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  • 1
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    Mitochondria, maternal inheritance, and asymmetric fitness: Why males die younger (2012)
    Wiley
    In: BioEssays
    Details
    Publication Date: 2012-12-28
    Description: Mitochondrial function is achieved through the cooperative interaction of two genomes: one nuclear (nuDNA) and the other mitochondrial (mtDNA). The unusual transmission of mtDNA, predominantly maternal without recombination is predicted to affect the fitness of male offspring. Recent research suggests the strong sexual dimorphism in aging is one such fitness consequence. The uniparental inheritance of mtDNA results in a selection asymmetry; mutations that affect only males will not respond to natural selection, imposing a male-specific mitochondrial mutation load. Prior work has implicated this male-specific mutation load in disease and infertility, but new data from fruit flies suggests a prominent role for mtDNA in aging; across many taxa males almost invariably live shorter lives than females. Here we discuss this new work and identify some areas of future research that might now be encouraged to explore what may be the underpinning cause of the strong sexual dimorphism in aging. Editor's suggested further reading in BioEssays: Mitonuclear match: Optimizing fitness and fertility over generations drives ageing within generations Abstract Mitochondrial manoeuvres: Latest insights and hypotheses on mitochondrial partitioning during mitosis in Saccharomyces cerevisiae Abstract Mitochondria and the culture of the Borg Abstract The maternal inheritance of mtDNA results in a selection asymmetry; natural selection cannot act on mutations that affect only males. This asymmetry imposes a male-specific mutation load previously implicated in male disease and infertility. New work suggests this asymmetry underpins the strong sexual dimorphism in aging observed across taxa.
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  • 2
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    What precision-protein-tuning and nano-resolved single molecule sciences can do for each other (2012)
    Wiley
    In: BioEssays
    Details
    Publication Date: 2012-11-14
    Description: While innovations in modern microscopy, spectroscopy, and nanoscopy techniques have made single molecule observation a standard in many laboratories, the actual design of meaningful fluorescence reporter systems now hinders major scientific breakthroughs. Even though the field of chemical biology is supercharging the fluorescence toolbox, surprisingly few strategies exist that make the transition from model systems to biologically relevant applications. At the same time, the number of microscopy techniques is growing dramatically. We explain our view on how the impact of modern technologies is influenced not only by further hard- and software developments, but also by the availability and suitability of protein-engineering tools. We identify how the largely independent research fields of chemical biology and fluorescence nanoscopy can influence each other to synergistically drive future technology that can visualize the localization, structure, and dynamics of molecular function without constraints. Fluorescence technologies provide key to study molecular structure and dynamics with super spatial and temporal resolution. We discuss how synergistic developments of novel labeling technologies combined with optical engineering can make the biggest contribution to advance state of the art tools for both, in vitro and non-invasive in vivo measurements.
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  • 3
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    New genes expressed in human brains: Implications for annotating evolving genomes (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-09-25
    Description: New genes have frequently formed and spread to fixation in a wide variety of organisms, constituting abundant sets of lineage-specific genes. It was recently reported that an excess of primate-specific and human-specific genes were upregulated in the brains of fetuses and infants, and especially in the prefrontal cortex, which is involved in cognition. These findings reveal the prevalent addition of new genetic components to the transcriptome of the human brain. More generally, these findings suggest that genomes are continually evolving in both sequence and content, eroding the conservation endowed by common ancestry. Despite increasing recognition of the importance of new genes, we highlight here that these genes are still seriously under-characterized in functional studies and that new gene annotation is inconsistent in current practice. We propose an integrative approach to annotate new genes, taking advantage of functional and evolutionary genomic methods. We finally discuss how the refinement of new gene annotation will be important for the detection of evolutionary forces governing new gene origination. Regardless of recent findings that new genes are important for human brain functions, we highlight that new genes are still generally under-characterized in functional studies and that new gene annotation is inconsistent in current practice. We propose an integrative approach to annotate new genes based on functional and evolutionary genomics.
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  • 4
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    BioEssays 11/2012 (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-10-13
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  • 5
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    BioEssays – Next Issue (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-10-13
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  • 6
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    BiotecVisions 2012, October (pages A1-A8) (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-10-13
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  • 7
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    The roots of cancer: Stem cells and the basis for tumor heterogeneity (2012)
    Wiley
    In: BioEssays
    Details
    Publication Date: 2012-10-03
    Description: Recent studies of prostate cancer and other tumor types have revealed significant support, as well as unexpected complexities, for the application of concepts from normal stem cell biology to cancer. In particular, the cell of origin and cancer stem cell models have been proposed to explain the heterogeneity of tumors during the initiation, propagation, and evolution of cancer. Thus, a basis of intertumor heterogeneity has emerged from studies investigating whether stem cells and/or non-stem cells can serve as cells of origin for cancer and give rise to tumor subtypes that vary in disease outcome. Furthermore, analyses of putative cancer stem cells have revealed the genetically diverse nature of cancers and expanded our understanding of intratumor heterogeneity and clonal evolution. Overall, the principles that have emerged from these stem cell studies highlight the challenges to be surmounted to develop effective treatment strategies for cancer. Concepts from stem cell biology can explain the basis for intertumoral heterogeneity between different tumors of the same tissue type, as well as intratumoral heterogeneity within a single tumor. In this review, we discuss the cell of origin, cancer stem cells, and clonal evolution, with a focus on prostate cancer.
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  • 8
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    Epigenetics meets mathematics: Towards a quantitative understanding of chromatin biology (2012)
    Wiley
    In: BioEssays
    Details
    Publication Date: 2012-08-23
    Description: How fast? How strong? How many? So what? Why do numbers matter in biology? Chromatin binding proteins are forever in motion, exchanging rapidly between bound and free pools. How do regulatory systems whose components are in constant flux ensure stability and flexibility? This review explores the application of quantitative and mathematical approaches to mechanisms of epigenetic regulation. We discuss methods for measuring kinetic parameters and protein quantities in living cells, and explore the insights that have been gained by quantifying and modelling dynamics of chromatin binding proteins. Current models for chromatin mediated gene regulation often describe molecules as binding, modifying or recruiting other molecules, but with little reference to the quantitative differences between them. In this review we explore how quantitative and mathematical approaches can give insights into mechanisms of epigenetic regulation.
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  • 9
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    Stress-induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine (2012)
    Wiley
    In: BioEssays
    Details
    Publication Date: 2012-08-23
    Description: Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress-induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress-induced mutation that are being revealed experimentally in laboratory settings provide compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double-strand-break-dependent stress-induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti-evolvability therapeutics for infectious disease and cancer. Stress-induced mutation molecular mechanism in Escherichia coli : repair of DNA double-strand breaks is switched to a mutagenic mode using DinB and other error-prone DNA polymerases during stress, by the RpoS stress response. This increases genetic diversity, and the ability to evolve, when cells are maladapted to their environment: when stressed.
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  • 10
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    Teaching peers to talk to peers (2012)
    Wiley
    In: BioEssays
    Details
    Publication Date: 2012-08-21
    Description: Scientists should learn to communicate effectively with their colleagues through long-term, sustained training instead of ad hoc, one-off “interventions” that may or may not occur during graduate school or postdoctoral work. Since such training may place unreasonable demands on research advisors, institutions should create career opportunities for “peer-peer communication teachers.”
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  • 11
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    Hedgehog signalling as an antagonist of ageing and its associated diseases (2012)
    Wiley
    In: BioEssays
    Details
    Publication Date: 2012-08-21
    Description: Hedgehog is an important morphogenic signal that directs pattern formation during embryogenesis, but its activity also remains present through adult life. It is now becoming increasingly clear that during the reproductive phase of life and beyond it continues to direct cell renewal (which is essential to combat the chronic environmental stress to which the body is constantly exposed) and counteracts vascular, osteolytic and sometimes oncological insults to the body. Conversely, down-regulation of hedgehog signalling is associated with ageing-related diseases such as type 2 diabetes, neurodegeneration, atherosclerosis and osteoporosis. Hence, in this essay we argue that hedgehog signalling is not only important at the start of life, but also constitutes an important anti-geriatric influence, and that enhanced understanding of its properties may contribute to developing rational strategies for healthy ageing and prevention of ageing-related diseases. Also watch the Video Abstract Hedgehog is a morphogenic signal during embryogenesis and adult life with many vital biological functions such as neuromodulators and anti-adipogenesis. Downregulation of Hedgehog signalling is associated with ageing-related diseases like Alzheimer/Parkinson and T2D diseases and upregulation of this signalling reduces risk of these diseases. Thus, Hedgehog signalling is antagonist of ageing.
