Tired T cells get a boost to fight HIV

New compounds give voice to silenced neural DNA, Quantum paradox predicted to occur in graphene, Spin-flow without electric currents, Fatherhood changes brain anatomy, Fighting Lyme disease, Cystic fibrosis: explaining persistent lung infections, Understanding leukaemia

NATURE AND THE NATURE RESEARCH JOURNALS PRESS RELEASE

For papers that will be published online on 20 August 2006

This press release is copyrighted to the Nature journals mentioned below.

This press release contains:

* Summaries of newsworthy papers:

Immunology: Tired T cells get a boost to fight HIV - Nature & Nature Medicine

New compounds give voice to silenced neural DNA - Nature Chemical Biology

Quantum paradox predicted to occur in graphene - Nature Physics

Spin-flow without electric currents - Nature Physics

Fatherhood changes brain anatomy - Nature Neuroscience

Fighting Lyme disease - Nature Immunology

Cystic fibrosis: explaining persistent lung infections - Nature Cell Biology

Understanding leukaemia - Nature Cell Biology

* Mention of papers to be published at the same time with the same embargo
* Geographical listing of authors

PDFs of all the papers mentioned on this release can be found in the relevant journal’s section of http://press.nature.com. Press contacts for the Nature journals are listed at the end of this release.

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[1] & [2] Immunology: Tired T cells get a boost to fight HIV

DOI: 10.1038/nature05115
DOI: 10.1038/nm1482

Blocking a protein called PD-1 (programmed death 1) might provide a way to boost the function of T cells crippled by HIV, according to two studies published online this week in Nature and Nature Medicine.

Earlier this year, a study showed that blocking the function of PD-1 in virally infected mice could restore the function of ailing T cells and help fight infection. In the paper published in Nature, Bruce Walker and his colleagues have now examined seventy one chronically infected HIV patients and found that their T cells have dramatically more PD-1 receptors on their surface, and that the degree of PD-1 production correlates with markers of disease progression including the extent to which T cells are disabled and the levels of virus within the body. In the Nature Medicine study, Rafick-Pierre Sekaly and his colleagues find similar correlations in nineteen HIV infected patients and show that, over time, fluctuations in HIV load mirror levels of PD-1 expression on the T cells.

Notably, both groups of researchers find that an antibody that blocks this receptor promotes the immune response to HIV in laboratory experiments, raising hope that a similar strategy might work to fight the disease in humans.

Author Contacts:
Nature paper [1]
Bruce Walker (Partners AIDS Research Center, Boston, MA, USA)
Tel: +1 617 724 7524; E-mail: [email protected]

Nature Medicine paper [2]
Rafick-Pierre Sekaly (Centre de Recherche du CHUM, Montreal, Canada)
Tel: +1 514 890 8000 x35288; E-mail: [email protected]

Other papers from Nature to be published online at the same time and with the same embargo:

[3] Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai
DOI: 10.1038/nature05108

[4] Orai1 is an essential pore subunit of the CRAC channel
DOI: 10.1038/nature05122

[5] Mast cells are essential intermediaries in regulatory T-cell tolerance
DOI: 10.1038/nature05010

*********************************Nature MEDICINE************************
(<http://www.nature.com/naturemedicine>)

Other papers from Nature Medicine to be published online at the same time and with the same embargo:

[6] TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis
DOI: 10.1038/nm1449

*************************NATURE CHEMICAL BIOLOGY ************************
http://www.nature.com/nchembio
http://www.nature.com/natureneuroscience)

[7] New compounds give voice to silenced neural DNA

DOI: 10.1038/nchembio815

A potential therapy for Friedreich’s ataxia, a neurodegenerative disease that is caused by gene activation, is described in the October issue of Nature Chemical Biology.

Frataxin, a protein that protects neurons from cell death caused by free radicals, is ‘silenced’ in the neurodegenerative disease Friedreich’s ataxia. The production of a gene can be regulated by changing the chemical tags attached to nearby histones, or beads that DNA is wrapped around inside the cell. In Friedreich’s ataxia, an expansion in the ‘noncoding‘ portion of FXN (the gene encoding frataxin) and modification of the gene’s associated histones results in silencing FXN transcription. Gottesfeld and colleagues have identified a class of inhibitors that reverse the silencing in cells in individuals with Friedreich’s ataxia; the inhibitors specifically changed the chemical modifications of the histones around FXN.

These compounds now join the handful of therapeutics that activate specific gene transcription in a human disease.

