PLoS Biology

Yeast survive by hedging their bets.

Publication Date: 2012 May PMID: 22589702
Authors: Meadows, R.
Journal: PLoS Biol

A new experimental approach reveals a bet hedging strategy in unstressed, clonal yeast cells, whereby they adopt a range of growth states that correlate with expression of a trehalose-synthesis regulator and predict resistance to future stress.

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Novel Role of NOX in Supporting Aerobic Glycolysis in Cancer Cells with Mitochondrial Dysfunction and as a Potential Target for Cancer Therapy.

Publication Date: 2012 May PMID: 22589701
Authors: Lu, W. - Hu, Y. - Chen, G. - Chen, Z. - Zhang, H. - Wang, F. - Feng, L. - Pelicano, H. - Wang, H. - Keating, M. J. - Liu, J. - McKeehan, W. - Wang, H. - Luo, Y. - Huang, P.
Journal: PLoS Biol

Elevated aerobic glycolysis in cancer cells (the Warburg effect) may be attributed to respiration injury or mitochondrial dysfunction, but the underlying mechanisms and therapeutic significance remain elusive. Here we report that induction of mitochondrial respiratory defect by tetracycline-controlled expression of a dominant negative form of DNA polymerase gamma causes a metabolic shift from oxidative phosphorylation to glycolysis and increases ROS generation. We show that upregulation of NOX is critical to support the elevated glycolysis by providing additional NAD+. The upregulation of NOX is also consistently observed in cancer cells with compromised mitochondria due to the activation of oncogenic Ras or loss of p53, and in primary pancreatic cancer tissues. Suppression of NOX by chemical inhibition or genetic knockdown of gene expression selectively impacts cancer cells with mitochondrial dysfunction, leading to a decrease in cellular glycolysis, a loss of cell viability, and inhibition of cancer growth in vivo. Our study reveals a previously unrecognized function of NOX in cancer metabolism and suggests that NOX is a potential novel target for cancer treatment.

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Bet hedging in yeast by heterogeneous, age-correlated expression of a stress protectant.

Publication Date: 2012 May PMID: 22589700
Authors: Levy, S. F. - Ziv, N. - Siegal, M. L.
Journal: PLoS Biol

Genetically identical cells grown in the same culture display striking cell-to-cell heterogeneity in gene expression and other traits. A crucial challenge is to understand how much of this heterogeneity reflects the noise tolerance of a robust system and how much serves a biological function. In bacteria, stochastic gene expression results in cell-to-cell heterogeneity that might serve as a bet-hedging mechanism, allowing a few cells to survive through an antimicrobial treatment while others perish. Despite its clinical importance, the molecular mechanisms underlying bet hedging remain unclear. Here, we investigate the mechanisms of bet hedging in Saccharomyces cerevisiae using a new high-throughput microscopy assay that monitors variable protein expression, morphology, growth rate, and survival outcomes of tens of thousands of yeast microcolonies simultaneously. We find that clonal populations display broad distributions of growth rates and that slow growth predicts resistance to heat killing in a probabalistic manner. We identify several gene products that are likely to play a role in bet hedging and confirm that Tsl1, a trehalose-synthesis regulator, is an important component of this resistance. Tsl1 abundance correlates with growth rate and replicative age and predicts survival. Our results suggest that yeast bet hedging results from multiple epigenetic growth states determined by a combination of stochastic and deterministic factors.

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Enhancement of asynchronous release from fast-spiking interneuron in human and rat epileptic neocortex.

Publication Date: 2012 May PMID: 22589699
Authors: Jiang, M. - Zhu, J. - Liu, Y. - Yang, M. - Tian, C. - Jiang, S. - Wang, Y. - Guo, H. - Wang, K. - Shu, Y.
Journal: PLoS Biol

Down-regulation of GABAergic inhibition may result in the generation of epileptiform activities. Besides spike-triggered synchronous GABA release, changes in asynchronous release (AR) following high-frequency discharges may further regulate epileptiform activities. In brain slices obtained from surgically removed human neocortical tissues of patients with intractable epilepsy and brain tumor, we found that AR occurred at GABAergic output synapses of fast-spiking (FS) neurons and its strength depended on the type of connections, with FS autapses showing the strongest AR. In addition, we found that AR depended on residual Ca(2+) at presynaptic terminals but was independent of postsynaptic firing. Furthermore, AR at FS autapses was markedly elevated in human epileptic tissue as compared to non-epileptic tissue. In a rat model of epilepsy, we found similar elevation of AR at both FS autapses and synapses onto excitatory neurons. Further experiments and analysis showed that AR elevation in epileptic tissue may result from an increase in action potential amplitude in the FS neurons and elevation of residual Ca(2+) concentration. Together, these results revealed that GABAergic AR occurred at both human and rat neocortex, and its elevation in epileptic tissue may contribute to the regulation of epileptiform activities.

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Bit by bit: the darwinian basis of life.

