Highlights from this week's Nature and August issues of Nature Research Journals

Cause of heart valve disease identified; Developing new cellular modules; A selective gene-repression probe; DNA adopts a new fold; Susceptibility to obesity and diabetes; Synaptic damage in Alzheimer disease; Tickling nerves prevents inflammation.

Genetics: Cause of heart valve disease identified - Nature
Developing new cellular modules – Nature Chemical Biology
A selective gene-repression probe – Nature Chemical Biology
DNA adopts a new fold – Nature Chemical Biology
Susceptibility to obesity and diabetes – Nature Genetics
Synaptic damage in Alzheimer disease – Nature Neuroscience
Tickling nerves prevents inflammation – Nature Immunology


[1] Genetics: Cause of heart valve disease identified

DOI: 10.1038/nature03940

Although calcification of the aortic valve is the third leading cause of heart disease in adults, a genetic basis has remained unknown until now. Researchers have identified the genetic mutations that can produce a spectrum of cardiac abnormalities of this type. Their findings appear online in this week’s Nature.
Deepak Srivastava and colleagues investigated the influence of mutations in the transcriptional regulator NOTCH1, and found that these caused heart valve defects in mice. By interacting with other proteins, NOTCH appears to have a role in the proper development of the aortic valve and the prevention of valve calcification over time. Scientists have studied the human NOTCH1 sequence for many years, but this represents the first time that they have linked inherited mutations in this gene with a disease.

Author contact
Deepak Srivastava

[2] Muscular dystrophy: Drug shows promise for strengthening hearts (pp)

A new drug offers hope for warding off heart failure associated with Duchenne muscular dystrophy. A study shows that the chemical, called poloxamer 188, strengthens heart muscle cells, making them less likely to break under strain.
Researchers led by Joseph Metzger studied individual heart muscle cells, or cardiac myocytes, from mice lacking the protein dystrophin, a deficiency that causes muscular dystrophy. These cells were more likely to break when stretched, because holes in the cell membrane allow in more calcium ions, which in turn trigger abnormal contraction that rips the cell apart.
Cells treated with poloxamer 188, however, did not show such weakness, the researchers report in a paper to be published online by Nature on 17 July. Mice with muscular dystrophy were also saved from stress-induced heart failure when treated with the drug. The chemical therefore shows promise for treating human sufferers, the authors add, but medical trials will be needed to determine the appropriate dose and ensure that the drug is safe.

Author contact
Joseph Metzger

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

[3] Developing new cellular modules

DOI: 10.1038/nchembio719

The development of new mRNA-ribosome pairs that function orthogonally—in parallel with, but without affecting, endogenous ribosomal translation, as reported by a paper in the August issue of Nature Chemical Biology. A major goal of synthetic biology is to reprogram cells to carry out non-natural functions. By designing an orthogonal translational system, Chin and colleagues have taken a step toward designing "synthetic" cellular pathways.
The authors first developed a method for selecting orthogonal ribosome-mRNA pairs that function together, but in which the ribosome does not recognize native cellular mRNA and the mRNA is not translated by native ribosomes. They then used one of these cognate mRNA-ribosome pairs to program cells with "Boolean logic"—requiring one term AND another term to be present to produce an outcome. To set up the system, the authors attached one piece of the enzyme beta-galactosidase to an orthogonal mRNA and the other fragment to a native cellular mRNA. As expected, a functional beta-galactosidase enzyme was only formed when both the orthogonal and endogenous ribosome-mRNA pairs were expressed.
By programming the cell to perform this simple logic function, Chin and coworkers show how these orthogonal modules can be used to generate new cellular networks.

Author contact:
Jason Chin (Cambridge University, UK)
Tel: +44 1223 402 362, E-mail: [email protected]

[4] A selective gene-repression probe

DOI: 10.1038/nchembio721

Researchers have identified a small-molecule inhibitor that may be a valuable tool for gene-repression studies, according to a paper in Nature Chemical Biology’s August issue. Certain disease states, including cancer and neurodegenerative diseases, have been associated with irregularities in gene-repression. The mature state of a cell is determined by its specific pattern of gene expression, which in turn is established and maintained by how DNA is packaged into DNA-protein bundles, called chromatin. The nucleosome, the basic unit of chromatin, consists of DNA wrapped around four core histone proteins. The addition of methyl groups to histone proteins is known to play an important role in establishing stable gene expression patterns and is coordinated by histone methyltransferase enzymes. Imhof and colleagues have identified from a panel of small molecules a fungal metabolite, chaetocin that specifically inhibits a class of histone methyltransferase responsible for the methylation of histone H3. The authors demonstrate the efficacy of chaetocin both in vitro and in vivo. Chaetocin could be a powerful tool for studying histone methylation–mediated gene repression, misregulation of which has been associated with various disease states.

