Mutations increase risk of common heart problem

Hsp90 inhibitors allow small cell lung cancer to die, What happened before the Big Bang?, A solid base for nitride semiconductors, The stress of gaining weight, Spermicide favors HPV infection, Genetic link between prostate cancer and type 2 diabetes, Male pheromone stimulates neurogenesis in the female brain.


For papers that will be published online on 01 July 2007

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

This press release contains:

· Summaries of newsworthy papers:

Genetics: Mutations increase risk of common heart problem - Nature
Genomics: Chromatin modification maps and cell state - Nature
Protein function from first principles – Nature Chemical Biology
Hsp90 inhibitors allow small cell lung cancer to die – Nature Chemical Biology
What happened before the Big Bang? – Nature Physics
A solid base for nitride semiconductors – Nature Materials
The stress of gaining weight – Nature Medicine
Spermicide favors HPV infection – Nature Medicine
Genetic link between prostate cancer and type 2 diabetes – Nature Genetics
Male pheromone stimulates neurogenesis in the female brain – Nature Neuroscience
The amygdala and persistent behavior in addiction – Nature Neuroscience
Analysis of enzymes with macrocycles – Nature Methods

· Mention of papers to be published at the same time with the same embargo

· Geographical listing of authors

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[1] Gene tics: Mutations increase risk of common heart problem
DOI: 10.1038/nature06007

Two mutations have been implicated in the most common heart rhythm abnormality. The findings, reported in this week’s Nature, could boost our understanding of atrial fibrillation and suggest new directions for future therapeutics.

Atrial fibrillation, an abnormal heart rhythm involving the upper two chambers of the heart, can cause life-threatening events such as heart failure and stroke. Daniel F. Gudbjartsson and colleagues conducted a genome-wide association scan in populations from around the globe, and found two mutations that lie adjacent to a gene known to be involved in early heart development. Each of the variants seems to contribute substantially to the risk of developing atrial fibrillation.

The finding should help researchers understand the biological mechanisms that underpin atrial fibrillation, and may even help in the development of diagnostic tests that would allow early detection and may improve treatment.

Author contact:

Daniel Gudbjartsson (deCode Genetics, Reykjavik, Iceland)
Tel: +354 570 1900; E-mail: [email protected]

Edward Farmer (Director of Corporate Communication, deCODE genetics Inc)
Tel: +1 646 417 4555; E-mail: [email protected]

[2] Genomics: Chromatin modification maps and cell state
DOI: 10.1038/nature06008

The generation of genome-wide maps of chromatin modification in mammalian cells is described in a paper published online by Nature this week. Using a technique known as single-molecule-based sequencing, Eric Lander and colleagues produced ‘chromatin-state’ maps that provide a rich source of information about cell state, and yield insights beyond what is typically achieved using other methods.

Although they have essentially identical genomes, the different cell types in a multicellular organism maintain markedly different behaviours that persist over extended periods. Previous research suggests that cellular state may be closely related to chromatin state — that is, modifications to histones and other proteins that package the genome. In the present study, the authors used single-molecule-based sequencing technology to construct chromatin-state maps for mouse embryonic stem cells and two other more developmentally advanced cell types, revealing the genome-wide distribution of important chromatin modifications. This allowed them to distinguish between genes that were active, poised for activation or stably repressed, reflecting cellular state and developmental potential.

The authors propose that their study provides a framework for applying comprehensive chromatin profiling towards characterizing diverse mammalian cell populations, including situations of abnormal development such as in cancer.

Author contact:

Eric S. Lander (Broad Institute of MIT and Harvard, Cambridge, MA, USA)
Tel: +1 617 252 1906; E-mail: [email protected]

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

[3] Structure-based activity prediction for an enzyme of unknown function [Shoichet]

DOI: 10.1038/nature05981

*************************************NATURE CHEMICAL BIOLOGY ****************************

[4] Hsp90 inhibitors allow small cell lung cancer to die
DOI: 10.1038/nchembio.2007.10

Scientists describe the role played by a protective protein called Hsp90 in maintaining the malignant state of small cell lung cancer cells, in a report in the August issue of Nature Chemical Biology.