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  • 12
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    Rethinking the origin of multicellularity: Where do epithelia come from? (Comment on DOI 10.1002/bies.201100187) (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-08-21
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  • 13
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    New in Hedgehog signaling: A possible role in aging, and chronic degenerative and inflammatory diseases? (Comment on DOI 10.1002/bies.201200049) (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-08-21
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  • 14
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    BioEssays 11/2012 (2012)
    Wiley
    In: BioEssays
    Details
    Publication Date: 2012-10-13
    Description: Control of osteogenesis by the canonical Wnt and BMP pathways in vivo: The cover image shows a transverse section through a Xenopus tropicalis metamorphosing tadpole phalange. This histological section was stained with Kernechtrot to reveal cell bodies (pink) and Alcian blue to show the cartilage (blue). The circular cartilaginous shaft is surrounded by a layer of bone mineralized matrix (grey ring) secreted by adjacent osteoblasts. On pages 953–962 Marcellini et al. review recent experimental evidence showing that the canonical Wnt and BMP pathways functionally interact as cells differentiate from osteochondroprogenitors to osteoblasts and osteocytes, in the context of the developing vertebrate embryo. BMP signalling specifies multipotent mesenchymal cells into osteochondroprogenitors which are subsequently driven towards the osteoblastic fate by the Wnt pathway. In osteoblasts, both pathways promote differentiation, albeit with notable mechanistic differences. Finally, in osteocytes, the Wnt and BMP pathways exert opposite effects on the control of bone resorption by osteoclasts. Cover by S. Marcellini.
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  • 15
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    Why does the immune system of Atlantic cod lack MHC II? (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-14
    Description: MHC II, a major feature of the adaptive immune system, is lacking in Atlantic cod, and there are different scenarios (metabolic cost hypothesis or functional shift hypothesis) that might explain this loss. The lack of MHC II coincides with an increased number of genes for MHC I and Toll-like receptors (TLRs).
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  • 16
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    Image analysis in fluorescence microscopy: Bacterial dynamics as a case study (2012)
    Wiley
    In: BioEssays
    Details
    Publication Date: 2012-04-15
    Description: Fluorescence microscopy is the primary tool for studying complex processes inside individual living cells. Technical advances in both molecular biology and microscopy have made it possible to image cells from many genetic and environmental backgrounds. These images contain a vast amount of information, which is often hidden behind various sources of noise, convoluted with other information and stochastic in nature. Accessing the desired biological information therefore requires new tools of computational image analysis and modeling. Here, we review some of the recent advances in computational analysis of images obtained from fluorescence microscopy, focusing on bacterial systems. We emphasize techniques that are readily available to molecular and cell biologists but also point out examples where problem-specific image analyses are necessary. Thus, image analysis is not only a toolkit to be applied to new images but also an integral part of the design and implementation of a microscopy experiment.
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  • 17
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    Super-resolution imaging prompts re-thinking of cell biology mechanisms (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: The use of super-resolution imaging techniques in cell biology has yielded a wealth of information regarding cellular elements and processes that were invisible to conventional imaging. Focusing on images obtained by stimulated emission depletion (STED) microscopy, we discuss how the new high-resolution data influence the ways in which we use and interpret images in cell biology. Super-resolution images have lent support to some of our current hypotheses. But, more significantly, they have revealed unexpectedly complex processes that cannot be accounted for by the simpler models based on diffraction-limited imaging. The super-resolution imaging data challenge cell biologists to change their theoretical framework, by including, for instance, interpretations that describe multiple functions, functional errors or lack of function for cellular elements. In this context, we argue that descriptive research using super-resolution microscopy is now as necessary as hypothesis-driven research.
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  • 18
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    Innovation in biological microscopy: Current status and future directions (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: The current revolution in biological microscopy stems from the realisation that advances in optics and computational tools and automation make the modern microscope an instrument that can access all scales relevant to modern biology – from individual molecules all the way to whole tissues and organisms and from single snapshots to time-lapse recordings sampling from milliseconds to days. As these and more new technologies appear, the challenges of delivering them to the community grows as well. I discuss some of these challenges, and the examples where openly shared technology have made an impact on the field.
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  • 19
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    Fluorescent proteins for FRET microscopy: Monitoring protein interactions in living cells (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: The discovery and engineering of novel fluorescent proteins (FPs) from diverse organisms is yielding fluorophores with exceptional characteristics for live-cell imaging. In particular, the development of FPs for fluorescence (or Förster) resonance energy transfer (FRET) microscopy is providing important tools for monitoring dynamic protein interactions inside living cells. The increased interest in FRET microscopy has driven the development of many different methods to measure FRET. However, the interpretation of FRET measurements is complicated by several factors including the high fluorescence background, the potential for photoconversion artifacts and the relatively low dynamic range afforded by this technique. Here, we describe the advantages and disadvantages of four methods commonly used in FRET microscopy. We then discuss the selection of FPs for the different FRET methods, identifying the most useful FP candidates for FRET microscopy. The recent success in expanding the FP color palette offers the opportunity to explore new FRET pairs.
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  • 20
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    Collegiality and careerism trump critical questions and bold new ideas: A student's perspective and solution (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
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  • 21
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    Slicing embryos gently with laser light sheets (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: Light sheet microscopy is an easy to implement and extremely powerful alternative to established fluorescence imaging techniques such as laser scanning confocal, multi-photon and spinning disk microscopy. By illuminating the sample only with a thin slice of light, photo-bleaching is reduced to a minimum, making light sheet microscopy ideal for non-destructive imaging of fragile samples over extended periods of time. Millimeter-sized samples can be imaged rapidly with high resolution and high depth penetration. A large variety of instruments have been developed and optimized for a number of different samples: Bessel beams form thin light sheets for single cells, and selective plane illumination microscopy (SPIM) offers multi-view acquisition to image entire embryos with isotropic resolution. This review explains how light sheet microscopy involves a conceptually new microscope design and how it changes modern imaging in biology.
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  • 22
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    Life defined (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
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  • 23
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    MHC-dependent mate choice in humans: Why genomic patterns from the HapMap European American dataset support the hypothesis (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: The role of the major histocompatibility complex (MHC) in mate choice in humans is controversial. Nowadays, the availability of genetic variation data at genomic scales allows for a careful assessment of this question. In 2008, Chaix et al. reported evidence for MHC-dependent mate choice among European American spouses from the HapMap 2 dataset. Recently, Derti et al. suggested that this observation was not robust. Furthermore, when Derti et al. applied similar analyses to the HapMap 3 European American samples, they did not see a significant effect. Although some of the points raised by Derti et al. are relevant, we disagree with the reported absence of evidence for MHC-dependent mate choice within the HapMap samples. More precisely, we show here that the MHC dissimilarity among HapMap 3 European American spouses is still extreme in comparison to the rest of the genome, even after multiple testing correction. This finding supports the hypothesis of MHC-dependent mate choice in some human populations. The MHC may influence mate choice in some human populations also depending on other variables such as socio-cultural factors, the level of genetic diversity and the strength of pathogenic pressures.
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  • 24
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    Biomarker development: Prudence, risk, and reproducibility (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: Is a two-fold approach — preliminary studies based on small samples followed by a large-sample study to check reproducibility — in the search for biomarkers really prudent?
