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  • 1
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    In: BioEssays
    Publication Date: 2013-09-15
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  • 2
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    In: BioEssays
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  • 3
    Publication Date: 2013-09-26
    Description: Long non-coding RNAs (lncRNAs) have recently gained increasing attention because of their crucial roles in gene regulatory processes. Functional studies using mammalian skin as a model system have revealed their role in controlling normal tissue homeostasis as well as the transition to a diseased state. Here, we describe how lncRNAs regulate differentiation to preserve an undifferentiated epidermal progenitor compartment, and to maintain a functional skin permeability barrier. Furthermore, we will reflect on recent work analyzing the impact of lncRNAs on the progression from normal epithelium to the development of skin disorders and cancer. Long non-coding RNAs (lncRNAs) have recently been shown to control a wide variety of gene regulatory processes. In mammalian skin, lncRNAs appear to regulate the intricate balance between progenitor cells undergoing continual regeneration in the basal layer and highly differentiated cells forming the epidermal permeability barrier.
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  • 4
    Publication Date: 2013-09-11
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  • 5
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    In: BioEssays
    Publication Date: 2013-09-15
    Description: General mechanism for exaggerated sexuallyselected traits. Many animals wield sexually-selected exaggerated traits. ‘Classic’ examples include the peacock's train, and the antlers observed in male deer, as well as fiddler crabs with enlarged claws, and the enlarged head-horns of rhinoceros beetles ( Trypoxylus dichotomus , cover). These traits are used for mate choice, or to deter rival males, because they act as unusually reliable signals of the condition of individual males: only the best-quality animals produce full-sized signal structures. But what keeps their expression honest? How can signal traits evolve that are resistant to invasion by cheaters who fake attractive signals? The answer may lie in the ancient insulin-like signalling pathway, which is found in all animals and directly links individual condition to growth in a dose dependent manner. Warren et al. discuss recent evidence suggesting that exaggerated sexually-selected signal traits arise when specific structures become extra-sensitive to physiological signals like insulins or insulin-like growth factors (pages 889–899 ).
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  • 6
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    In: BioEssays
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  • 7
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    In: BioEssays
    Publication Date: 2013-09-15
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  • 8
    Publication Date: 2013-09-18
    Description: mRNA synthesis in all organisms is performed by RNA polymerases, which work as nanomachines on DNA templates. The rate at which their product is made is an important parameter in gene expression. Transcription rate encompasses two related, yet different, concepts: the nascent transcription rate, which measures the in situ mRNA production by RNA polymerase, and the rate of synthesis of mature mRNA, which measures the contribution of transcription to the mRNA concentration. Both parameters are useful for molecular biologists, but they are not interchangeable and they are expressed in different units. It is important to distinguish when and where each one should be used. We propose that for functional genomics the use of nascent transcription rates should be restricted to the evaluation of the transcriptional process itself, whereas mature mRNA synthesis rates should be employed to address the transcriptional input to mRNA concentration balance leading to variation of gene expression. Transcription rate encompasses two related, yet different, concepts: the nascent transcription rate, which measures the in situ mRNA production by RNA polymerase, and the rate of synthesis of mature mRNA, which measures the contribution of transcription to the mRNA concentration. It is important to distinguish when to use each one.
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  • 9
    Publication Date: 2013-09-18
    Description: CALHM1 was recently demonstrated to be a voltage-gated ATP-permeable ion channel and to serve as a bona fide conduit for ATP release from sweet-, umami-, and bitter-sensing type II taste cells. Calhm1 is expressed in taste buds exclusively in type II cells and its product has structural and functional similarities with connexins and pannexins, two families of channel protein candidates for ATP release by type II cells. Calhm1 knockout in mice leads to loss of perception of sweet, umami, and bitter compounds and to impaired gustatory nerve responses to these tastants. These new studies validate the concept of ATP as the primary neurotransmitter from type II cells to gustatory neurons. Furthermore, they identify voltage-gated ATP release through CALHM1 as an essential molecular mechanism of ATP release in taste buds. We discuss these new findings, as well as unresolved issues in peripheral taste signaling that we hope will stimulate future research. Sweetness, umami, and bitterness are transmitted to the nervous system via ion channel-mediated ATP release from taste cells. A recent study demonstrated that CALHM1 is essential for taste cell ATP release and perception of sweetness, umami, and bitterness. We discuss the new findings and unresolved issues in peripheral taste signaling.
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  • 10
    Publication Date: 2013-09-20
    Description: The precise orchestration of two opposing protein complexes – one in the cytoplasm (β-catenin destruction complex) and the other at the plasma membrane (LRP6 signaling complex) – is critical for controlling levels of the transcriptional co-factor β-catenin, and subsequent activation of the Wnt/β-catenin signal transduction pathway. The Wnt pathway component Axin acts as an essential scaffold for the assembly of both complexes. How the β-catenin destruction and LRP6 signaling complexes are modulated following Wnt stimulation remains controversial. A recent study in Science by He and coworkers reveals an underlying logic for Wnt pathway control in which Axin phosphorylation toggles a switch between the active and inactive states. This mini-review focuses on this and two other recent studies that provide insight into the initial signaling events triggered by Wnt exposure. We emphasize regulation of the β-catenin destruction and LRP6 signaling complexes and propose a framework for future work in this area. The mechanism by which the Wnt pathway stabilizes β-catenin, a key transcriptional co-factor, remains controversial. Recent studies have revealed that the phosphorylation state of an essential regulator of the pathway, Axin, controls its conformation and, consequently, its availability to scaffold two opposing Wnt pathway protein complexes that regulate β-catenin stability.