Hsp90 is a chaperone protein that helps cellular proteins fold and mature. This protective function can also stabilise oncogenic proteins in cancer cells, exacerbating their cancer-causing potential. Gabriela Chiosis and colleagues show that Hsp90 plays a particularly important role in small cell lung cancer (SCLC) cells by inhibiting apoptosis, the programmed destruction of cells. The results in SCLC cell lines help explain why SCLC tumours are so malignant, resulting in relapses even after responding well to chemotherapy.

Various selective compounds identified by the authors are potential candidates for treating SCLC patients in the future, since they allow SCLC to overcome their apoptosis defects. Further studies should help to explore this possibility.

Author contact:
Gabriela Chiosis (Memorial Sloan-Kettering Cancer Center, New York, NY, USA)
Tel: +1 212 639 8929; E-mail: [email protected]

[5] Protein function from first principles
DOI: 10.1038/nchembio.2007.11

Scientists have identified the function of a previously uncharacterized enzyme using a novel approach, according to a paper to be published in the August issue of Nature Chemical Biology.

As an increasing number of genomes are sequenced, scientists gain information on what proteins might exist but are still limited in understanding what these proteins do, or where and when they perform their unknown functions. Previous attempts to uncover the roles of new proteins have been based on their similarity to other known proteins, but this approach can fail for a variety of reasons.

John Gerlt and colleagues now apply computational docking of potential enzyme substrates into a structural model to assign the function of BC0371, a protein that had previously been misassigned based on its close relationship with another protein. The authors found that allowing the amino acid side chains in the protein to vary their position during the experiments resulted in improved docking and pointed towards a specific group of compounds as likely substrates. Experimental confirmation of these preferences allowed the team to reassign the protein with its proper function. Application of these ideas should lead to similar advances for other proteins, particularly those in protein superfamilies.

Author contact:
John A. Gerlt (University of Illinois, Urbana, IL, USA)
Tel: +1 217 244 7414, Email: [email protected]

***********************************************NATURE PHYSICS*****************************************

[6] What happened before the Big Bang?

DOI: 10.1038/nphys654

Will we ever know what happened before the Big Bang? That’s the question posed by Martin Bojowald, online this week in Nature Physics. His analysis, using quantum gravity, suggests that our picture can never be complete.

The Big Bang has been imagined as the beginning of the Universe, the point at which all physical theories break down. A more modern interpretation, however, has the Big Bang as a ‘singularity’ that marks a transition between states — a cataclysmic bounce through which, using the theory of quantum gravity, we can track back from our existing Universe to whatever state preceded it.

The author’s calculations show that, although it’s possible to know something of what came before, the subtle effects of quantum physics make it impossible to know everything: some aspects of the previous universe are irretrievably lost through the Big Bang transition. As some scientists favour a ‘cyclic’ model of recurring Big Bangs, Bojowald points out that no two universes in the sequence would ever be the same — owing to, as he puts it, this “cosmic forgetfulness”.

Author contact:
Martin Bojowald (Pennsylvania State University, University Park, PA, USA)
Tel: +1 814 865 3502; E-mail: [email protected]

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

[7] A non-volatile-memory device on the basis of engineered anisotropies in (Ga,Mn)As
DOI: 10.1038/nphys652

[8] The energization of relativistic electrons in the outer Van Allen radiation belt
DOI: 10.1038/nphys655

[9] Itinerant to localized transition of f electrons in the antiferromagnetic superconductor UPd2Al3
DOI: 10.1038/nphys651

[10] Fractional quantum Hall effect in a quantum point contact at filling fraction 5/2
DOI: 10.1038/nphys658

********************************************* NATURE MATERIALS **************************************

[11] A solid base for nitride semiconductors
DOI: 10.1038/nmat1955

High-quality gallium nitride (GaN) blocks, which can be used as substrates for optoelectronic devices, can be grown at low cost, as suggested in a report online this week in Nature Materials.

Tadao Hashimoto and colleagues succeeded in growing up to 180 layers of micrometre-thick single-crystalline layers of GaN on a seed of the same material by ammonothermal growth. This method is based on immersing both the source material — polycrystalline GaN in this case — and the seed in ammonia. The grown material contained only a small number of defects and dislocations.

Solid-state structures based on GaN and other nitride semiconductors are very promising for optoelectronics devices, but the absence of high-quality and low-cost substrates has been a great obstacle to large-scale production — these results represent a definite leap towards resolving this problem.