Author contact:
Joel M Gottesfeld (The Scripps Research Institute, La Jolla, CA, USA)
Tel: +1 858 784 8913; E-mail: [email protected]

***********************************NATURE PHYSICS**************************
http://www.nature.com/naturephysics
http://www.nature.com/naturematerials

[8] Quantum paradox predicted to occur in graphene
DOI: 10.1038/nphys384

A report by Andre Geim and colleagues in the September issue of Nature Physics suggests that that the recently discovered exotic properties of graphene - which enable electrons to move as if they have no mass, and at speeds of around a million metres per second - could also enable an effect analogous to the Klein Paradox, which is usually only expected to occur under extreme conditions, such as in the vicinity of a black hole.

The Klein Paradox was first formulated in 1929 by Oskar Klein to highlight the bizarre implications of an equation that Paul Dirac had developed in an attempt to unify the fields of quantum mechanics and special relativity, and has become one of the cornerstones of modern physics. A consequence of this paradox is that when a fast-moving electron meets an extremely strong barrier, instead of bouncing directly off it, it will pass right through it as if it wasn't even there.

In addition to providing a potent example of the sorts of previously inaccessible fundamental physical phenomena that could soon be studied in graphene, the work suggests novel avenues for controlling the flow of electrons in future graphene circuits.

Author contact:
Andre Geim (Department of Physics and Astronomy, University of Manchester, UK)
Tel: +44 161 275 4120 ; E-mail: [email protected] <mailto:[email protected]>

[9] Spin-flow without electric currents
DOI: 10.1038/nphys390

In the September issue of Nature Physics, Sergey Ganichev and colleagues demonstrate a way to generate a flow of electron spins without applying an electrical current. This new phenomenon could become a useful tool in the emergent field of spintronics, which is working towards the development of electronic devices that rely on the electron’s spin rather than its charge.

The putative advantages of spin-based circuits compared with charge-based ones include not only lower power consumption, lower heat generation, higher speed, and smaller devices, but also the potential to do things, such as quantum computation, that are not possible in conventional charge-based electronics.

Sergey Ganichev and colleagues used the fact that in a magnetic field, the electron spin can only point in one of two directions - either in the same direction as the field, or in the opposite direction - and separated the spins of different orientations. Spin separation has been achieved before, but by using electrical fields that move the charges, a method that retains many of the problems of pure charge-based devices.

Author contact:

Sergey Ganichev (Universität Regensburg, Germany)
Tel: +49 941 943 2050; E-mail: [email protected]

Other papers from Nature Physics to be published online at the same time and with the same embargo:

[10] The ‘strange metal’ is a projected Fermi liquid with edge singularities
DOI: 10.1038/nphys388

******************************NATURE NEUROSCIENCE **************************
(<http://www.nature.com/natureneuroscience>)

[11] Fatherhood changes brain anatomy

DOI: 10.1038/nn1753

Marmoset fathers show changes in brain structure and hormone receptors in a region called the prefrontal cortex when compared with non-fathers, reports a paper in the September issue of Nature Neuroscience.

Male marmosets provide extensive parental care, carrying their babies more than half the time during the first three months of an infant’s life. Elizabeth Gould and colleagues found that first-time or experienced marmoset fathers had a higher density of ‘spines’ - a major site of connections between brain cells - on the dendrites of prefrontal neurons than non-fathers, who also lived in mated pairs. Fathers also had more of a particular receptor for the neuropeptide vasopressin, which is involved in parental behavior; expression of the receptors was higher in fathers whose babies were younger, suggesting that this change may be caused by contact with infants.

These findings demonstrate that fatherhood causes changes in brain structure, but further work is necessary to determine their precise functional effects.

Author contact:
Elizabeth Gould (Princeton University, NJ, USA)
Tel: +1 609 258 4483; E-mail: [email protected]

Other papers from Nature Neuroscience to be published online at the same time and with the same embargo:

[12] C-terminal modulator controls Ca2+-dependent gating of Cav1.4 L-type Ca2+ channels
DOI: 10.1038/nn1751

[13] Postsynaptic excitability is necessary for strengthening of cortical sensory responses during experience-dependent development

DOI: 10.1038/nn1752

[14] Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy
DOI: 10.1038/nn1754

[15] Representation of interaural time delay in the human auditory midbrain
DOI: 10.1038/nn1755

[16] Separate neural pathways process different decision costs
DOI: 10.1038/nn1756

*****************************NATURE IMMUNOLOGY *************************
(<http://www.nature.com/natureimmunology>)

[17] Fighting Lyme disease

DOI: 10.1038/ni1380

A specific type of immune cell can attack the bacteria that cause Lyme disease, according to a paper to be published in the September issue of Nature Immunology.

Lyme disease is a chronic, debilitating disorder caused by infection with the bacteria Borrelia burgdorferi, which usually enters the bloodstream after a bite by an infected tick. Mice lacking a specific type of immune cell called natural killer T (NKT) cells are overcome with B. burgdorferi. Mitchell Kronenberg and colleagues now show that NKT cells from both mice and humans can detect B. burgdorferi, triggering an immune response against these bacteria.