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  • 11
    Publication Date: 2013-06-12
    Description: Metagenomics is a culture- and PCR-independent approach that is now widely exploited for directly studying microbial evolution, microbial ecology, and developing biotechnologies. Observations and discoveries are critically dependent on DNA extraction methods, sequencing technologies, and bioinformatics tools. The potential pitfalls need to be understood and, to some degree, mastered if the resulting data are to survive scrutiny. In particular, methodological variations appear to affect results from different ecosystems differently, thus increasing the risk of biological and ecological misinterpretation. Part of the difficulty is derived from the lack of knowledge concerning the true microbial diversity and because no approach can guarantee accessing microorganisms in the same proportion in which they exist in the environment. However, the variation between different approaches (e.g. DNA extraction techniques, sequence annotation systems) can be used to evaluate whether observations are meaningful. These methodological variations can be integrated into the error analysis before comparing microbial communities. Metagenomics is a powerful approach targeting environmental nucleic diversity but represents also a methodological jungle where pitfalls are challenging when quantitative observations are desired. Here we describe the effect of critical parameters (especially DNA extraction and annotation stringency) required to represent microbial communities function and structure in the metagenomic era.
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  • 12
    Publication Date: 2013-06-12
    Description: Pericytes, typically attached to the walls of microvessels in almost all organs, interact with endothelial cells and take part in diverse biological processes, e.g. blood vessel regulation and tissue repair. This suggests that pericytes harbor a remarkable degree of cellular plasticity, which could potentially be employed for the treatment of diseases affecting diverse tissues such as the skeletal muscle and the central nervous system. Here, we follow pericytes on their journey across Waddington's epigenetic landscape, descending from their origin, along a path guided by environmental signals or ectopic transcription factors, at the end of which they acquire a new identity, e.g. muscle or nerve cells. The central theme of this review is the question of whether pericytes can be enticed to differentiate into whatever cell type is needed, and thus provide an endogenous cellular source for treating as yet incurable diseases – like a magic bullet. Also watch the Video Abstract. http://youtu.be/J4b-cmRWLWI Recent studies show that microvessel-associated pericytes exhibit an unprecedented degree of plasticity and implicate these cells as a physiological cellular source or therapeutic target for tissue repair. They have potential for therapeutic applications in areas ranging from muscle degeneration to heart infarction and CNS injury.
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  • 13
    Publication Date: 2013-04-03
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  • 14
    Publication Date: 2013-04-11
    Description: Factors affecting transcriptional elongation have been characterized extensively in in vitro, single cell (yeast) and cell culture systems; however, data from the context of multicellular organisms has been relatively scarce. While studies in homogeneous cell populations have been highly informative about the underlying molecular mechanisms and prevalence of polymerase pausing, they do not reveal the biological impact of perturbing this regulation in an animal. The core components regulating pausing are expressed in all animal cells and are recruited to the majority of genes, however, disrupting their function often results in discrete phenotypic effects. Mutations in genes encoding key regulators of transcriptional pausing have been recovered from several genetic screens for specific phenotypes or interactions with specific factors in mice, zebrafish and flies. Analysis of these mutations has revealed that control of transcriptional pausing is critical for a diverse range of biological pathways essential for animal development and survival. Animal studies reveal that correct regulation of promoter proximal pausing is critical for a diverse range of biological pathways during embryo development and also for health in adult life. This regulation facilitates fine control of gene expression levels and may also act as a barrier to uncontrolled cell proliferation.
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  • 15
    Publication Date: 2013-04-11
    Description: Phosphatidylinositol 4,5-bisphosphate (PI4,5P 2 ) is a key lipid signaling molecule that regulates a vast array of biological activities. PI4,5P 2 can act directly as a messenger or can be utilized as a precursor to generate other messengers: inositol trisphosphate, diacylglycerol, or phosphatidylinositol 3,4,5-trisphosphate. PI4,5P 2 interacts with hundreds of different effector proteins. The enormous diversity of PI4,5P 2 effector proteins and the spatio-temporal control of PI4,5P 2 generation allow PI4,5P 2 signaling to control a broad spectrum of cellular functions. PI4,5P 2 is synthesized by phosphatidylinositol phosphate kinases (PIPKs). The array of PIPKs in cells enables their targeting to specific subcellular compartments through interactions with targeting factors that are often PI4,5P 2 effectors. These interactions are a mechanism to define spatial and temporal PI4,5P 2 synthesis and the specificity of PI4,5P 2 signaling. In turn, the regulation of PI4,5P 2 effectors at specific cellular compartments has implications for understanding how PI4,5P 2 controls cellular processes and its role in diseases. Site-directed synthesis of phosphatidylinositol-4,5-bisphosphate (PI4,5P 2 ) at distinct sub-cellular compartments mediates a variety of events, such as migration, cell-cell adhesion, transcription and vesicle trafficking. PI4,5P 2 regulated processes are critical for function at the cellular level, which is evident in neurons, platelet, and macrophage function.
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  • 16
    Publication Date: 2013-04-11
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  • 17
    Publication Date: 2013-04-11
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  • 18
    Publication Date: 2013-04-11
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  • 19
    Publication Date: 2013-04-11
    Description: The increased incidence of morbidity and mortality due to Clostridium difficile infection, had led to the emergence of fecal microbial transplantation (FMT) as a highly successful treatment. From this, a 32 strain stool substitute has been derived, and successfully tested in a pilot human study. These approaches could revolutionize not only medical care of infectious diseases, but potentially many other conditions linked to the human microbiome. But a second revolution may be needed in order for regulatory agencies, society and medical practitioners to accept and utilize these interventions, monitor their long term effects, have a degree of control over their use, or at a minimum provide guidelines for donors and recipients. If a simple replacement of your gut microbiota by someone else's could improve your health and ability to function, would you do it? How would you select the donor and would the “authorities” let you perform the transplant? The age of the microbiome is here, but is society ready?