Author contact:
Tadao Hashimoto (University of California, Santa Barbara, CA, USA)
Tel: +1 805 893 5145; E-mail: [email protected]

*******************************************Nature MEDICINE********************************************

[16] The stress of gaining weight
DOI: 10.1038/nm1611

A hormone involved in the neural control of feeding might also be linked to stress-induced obesity, suggests a paper in the July issue of Nature Medicine.

Neuropeptide Y (NPY) acts on the brain to drive the urge to eat. Zofia Zukowska and colleagues found that NPY from peripheral nerves can also act directly on adipose tissue, making mice obese in response to physical or emotional stress. This effect seemed to depend on the release of another well-characterized stress hormone — cortisol.

Importantly, blocking the receptor for NPY on fat cells prevented the weight gain, pointing to a possible target to oppose this negative side effect of stress.

Author contact:
Zofia Zukowska (Georgetown University, Washington, DC, USA)
Tel. +1 202 687 1034; E-mail: [email protected]

[17] Spermicide might favour HPV infection
DOI: 10.1038/nm1598

A molecule widely used in vaginal spermicides could increase genital transmission of the human papilomavirus (HPV), according to a study published in the July issue of Nature Medicine.

HPV is the most common sexually transmitted virus and causes virtually all cases of cervical cancer. However, studying its genital transmission has been difficult owing to the lack of a suitable animal model. In the present study, John Schiller and colleagues developed a mouse model of vaginal infection with HPV that mirrors the early phase of human infection. Using this model, they found that nonoxynol-9, a molecule widely used in vaginal spermicides, greatly increased susceptibility to HPV infection. By contrast, carrageenan – a molecule present in some vaginal lubricants – prevented infection even in the presence of nonoxynol-9, suggesting that carrageenan might serve as an effective topical HPV microbicide.

Author contact:
John Schiller (National Cancer Institute, NIH, Bethesda, MD, USA)
Tel: +1 301 496 6539; E-mail: [email protected]

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

[18] Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis
DOI: 10.1038/nm1605

[19] Real-time measurement of free Ca2+ changes in CNS myelin by two-photon microscopy
DOI: 10.1038/nm1568

[20] Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer
DOI: 10.1038/nm1609

***********************************************NATURE GENETICS **************************************

[21] Genetic link between prostate cancer and type 2 diabetes
DOI: 10.1038/ng2062

Two variants on chromosome 17 confer risk of prostate cancer, one of which also protects against type 2 diabetes, suggests an article online this week in Nature Genetics. Although epidemiological studies have noted an inverse relationship between type 2 diabetes and risk of prostate cancer, this paper provides the first genetic evidence to support a link between susceptibility to the two diseases.

Julius Gudmundsson, Kari Stefansson and colleagues initially carried out a genome-wide association study of prostate cancer in men from Iceland. Based on previous work suggesting that a particular region on chromosome 17 harbours risk variants, they followed up with association studies of men from three other populations of European descent. Two variants showed strong association with prostate cancer, one within the gene TCF2 (the other is not obviously associated with a gene). As mutations in TCF2 have been reported in individuals with a rare hereditary form of diabetes, the authors carried out additional association studies of individuals with the more common type 2 diabetes from seven populations of European, Asian and African ancestry. They found a modest but consistent association of the TCF2 variant with protection against type 2 diabetes (approximately 10% lower risk compared with healthy controls). The authors suggest that TCF2 may affect a metabolic or hormonal pathway that independently modulates the risk of prostate cancer and type 2 diabetes.

Author contacts:
Kari Stefansson (deCODE Genetics, Reykjavik, Iceland)
Tel: +354 570 1900; E-mail: [email protected]

Julius Gudmundsson (deCODE Genetics, Reykjavik, Iceland)
Tel: +354 570 1900; E-mail: [email protected]

Edward Farmer (Director of Corporate Communication, deCODE genetics Inc)
Tel: +1 646 417 4555; E-mail: [email protected]

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

[22] Common variants in WFS1 confer risk of type 2 diabetes
DOI: 10.1038/ng2067

[23] Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy
DOI: 10.1038/ng2073

[24] Germline gain-of-function mutations in RAF1 cause Noonan syndrome
DOI: 10.1038/ng2078

*******************************************NATURE NEUROSCIENCE ***********************************

[25] Male pheromone stimulates neurogenesis in the female brain

DOI: 10.1038/nn1928

Pheromone signals from dominant males stimulate the production of new neurons in the olfactory bulb and hippocampus of the brain in female mice, reports a paper in the August issue of Nature Neuroscience. This neurogenesis appears to be necessary for the normal female preference to mate with dominant males.