Author contact:
Axel Imhof (Ludwig-Maximillians University of Munich, Germany)
Tel: +49 89 2180 75435, E-mail: [email protected]

[5] DNA adopts a new fold

DOI: 10.1038/nchembio723

A new structure formed by a DNA sequence that is known to be important in cancer development is reported in the August issue of Nature Chemical Biology. This structural information should help scientists develop a new range of anticancer drugs.
Human c-Myc is a transcription factor that is central to regulation of cell proliferation. The MYC gene in normal cells is tightly regulated and is only expressed when cells actively divide. In contrast, cancer cells may express the gene in an uncontrolled fashion. One particular region of MYC DNA, which controls up to 90% of its transcription, is composed of a purine-rich strand that adopts other biologically relevant structures beyond the Watson-Crick double helix. One such DNA structure, the G-quadruplex, is formed by the stacking of guanine tetrads, comprising four guanines arranged in a planar ring. Stabilization of G-quadruplex structures, by small-molecule ligands is known to decrease MYC expression levels.
Patel and coworkers used nuclear magnetic resonance spectroscopy to characterize an entirely new G-quadruplex structure of a five-guanine-tract MYC DNA sequence, in contrast to previous structures containing four-guanine-tract sequences. They also showed the structure of this new five-guanine-tract sequence in complex with a small-molecule porphyrin, which is known to stabilize G-quadruplex structures.
The authors suggest that the structural information derived from this and other small-molecule interactions with G-quadruplex structures will provide a platform for the development of a new class of anticancer compounds that target G-quadruplex DNA structures.

Author contacts:
Dinshaw J. Patel (Memorial Sloan-Kettering Cancer Center, New York, NY, USA)
Tel: +1 212 639 7207, E-mail: [email protected]

Anh Tuan Phan (Memorial Sloan-Kettering Cancer Center, New York, NY, USA)
Tel: +1 212 639 2772, E-mail: [email protected]

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

[6] Susceptibility to obesity and diabetes

DOI: 10.1038/ng1604

A genetic variant associated with susceptibility to obesity and diabetes has been reported in a study in the August issue of Nature Genetics. Philippe Froguel and colleagues conducted a large-scale study, including several thousand individuals with childhood or adult obesity and type II diabetes, to examine the genetic factors predisposing to disease. They identified a gene associated with increased risk of obesity and diabetes. The gene, ENPP1, is involved with the cellular response to insulin, and may interfere with normal insulin induced signals. Higher expression of this protein, as was found in this study amongst children with obesity or diabetes, may mimic the effects of insulin resistance in the brain, where insulin causes appetite suppression. The authors suggest that inherited increased expression of this protein may exaggerate insulin resistance and contribute to excessive fat accumulation.

Author Contact:
Philippe Froguel (Institut Pasteur de Lille, France)
Tel: +33 03 20 87 79 54, E-mail: [email protected]

Other papers from Nature Genetics:

A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse
DOI: 10.1038/ng1603

Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis
DOI: 10.1038/ng1605

Recombination of mitochondrial DNA in skeletal muscle of individuals with multiple mitochondrial DNA heteroplasmy
DOI: 10.1038/ng1606

Short double-stranded RNA induces transcriptional gene silencing in human cancer cells in the absence of DNA methylation
DOI: 10.1038/ng1611

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

[7] Synaptic damage in Alzheimer disease

DOI: 10.1038/nn1503

Researchers are not certain how Alzheimer disease produces the dementia and memory loss that are its major symptoms. However, a study in the August issue of Nature Neuroscience suggests a molecular mechanism that could shed light on this question.
An abnormal protein fragment, dubbed “Abeta”, is suspected to be pivotal in the disease process because all the genetic mutations that cause the disease increase its accumulation. The catch is that accumulation of this protein in cellular aggregates does not correlate well with the timing or severity of symptoms. Researchers have proposed that symptoms may instead relate to accumulation of Abeta at synapses, the connections between neurons, because cognitive decline does correlate with synapse loss. Now, Paul Greengard and colleagues report that Abeta triggers a cellular mechanism that removes so-called NMDA receptors from the cell surface in mutant mice, which express a protein that causes Alzheimer disease in humans. These receptors are essential for adjusting the strength of signals between nerve cells. When their levels decline, connections between nerve cells cannot be strengthened, as they usually are when we learn something. If these findings are confirmed in humans, they might provide a link between the Abeta fragment and memory loss in Alzheimer disease.