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  • 20
    Publication Date: 2013-09-10
    Description: Many species maintain cytosine DNA methyltransferase (MTase) genes belonging to the Dnmt2 family. Prokaryotic modification-restriction systems utilize DNA methylation to distinguish between self and foreign DNA, and cytosine methylation in eukaryotic DNA contributes to epigenetic mechanisms that control gene expression. However, Dnmt2 proteins display only low or no DNA MTase activity, making this protein family the odd and enigmatic family member. Recent evidence showed that Dnmt2 proteins are not DNA but RNA MTases with functions in biological processes as diverse as stress responses and RNA-mediated inheritance. These observations not only raise profound questions regarding the perceived substrate specificities of cytosine MTase, but also suggest links between DNA and RNA modification systems. Here, we speculate that Dnmt2 proteins might be part of an ancient cytosine modification toolbox that is used to successfully respond to environmental challenges, including constantly evolving RNA and DNA substrates. Recent observations indicated that Dnmt2 proteins, which belong to a highly conserved DNA cytosine methyltransferase family, are important for the response to RNA-based stressors, including transposons, viruses, and experimentally introduced small RNAs. Is Dnmt2 part of an ancient defense system that employs nucleotide modifications against invading pathogens?
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  • 21
    Publication Date: 2013-09-15
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  • 22
    Publication Date: 2013-09-21
    Description: Inflammatory immune cells, when activated, display much the same metabolic profile as a glycolytic tumor cell. This involves a shift in metabolism away from oxidative phosphorylation towards aerobic glycolysis, a phenomenon known as the Warburg effect. The result of this change in macrophages is to rapidly provide ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins. In addition, a rise in certain tricarboxylic acid cycle intermediates occurs notably in citrate for lipid biosynthesis, and succinate, which activates the transcription factor Hypoxia-inducible factor. In this review we take a look at the emerging evidence for a role for the Warburg effect in the immune and inflammatory responses. The reprogramming of metabolic pathways in macrophages, dendritic cells, and T cells could have relevance in the pathogenesis of inflammatory and metabolic diseases and might provide novel therapeutic strategies. Recent studies reveal that inflammatory cells, when activated, display similar metabolic traits as cancer cells. During an inflammatory response or infection pro-inflammatory immune cells can shift their metabolism away from oxidative phosphorylation towards a high rate of glycolysis, a phenomenon known as the Warburg effect.
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  • 23
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    In: BioEssays
    Publication Date: 2013-09-21
    Description: The fast advancing RNA-seq technology has unveiled an unexpected diversity and expression specificity of 3′ untranslated regions (3′UTRs) of mRNAs. In particular, neural mRNAs seem to express significantly longer 3′UTRs, some of which are over 10 kb in length. The extensive elongation of 3′UTRs in neural tissues provides intriguing possibilities for cell type-specific regulations that are governed by miRNAs, RNA-binding proteins and ribonucleoprotein aggregates. In this article, we review recent progress in the characterization of mRNA 3′UTRs and discuss their implications in the understanding of 3′UTR-mediated gene regulation. Differential expression of short and long 3′UTRs, especially in neurons, presents technical challenges for experimental characterization. Such dynamic expression of 3′UTR isoforms, however, provides a mechanism to regulate protein production of both individual and a pool of transcripts in physiological and pathological conditions.
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  • 24
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    In: BioEssays
    Publication Date: 2013-01-16
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  • 25
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    In: BioEssays
    Publication Date: 2013-01-16
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  • 26
    Publication Date: 2013-01-16
    Description: Simple DNA repeats (trinucleotide repeats, micro- and minisatellites) are prone to expansion/contraction via formation of secondary structures during DNA synthesis. Such structures both inhibit replication forks and create opportunities for template-primer slippage, making these repeats unstable. Certain aspects of simple repeat instability, however, suggest additional mechanisms of replication inhibition dependent on the primary DNA sequence, rather than on secondary structure formation. I argue that expanded simple repeats, due to their lower DNA complexity, should transiently inhibit DNA synthesis by locally depleting specific DNA precursors. Such transient inhibition would promote formation of secondary structures and would stabilize these structures, facilitating strand slippage. Thus, replication problems at simple repeats could be explained by potentiated toxicity, where the secondary structure-driven repeat instability is enhanced by DNA polymerase stalling at the low complexity template DNA. This minireview is dedicated to the FASEB-2012 meeting “Dynamic DNA Structures in Biology”, organized by Nancy Maizels and Sergei Mirkin. Expanded trinucleotide repeats are inherently unstable due to their propensity for strand slippage. I hypothesize that strand slippage is further promoted by local transient depletion of specific dNTPs during synthesis across this low-complexity DNA. Possible hairpin extrusion between polymerase and the clamp (the scheme) may explain saltatory repeat expansion.
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  • 27
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    In: BioEssays
    Publication Date: 2013-01-16
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  • 28
    Publication Date: 2013-02-27
    Description: Clathrin-mediated endocytosis is a major route for the retrieval of plasma-membrane cargoes, and defects of this process can cause catastrophic human dysfunctions. However, the processes governing how a clathrin-coated profile (ccp) is initiated are still murky. Despite an ever-growing cast of molecules proposed as triggers of ccp nucleation and increasingly sophisticated bioimaging techniques examining clathrin-mediated endocytosis, it is yet unknown if ccp formation is governed by a universal mechanism. A recent paper by Cocucci et al. has tracked single-molecule events to identify that stable accumulation of ccps requires the near-simultaneous arrival of two AP2 adaptors bridged by one clathrin triskelion. This commentary examines the role of AP2 in cargo-mediated endocytosis in the light of recent advances in biophotonics, chemical inhibitors and genetics, examines the claims of other molecules to be the initiators of ccp formation and proposes future directions in research into this topic. Editor's suggested further reading in BioEssays: The evolution of dynamin to regulate clathrin-mediated endocytosis Abstract Clathrin-mediated endocytosis: What works for small, also works for big Abstract Coccuci et al. propose that clathrin coated pits (ccps) randomly nucleate via simultaneous arrival of two AP2 complexes and a clathrin triskelion at the plasma membrane. The nascent ccp stabilizes by incorporating more clathrin/AP2 complexes and early factors such as FCHo1/2, before integrating transmembrane cargoes and acquiring curvature.