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  • 25
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    Excitable behavior can explain the “ping-pong” mode of communication between cells using the same chemoattractant (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: Here we elucidate a paradox: how a single chemoattractant-receptor system in two individuals is used for communication despite the seeming inevitability of self-excitation. In the filamentous fungus Neurospora crassa , genetically identical cells that produce the same chemoattractant fuse via the homing of individual cell protrusions toward each other. This is achieved via a recently described “ping-pong” pulsatile communication. Using a generic activator-inhibitor model of excitable behavior, we demonstrate that the pulse exchange can be fully understood in terms of two excitable systems locked into a stable oscillatory pattern of mutual excitation. The most puzzling properties of this communication are the sudden onset of oscillations with final amplitude, and the absence of seemingly inevitable self-excitation. We show that these properties result directly from both the excitability threshold and refractory period characteristic of excitable systems. Our model suggests possible molecular mechanisms for the ping-pong communication. Fusion of genetically identical cells in Neurospora crassa is achieved by the cells taking turns in releasing a chemoattractant and sensing it.
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  • 26
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    Beyond nutrients: Food-derived microRNAs provide cross-kingdom regulation (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: Food turns out to be not only the nutrient supplier for our body but also a carrier of regulatory information. Interestingly, a recent study made the discovery that some plant/food-derived microRNAs (miRNAs) accumulate in the serum of humans or plant-feeding animals, and regulate mammalian gene expression in a sequence-specific manner. The authors provided striking evidence that miRNAs could function as active signaling molecules to transport information across distinct species or even kingdoms. Although the mechanism of how miRNAs are shuttled between different organisms is still not well characterized, initial results point to the involvement of microvesicles and specific RNA-transporter-like proteins. These findings raise both speculation about the potential impact that plants may have on animal physiology at the molecular level, and an appealing possibility that food-derived miRNAs may offer us another means to deliver necessary nutrients or therapeutics to our bodies. There is recent evidence that microRNAs derived from ingested food sources can be taken up, packaged into microvesicles and, upon reaching the final recipient cells, regulate a target gene in a sequence-specific manner.
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  • 27
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    Contagious cancer: Lessons from the devil and the dog (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: Cancer is generally defined as uncontrollable growth of cells caused by genetic aberrations and/or environmental factors. Yet contagious cancers also occur. The recent emergence of a contagious cancer in Tasmanian devils has reignited interest in transmissible cancers. Two naturally occurring transmissible cancers are known: devil facial tumour disease and canine transmissible venereal tumour. Both cancers evolved once and have then been transmitted from one individual to another as clonal cell lines. The dog cancer is ancient; having evolved more than 6,000 years ago, while the devil disease was first seen in 1996. In this review I will compare and contrast the two diseases focusing on the life histories of the clonal cell lines, their evolutionary trajectories and the mechanisms by which they have achieved immune tolerance. A greater understanding of these contagious cancers will provide unique insights into the role of the immune system in shaping tumour evolution and may uncover novel approaches for treating human cancer. A better understanding of the two known transmissible cancers (Tasmanian devil facial tumour and canine transmissible venereal tumour) may provide unique insights into the role of the immune system in shaping tumour evolution and may uncover novel approaches for treating human cancer.
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  • 28
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    Balancing self-renewal and differentiation by asymmetric division: Insights from brain tumor suppressors in Drosophila neural stem cells (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: Balancing self-renewal and differentiation of stem cells is an important issue in stem cell and cancer biology. Recently, the Drosophila neuroblast (NB), neural stem cell has emerged as an excellent model for stem cell self-renewal and tumorigenesis. It is of great interest to understand how defects in the asymmetric division of neural stem cells lead to tumor formation. Here, we review recent advances in asymmetric division and the self-renewal control of Drosophila NBs. We summarize molecular mechanisms of asymmetric cell division and discuss how the defects in asymmetric division lead to tumor formation. Gain-of-function or loss-of-function of various proteins in the asymmetric machinery can drive NB overgrowth and tumor formation. These proteins control either the asymmetric protein localization or mitotic spindle orientation of NBs. We also discuss other mechanisms of brain tumor suppression that are beyond the control of asymmetric division. Drosophila neuroblasts represent an excellent model system to study the molecular mechanisms of asymmetric divisions during stem cell self-renewal and how defects in this system lead to tumourigenesis.
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  • 29
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    Genes at work in random bouts (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
    Description: Cell interdivision periods (IDP) in homogenous cell populations vary stochastically. Another aspect of probabilistic cell behavior is randomness in cell differentiation. These features are suggested to result from competing stochastic events of assembly/disassembly of the transcription pre-initiation complex (PIC) at gene promoters. The time needed to assemble a proper PIC from different proteins, which must be numerous enough to make their combination gene specific, may be comparable to the IDP. Nascent mRNA visualization at defined genes and inferences from protein level fluctuations in single cells suggest that some genes do operate in this way. The onset of mRNA production by such genes may miss the time windows provided by the cell cycle, resulting in cells differentiating into those in which the respective mRNAs are either present or absent. This creates a way to generate cell phenotype diversity in multicellular organisms.
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    BioEssays 5/2012 (2012)
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    Publication Date: 2012-04-17
    Description: Light Microscopy: From imaging probes to high resolution techniques andcomputational image analysis . On pages 333–340 Jason Swedlow gives a nice overview over the topics covered in this Special Issue. Advances in optics, automation, computational tools and imaging probes allow the visualization of ever smaller structures at increasing resolution. Furthermore, these techniques can be used for a wide variety of applications from basic research to clinical domains, e.g. by employing imaging techniques for screening. The image shows a section of mouse small intestine stained with DAPI (blue), anti-tubulin (red) and phalloidin (green).
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    Biology and microscopy: The friendship strengthens… (2012)
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    Publication Date: 2012-04-17
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    SHG nanoprobes: Advancing harmonic imaging in biology (2012)
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    Publication Date: 2012-04-15
    Description: Second harmonic generating (SHG) nanoprobes have recently emerged as versatile and durable labels suitable for in vivo imaging, circumventing many of the inherent drawbacks encountered with classical fluorescent probes. Since their nanocrystalline structure lacks a central point of symmetry, they are capable of generating second harmonic signal under intense illumination – converting two photons into one photon of half the incident wavelength – and can be detected by conventional two-photon microscopy. Because the optical signal of SHG nanoprobes is based on scattering, rather than absorption as in the case of fluorescent probes, they neither bleach nor blink, and the signal does not saturate with increasing illumination intensity. When SHG nanoprobes are used to image live tissue, the SHG signal can be detected with little background signal, and they are physiologically inert, showing excellent long-term photostability. Because of their photophysical properties, SHG nanoprobes provide unique advantages for molecular imaging of living cells and tissues with unmatched sensitivity and temporal resolution.
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    The male fight-flight response: A result of SRY regulation of catecholamines? (2012)
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    FRET microscopy in the living cell: Different approaches, strengths and weaknesses (2012)
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    Publication Date: 2012-04-15
    Description: New imaging methodologies in quantitative fluorescence microscopy, such as Förster resonance energy transfer (FRET), have been developed in the last few years and are beginning to be extensively applied to biological problems. FRET is employed for the detection and quantification of protein interactions, and of biochemical activities. Herein, we review the different methods to measure FRET in microscopy, and more importantly, their strengths and weaknesses. In our opinion, fluorescence lifetime imaging microscopy (FLIM) is advantageous for detecting inter-molecular interactions quantitatively, the intensity ratio approach representing a valid and straightforward option for detecting intra-molecular FRET. Promising approaches in single molecule techniques and data analysis for quantitative and fast spatio-temporal protein-protein interaction studies open new avenues for FRET in biological research.