These results emphasize NKT cells as potential therapeutic targets for the treatment of Lyme disease. Whether NKT cells also spot other dangerous bacteria remains to be investigated.

Author contact:
Mitchell Kronenberg (La Jolla Institute for Allergy and Immunology, CA, USA.)
Tel: +1 858 752 6540; E-mail: [email protected]

***************************NATURE CELL BIOLOGY *****************************
http://www.nature.com/naturecellbiology

[18] Cystic fibrosis: explaining persistent lung infections

DOI: 10.1038/ncb1456

In the September issue of Nature Cell Biology, Deborah Nelson and colleagues show that CFTR - cystic fibrosis transmembrane regulator, the protein that malfunctions in cystic fibrosis - can control the acidity of digestive compartments in the cell, causing a defect in their ability to kill bacteria.

Bacterial infections in the lungs of cystic fibrosis patients can cause chronic inflammation, which in turn induces tissue damage and worsens the symptoms of the disease. One way that cells clear bacterial infection is through phagocytosis - where specialized cells, called macrophages, ingest the bacteria and destroy them by digestion in acidic compartments. The authors found that CFTR, a chloride ion channel, is present in particular macrophage cells that function specifically in the lung. Using macrophages obtained from mice that are genetically engineered to no longer express the CFTR protein, or by specifically inhibiting CFTR, the authors show that there is a defect in acidification of the digestive compartment in the cell. As a result, an alkaline environment persists, permitting bacterial growth and division.

Macrophages are a key player in the body’s defence mechanism. Compromising their function, as shown by Nelson and colleagues, may begin to explain the persistent infections observed in cystic fibrosis patients.

Author contact:
Deborah J Nelson (University of Chicago, IL, USA)
Tel: +1 773 702 0126; E-mail: [email protected]

[19] Understanding leukaemia
DOI: 10.1038/ncb1464

Important insights into the process underlying two kinds of leukaemias associated with the CALM-AF10 translocation are reported in a study in the September issue of Nature Cell Biology.

Chromosomal translocations, where a fragment of a chromosome is broken off and joins another, can generate fusion proteins that are comprised of two gene products. These fusion proteins often ‘misregulate’ genes that can cause leukaemia. One of the genes most frequently translocated in leukaemia is MLL - mixed lineage leukaemia - and one of its fusion partners is AF10. AF10 has also been shown to fuse with another protein, CALM, in patients with T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia. But it is unclear whether the CALM-AF10 fusion is causal for the disease and there is very little understanding of how this fusion may lead to leukaemia. Yi Zhang and colleagues show that the CALM-AF10 fusion is necessary and sufficient for leukaemic transformation in a mouse model. They found that the fusion leads to atypical expression of the Hoxa5 gene and moreover, that turning on Hoxa5 is necessary for leukaemic transformation induced by the fusion protein. They also identified an enzyme that modifies chromatin as being important for turning up gene expression by the fusion protein.

Whether these findings will result in new and useful therapeutic treatments is unclear at present but understanding the fundamental processes that go awry during cancer development is clearly the first step to developing new treatments.

Author contact:
Yi Zhang (University of North Carolina at Chapel Hill, NC, USA)
Tel: +919-843-8225 ; E-mail: [email protected]

Other papers from Nature Cell Biology to be published online at the same time and with the same embargo:

[20] Phosphatidylinositol-3,4,5-trisphosphate regulates the formation of the basolateral plasma membrane in epithelial cells
DOI: 10.1038/ncb1461

[21] Sequential functioning of the ECT-2 RhoGEF, RHO-1 and CDC-42 establishes cell polarity in Caenorhabditis elegans embryos
DOI: 10.1038/ncb1459

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Items from other Nature journals to be published online at the same time and with the same embargo:

NATURE MATERIALS (<http://www.nature.com/naturematerials>)

[22] Redox-controlled molecular permeability of composite-wall microcapsules

DOI: 10.1038/nmat1716

[23] Fast fabrication of long-range ordered porous alumina membranes by hard anodization

DOI: 10.1038/nmat1717

[24] Actin-binding proteins sensitively mediate F-actin bundle stiffness

DOI: 10.1038/nmat1718

[25] Terahertz all-optical modulation in a silicon-polymer hybrid system

DOI: 10.1038/nmat1719

NATURE GENETICS (<http://www.nature.com/naturegenetics>)

[26] Unraveling adaptive evolution: how a single point mutation affects the protein coregulation network
DOI: 10.1038/ng1867