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  • 29
    Publication Date: 2013-03-02
    Description: When a cell divides, it produces two daughter cells initially connected by a cytokinesis bridge, which is eventually cut through abscission. One of the two daughter cells inherits a bridge “remnant”, which has been proposed to be degraded by autophagy. The fate and function of remnants is attracting increasing attention, as their accumulation appears to influence proliferation versus differentiation of the daughter cells. Here, we present a simple model for bridge and remnant turnover in a dynamic cell population. We demonstrate that remnant proportions depend on the ratio of remnant and bridge lifetimes to the cell population doubling time. Our results yield new alternative interpretations for published experimental data, leading us to believe that autophagy-independent pathways for remnant degradation may exist. In addition, using the model, we determined experimentally inaccessible parameters such as remnant lifetime. Our model proves to be a useful tool for studying bridge and remnant populations. As cells divide, they produce bridges, which decay into remnants. Remnants are then thought to decay by autophagy. Defective remnant decay correlates with enhanced proliferation. We generated a model for remnant turnover, measured remnant lifetime, and simulated published experiments. We find that remnant decay can occur by autophagy-independent pathways.
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  • 30
    Publication Date: 2013-03-02
    Description: Culture-independent high-throughput sequencing has provided unprecedented insights into microbial ecology, particularly for Earth's most ubiquitous and diverse inhabitants – the viruses. A plethora of methods now exist for amplifying the vanishingly small amounts of nucleic acids in natural viral communities in order to sequence them, and sequencing depth is now so great that viral genomes can be detected and assembled even amid large concentrations of non-viral DNA. Complementing these advances in amplification and sequencing is the ability to physically link fluorescently labeled viruses to their host cells via high-throughput flow sorting. Sequencing of such isolated virus–host pairs facilitates cultivation-independent exploration of the natural host range of viruses. Within the next decade, as these technologies become widespread, we can expect to see a systematic expansion of our knowledge of viruses and their hosts. Recent advances in viral metagenomics include techniques for sequencing limiting amounts of viral nucleic acids, the use of ultra-deep sequencing, and viral tagging to determine virus–host interactions. Mock communities should be used to rigorously evaluate new protocols, and special consideration must be given to the storage of metagenomic data.
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  • 31
    Publication Date: 2013-03-02
    Description: The Hippo pathway, a cascade of protein kinases that inhibits the oncogenic transcriptional coactivators YAP and TAZ, was discovered in Drosophila as a major determinant of organ size in development. Known modes of regulation involve surface proteins that mediate cell-cell contact or determine epithelial cell polarity which, in a tissue-specific manner, use intracellular complexes containing FERM domain and actin-binding proteins to modulate the kinase activities or directly sequester YAP. Unexpectedly, recent work demonstrates that GPCRs, especially those signaling through Galpha 12/13 such as the protease activated receptor PAR1, cause potent YAP dephosphorylation and activation. This response requires active RhoA GTPase and increased assembly of filamentous (F-)actin. Morever, cell architectures that promote F-actin assembly per se also activate YAP by kinase-dependent and independent mechanisms. These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells. The hippo pathway, a protein kinase cascade activated by cell contact, phosphorylates the YAP oncogene to inhibit proliferation. GPCRs like PAR1 that recruit Gα 12/13 and activate RhoA can dephosphorylate and activate YAP through an inhibition of the hippo pathway. This requires F-actin assembly, which also activates YAP through hippo-independent mechanisms.
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  • 32
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    In: BioEssays
    Publication Date: 2013-02-12
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  • 33
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    In: BioEssays
    Publication Date: 2013-02-12
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  • 34
    Publication Date: 2013-02-12
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  • 35
    Publication Date: 2013-02-19
    Description: Upon emerging from the ribosome exiting tunnel, polypeptide folding occurs immediately with the assistance of both ribosome-associated and free chaperones. While many chaperones known to date are dedicated folding catalysts, recent studies have revealed a novel chaperoning system that functions at the interface of protein biogenesis and quality control by using a special “holdase” activity in order to sort and channel client proteins to distinct destinations. The key component, Bag6/Bat3/Scythe, can effectively shield long hydrophobic segments exposed on the surface of a polypeptide, preventing aggregation or inappropriate interactions before a triaging decision is made. The biological consequences of Bag6-mediated chaperoning are divergent for different substrates, ranging from membrane integration to proteasome targeting and destruction. Accordingly, Bag6 can act in various cellular contexts in order to execute many essential cellular functions, while dysfunctions in the Bag6 system can cause severe cellular abnormalities that may be associated with some pathological conditions. Here we discuss a newly discovered chaperone complex that uses a special “holdase” activity to channel client proteins to distinct cellular destinations. This activity modulates various cellular processes including tail-anchored (TA) protein biogenesis, ER-associated degradation (ERAD), quality control of mislocalized proteins and defective ribosome products, transcriptional regulation, DNA damage response, and apoptosis.