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    BioEssays 4/2012 (2012)
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    Publication Date: 2012-04-15
    Description: The Tasmanian devil is threatened by the incidence of a transmissible cancer (devil facial tumour disease, DFTD). On pages 285–292 Katherine Belov compares and contrasts this disease with canine transmissible venereal tumour (CTVT), focusing on the life histories of the clonal cell lines, their evolutionary trajectories and the mechanisms by which they have achieved immune tolerance. These two diseases provide unique models for understanding cancer biology and immunobiology, particularly the evolution of immune evasion strategies. Recently, whole-genome sequences of the Tasmanian devil, and of two distinct cancer subclones, have been published; these data provide further information about the pattern of evolution and spread of this parasitic clonal disease. Cover photo © melanieplusdaniel.de - Fotolia.com
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    Beyond the connectome: How neuromodulators shape neural circuits (2012)
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    Publication Date: 2012-04-15
    Description: Powerful ultrastructural tools are providing new insights into neuronal circuits, revealing a wealth of anatomically-defined synaptic connections. These wiring diagrams are incomplete, however, because functional connectivity is actively shaped by neuromodulators that modify neuronal dynamics, excitability, and synaptic function. Studies of defined neural circuits in crustaceans, C. elegans , Drosophila , and the vertebrate retina have revealed the ability of modulators and sensory context to reconfigure information processing by changing the composition and activity of functional circuits. Each ultrastructural connectivity map encodes multiple circuits, some of which are active and some of which are latent at any given time.
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    The mystery of C. elegans aging: An emerging role for fat (2012)
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    Publication Date: 2012-04-15
    Description: New C. elegans studies imply that lipases and lipid desaturases can mediate signaling effects on aging. But why might fat homeostasis be critical to aging? Could problems with fat handling compromise health in nematodes as they do in mammals? The study of signaling pathways that control longevity could provide the key to one of the great unsolved mysteries of biology: the mechanism of aging. But as our view of the regulatory pathways that control aging grows ever clearer, the nature of aging itself has, if anything, grown more obscure. In particular, focused investigations of the oxidative damage theory have raised questions about an old assumption: that a fundamental cause of aging is accumulation of molecular damage. Could fat dyshomeostasis instead be critical?
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    Fluorescence correlation spectroscopy (2012)
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    Publication Date: 2012-04-15
    Description: Fluorescence correlation spectroscopy (FCS) is a powerful technique to measure concentrations, mobilities, and interactions of fluorescent biomolecules. It can be applied to various biological systems such as simple homogeneous solutions, cells, artificial, or cellular membranes and whole organisms. Here, we introduce the basic principle of FCS, discuss its application to biological questions as well as its limitations and challenges, present an overview of novel technical developments to overcome those challenges, and conclude with speculations about the future applications of fluorescence fluctuation spectroscopy.
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    A network of paths toward innovation (2012)
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    Hiccups: A new explanation for the mysterious reflex (2012)
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    Visualizing and quantifying cell phenotype using soft X-ray tomography (2012)
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    Publication Date: 2012-04-15
    Description: Soft X-ray tomography (SXT) is an imaging technique capable of characterizing and quantifying the structural phenotype of cells. In particular, SXT is used to visualize the internal architecture of fully hydrated, intact eukaryotic and prokaryotic cells at high spatial resolution (50 nm or better). Image contrast in SXT is derived from the biochemical composition of the cell, and obtained without the need to use potentially damaging contrast-enhancing agents, such as heavy metals. The cells are simply cryopreserved prior to imaging, and are therefore imaged in a near-native state. As a complement to structural imaging by SXT, the same specimen can now be imaged by correlated cryo-light microscopy. By combining data from these two modalities specific molecules can be localized directly within the framework of a high-resolution, three-dimensional reconstruction of the cell. This combination of data types allows sophisticated analyses to be carried out on the impact of environmental and/or genetic factors on cell phenotypes. Soft X-ray tomography is an imaging technique that can be used to visualize the internal architecture of fully hydrated, intact eukaryotic and prokaryotic cells at high spatial resolution.
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    The potential of 3D-FISH and super-resolution structured illumination microscopy for studies of 3D nuclear architecture (2012)
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    Publication Date: 2012-04-17
    Description: Three-dimensional structured illumination microscopy (3D-SIM) has opened up new possibilities to study nuclear architecture at the ultrastructural level down to the ∼100 nm range. We present first results and assess the potential using 3D-SIM in combination with 3D fluorescence in situ hybridization (3D-FISH) for the topographical analysis of defined nuclear targets. Our study also deals with the concern that artifacts produced by FISH may counteract the gain in resolution. We address the topography of DAPI-stained DNA in nuclei before and after 3D-FISH, nuclear pores and the lamina, chromosome territories, chromatin domains, and individual gene loci. We also look at the replication patterns of chromocenters and the topographical relationship of Xist -RNA within the inactive X-territory. These examples demonstrate that an appropriately adapted 3D-FISH/3D-SIM approach preserves key characteristics of the nuclear ultrastructure and that the gain in information obtained by 3D-SIM yields new insights into the functional nuclear organization. 3D-structured illumination microscopy (3D-SIM) can be used to study nuclear architecture at the ultrastructural level.This method can also be combined with 3D fluorescence in situ hybridization (3D-FISH) for the topographical analysis of defined nuclear targets. The proof of principle of this combination of methods lies in the high degree of structural preservation of chromatin presented here.
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    BioEssays 5/2012 (2012)
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    Publication Date: 2012-04-17
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    BioEssays 5/2012 (2012)
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    BiotecVisions 2012, April (pages A1-A8) (2012)
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    BioEssays – Next Issue (2012)
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    Instructive reconstruction: A new role for apoptosis in pattern formation (2012)
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    In: BioEssays
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    Publication Date: 2012-04-11
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    Waddington's epigenetic landscape and post-Darwinian biology (2012)
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    Publication Date: 2012-04-11
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    Why does the immune system of Atlantic cod lack MHC II? (2012)
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    Publication Date: 2012-04-15
    Description: MHC II, a major feature of the adaptive immune system, is lacking in Atlantic cod, and there are different scenarios (metabolic cost hypothesis or functional shift hypothesis) that might explain this loss. The lack of MHC II coincides with an increased number of genes for MHC I and Toll-like receptors (TLRs).
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    Response to “MHC-dependent mate choice in humans: Why genomic patterns from the HapMap European American data set support the hypothesis” (DOI: 10.1002/bies.201100150) (2012)
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    Newly evolved genes: Moving from comparative genomics to functional studies in model systems (2012)
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    Publication Date: 2012-04-15
    Description: Genes are gained and lost over the course of evolution. A recent study found that over 1,800 new genes have appeared during primate evolution and that an unexpectedly high proportion of these genes are expressed in the human brain. But what are the molecular functions of newly evolved genes and what is their impact on an organism's fitness? The acquisition of new genes may provide a rich source of genetic diversity that fuels evolutionary innovation. Although gene manipulation experiments are not feasible in humans, studies in model organisms, such as Drosophila melanogaster , have shown that new genes can quickly become integrated into genetic networks and become essential for survival or fertility. Future studies of new genes, especially chimeric genes, and their functions will help determine the role of genetic novelty in the adaptation and diversification of species.
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    Characterization of chromatin domains by 3D fluorescence microscopy: An automated methodology for quantitative analysis and nuclei screening (2012)
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    Publication Date: 2012-04-15
    Description: Fluorescence microscopy has provided a route to qualitatively analyze features of nuclear structures and chromatin domains with increasing resolution. However, it is becoming increasingly important to develop tools for quantitative analysis. Here, we present an automated method to quantitatively determine the enrichment of several endogenous factors, immunostained in pericentric heterochromatin domains in mouse cells. We show that this method permits an unbiased characterization of changes in the enrichment of several factors with statistical significance from a large number of nuclei. Furthermore, the nuclei can be sorted according to the enrichment value of these factors. This method should prove useful to monitor events related to changes in the amount, rather than the presence or absence, of any factor. By adapting a few parameters, it could be extended to other nuclear structures and the benefit of using available software will permit its use in many biological labs. This method allows the quantitative analysis of the localisation of several endogenous markers (e.g. heterochromatin protein 1, HP1) at pericentric heterochromatin domains imaged via immunofluorescence microscopy.
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    Has removal of excess cysteine led to the evolution of pheomelanin? (2012)
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    Description: Pheomelanogenesis may have evolved as an excretory mechanism to remove excess cysteine, and in humans this might potentially confer a greater ability to avoid disease such as Parkinson's and Alzheimer's disease, in which excess cysteine is a contributory cause.
