Editors' Choice

Science  07 Nov 2008:
Vol. 322, Issue 5903, pp. 823

    Healing a Broken Heart

    The ability to regenerate damaged tissues and organs varies widely across animals. While mammals are able to repair ruptured muscles and to regrow fingertips, amphibia and fish have the more resilient tissues, being able to regenerate tails, fins, and even hearts. Although heart regeneration was thought to be restricted to a few species of amphibia, it is of particular interest to humans, because coronary heart disease remains a leading cause of death. Drenckhahn et al. have found that the fetal mouse heart is able to replace damaged tissue. The enzyme holocytochrome c synthase (Hccs) is involved in mitochondrial energy generation, and the authors inactivated the X-linked Hccs gene in female mice. At mid-gestation, heterozygous female hearts contained equal numbers of healthy and damaged cells; by the time of birth, these mice had fully functioning hearts, with less than 10% damaged cells. Thus, the mouse fetal heart appears to be regenerated predominantly from differentiated cardiac cells, suggesting that differentiated cells in the adult might retain an intrinsic capacity to expand and replace damaged tissue. Further studies aimed at understanding the molecular mechanisms involved could lead to ways of stimulating the regeneration of adult diseased hearts. — HP*

    Dev. Cell 15, 521 (2008).

    • *Helen Pickersgill and Chris Surridge are locum editors in Science's editorial department.


    Lymphocyte Identity Cards

    The determination of lineage, whether in genealogy, paleontology, or cell biology, can be very difficult. Schepers et al. have developed a retroviral tagging procedure by introducing a “bar code” into individual cells that persists in all of their progeny. The authors used a library of around 5000 tags, which can be identified by PCR amplification and microarray analysis, to monitor the life histories of T cells during the course of an infection.

    A T cell population, specific for the antigen OVA, was transformed with the bar-code library and introduced into mice, which were subsequently injected with tumor cells and infected with influenza virus, both bearing the OVA antigen. At first, T cells in lymph nodes draining the two sites of invasion formed genetically distinct populations, distinguishable by their bar codes; however, the T cell populations in lung and tumor tissues had similar bar-code distributions, showing that they had originated from several lymph nodes. Over time, both lymph node T cell populations became similar as the infections stimulated the migration of T cells throughout the mouse. This technology has the potential to unravel lineage relationships in a wide range of cells, and the authors have already created a lentivirus library for use with quiescent cell types resistant to retroviral infection. — CS*

    J. Exp. Med. 205, 2309 (2008).

    • *Helen Pickersgill and Chris Surridge are locum editors in Science's editorial department.


    Sizing Up the Foam

    Bulk metallic glasses have high plastic yield strengths, and thus have the potential for making ultrastrong foams. However, the foam will only inherit the strength of the parent glassy material if it fails by plastic yielding, rather than by brittle fracture (which is associated with the solid fracture stress) or by elastic buckling (associated with the solid modulus). Demetriou et al. look at a number of critical structural scales that influence the failure mode and find that they can make ultrastrong glassy foams from a Pd43Ni10Cu27P20 alloy with up to 92% porosity. The foams were engineered against buckling and fracture though a process that limited membrane thickness and promoted cellular periodicity. Evaluation of compressed, collapsed specimens showed both crushed cells and shear banding, indicating that although the failure was due to fracture, the initial response of the foam involved plastic deformation. Thus, the foams inherited the best properties of the parent glassy material. The compressive strength of the glassy foams rivaled those obtained for highly engineered Ti-6Al-4V or ferrous metal foams. — MSL

    Phys. Rev. Lett. 101, 145702 (2008).