Publication Date: 2012 May PMID: 22589698
Authors: Joyce, G. F.
Journal: PLoS Biol

All known examples of life belong to the same biology, but there is increasing enthusiasm among astronomers, astrobiologists, and synthetic biologists that other forms of life may soon be discovered or synthesized. This enthusiasm should be tempered by the fact that the probability for life to originate is not known. As a guiding principle in parsing potential examples of alternative life, one should ask: How many heritable "bits" of information are involved, and where did they come from? A genetic system that contains more bits than the number that were required to initiate its operation might reasonably be considered a new form of life.

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Hear less, feel less: one mutation causes loss of two senses.

Publication Date: 2012 May PMID: 22574068
Authors: Robinson, R.
Journal: PLoS Biol

Hearing and touch are genetically related, and people with excellent hearing are more likely to have a fine sense of touch and vice versa.

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Regulation of Brain Tumor Dispersal by NKCC1 Through a Novel Role in Focal Adhesion Regulation.

Publication Date: 2012 May PMID: 22570591
Authors: Garzon-Muvdi, T. - Schiapparelli, P. - Ap Rhys, C. - Guerrero-Cazares, H. - Smith, C. - Kim, D. H. - Kone, L. - Farber, H. - Lee, D. Y. - An, S. S. - Levchenko, A. - Quinones-Hinojosa, A.
Journal: PLoS Biol

Glioblastoma (GB) is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF), which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1) through the regulation of focal adhesion dynamics and cell contractility and (2) through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms.

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Disentangling the benefits of sex.

Publication Date: 2012 May PMID: 22563302
Authors: Roze, D.
Journal: PLoS Biol

Understanding the evolutionary advantage of sexual reproduction remains one of the most fundamental questions in evolutionary biology. Most of the current hypotheses rely on the fact that sex increases genetic variation, thereby enhancing the efficiency of natural selection; an important body of theoretical work has defined the conditions under which sex can be favoured through this effect. Over the last decade, experimental evolution in model organisms has provided evidence that sex indeed allows faster rates of adaptation. A new study on facultatively sexual rotifers shows that increased rates of sex can be favoured during adaptation to new environmental conditions and explores the cause of this effect. The results provide support for the idea that the benefits of increasing genetic variation may compensate for the short-term costs of sexual reproduction.

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Competing sound sources reveal spatial effects in cortical processing.

Publication Date: 2012 May PMID: 22563301
Authors: Maddox, R. K. - Billimoria, C. P. - Perrone, B. P. - Shinn-Cunningham, B. G. - Sen, K.
Journal: PLoS Biol

Why is spatial tuning in auditory cortex weak, even though location is important to object recognition in natural settings? This question continues to vex neuroscientists focused on linking physiological results to auditory perception. Here we show that the spatial locations of simultaneous, competing sound sources dramatically influence how well neural spike trains recorded from the zebra finch field L (an analog of mammalian primary auditory cortex) encode source identity. We find that the location of a birdsong played in quiet has little effect on the fidelity of the neural encoding of the song. However, when the song is presented along with a masker, spatial effects are pronounced. For each spatial configuration, a subset of neurons encodes song identity more robustly than others. As a result, competing sources from different locations dominate responses of different neural subpopulations, helping to separate neural responses into independent representations. These results help elucidate how cortical processing exploits spatial information to provide a substrate for selective spatial auditory attention.

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A genetic basis for mechanosensory traits in humans.

Publication Date: 2012 May PMID: 22563300
Authors: Frenzel, H. - Bohlender, J. - Pinsker, K. - Wohlleben, B. - Tank, J. - Lechner, S. G. - Schiska, D. - Jaijo, T. - Ruschendorf, F. - Saar, K. - Jordan, J. - Millan, J. M. - Gross, M. - Lewin, G. R.
Journal: PLoS Biol

In all vertebrates hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. There is an extensive literature describing single gene mutations in humans that cause hearing impairment, but there are essentially none for touch. Here we first asked if touch sensitivity is a heritable trait and second whether there are common genes that influence different mechanosensory senses like hearing and touch in humans. Using a classical twin study design we demonstrate that touch sensitivity and touch acuity are highly heritable traits. Quantitative phenotypic measures of different mechanosensory systems revealed significant correlations between touch and hearing acuity in a healthy human population. Thus mutations in genes causing deafness genes could conceivably negatively influence touch sensitivity. In agreement with this hypothesis we found that a proportion of a cohort of congenitally deaf young adults display significantly impaired measures of touch sensitivity compared to controls. In contrast, blind individuals showed enhanced, not diminished touch acuity. Finally, by examining a cohort of patients with Usher syndrome, a genetically well-characterized deaf-blindness syndrome, we could show that recessive pathogenic mutations in the USH2A gene influence touch acuity. Control Usher syndrome cohorts lacking demonstrable pathogenic USH2A mutations showed no impairment in touch acuity. Our study thus provides comprehensive evidence that there are common genetic elements that contribute to touch and hearing and has identified one of these genes as USH2A.

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The evolution of sex is favoured during adaptation to new environments.