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    Quantitative analysis of photoactivated localization microscopy (PALM) datasets using pair-correlation analysis (2012)
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    In: BioEssays
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    Publication Date: 2012-04-15
    Description: Pointillistic based super-resolution techniques, such as photoactivated localization microscopy (PALM), involve multiple cycles of sequential activation, imaging, and precise localization of single fluorescent molecules. A super-resolution image, having nanoscopic structural information, is then constructed by compiling all the image sequences. Because the final image resolution is determined by the localization precision of detected single molecules and their density, accurate image reconstruction requires imaging of biological structures labeled with fluorescent molecules at high density. In such image datasets, stochastic variations in photon emission and intervening dark states lead to uncertainties in identification of single molecules. This, in turn, prevents the proper utilization of the wealth of information on molecular distribution and quantity. A recent strategy for overcoming this problem is pair-correlation analysis applied to PALM. Using rigorous statistical algorithms to estimate the number of detected proteins, this approach allows the spatial organization of molecules to be quantitatively described.
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    Microbial manipulation of host sex determination (2012)
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    Publication Date: 2012-04-15
    Description: A recent study in the lepidopteran Ostrinia scapulalis shows that endosymbionts can actively manipulate the sex determination mechanism of their host. Wolbachia bacteria alter the sex-specific splicing of the doublesex master switch gene. In ZZ males of this female heterogametic system, the female isoform of doublesex is produced in the presence of the bacteria. The effect is a lethal feminization of genotypic males. Curing of ZW females leads to males that die, indicating that the bacteria have an obligate role in proper sex determination and development of their host. Microbial intervention with host sex determination may be a driving force behind the evolutionary turnover of sex determination mechanisms. Sex determination in insects is achieved through the action of a cascade of genes, and symbionts may interfere with their host at different levels of this cascade. One example is the lepidopteran Ostrinia scapulalis , where Wolbachia bacteria alter the sex-specific splicing of the doublesex master switch gene.
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    Proteolytic processing of the p75 neurotrophin receptor: A prerequisite for signalling? (2012)
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    Somatic cell reprogramming for regenerative medicine: SCNT vs. iPS cells (2012)
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    Publication Date: 2012-04-15
    Description: Reprogramming of somatic cells to a pluripotent state holds huge potentials for regenerative medicine. However, a debate over which method is better, somatic cell nuclear transfer (SCNT) or induced pluripotent stem (iPS) cells, still persists. Both approaches have the potential to generate patient-specific pluripotent stem cells for replacement therapy. Yet, although SCNT has been successfully applied in various vertebrates, no human pluripotent stem cells have been generated by SCNT due to technical, legal and ethical difficulties. On the other hand, human iPS cell lines have been reported from both healthy and diseased individuals. A recent study reported the generation of triploid human pluripotent stem cells by transferring somatic nuclei into oocytes, a variant form of SCNT. In this essay, we discuss this progress and the potentials of these two reprogramming approaches for regenerative medicine. The generation of patient-specific pluripotent stem cells holds great potential for regenerative medicine and can be achieved by somatic cell nuclear transfer (SCNT) or by the forced expression of a just a few transcription factors in somatic cells to generate induced pluripotent stem (iPS) cells.
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    Banding patterns in Drosophila melanogaster polytene chromosomes correlate with DNA-binding protein occupancy (2012)
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    Publication Date: 2012-04-15
    Description: The most enigmatic feature of polytene chromosomes is their banding pattern, the genetic organization of which has been a very attractive puzzle for many years. Recent genome-wide protein mapping efforts have produced a wealth of data for the chromosome proteins of Drosophila cells. Based on their specific protein composition, the chromosomes comprise two types of bands, as well as interbands. These differ in terms of time of replication and specific types of proteins. The interbands are characterized by their association with “active” chromatin proteins, nucleosome remodeling, and origin recognition complexes, and so they have three functions: acting as binding sites for RNA pol II, initiation of replication and nucleosome remodeling of short fragments of DNA. The borders and organization of the same band and interband regions are largely identical, irrespective of the cell type studied. This demonstrates that the banding pattern is a universal principle of the organization of interphase polytene and non-polytene chromosomes. Editor's suggested further reading in BioEssays Caught in the act: Rapid, symbiont-driven evolution Abstract Function and evolution of sex determination mechanisms, genes and pathways in insects Abstract Recent genome-wide protein mapping efforts in Drosophila have provided information on the proteins associated with interbands as well as on the correspondence between the genomic maps and the polytene chromosome structure, and have shown that the polytene chromosome structure is likely to provide a good representation of the organisation of interphase chromatin in diploid cells.
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    Instructive reconstruction: A new role for apoptosis in pattern formation (2012)
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    Description: Apoptosis is not only involved in patterning by removal of tissue (destructive apoptotic patterning), but it can also function in signalling the site of de novo tissue generation via morphogenic signals (instructive apoptotic patterning).
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    Scanning image correlation spectroscopy (2012)
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    Description: Molecular interactions are at the origin of life. How molecules get at different locations in the cell and how they locate their partners is a major and partially unresolved question in biology that is paramount to signaling. Spatio-temporal correlations of fluctuating fluorescently tagged molecules reveal how they move, interact, and bind in the different cellular compartments. Methods based on fluctuations represent a remarkable technical advancement in biological imaging. Here we discuss image analysis methods based on spatial and temporal correlation of fluctuations, raster image correlation spectroscopy, number and brightness, and spatial cross-correlations that give us information about how individual molecules move in cells and interact with partners at the single molecule level. These methods can be implemented with a standard laser scanning microscope and produce a cellular level spatio-temporal map of molecular interactions.
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    Extracellular vesicles – vehicles that spread cancer genes (2012)
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    Publication Date: 2012-04-15
    Description: Once regarded as cellular ‘debris’ extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor receptor, Ras), and tumour suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers. Extracellular vesicles (EVs) are capable of transferring a wide spectrum of macromolecules, such as oncogenes and tumour suppressors, from one cell to another (e.g. also from a mutant cancer cell to a normal one). The molecular analysis of EV-derived material holds potential to be used for clinical purposes.
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    Waddington's epigenetic landscape and post-Darwinian biology (2012)
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    Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity? (2012)
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    In: BioEssays
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    Publication Date: 2012-04-15
    Description: The potential for self-reactive T cells to cause autoimmune disease is held in check by Foxp3 + regulatory T cells (Tregs), essential mediators of peripheral immunological tolerance. Tregs have the capacity to suppress multiple branches of the immune system, tightly controlling the different subsets of effector T cells across multiple different tissue environments. Recent genetic experiments have found mutations that disrupt specific Treg: effector T cell relationships, leading to the possibility that subsets of Tregs are required to suppress each subset of effector T cells. Here we review the environmental factors and mechanisms that allow Tregs to suppress specific subsets of effector T cells, and find that a parsimonious explanation of the genetic data can be made without invoking Treg subsets. Instead, Tregs show a functional and chemotactic plasticity based on microenvironmental influences that allows the common pool of cells to suppress multiple distinct immune responses. There is evidence that Tregs are multipotent suppressors that have the ability to suppress all effector T cell lineages through different molecular mechanisms.
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    BioEssays 4/2012 (2012)
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    In: BioEssays
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    Publication Date: 2012-04-15
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    Is cell fusion driven by excitation? (Comment on DOI: 10.1002/bies.201100135) (2012)
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    In: BioEssays
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    Publication Date: 2012-04-15
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    BioEssays – Next Issue (2012)
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    In: BioEssays
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    Publication Date: 2012-04-15
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    Brains have a gut feeling about fat storage (2012)
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    In: BioEssays
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    Publication Date: 2012-04-15
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    BiotecVisions 2012, March (pages A1-A8) (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-04-15
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    CREB signalling in neural stem/progenitor cells: Recent developments and the implications for brain tumour biology (2012)
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    In: BioEssays
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    Publication Date: 2012-04-15
    Description: This paper discusses the evidence for the role of CREB in neural stem/progenitor cell (NSPC) function and oncogenesis and how these functions may be important for the development and growth of brain tumours. The cyclic-AMP response element binding (CREB) protein has many roles in neurons, ranging from neuronal survival to higher order brain functions such as memory and drug addiction behaviours. Recent studies have revealed that CREB also has a role in NSPC survival, differentiation and proliferation. Recent work has shown that over-expression of CREB in transgenic animals can impart oncogenic properties on cells in various tissues and that aberrant CREB expression is associated with tumours in patients. It is the central position of CREB, downstream of key developmental and growth signalling pathways, which give CREB the ability to influence a spectrum of cell activities, such as cell survival, growth and differentiation in both normal and cancer cells. There is significant experimental data implicating the CREB signalling pathway in the development and maintenance of brain tumours, and this knowledge will provide an opportunity to investigate novel drug targeting approaches in glioma treatment.