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  • 36
    Publication Date: 2013-02-19
    Description: The Homeric epics are among the greatest masterpieces of literature, but when they were produced is not known with certainty. Here we apply evolutionary-linguistic phylogenetic statistical methods to differences in Homeric, Modern Greek and ancient Hittite vocabulary items to estimate a date of approximately 710–760 BCE for these great works. Our analysis compared a common set of vocabulary items among the three pairs of languages, recording for each item whether the words in the two languages were cognate – derived from a shared ancestral word – or not. We then used a likelihood-based Markov chain Monte Carlo procedure to estimate the most probable times in years separating these languages given the percentage of words they shared, combined with knowledge of the rates at which different words change. Our date for the epics is in close agreement with historians' and classicists' beliefs derived from historical and archaeological sources. The Homeric epics are among the greatest masterpieces of literature, but when they were produced is not known with certainty. Here we apply evolutionary-linguistic phylogenetic statistical methods to differences in Homeric, Modern Greek and ancient Hittite vocabulary items to estimate a date of approximately 710–760 BCE for these great works.
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  • 37
    Publication Date: 2013-02-07
    Description: The position of leaves and flowers along the stem axis generates a specific pattern, known as phyllotaxis. A growing body of evidence emerging from recent computational modeling and experimental studies suggests that regulators controlling phyllotaxis are chemical, e.g. the plant growth hormone auxin and its dynamic accumulation pattern by polar auxin transport, and physical, e.g. mechanical properties of the cell. Here we present comprehensive views on how chemical and physical properties of cells regulate the pattern of leaf initiation. We further compare different computational modeling studies to understand their scope in reproducing the observed patterns. Despite a plethora of experimental studies on phyllotaxis, understanding of molecular mechanisms of pattern initiation in plants remains fragmentary. Live imaging of growth dynamics and physicochemical properties at the shoot apex of mutants displaying stable changes from one pattern to another should provide mechanistic insights into organ initiation patterns. Editor's suggested further reading in BioEssays Computer simulation: The imaginary friend of auxin transport biology Abstract Local auxin accumulation marks the organ initiation and controls the organ positioning in plants. The dynamics of auxin accumulation is mediated by the concentration and orientation of auxin transporters, which in turn are controlled by an intricate feedback mechanism involving both transport and mechanical strain.
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  • 38
    Publication Date: 2013-02-07
    Description: The fateful combination of (i) the Dunning-Kruger effect (ignorance of one's own ignorance) with (ii) the nonlinear dynamics of the echo-chamber between reviewers and editors fuels a self-reinforcing collective delusion system that sometimes spirals uncontrollably away from objectivity and truth. Escape from this subconscious meta-ignorance is a formidable challenge but if achieved will help correct a central deficit of the peer-review process that stifles innovation and paradigm shifts.
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  • 39
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    In: BioEssays
    Publication Date: 2013-02-12
    Description: Epithelial to mesenchymal transition as a portal to stem cell characters embedded in gene networks. The cover image shows the mouse proepicardial organ (PEO) at 9.5 dpc highlighted by Wt1 expression (bright red, centre). Bridges formed to the myocardium are a prelude to migration of proepicardial cells over the surface of the heart to form the epicardium. On pages 191–200 Naisana Asli and Richard Harvey review epithelial to mesenchymal transition (EMT) from a newly emerging angle that repositions this historically well-regarded process as central to stem cell character. The authors suggest that EMT is embedded within the gene regulatory network of certain stem cell populations, and postulate that ectopic induction of EMT might well be benefi cial to tissue regeneration.
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  • 40
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    In: BioEssays
    Publication Date: 2013-02-12
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  • 41
    Publication Date: 2013-02-20
    Description: Human lifespan variation is mainly determined by environmental factors, whereas the genetic contribution is 25–30% and expected to be polygenic. Two complementary fields go hand in hand in order to unravel the mechanisms of biological aging: genomic and biomarker research. Explorative and candidate gene studies of the human genome by genetic, transcriptomic, and epigenomic approaches have resulted in the identification of a limited number of interesting positive linkage regions, genes, and pathways that contribute to lifespan variation. The possibilities to further exploit these findings are rapidly increasing through the use of novel technologies, such as next-generation sequencing. Genomic research is progressively being integrated with biomarker studies on aging, including the application of (noninvasive) deep phenotyping and omics data – generated using novel technologies – in a wealth of studies in human populations. Hence, these studies may assist in obtaining a more holistic perspective on the role of the genome in aging and lifespan regulation. Editor's suggested further reading in BioEssays: On the cause of aging and control of lifespan Abstract The free-radical theory of ageing – older, wiser and still alive Abstract Longevity and the long arm of epigenetics: Acquired parental marks influence lifespan across several generations Abstract The mystery of C. elegans aging: An emerging role for fat Abstract A review on the accomplishments of genetic, transcriptomic, and epigenetic studies into the biology of aging and longevity by molecular and epidemiological analysis of human populations using family- and population-based study designs. In addition, the development of novel biomarkers of aging and their use for integrated data analysis is discussed.
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  • 42
    Publication Date: 2013-02-05
    Description: A series of recent studies on extant coelacanths has emphasised the slow rate of molecular and morphological evolution in these species. These studies were based on the assumption that a coelacanth is a ‘living fossil’ that has shown little morphological change since the Devonian, and they proposed a causal link between low molecular evolutionary rate and morphological stasis. Here, we have examined the available molecular and morphological data and show that: (i) low intra-specific molecular diversity does not imply low mutation rate, (ii) studies not showing low substitution rates in coelacanth are often neglected, (iii) the morphological stability of coelacanths is not supported by paleontological evidence. We recall that intra-species levels of molecular diversity, inter-species genome divergence rates and morphological divergence rates are under different constraints and they are not necessarily correlated. Finally, we emphasise that concepts such as ‘living fossil’, ‘basal lineage’, or ‘primitive extant species’ do not make sense from a tree-thinking perspective. Editor's suggested further reading in BioEssays Tree thinking for all biology: the problem with reading phylogenies as ladders of progress Abstract Recent studies that concluded that a slow rate of molecular evolution is linked to morphological conservatism in coelacanths are biased by the a priori hypothesis that these species are ‘living fossils’. We show that this outdated concept is not supported by actual molecular or paleontological data and does not make sense from a tree-thinking perspective.