Author contact:
Eric M. Snyder (68 West 82nd St. Apt 1B, New York, NY 10024, USA)
Tel: +1 862 452 0610; Email: [email protected]

Additional contact for comment on paper:
Rudolph Tanzi (Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA)
Tel: +1 617 726 6845; E-mail: [email protected]

Other papers from Nature Neuroscience:

Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses
DOI: 10.1038/nn1506

Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus
DOI: 10.1038/nn1505

Visual field maps and stimulus selectivity in human ventral occipital cortex
DOI: 10.1038/nn1507

Ephrin-As and neural activity are required for eyespecific patterning during retinogeniculate mapping
DOI: 10.1038/nn1508

*******************************************NATURE IMMUNOLOGY ************************************

[8] Tickling nerves prevents inflammation

DOI: 10.1038/ni1229

Stimulation of nicotinic acetylcholine receptors (nAChRs), which are found on both nerves and immune cells, can initiate a program that shuts down the inflammatory machinery of immune cells, according to a paper in the August issue of Nature Immunology. Such a trigger can be exploited to prevent inflammation. This new work adds to accumulating evidence that suggests the nervous system is intimately linked to the immune system.
Macrophages are immune cells that produce large amounts of proteins and chemicals to produce inflammatory effects. Wouter de Jonge and colleagues find that triggering nAChRs on macrophages sets off certain small molecules known as Jak2 and STAT3 in the cells to reduce inflammation by decreasing the production of offending proteins. To demonstrate the usefulness of this finding, they stimulate a major nerve (the vagus nerve) that links the brain to the gut in a mouse experiment that imitates inflammation after intestinal surgery. Normally, intestinal surgery can induce severe inflammation that leads to a condition known as postoperative ileus, which causes patients to suffer pain, nausea and vomiting. However, stimulation of the nerve, which specifically works through nAChR and STAT3, prevents inflammation of the intestine after surgery. Hence, therapies aimed at tickling nerves might provide new clinical avenues to treat postoperative ileus and other inflammatory conditions.

Author contact:
Wouter de Jonge (Academic Medical Center, Amsterdam, The Netherlands)
Tel: +31 20 566 6309, E-mail: [email protected]

Additional contacts for comments:
Kevin J. Tracey (North Shore - Long Island Jewish Health System, Manhasset, NY, USA)
Tel: +1 516 562 2416, E-mail: [email protected]

Christine N. Metz (The Picower Institute for Medical Research, Manhasset, NY, USA)
Tel: +1 516 562 9471, E-mail: [email protected]

Other papers from Nature Immunology:

Regulation of interleukin 7–dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5
DOI: 10.1038/ni1226

Initial T cell frequency dictates memory CD8+ T cell lineage commitment
DOI: 10.1038/ni1227

Loss of adenomatous polyposis coli gene function disrupts thymic development
DOI: 10.1038/ni1228

Items from other Nature journals:

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

Organic thin-film electronics from vitreous solution-processed rubrene hypereutectics
DOI: 10.1038/nmat1426

Electronic devices based on purified carbon nanotubes grown by high-pressure decomposition of carbonmonoxide
DOI: 10.1038/nmat1427

Sacrificial bonds and hidden length dissipate energy as mineralized fibrils separate during bone fracture
DOI: 10.1038/nmat1428

Quantitative insight into dislocation nucleation from high-temperature nanoindentation experiments
DOI: 10.1038/nmat1429

The role of van der Waals forces in adhesion of micromachined surfaces
DOI: 10.1038/nmat1431

NATURE MEDICINE (http://www.nature.com/naturemedicine)

The transcriptional repressor NAB1 is a specific regulator of pathological cardiac hypertrophy
DOI: 10.1038/nm1272

Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization
DOI: 10.1038/nm1274

NATURE BIOTECHNOLOGY (http://www.nature.com/naturebiotechnolgy)

Design of a genome-wide siRNA library using an artificial neural network
DOI: 10.1038/nbt1118

Integrative model of the response of yeast to osmotic shock Q1
DOI: 10.1038/nbt1114

NATURE CELL BIOLOGY (http://www.nature.com/naturecellbiology)

Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes
DOI: 10.1038/ncb1279

A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signalling
DOI: 10.1038/ncb1280

NATURE STRUCTURAL AND MOLECULAR BIOLOGY (http://www.nature.com/natstructmolbiol)

Slipped (CTG)-(CAG) repeats can be repairs, escape repair or undergo error-prone repair
DOI: 10.1038/nsmb959

Altered states: (CAG)n-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition
DOI: 10.1038/nsmb965

A ‘loop recapture’ mechanism for ACF-dependent nucleosome remodeling
DOI: 10.1038/nsmb966


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Published: 18 Jul 2005

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