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    Mitochondria: Starving to reach quorum? (2012)
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    In: BioEssays
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    Publication Date: 2012-04-15
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    Whole chromosome aneuploidy: Big mutations drive adaptation by phenotypic leap (2012)
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    In: BioEssays
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    Publication Date: 2012-08-25
    Description: Despite its widespread existence, the adaptive role of aneuploidy (the abnormal state of having an unequal number of different chromosomes) has been a subject of debate. Cellular aneuploidy has been associated with enhanced resistance to stress, whereas on the organismal level it is detrimental to multicellular species. Certain aneuploid karyotypes are deleterious for specific environments, but karyotype diversity in a population potentiates adaptive evolution. To reconcile these paradoxical observations, this review distinguishes the role of aneuploidy in cellular versus organismal evolution. Further, it proposes a population genetics perspective to examine the behavior of aneuploidy on a populational versus individual level. By altering the copy number of a significant portion of the genome, aneuploidy introduces large phenotypic leaps that enable small cell populations to explore a wide phenotypic landscape, from which adaptive traits can be selected. The production of chromosome number variation can be further increased by stress- or mutation-induced chromosomal instability, fueling rapid cellular adaptation. Big mutations, such as whole chromosome aneuploidy, can drive rapid cellular adaptation by phenotypic leap. The figure illustrates that under severe stress, the survival probability of genetic variants increases drastically along with the amount of phenotypic variations generated (represented by width ratio).
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    Synthesizing artificial cells from giant unilamellar vesicles: State-of-the art in the development of microfluidic technology (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-08-25
    Description: Microfluidic technology – the manipulation of fluids at micrometer scales – has revolutionized many areas of synthetic biology. The bottom-up synthesis of “minimal” cell models has traditionally suffered from poor control of assembly conditions. Giant unilamellar vesicles (GUVs) are good models of living cells on account of their size and unilamellar membrane structure. In recent years, a number of microfluidic approaches for constructing GUVs has emerged. These provide control over traditionally elusive parameters of vesicular structure, such as size, lamellarity, membrane composition, and internal contents. They also address sophisticated cellular functions such as division and protein synthesis. Microfluidic techniques for GUV synthesis can broadly be categorized as continuous-flow based approaches and droplet-based approaches. This review presents the state-of-the-art of microfluidic technology, a robust platform for recapitulating complex cellular structure and function in synthetic models of biological cells. Microfluidics has emerged as a powerful technology for the synthesis of artificial cells from giant unilamellar vesicles by dramatically improving control over size, lamellarity, internal contents, and membrane composition and addressing sophisticated cellular functions such as protein synthesis.
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    Genome instability: Does genetic diversity amplification drive tumorigenesis? (2012)
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    In: BioEssays
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    Publication Date: 2012-09-06
    Description: Recent data show that catastrophic events during one cell cycle can cause massive genome damage producing viable clones with unstable genomes. This is in contrast with the traditional view that tumorigenesis requires a long-term process in which mutations gradually accumulate over decades. These sudden events are likely to result in a large increase in genomic diversity within a relatively short time, providing the opportunity for selective advantages to be gained by a subset of cells within a population. This genetic diversity amplification, arising from a single aberrant cell cycle, may drive a population conversion from benign to malignant. However, there is likely a period of relative genome stability during the clonal expansion of tumors – this may provide an opportunity for therapeutic intervention, especially if mechanisms that limit tolerance of aneuploidy are exploited. Acute genome instability is a period of rapid volatility in which a catastrophic failure within a single cell cycle results in aneuploidy and complex chromosome rearrangements. If tolerated by the progeny, the massive genome damage can be exploited by cancer cells to gain a proliferative advantage and adaptability.
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    The promise and challenges of stem cell-based therapies for skeletal diseases (2012)
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    In: BioEssays
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    Publication Date: 2012-09-06
    Description: Despite decades of research, remaining safety concerns regarding disease transmission, heterotopic tissue formation, and tumorigenicity have kept stem cell-based therapies largely outside the standard-of-care for musculoskeletal medicine. Recent insights into trophic and immune regulatory activities of mesenchymal stem cells (MSCs), although incomplete, have stimulated a plethora of new clinical trials for indications far beyond simply supplying progenitors to replenish or re-build lost/damaged tissues. Cell banks are being established and cell-based products are in active clinical trials. Moreover, significant advances have also been made in the field of pluripotent stem cells, in particular the recent development of induced pluripotent stem cells. Their indefinite proliferation potential promises to overcome the limited supply of tissue-specific cells and adult stem cells. However, substantial hurdles related to their safety must be overcome for these cells to be clinically applicable. Multipotent adult mesenchymal stem cells, with their recently demonstrated trophic and immune regulatory activities, hold high promise for cell-based therapies for skeletal diseases, although their origin and nature remain incompletely understood. Recent developments in pluripotent stem cells have also advanced their potential as another cell source for regenerative medicine.
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    Should Y stay or should Y go: The evolution of non-recombining sex chromosomes (2012)
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    In: BioEssays
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    Publication Date: 2012-09-06
    Description: Gradual degradation seems inevitable for non-recombining sex chromosomes. This has been supported by the observation of degenerated non-recombining sex chromosomes in a variety of species. The human Y chromosome has also degenerated significantly during its evolution, and theories have been advanced that the Y chromosome could disappear within the next ∼5 million years, if the degeneration rate it has experienced continues. However, recent studies suggest that this is unlikely. Conservative evolutionary forces such as strong purifying selection and intrachromosomal repair through gene conversion balance the degeneration tendency of the Y chromosome and maintain its integrity after an initial period of faster degeneration. We discuss the evidence both for and against the extinction of the Y chromosome. We also discuss potential insights gained on the evolution of sex-determining chromosomes by studying simpler sex-determining chromosomal regions of unicellular and multicellular microorganisms. People might think that the evolutionary forces acting upon sex chromosomes and mating type loci would necessarily differ dramatically between multicellular animals and unicellular fungi, alga, or slime molds. However, a series of studies over the past decade have contributed to reveal a number of shared features among these systems.
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    Does human evolution in different latitudes influence susceptibility to obesity via the circadian pacemaker? (2012)
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    In: BioEssays
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    Publication Date: 2012-08-31
    Description: The variable photoperiods of Northern latitudes challenge the entrainment capacity of the circadian pacemaker, which evolved under constant photoperiods in Equatorial regions. Entrainment to the erratic photoperiods facilitated by artificial light presents an additional challenge. Metabolic dysfunction and obesity are potential consequences of such desynchronization of circadian and environmental rhythms.
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    On the cause of aging and control of lifespan (2012)
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    In: BioEssays
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    Publication Date: 2012-08-24
    Description: What the causes of aging are and which factors define lifespan are key questions in the understanding of aging. Here, it is argued that cellular life involves (i) inevitable accumulation of damage resulting from imperfectness and heterogeneity of every cellular process, and (ii) dilution of damage when cells divide. While severe damage is cleared by protective systems, milder damage can only be diluted. This is due to the high cost of accuracy, the greater number of damage forms compared to protective systems, and the constraints on cellular life inherited from the prokaryotic world. This strategy also applies to cancer cells, which are particularly dependent on damage dilution. Imposing restriction on cell division necessarily leads to aging. Interventions that extend lifespan act through metabolic reprogramming, thereby changing both damage composition and the rate of damage accumulation. Thus, heterogeneity leading to myriad mild damage forms represents the cause of aging, whereas the processes that affect the damage landscape and damage accumulation are lifespan regulators. What the causes of aging are and which factors define species lifespan are key questions in the understanding of aging. The author describes a concept that heterogeneity leads to inevitable damage accumulation causing aging, and that control of damage composition and rate of accumulation define lifespan.