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  • 43
    Publication Date: 2013-02-05
    Description: Recent results show that, during the process known as cell competition, winner cells identify and kill viable cells from a growing population without requiring engulfment. The engulfment machinery is mainly required in circulating macrophages (hemocytes) after the discrimination between winners and losers is completed and the losers have been killed and extruded from the epithelium. Those new results leave us with the question as to which molecules allow winner cells to recognize and impose cell death on the loser cells during cell competition. During cell competition, winner cells induce apoptosis in loser cells by unknown mechanisms. Apoptotic debris is extruded basally from the epithelium to be cleared by hemocytes.
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  • 44
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    In: BioEssays
    Publication Date: 2013-01-16
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  • 45
    Publication Date: 2013-12-10
    Description: The establishment of a functional vascular system requires multiple complex steps throughout embryogenesis, from endothelial cell (EC) specification to vascular patterning into venous and arterial hierarchies. Following the initial assembly of ECs into a network of cord-like structures, vascular expansion and remodeling occur rapidly through morphogenetic events including vessel sprouting, fusion, and pruning. In addition, vascular morphogenesis encompasses the process of lumen formation, critical for the transformation of cords into perfusable vascular tubes. Studies in mouse, zebrafish, frog, and human endothelial cells have begun to outline the cellular and molecular requirements underlying lumen formation. Although the lumen can be generated through diverse mechanisms, the coordinated participation of multiple conserved molecules including transcription factors, small GTPases, and adhesion and polarity proteins remains a fundamental principle, leading us closer to a more thorough understanding of this complex event. During blood vessel development, endothelial cells first coalesce into cord-like structures that must transition into tubes containing a central lumen in order to become functional transporters of blood throughout the body. The diverse mechanisms by which vessels form lumens will be discussed in the following review.
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  • 46
    Publication Date: 2013-12-10
    Description: Scaling of pattern with size has been described and studied for over a century, yet its molecular basis is understood in only a few cases. In a recent, elegant study, Inomata and colleagues proposed a new model explaining how bone morphogenic protein (BMP) activity gradient scales with embryo size in the early Xenopus laevis embryo. We discuss their results in conjunction with an alternative model we proposed previously. The expansion-repression mechanism (ExR) provides a conceptual framework unifying both mechanisms. Results of Inomata and colleagues implicate the chordin-stabilizing protein sizzled as the expander molecule enabling scaling, while we attributed this role to the BMP ligand Admp. The two expanders may work in concert, as suggested by the mathematical model of Inomata et al. We discuss approaches for differentiating the contribution of sizzled and Admp to pattern scaling. Inomata and colleagues proposed an elegant model explaining how sizzled scales patterning in Xenopus laevis embryo with embryo size. We review this work in context of the expansion-repression framework, and suggest both sizzled and Admp function as expanders of the bone morphogenic protein (BMP) activation gradient, to robustly scale its pattern with size.
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  • 47
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    In: BioEssays
    Publication Date: 2013-12-11
    Description: What fuels appendage regeneration? On pages 27-32 of this issue, Love et al. examine the role of carbohydrate metabolism during vertebrate appendage regeneration. The authors largely focus their examination on recent studies using the Xenopus model, whose tadpoles and froglets (shown on the cover, tissues visualized with immunostaining and transgenesis) have the impressive ability to regenerate some of their appendages. The authors argue that increasing carbohydrate entry into anabolic pathways is critical to the regeneration program and that Xenopus represents a good model system to study the interplay between cellular metabolism and appendage regeneration. Cover by Nick R. Love.
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  • 48
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  • 49
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  • 50
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  • 51
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  • 52
    Publication Date: 2013-12-11
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  • 53
    Publication Date: 2013-12-11
    Description: The Cas9 endonuclease is the central component of the Type II CRISPR/Cas system, a prokaryotic adaptive restriction system against invading nucleic acids, such as those originating from bacteriophages and plasmids. Recently, this RNA-directed DNA endonuclease has been harnessed to target DNA sequences of interest. Here, we review the development of Cas9 as an important tool to not only edit the genomes of a number of different prokaryotic and eukaryotic species, but also as an efficient system for site-specific transcriptional repression or activation. Additionally, a specific Cas9 protein has been observed to target an RNA substrate, suggesting that Cas9 may have the ability to be programmed to target RNA as well. Cas proteins from other CRISPR/Cas subtypes may also be exploited in this regard. Thus, CRISPR/Cas systems represent an effective and versatile biotechnological tool, which will have significant impact on future advancements in genome engineering. The CRISPR/Cas endonuclease, Cas9, has been exploited to specifically target DNA sequences of interest. This has created rapid genome editing technologies, as well as transcriptional repression and activation systems. Cas9 may allow development of a direct RNA interference system, and may ultimately be the foundation for future gene therapy technologies.
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  • 54
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    In: BioEssays
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  • 55
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    In: BioEssays
    Publication Date: 2013-10-12
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  • 56
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    In: BioEssays
    Publication Date: 2013-10-12
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  • 57
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    In: BioEssays
    Publication Date: 2013-10-12
    Description: Unfold, rotate and activate: New insights into insulin receptor activation. On pages 945–954 , Ward et al. review the most recent data on how insulin binds to its receptor and speculate on the ensuing conformational changes that lead to signal transduction within the cell. The cover shows the ectodomain of the insulin receptor (αβ) 2 homodimer (orange/purple). Binding of insulin (represented in cyan) leads to a conformational change within the ectodomain that is as yet only partially understood, ultimately resulting in the activation of the intracellular tyrosine kinase domains.