Pheromones are chemical cues that female mice use to recognize and select their mates. In the present study, Samuel Weiss and colleagues report that pheromones from dominant males, but not from subordinate or castrated males, stimulated the production of neurons. Females with damage to the main olfactory system did not show neurogenesis in response to pheromones. Male pheromones are known to stimulate the release of luteinizing hormone and prolactin in females. Luteinizing hormone mimicked the effect of male pheromones in the dentate gyrus of the hippocampus, while females lacking the receptor for this hormone did not respond to male pheromones. Similarly, prolactin increased neurogenesis in the olfactory bulb, and females lacking the receptor for prolactin did not respond to pheromones.

Disrupting neurogenesis during initial exposure to the pheromone eliminated a female’s subsequent preference for the dominant male, though the females were still able to detect novel odours and showed normal locomotor behaviour. The authors conclude that the birth of new neurons may be important for female reproductive success.

Author contact:

Samuel Weiss (University of Calgary, Alberta, Canada)
Tel: +1 403 220 3394; E-mail: [email protected]

Additional contact for comment on paper:

Zhengui Xia (University of Washington, Seattle, WA, USA)
Tel: +1 206 616 9433; E-mail: [email protected]

[26] The amygdala and persistent behaviour in addiction
DOI: 10.1038/nn1931

Neurons in part of the brain known as the basolateral amygdala mediate persistent behaviour induced by cocaine exposure, reports a study in the August issue of Nature Neuroscience. These results suggest that the amygdala may be involved in the inability of addicts to modify their behaviour in the face of adverse consequences.

Goeffrey Schoenbaum and colleagues trained rats to respond to one odour to receive a reward and to avoid responding to another, which led to a punishment. When the association between odour and outcome was reversed, animals exposed to cocaine before learning had particular difficulty learning to stop responding to the previously rewarded cue. The authors also recorded from the basolateral amygdala of the rats’ brains during this task and identified neurons that responded separately to either odour, once the animal had learned which odour predicted which outcome. When the association between odour and outcome was reversed, the responses of most neurons switched between the two. In contrast, in rats that had been exposed to cocaine before learning, very few of the neurons switched their responses.

In another experiment, the authors lesioned the basolateral amygdala of both control and cocaine-exposed rats before learning and reversal. While the lesions did not affect the acquisition of the odour-outcome associations, they did abolish the reversal deficit in cocaine-exposed animals. This further supports the idea that the basolateral amygdala inhibits the ability of drug exposed rats to adapt their behaviour to changing contingencies in the environment.

Author Contact:
Geoffrey Schoenbaum (University of Maryland School of Medicine, Baltimore, MD, USA)
Tel: +1 410 706 3814; E-mail: [email protected]

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

[27] Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens
DOI: 10.1038/nn1923

[28] Adaptation reveals independent control networks for human walking
DOI: 10.1038/nn1930

[29] Genetically encoding unnatural amino acids for cellular and neuronal studies
DOI: 10.1038/nn1932

********************************************NATURE METHODS******************************************

[30] Analysis of enzymes with macrocycles

DOI: 10.1038/nmeth1064

A new concept for assaying enzyme activity with cyclic macromolecules and fluorescent dyes is reported online this week in Nature Methods.

Many of these cyclic macromolecules, or macrocycles, are commercially available and are known to bind various fluorescent dyes in their central ‘pocket’. Werner Nau and colleagues show that by carefully choosing the right macrocycle these molecules can serve as detectors of enzyme activity. The authors selected macrocycles that bind the substrate of an enzyme only weakly, but its product strongly; as the product is generated it displaces the fluorescent dye from the macrocycle’s pocket. Enzyme activity can then be easily monitored by observing the switch-on in fluorescence as the dye is displaced from the macrocycle.

This concept should be of particular interest for practical applications in industries where cheap and simple enzyme assays are needed.