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    An epithelial tissue in Dictyostelium challenges the traditional origin of metazoan multicellularity (2012)
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    In: BioEssays
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    Publication Date: 2012-08-30
    Description: We hypothesize that aspects of animal multicellularity originated before the divergence of metazoans from fungi and social amoebae. Polarized epithelial tissues are a defining feature of metazoans and contribute to the diversity of animal body plans. The recent finding of a polarized epithelium in the non-metazoan social amoeba Dictyostelium discoideum demonstrates that epithelial tissue is not a unique feature of metazoans, and challenges the traditional paradigm that multicellularity evolved independently in social amoebae and metazoans. An alternative view, presented here, is that the common ancestor of social amoebae, fungi, and animals spent a portion of its life cycle in a multicellular state and possessed molecular machinery necessary for forming an epithelial tissue. Some descendants of this ancestor retained multicellularity, while others reverted to unicellularity. This hypothesis makes testable predictions regarding tissue organization in close relatives of metazoans and provides a novel conceptual framework for studies of early animal evolution. Editor's suggested further reading in BioEssays Searching for Eve: Basal metazoans and the evolution of multicellular complexity Abstract Epithelial tissue, a hallmark of animal body plans, was recently discovered in the non-metazoan Dictyostelium . These findings challenge conventional views of the origins of multicellularity, but can be explained if metazoans and Dictyostelium shared a common ancestor that spent a portion of its life cycle as a multicellular organism.
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    Control of osteogenesis by the canonical Wnt and BMP pathways in vivo (2012)
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    In: BioEssays
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    Publication Date: 2012-08-30
    Description: Although many regulators of skeletogenesis have been functionally characterized, one current challenge is to integrate this information into regulatory networks. Here, we discuss how the canonical Wnt and Smad-dependent BMP pathways interact together and play antagonistic or cooperative roles at different steps of osteogenesis, in the context of the developing vertebrate embryo. Early on, BMP signaling specifies multipotent mesenchymal cells into osteochondroprogenitors. In turn, the function of Wnt signaling is to drive these osteochondroprogenitors towards an osteoblastic fate. Subsequently, both pathways promote osteoblast differentiation, albeit with notable mechanistic differences. In osteocytes, the ultimate stage of osteogenic differentiation, the Wnt and BMP pathways exert opposite effects on the control of bone resorption by osteoclasts. We describe how the dynamic molecular wiring of the canonical Wnt and Smad-dependent BMP signaling into the skeletal cell genetic programme is critical for the generation of bone-specific cell types during development. The canonical Wnt and Smad-dependent BMP signaling are critical for skeletal cell specification and differentiation, but the way these pathways affect each other remains largely unknown. We discuss recent data showing how Wnt and BMP signaling interact to generate osteochondroprogenitors, osteoblasts, and osteocytes, in the context of the developing embryo.
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    Circadian clocks in changing weather and seasons: Lessons from the picoalga Ostreococcus tauri (2012)
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    In: BioEssays
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    Publication Date: 2012-07-17
    Description: Daylight is the primary cue used by circadian clocks to entrain to the day/night cycle so as to synchronize physiological processes with periodic environmental changes induced by Earth rotation. However, the temporal daylight pattern is not the same every day due to erratic weather fluctuations or regular seasonal changes. Then, how do circadian clocks operate properly in varying weather and seasons? In this paper, we discuss the strategy unveiled by recent studies of the circadian clock of Ostreococcus tauri , the smallest free-living eukaryotic organism. It combines mechanisms controlling light inputs and clock sensitivity, shaping both the dynamics of the core circadian oscillator and its forcing by light so as to ensure stable and precise synchronization in all weather and seasons. Editor's suggested further reading in BioEssays: Another place, another timer: Marine species and the rhythms of life Abstract How circadian clocks keep accurate time of the day even though they are entrained by a variable day/night cycle has been little studied. Recent studies of the microscopic green alga Ostreococcus tauri have revealed a remarkably simple strategy allowing reliable clock operation in all weather and seasons.
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    A critical assessment of the h-index (2012)
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    In: BioEssays
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    Publication Date: 2012-07-19
    Description: Editor's suggested further reading in BioEssays: Can we do better than existing author citation metrics? Abstract and Counting citations in texts rather than reference lists to improve the accuracy of assessing scientific contribution Abstract The h-index is used to assess an individual researcher's publication record. An analysis of the publication record of 248 professors in the health sciences revealed that the h-index is closely associated to a scientist's number of publications. The nature of the h-index is therefore rather quantitative than qualitative.
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    Menin as a hub controlling mixed lineage leukemia (2012)
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    In: BioEssays
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    Publication Date: 2012-07-25
    Description: Mixed lineage leukemia (MLL) fusion protein (FP)-induced acute leukemia is highly aggressive and often refractory to therapy. Recent progress in the field has unraveled novel mechanisms and targets to combat this disease. Menin, a nuclear protein, interacts with wild-type (WT) MLL, MLL-FPs, and other partners such as the chromatin-associated protein LEDGF and the transcription factor C-Myb to promote leukemogenesis. The newly solved co-crystal structure illustrating the menin–MLL interaction, coupled with the role of menin in recruiting both WT MLL and MLL-FPs to target genes, highlights menin as a scaffold protein and a central hub controlling this type of leukemia. The menin/WT MLL/MLL-FP hub may also cooperate with several signaling pathways, including Wnt, GSK3, and bromodomain-containing Brd4-related pathways to sustain MLL-FP-induced leukemogenesis, revealing new therapeutic targets to improve the treatment of MLL-FP leukemias. In MLL fusion protein-induced leukemias, menin is a central hub due to its role in recruiting WT MLL and MLL-FPs to target genes. Menin also links C-Myb/LEDGF to the MLL N-terminus, underscoring menin's central role. Targeting menin may be especially effective due to its hub role in MLL fusion leukemias.
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    Improved vaccines through targeted manipulation of the body's immunological risk-assessment? (2012)
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    In: BioEssays
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    Publication Date: 2012-07-21
    Description: Recent advances have highlighted the outstanding role of the innate immune system for instructing adaptive immunity. Translating this knowledge into successful immunotherapies like vaccines, however, has proven to be a difficult task. This essay is based on the hypothesis that immune responses are tightly scaled to the infectious threat posed by a given microbial stimulus. A meticulous immunological risk-assessment process is therefore instrumental for eliciting well-balanced responses and maintaining immune homeostasis. The immune system makes fine distinctions, for example, between live and dead bacteria, or pathogenic and non-pathogenic microorganisms. Here, I discuss recent evidence for some of the mechanisms underlying these distinctions and speculate on strategies for therapeutically targeting the immunological risk-assessment machinery. Microbial threat levels physiologically correlate with the robustness of resulting immune responses (blue line). Threat evaluation could be harnessed to skew this correlation (red line) to improve vaccine efficiency. low threat stimulus (e.g., dead microbes), high threat stimulus (e.g., viable microbes), and modified low threat stimulus (e.g., killed microbes + vita-PAMPs).