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  • 58
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    In: BioEssays
    Publication Date: 2013-10-12
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  • 59
    Publication Date: 2013-10-09
    Description: It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na + , Ca 2+ , and K + ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand-gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels. Also watch the Video Abstract . Receptor signaling is thought to occur on two time scales: fast and slow. Ligand-gated ion channels, such as the nicotinic receptor, are known to operate by rapidly conducting ions into the cell. We explore new evidence of an interaction between nicotinic receptors and G protein signaling in neurons.
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  • 60
    Publication Date: 2013-10-08
    Description: In Europe ≈15,000 patients receive larval therapy for wound treatment annually. Over the past few years, clinical studies have demonstrated the success of larvae of Lucilia sericata as debridement agents. This is based on a combination of physical and biochemical actions. Laboratory investigations have advanced our understanding of the biochemical mechanisms underlying the beneficial effects of larval secretions, including removal of dead tissue, reduction of the bacterial burden, and promotion of tissue regeneration. The present article summarizes our current understanding of the microbiological, immunological, and wound healing actions of larval therapy, and the molecules involved in these beneficial effects. Future studies will focus on the isolation, identification, and (pre)clinical testing of the effective molecules of L. sericata larvae. These molecules may be candidates for the development of new agents for the treatment of several infectious and inflammatory diseases, including chronic wounds. The FDA has approved larval therapy as a device for debridement of chronic wounds. Other beneficial effects of larvae of Lucilia sericata and their secretions on wounds have been observed, such as antibacterial, antibiofilm, and anti-inflammatory activities. These effects can explain how chronic wounds may shift into healing wounds.
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  • 61
    Publication Date: 2013-10-12
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  • 62
    Publication Date: 2013-10-25
    Description: The evolution of a variety of important chromophore-dependent biological processes, including microbial light sensing and mammalian color vision, relies on protein modifications that alter the spectral characteristics of a bound chromophore. Three different color opsins share the same chromophore, but have three distinct absorptions that together cover the entire visible spectrum, giving rise to trichromatic vision. The influence of opsins on the absorbance of the chromophore has been studied through methods such as model compounds, opsin mutagenesis, and computational modeling. The recent development of rhodopsin mimic that uses small soluble proteins to recapitulate the binding and wavelength tuning of the native opsins provides a new platform for studying protein-regulated spectral tuning. The ability to achieve far-red shifted absorption in the rhodopsin mimic system was attributed to a combination of the lack of a counteranion proximal to the iminium, and a uniformly neutral electrostatic environment surrounding the chromophore. Nature regulates the interactions of retinal with its protein binder to tune its absorption across the entire visible range. This spectral regulation has been recapitulated in reengineered human cellular retinol binding protein (hCRBPII), which binds retinal as an iminium. Spectral tuning was achieved by changing the binding pocket's electrostatic environment.
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  • 63
    Publication Date: 2013-10-25
    Description: Understanding the impact of the p53 tumor suppressor pathway on the regulation of genome integrity, cancer development, and cancer treatment has intrigued scientists and clinicians for decades. It appears that the p53 pathway is a central node for nearly all cell stress responses, including: gene expression, DNA repair, cell cycle arrest, metabolic adjustments, apoptosis, and senescence. In the past decade, it has become increasingly clear that p53 function is directly regulated by poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme involved in DNA repair signaling. Here, we will discuss the impact of PARP-1 on p53 function, along with a recently described novel role for the reciprocal regulation of p53 regulated, PARP-1 dependent necrosis following DNA damage. In response to ROS-induced DNA damage, both the p53 and PARP-1 pathways are activated. A role for PARP-1 in regulating p53-mediated functions is established. Now, an emerging literature suggests that a reciprocal functional relationship exists between p53 and PARP-1, which impacts upon p53-dependent apoptotic and necrotic cell death programs.
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  • 64
    Publication Date: 2013-10-16
    Description: Most land plants associate with mycorrhizal fungi that can connect roots of neighboring plants in common mycelial networks (CMNs). Recent evidence shows that CMNs transfer warning signals of pathogen and aphid attack between plants. However, we do not know how defence-related signaling via CMNs operates or how ubiquitous it is. Nor do we know what the ecological relevance and fitness consequences are, particularly from the perspective of the mycorrhizal fungus. Here, we focus on the potential fitness benefits for mycorrhizal fungi and outline hypothetical scenarios in which signal transfer via CMNs is modulated in order to acquire the most benefit for the fungus (i.e. acquisition of carbon) for minimal cost. We speculate that the signal may be quantitative and may elicit plant defence responses on different levels depending on the distance the signal is transferred. Finally, we discuss the possibility of practical applications of this phenomenon for crop protection. Mycorrhizal fungi connect roots of neighboring plants in common mycelial networks. Recent research demonstrates that these networks transfer warning signals of aphid attack between plants. Here, we speculate about the ecological implications of this signaling pathway, how is it regulated, and the benefits to the fungi of transferring the signal.