Publication Date: 2012 May PMID: 22563299
Authors: Becks, L. - Agrawal, A. F.
Journal: PLoS Biol

Both theory and experiments have demonstrated that sex can facilitate adaptation, potentially yielding a group-level advantage to sex. However, it is unclear whether this process can help solve the more difficult problem of the maintenance of sex within populations. Using experimental populations of the facultatively sexual rotifer Brachionus calyciflorus, we show that rates of sex evolve to higher levels during adaptation but then decline as fitness plateaus. To assess the fitness consequences of genetic mixing, we directly compare the fitnesses of sexually and asexually derived genotypes that naturally occur in our experimental populations. Sexually derived genotypes are more fit than asexually derived genotypes when adaptive pressures are strong, but this pattern reverses as the pace of adaptation slows, matching the pattern of evolutionary change in the rate of sex. These fitness assays test the net effect of sex but cannot be used to disentangle whether selection on sex arises because highly sexual lineages become associated with different allele combinations or with different allele frequencies than less sexual lineages (i.e., "short-" or "long-term" effects, respectively). We infer which of these mechanisms provides an advantage to sex by performing additional manipulations to obtain fitness distributions of sexual and asexual progeny arrays from unbiased parents (rather than from naturally occurring, and thereby evolutionarily biased, parents). We find evidence that sex breaks down adaptive gene combinations, resulting in lower average fitness of sexual progeny (i.e., a short-term disadvantage to sex). As predicted by theory, the advantage to sex arises because sexually derived progeny are more variable in fitness, allowing for faster adaptation. This "long-term advantage" builds over multiple generations, eventually resulting in higher fitness of sexual types.

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Lipids in HIV's Envelope Help the Virus to Spread.

Publication Date: 2012 Apr PMID: 22563298
Authors: Sedwick, C.
Journal: PLoS Biol

An accessible sialyllactose moiety on viral membrane gangliosides is shown to be essential for HIV-1 uptake into mature dendritic cells, thereby promoting viral transfer and infection of bystander CD4+ T lymphocytes.

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Sialyllactose in Viral Membrane Gangliosides Is a Novel Molecular Recognition Pattern for Mature Dendritic Cell Capture of HIV-1.

Publication Date: 2012 Apr PMID: 22545022
Authors: Izquierdo-Useros, N. - Lorizate, M. - Contreras, F. X. - Rodriguez-Plata, M. T. - Glass, B. - Erkizia, I. - Prado, J. G. - Casas, J. - Fabrias, G. - Krausslich, H. G. - Martinez-Picado, J.
Journal: PLoS Biol

HIV-1 is internalized into mature dendritic cells (mDCs) via an as yet undefined mechanism with subsequent transfer of stored, infectious virus to CD4(+) T lymphocytes. Thus, HIV-1 subverts a DC antigen capture mechanism to promote viral spread. Here, we show that gangliosides in the HIV-1 membrane are the key molecules for mDC uptake. HIV-1 virus-like particles and liposomes mimicking the HIV-1 lipid composition were shown to use a common internalization pathway and the same trafficking route within mDCs. Hence, these results demonstrate that gangliosides can act as viral attachment factors, in addition to their well known function as cellular receptors for certain viruses. Furthermore, the sialyllactose molecule present in specific gangliosides was identified as the determinant moiety for mDC HIV-1 uptake. Thus, sialyllactose represents a novel molecular recognition pattern for mDC capture, and may be crucial both for antigen presentation leading to immunity against pathogens and for succumbing to subversion by HIV-1.

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Essential Role for miR-196a in Brown Adipogenesis of White Fat Progenitor Cells.

Publication Date: 2012 Apr PMID: 22545021
Authors: Mori, M. - Nakagami, H. - Rodriguez-Araujo, G. - Nimura, K. - Kaneda, Y.
Journal: PLoS Biol

The recent discovery of functional brown adipocytes in adult humans illuminates the potential of these cells in the treatment of obesity and its associated diseases. In rodents, brown adipocyte-like cells are known to be recruited in white adipose tissue (WAT) by cold exposure or beta-adrenergic stimulation, but the molecular machinery underlying this phenomenon is not fully understood. Here, we show that inducible brown adipogenesis is mediated by the microRNA miR-196a. We found that miR-196a suppresses the expression of the white-fat gene Hoxc8 post-transcriptionally during the brown adipogenesis of white fat progenitor cells. In mice, miR-196a is induced in the WAT-progenitor cells after cold exposure or beta-adrenergic stimulation. The fat-specific forced expression of miR-196a in mice induces the recruitment of brown adipocyte-like cells in WAT. The miR-196a transgenic mice exhibit enhanced energy expenditure and resistance to obesity, indicating the induced brown adipocyte-like cells are metabolically functional. Mechanistically, Hoxc8 targets and represses C/EBPbeta, a master switch of brown-fat gene program, in cooperation with histone deacetylase 3 (HDAC3) through the C/EBPbeta 3' regulatory sequence. Thus, miR-196a induces functional brown adipocytes in WAT through the suppression of Hoxc8, which functions as a gatekeeper of the inducible brown adipogenesis. The miR-196a-Hoxc8-C/EBPbeta signaling pathway may be a therapeutic target for inducing brown adipogenesis to combat obesity and type 2 diabetes.

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