of
genes essential for development, differentiation and maintenance
of cell fates. Here, Polycomb repressive complex 2 (PRC2) is shown
to form a complex with JARID2, a Jumonji domain protein. JARID2 is
required for the binding of Polycomb proteins to target genes in
embryonic stem cells as well as for the proper differentiation of
ES cells.
Diego Pasini et al.
doi:10.1038/nature08788
Abstract: http://links.ealert.nature.com/ctt?kn=89&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=174&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
NATUREJOBS
———————-
Prospects
Speak up p312
Peter Fiske argues that too many young scientists adopt a passive
voice, to the detriment of their careers.
Peter Fiske
doi:10.1038/nj7286-312a
http://links.ealert.nature.com/ctt?kn=144&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Careers Q&A
Q&A p313
Lidia Brito, Mozambique's former science minister, now heads the
science-policy division at the United Nations Educational, Scientific
and Cultural Organization (UNESCO) in Paris.
Virginia Gewin
doi:10.1038/nj7286-313a
http://links.ealert.nature.com/ctt?kn=144&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

In Brief
Better prospects p313
UK oil, gas and petrochemical employers expect to hire researchers
this year.
doi:10.1038/nj7286-313b
http://links.ealert.nature.com/ctt?kn=144&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

In Brief
Salary freeze p313
US universities are expected to restrict hiring this year.
doi:10.1038/nj7286-313c
http://links.ealert.nature.com/ctt?kn=144&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

In Brief
Wellcome translation p313
The UK Wellcome Trust launches new PhD studentships in several fields.
doi:10.1038/nj7286-313d
http://links.ealert.nature.com/ctt?kn=144&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
FUTURES
———————-
The Omniplus Ultra p316
You can't live without it.
Paul Di Filippo
doi:10.1038/464316a
http://links.ealert.nature.com/ctt?kn=171&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

———————-
Advance Online Publication
———————-
10 March 2010
Whole-genome resequencing reveals loci under selection during
chicken domestication
Carl-Johan Rubin et al.
doi:10.1038/nature08832
Abstract: http://links.ealert.nature.com/ctt?kn=288&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=288&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

MONOPTEROS controls embryonic root initiation by regulating a
mobile transcription factor
Alexandra Schlereth et al.
doi:10.1038/nature08836
Abstract: http://links.ealert.nature.com/ctt?kn=296&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=296&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

A computational model of teeth and the developmental origins of
morphological variation
Isaac Salazar-Ciudad and Jukka Jernvall
doi:10.1038/nature08838
Abstract: http://links.ealert.nature.com/ctt?kn=305&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=305&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Understanding mechanisms underlying human gene expression variation
with RNA sequencing
Joseph K. Pickrell et al.
doi:10.1038/nature08872
Abstract: http://links.ealert.nature.com/ctt?kn=323&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=323&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Transcriptome genetics using second generation sequencing in a
Caucasian population
Stephen B. Montgomery et al.
doi:10.1038/nature08903
Abstract: http://links.ealert.nature.com/ctt?kn=328&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=328&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

07 March 2010
Transcription-independent ARF regulation in oncogenic
stress-mediated p53 responses
Delin Chen et al.
doi:10.1038/nature08820
Abstract: http://links.ealert.nature.com/ctt?kn=326&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=326&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Spatial control of EGF receptor activation by reversible
dimerization on living cells
Inhee Chung et al.
doi:10.1038/nature08827
Abstract: http://links.ealert.nature.com/ctt?kn=332&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=332&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

Control of female gamete formation by a small RNA pathway
in Arabidopsis
Vianey Olmedo-Monfil et al.
doi:10.1038/nature08828
Abstract: http://links.ealert.nature.com/ctt?kn=236&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0
Article: http://links.ealert.nature.com/ctt?kn=236&m=34691819&r=MjA1NTkxMDA2MAS2&b=2&j=Njg3NDgzODAS1&mt=1&rt=0

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