[27] A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers

DOI: 10.1038/ng1861

[28] In silico method for inferring genotypes in pedigrees
DOI: 10.1038/ng1863

Nature STRUCTURAL & MOLECULAR BIOLOGY (<http://www.nature.com/natstructmolbiol>)

[29] Cotranscriptional coupling of splicing factor recruitment and precursor messenger RNA splicing in mammalian cells
DOI: 10.1038/nsmb1135

[30] The Swi5-Sfr1complex stimulates Rhp51/Rad51- and Dmc1-mediated strand exchange in vitro
DOI: 10.1038/nsmb1136

[31] Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions
DOI: 10.1038/nsmb1138

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GEOGRAPHICAL LISTING OF AUTHORS

The following list of places refers to the whereabouts of authors on the papers numbered in this release. The listing may be for an author's main affiliation, or for a place where they are working temporarily. Please see the PDF of the paper for full details.

AUSTRIA
Innsbruck: 12
Linz: 12

BELGIUM
Brussels: 5
Leuven: 9

CANADA
Montreal: 2
Quebec City: 19

DENMARK
Lyngby: 27

FRANCE
Nantes: 6
Toulouse: 20

GERMANY
Dresden: 29
Garching: 24
Golm/Potsdam: 22
Halle: 23
Heidelberg: 13
Munich: 24
Regensurg: 9

INDIA
Hyderabad: 26

ITALY
Milan: 14

JAPAN
Fukuoka: 6
Kobe: 21
Mishima: 30
Nara: 13
Yokohama: 30

NETHERLANDS
Enschede: 22
Nijmegen: 8
Rotterdam: 13

NEW ZEALAND
Auckland: 26
Lower Hutt: 17

REPUBLIC OF KOREA
Seoul: 6

RUSSIA
St Petersburg: 9

SOUTH AFRICA
Durban: 1

UNITED KINGDOM
London: 15
Manchester: 8, 26
Newcastle: 15
Oxford: 1, 16, 26

UNITED STATES OF AMERICA

California
Irvine: 3
La Jolla: 7, 17
Los Angeles: 7
Pasadena: 25
San Diego: 2
San Francisco: 2, 20

Connecticut
New Haven: 27

Georgia
Atlanta: 1

Illinois
Chicago: 4, 13, 18

Maryland
Bethesda: 17
Chevy Chase: 1
Gaithersburg: 5

Massachusetts
Boston: 1, 4, 5, 17, 27
Cambridge: 17, 27

New Hampshire
Lebanon: 5

New Jersey
Princeton: 10, 11

New York
Albany: 17
New York: 17, 30, 31

North Carolina
Chapel Hill: 19

Ohio
Cincinnati: 20

Pennsylvania
Philadelphia: 1, 6, 28

Tennessee
Memphis: 18

Washington
Seattle: 14, 25

PRESS CONTACTS…

For media inquiries relating to embargo policy for all the Nature Research Journals:

Helen Jamison (Nature London)
Tel: +44 20 7843 4658; E-mail: [email protected]

Ruth Francis (Senior Press Officer, Nature, London)
Tel: +44 20 7843 4562; E-mail: [email protected]

For media inquiries relating to editorial content/policy for the Nature Research Journals, please contact the journals individually:

Nature Cell Biology (London)
Bernd Pulverer
Tel: +44 20 7843 4892; E-mail: [email protected]

Nature Chemical Biology (Boston)
Andrea Garvey
Tel: +1 617 475 9241, E-mail: [email protected]

Nature Genetics (New York)
Orli Bahcall
Tel: +1 212 726 9311; E-mail: [email protected]

Nature Immunology (New York)
Laurie Dempsey
Tel: +1 212 726 9372; E-mail: [email protected]

Nature Materials (London)
Maria Bellantone
Tel: +44 20 7843 4556; E-mail: [email protected]

Nature Medicine (New York)
Juan Carlos Lopez
Tel: +1 212 726 9325; E-mail: [email protected]

Nature Neuroscience (New York)
Sandra Aamodt (based in California)
Tel: +1 530 795 3256; E-mail: [email protected]

Nature Physics (London)
Alison Wright
Tel: +44 20 7843 4555; E-mail: [email protected]

Nature Structural & Molecular Biology (New York)
Michelle Montoya
Tel: +1 212 726 9326; E-mail: [email protected]

About Nature Publishing Group

Nature Publishing Group (NPG) is a division of Macmillan Publishers Ltd, dedicated to serving the academic, professional scientific and medical communities. NPG's flagship title, Nature, was first published in 1869. Other publications include Nature research journals, Nature Reviews, Nature Clinical Practice and a range of prestigious academic journals including society-owned publications. NPG also provides news content through [email protected] and scientific career information through Naturejobs.

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Published: 20 Aug 2006

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