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    Is adult stem cell aging driven by conflicting modes of chromatin remodeling? (2012)
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    In: BioEssays
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    Publication Date: 2012-07-24
    Description: Epigenetic control of gene expression by chromatin remodeling is critical for adult stem cell function. A decline in stem cell function is observed during aging, which is accompanied by changes in the chromatin structure that are currently unexplained. Here, we hypothesize that these epigenetic changes originate from the limited cellular capability to inherit epigenetic information. We suggest that spontaneous loss of histone modification, due to fluctuations over short time scales, gives rise to long-term changes in DNA methylation and, accordingly, in gene expression. These changes are assumed to impair stem cell function and, thus, to contribute to aging. We discuss cell replication as a major source of fluctuations in histone modification patterns. Gene silencing by our proposed mechanism can be interpreted as a manifestation of the conflict between the stem cell plasticity required for tissue regeneration and the permanent silencing of potentially deleterious genomic sequences. We hypothesize that age-related changes of chromatin structure originate in the limited cellular capability to inherit epigenetic information. Spontaneous loss of histone modification, e.g., during replication gives rise to changes in DNA methylation and accordingly in gene expression, manifesting a conflict between stem cell plasticity and long term gene silencing.
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    Putting proteins in context (2012)
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    In: BioEssays
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    Publication Date: 2012-07-17
    Description: Scientific illustrations, such as this cross-section through part of an E. coli cell, can give an impression of the complexity of a cell's interior and of the way its macromolecules are arranged.
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    Amedeo Avogadro's cry: What is 1 µg of exosomes? (2012)
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    In: BioEssays
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    Publication Date: 2012-07-21
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    Chaperone discovery (2012)
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    In: BioEssays
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    Publication Date: 2012-09-13
    Description: Molecular chaperones assist de novo protein folding and facilitate the refolding of stress-denatured proteins. The molecular chaperone concept was coined nearly 35 years ago, and since then, tremendous strides have been made in understanding how these factors support protein folding. Here, we focus on how various chaperone proteins were first identified to play roles in protein folding. Examples are used to illustrate traditional routes of chaperone discovery and point out their advantages and limitations. Recent advances, including the development of folding biosensors and promising methods for the stabilization of proteins in vivo, provide new routes for chaperone discovery. With new methods of chaperone discovery, the question as to whether we have discovered all the chaperones that exist is very pertinent: there may well be important new surprises on the horizon. The image depicts one method of monitoring protein folding, namely the coupling of protein folding to the host stress response. This review cover is the past, present, and future of chaperone discovery.
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    BioEssays 10/2012 (2012)
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    In: BioEssays
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    Publication Date: 2012-09-14
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    BioEssays – Next Issue (2012)
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    Publication Date: 2012-09-14
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    BiotecVisions 2012, September (pages A1-A8) (2012)
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    In: BioEssays
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    Publication Date: 2012-09-14
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    The future of the h-index: Can bending an already non-linear metric work? (2012)
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    In: BioEssays
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    Publication Date: 2012-09-14
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    Ohno's hypothesis and Muller's paradox: Sex chromosome dosage compensation may serve collective gene functions (2012)
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    In: BioEssays
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    Publication Date: 2012-09-08
    Description: Muller found halving gene dosage, as in males with one X chromosome, did not affect specific gene function. Why then was dosage “compensated?” This paradox was solved by invoking collective gene functions such as self/not self discrimination afforded by protein aggregation pressure. This predicts female susceptibility to autoimmune disease.
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    Neurospora as a model to empirically test central hypotheses in eukaryotic genome evolution (2012)
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    In: BioEssays
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    Publication Date: 2012-09-13
    Description: The fungus Neurospora comprises a novel model for testing hypotheses involving the role of sex and reproduction in eukaryotic genome evolution. Its variation in reproductive mode, lack of sex-specific genotypes, availability of phylogenetic species, and young sex-regulating chromosomes make research in this genus complementary to animal and plant models.
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    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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    BioEssays 10/2012 (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-09-14
    Description: Genome rocks . The genome of each species consists of a defined number of chromosomes. However, this number can change in cells, leading to chromosome copy number variations (aneuploidy) with large phenotypic consequence. Interestingly, aneuploidy is associated with both adaptation and pathogenesis. On pages 893–900 of this issue Guangbo Chen et al. review the widespread existence of aneuploidy in different species under different conditions. To reconcile the seemingly contradictory role of aneuploidy in both adaptation and pathogenesis, the review highlights the difference between organismal versus cellular evolution in multi-cellular species. The proposed mathematical model suggests that aneuploidy drives rapid evolution through phenotypic leap in cell populations with restricted size. The production of chromosome number variation can be further increased by stress- or mutation-induced chromosomal instability, fueling rapid cellular adaptation. The comparative genomic hybridization data of aneuploid cells is presented as music spectrum. Cover by Xiang Yuan and Guangbo Chen.
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    Mammalian chromosomes contain cis-acting elements that control replication timing, mitotic condensation, and stability of entire chromosomes (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-06-19
    Description: Recent studies indicate that mammalian chromosomes contain discrete cis -acting loci that control replication timing, mitotic condensation, and stability of entire chromosomes. Disruption of the large non-coding RNA gene ASAR6 results in late replication, an under-condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono-allelic expression and asynchronous replication timing. Additional “chromosome engineering” studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain “inactivation/stability centers” that control proper replication, condensation, and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types of cis -acting elements, origins, telomeres, centromeres, and “inactivation/stability centers”, all functioning to ensure proper replication, condensation, segregation, and stability of individual chromosomes. Mammalian chromosomes contain four types of cis -acting elementsthat function to regulate chromosome-wide replication timing, mitotic condensation and stability of individual chromosomes: origins of replication, telomeres, centrosomes and loci such as Xist and ASAR6 functioning as “inactivation/stability centers”.
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    Compensation as a strategy for unavoidable oxidative damage in mitochondria? (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-07-13
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    Organelle size control systems: From cell geometry to organelle-directed medicine (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-07-05
    Description: Organelles are reaction vessels containing metabolic pathways. As in a chemical factory, the size of the reaction vessels limits the rate of product formation. Organelle size is tuned to metabolic needs, hence reprogramming organelle size could be a novel therapeutic strategy as well as a new tool for metabolic engineering.
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    Are expression profiles meaningless for cancer studies? (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-07-05
    Description: Expression signatures obtained from tumour samples are widely used to characterise tumour subtypes and to provide prognostic information. This commentary, based on a recent paper, questions the scientific validity of such signatures as a means of understanding the underlying biology.
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    Evolution in response to climate change: In pursuit of the missing evidence (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-07-12
    Description: Climate change is imposing intensified and novel selection pressures on organisms by altering abiotic and biotic environmental conditions on Earth, but studies demonstrating genetic adaptation to climate change mediated selection are still scarce. Evidence is accumulating to indicate that both genetic and ecological constrains may often limit populations' abilities to adapt to large scale effects of climate warming. These constraints may predispose many organisms to respond to climate change with range shifts and phenotypic plasticity, rather than through evolutionary adaptation. In general, broad conclusions about the role of evolutionary adaptation in mitigating climate change induced fitness loss in the wild are as yet difficult to make. Editor's suggested further reading in BioEssays: How will fish that evolved at constant sub-zero temperatures cope with global warming? Notothenioids as a case study Abstract Climate change is imposing intensified selection pressures on organisms, but studies demonstrating genetic adaptation to climate change mediated selection are still scarce. Evidence is accumulating to indicate that both genetic and ecological constrains may often limit populations' abilities to adapt and predispose them respond with range shifts and phenotypic plasticity.
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    BioEssays 8/2012 (2012)
    Wiley
    In: BioEssays
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    Publication Date: 2012-07-13
    Description: Immunological insights from fish. Among vertebrates, teleosts comprise particularly diverse and ancient lineages that can provide alternative immunological solutions to biological and environmental challenges. For example, Atlantic cod is the first species reported that has lost the major histocompatibility complex (MHC) II, one of the antigen presentation systems previously believed to be conserved among all jawed vertebrates, and this loss coincides with a distinct immune gene repertoire. In this issue (pages 648–651 ), Star and Jentoft propose several scenarios, with different selective assumptions, that may have lead to the emergence of these phenomena. Through comparative studies of immune genes in multiple teleost lineages, we may be able to infer a causal link between the loss of MHC II and the emergence of such distinct immune gene repertoire. Additionally, these studies can identify which biological and environmental factors have promoted their evolution and provide a deeper understanding of the selective processes that have affected the vertebrate immune system.
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