Author contact:
Werner Nau (Jacobs University Bremen, Germany)
Tel: +49 421 200 3233; E-mail: [email protected]

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

[31] LambdaN-GFP: a novel RNA reporter system for live cell imaging
DOI: 10.1038/nmeth1065


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


[32] Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases

DOI: 10.1038/nbt1317

[33] An improved zinc-finger nuclease architecture for highly specific genome editing

DOI: 10.1038/nbt1319


[34] Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3

DOI: 10.1038/ni1486

[35] Redox regulation of peptide loading of major histocompatibility complex I by ERp57 and tapasin

DOI: 10.1038/ni1483

[36] Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer

DOI: 10.1038/ni1485


[37] Physical and functional coupling of RNA-dependent RNA polymerase and Dicer in biogenesis of endogenous siRNAs

DOI: 10.1038/nsmb1262

[38] RS domain–splicing signal interactions in splicing of U12-type and U2-type introns

DOI: 10.1038/nsmb1263

[39] Holoenzyme assembly and ATP-mediated conformational dynamics of topoisomerase VI

DOI: 10.1038/nsmb1264

[40] Role for BLM in replication-fork restart and suppression of origin firing after replicative stress

DOI: 10.1038/nsmb1267


***FOR IMMEDIATE RELEASE: The following article was published on Nature Immunology’s website on 20 June so is not under embargo. We have included it on this release to avoid multiple mailings. This will not affect the rest of this week’s press release, which is under embargo as normal, until 1800 London time / 1300 US Eastern time on Sunday 01 July.***

[41] IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways




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.

Sydney: 16

Ghent: 34

Calgary: 25
Montreal: 33
Ottawa: 19, 25

Hong Kong: 1, 21
Shanghai: 14

Aarhus: 21
Ballerup: 21
Copenhagen: 21
Glostrup: 21

Turku: 25

Berlin: 32
Bremen: 30
Heidelberg: 31, 35
Wurzburg: 7

Akureyri: 1
Kopavogur: 21
Reykjavik: 1, 21

Jerusalem: 22

Bologna: 23
Milan: 23
Padua: 23, 39
Rome: b23


Aichi: 24

Chiba: 24

Fukuoka: 24

Ibaraki: 9

Kanagawa: 24

Kyoto: 9

Osaka: 9, 24

Sayo: 9

Shiga: 24

Tokyo: 9, 24

Tsukuba: 12


Ede: 21

Groningen: 21

Nijmegen: 21

Utrecht: 21


Bratislava: 16


Barcelona: 32

Malaga: 23

Zaragoza: 21


Huddinge: 1


Basel: 10

Lausanne: 18

Zurich: 18


Cambridge: 22

Dundee: 21, 22

Exeter: 22

London: 18, 22, 25

Newcastle: 22

Oxford: 22, 40



Berkeley: 15, 23, 37, 39

Davis: 32

La Jolla: 29

Los Angeles: 16

Pasadena: 34

Richmond: 33

San Francisco: 3, 5

Santa Barbara: 11

Stanford: 13

Walnut Creek: 23


New Haven: 36

District of Columbia

Washington: 16, 21


Tampa: 20


Chicago: 21

Urbana: 5


Baltimore: 20, 26, 28

Bethesda: 17, 19

Frederick: 17


Boston: 1, 2, 33, 39

Cambridge: 2, 10, 18, 25

Charlestown: 2

Worcester: 38


Rochester: 4, 23


St Louis: 21, 22


Omaha: 20


Reno: 14

New Jersey

Murray Hill: 10

Nutley: 4

Princeton: 14

New Mexico

Los Alamos: 8

New York

Bronx: 3, 5

New York: 4, 23

Troy: 14

North Carolina

Chapel Hill: 27


Philadelphia: 21

Pittsburgh: 4

University Park: 6

Rhode Island

Providence: 13


College Station: 3


Richmond: 4


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Tel: +44 20 7843 4502; E-mail: [email protected]

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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 Methods (New York)

Allison Doerr

Tel: +1 212 726 9393; E-mail: [email protected]

Nature Nanotechnology (London)

Peter Rodgers
Tel: +44 20 7014 4019; Email: [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

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Michelle Montoya

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Published: 01 Jul 2007

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