    Network Failure

    Models of metabolic and signalling networks have been characterized, perhaps unfairly, as reannotations of previously discovered interactions. To counter this concern (and the statistical issue of sorting through hundreds of correlations), Janes et al. describe an approach called “model breakpoint analysis” that stresses the network by using nonphysiological inputs in a manner similar to that of engineers performing failure analysis of bridges or cars. They began with their model of cytokine-induced apoptosis and proceeded to introduce implausible data that stretched the dynamic range of the cell (defined as the responsiveness of cell outcomes to incremental changes in cell activation). Surprisingly, network function did not degrade in parallel, but worked perfectly well until a threshold (or breakpoint) was reached, at which point the predictions were no longer useful. Pinpointing the signals and stimuli that were responsible for the system failure enabled them to distinguish epiphenomena from causal factors and to make predictions about the dynamic roles of three kinases (Akt, ERK, and Mk2) in cytokine-induced apoptosis. These predictions were then confirmed in inhibitor- and mutant-based experiments, suggesting that differences in dynamic range can be more important to cellular function than the strength of a particular signal. — BJ

    Cell 135, 343 (2008).


    Depotentiating via Dopamine

    The capacity to associate events, in a neuronal context, is thought to rely on long-term potentiation (LTP), a mechanism that strengthens glutamatergic (excitatory) synaptic connections. Strong novel stimuli can selectively reverse or overwrite LTP by a mechanism known as depotentiation, which is thought to keep synapses from becoming saturated and thereby to maintain them in a dynamically responsive range. Neuregulin-1 is a factor expressed in brain and can effectively depotentiate LTP in the hippocampus. Kwon et al. found that neuregulin depotentiates LTP by recruiting a dopaminergic signaling pathway involving the dopamine D4 receptor (D4R), which is a target of the antipsychotic clozapine. Neuregulin acutely triggers dopamine release in the hippocampus, which in turn depotentiates LTP by activating D4Rs. The direct activation of D4Rs by selective agonists mimics the action of neuregulin in removing AMPA-type glutamate receptors from synapses. Mutant mice lacking D4Rs fail to depotentiate LTP in response either to neuregulin or to electrical stimuli. These observations thus functionally associate three signaling pathways (dopamine, glutamate, and neuregulin) in the regulation of synaptic plasticity. — PRS

    Proc. Natl. Acad. Sci. U.S.A. 105, 15587 (2008).


    Warming Vapors

    Water vapor is the atmospheric gas that collectively has the greatest greenhouse effect on climate, although it does not directly instigate warming or cooling trends, because the amount of water vapor in the atmosphere varies only in response to temperature change. Instead, water vapor only amplifies temperature trends being caused by other factors such as atmospheric CO2 concentration or Earth's albedo. The extent to which humidity changes in response to temperature variation is therefore a key parameter in global climate models, because that quantity determines the strength of the associated warming or cooling. Dessler et al. present satellite data from 2003 to 2008 which show that models have gotten that relationship correct, and that relative humidity is effectively constant at any given temperature. Thus, the temperature increases predicted by global models are virtually guaranteed to be several degrees Celsius by the year 2100. Knowing the water vapor content of a warmer atmosphere is also important for predicting rainfall and storminess. — HJS

    Geophys. Res. Lett. 35, L20704 (2008).


    Curing Disease in Yeast

    Batten disease is a neurodegenerative disorder linked to the pathological accumulation of material in lysosomes. In yeast the [URE3] phenotype is a prion (infectious protein) generated by the self-propagating amyloid form of the Ure2 protein, which regulates nitrogen catabolism. Yeast prions can arise and disappear spontaneously within populations, reflecting in part changes in the protein folding milieu. Kryndushkin et al. show that increased production of Btn2 protein or its homolog Cur1 can cure [URE3]. Conversely, deletion of BTN2 and CUR1 genes stabilizes the [URE3] phenotype. In cells expressing a fluorescently tagged version of Btn2p, fluorescence accumulated at a single point close to the nucleus and vacuole, where aggregates of Ure2p also accumulated. This accumulation of protein aggregates reduced the ability of the Ure2p amyloid seeds to enter budding daughter cells, explaining the cure of daughter cells. This accumulation of protein aggregates mirrors aggresome formation observed in mammalian cells, which may also function to remove potentially harmful protein aggregates. — SMH

    EMBO J. 27, 2725 (2008).

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