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  • 65
    Publication Date: 2013-10-16
    Description: Here we present and develop the hypothesis that the derepression of endogenous retrotransposable elements (RTEs) – “genomic parasites” – is an important and hitherto under-unexplored molecular aging process that can potentially occur in most tissues. We further envision that the activation and continued presence of retrotransposition contribute to age-associated tissue degeneration and pathology. Chromatin is a complex and dynamic structure that needs to be maintained in a functional state throughout our lifetime. Studies of diverse species have revealed that chromatin undergoes extensive rearrangements during aging. Cellular senescence, an important component of mammalian aging, has recently been associated with decreased heterochromatinization of normally silenced regions of the genome. These changes lead to the expression of RTEs, culminating in their transposition. RTEs are common in all kingdoms of life, and comprise close to 50% of mammalian genomes. They are tightly controlled, as their activity is highly destabilizing and mutagenic to their resident genomes. Transposable elements are autonomous DNA parasites that are largely deleterious to their host genomes. Cells use multiple mechanisms to silence them but activation is increasingly being found in somatic tissues. Surveillance can break down with aging, and genome destabilization caused by active transposition may be an important molecular aging process.
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  • 66
    Publication Date: 2013-10-21
    Description: In this paper we contrast the simple role of FOXO in the seemingly non-aging Hydra with its more diversified function in multicellular eukaryotes that manifest aging and limited life spans. From this comparison we develop the concept that, whilst once devoted to life-prolonging cell-renewal (in Hydra), evolutionary accumulation of coupled functionality in FOXO has since ‘distracted’ it from this role. Seen in this light, aging may not be the direct cost of competing functions, such as reproduction or growth, but the result of a shift in emphasis in a protein, which is accompanied by advantages such as greater organismal complexity and adaptability, but also disadvantages such as reduced regeneration capacity. Studying the role of FOXO in non-aging organisms might, therefore, illuminate the path to extend life span in aging organisms. Editor's suggested further reading in BioEssays Stem cells and aging from a quasi-immortal point of view   Abstract Recent studies on the role of FOXO in the non-aging Hydra model might explain how aging evolved by a shift from FOXO-mediated renewal to mediating maintenance. In our paper we explain how the uncoupling of FOXO may enable life span extension in aging organisms, including humans.
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  • 67
    Publication Date: 2013-12-11
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  • 68
    Publication Date: 2013-11-28
    Description: The idea that oxidative stress may underpin life history trade-offs has become extremely popular. However, experimental support for the concept has proved equivocal. It has recently been suggested that this might be because of flaws in the design of existing studies. Here, we explore the background to the oxidative stress hypothesis and highlight some of the complexities in testing it. We conclude that the approach recently suggested to be least useful in this context (comparing reproducing to non-reproducing animals) may in fact be the most powerful. Moreover, suggested alternative approaches of limiting food supply or manipulating litter sizes have many complexities and problems. We suggest some useful alternative approaches that have not been previously advocated, particularly the study of individuals reproducing at greater parity later in life. Finally, the measures of oxidative stress and tissues that are analysed influence the experimental outcome. This suggests our conceptual model of the trade-off is currently too simplistic, and that studies based on single or limited numbers of assays, or restricted to single tissues, whether they support or refute the theory, should be interpreted with great caution. Recent evidence suggests reproduction, possibly mediated via reproductive hormones, in combination with uncoupling, and energy supply results in different levels of free-radical production in different tissues. Consequent damage to Protein, DNA and Fat depends on selective allocation of protection. Survival may be a consequence of effects across all tissues or a single crucially important impact.
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  • 69
    Publication Date: 2013-11-28
    Description: Paradoxically, DNA sequence polymorphisms in cancer risk loci rarely correlate with the expression of cancer genes. Therefore, the molecular mechanism underlying an individual's susceptibility to cancer has remained largely unknown. However, recent evaluations of the correlations between DNA methylation and gene expression levels across healthy and cancerous genomes have revealed enrichment of disease-related DNA methylation variations within disease-associated risk loci. Moreover, it appears that transcriptional enhancers embedded in cancer risk loci often contain DNA methylation sites that closely define the expression of prominent cancer genes, despite the lack of significant correlations between gene expression levels and the surrounding disease-associated polymorphic sequences. We suggest that DNA methylation variations may obscure the effect of co-residing risk sequence alleles. Analysis of enhancer methylation data may help to reveal the regulatory circuits underlying predisposition to cancers and other common diseases. Editor's suggested further reading in BioEssays DNA methylation reprogramming in cancer: Does it act by re-configuring the binding landscape of Polycomb repressive complexes?   Abstract Tumor samples exhibit genetic and epigenetic variations across individuals. However, cancer-associated risk sequence alleles failed to reveal the link with the mechanism of cancer ( left ). Implementation of DNA methylation data helps to resolve the effect on drivers of cancer development, and hence to explains the biology of cancer susceptibility ( right ).
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  • 70
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    In: BioEssays
    Publication Date: 2013-03-15
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  • 71
    Publication Date: 2013-03-15
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  • 72
    Publication Date: 2013-07-18
    Description: A number of observations have led researchers to postulate that, despite being replication-defective, human endogenous retroviruses (HERVs) may have retained the potential to cause or contribute to disease. However, mechanisms of HERV pathogenicity might differ substantially from those of modern infectious retroviruses or of the infectious precursors of HERVs. Therefore, novel pathways of HERV involvement in disease pathogenesis should be investigated. Recent technological advances in sequencing and bioinformatics are making this task increasingly feasible. The accumulating knowledge of HERV biology may also facilitate the definition and general acceptance of criteria that establish HERV pathogenicity. Here, we explore possible mechanisms whereby HERVs may cause disease and examine the evidence that either has been or should be obtained in order to decisively address the pathogenic potential of HERVs. The human genome contains numerous and repetitive human endogenous retroviruses (HERVs), relics of ancestral infection. Their mere presence in the genome, as well as distinct nucleic acid intermediates of retroviral replication and proteins produced by intact open reading frames may cause or contribute to pathology through the mechanism depicted.
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  • 73
    Publication Date: 2013-07-25
    Description: Phosphatidylinositol 3-phosphate (PtdIns3P) is generated on the cytosolic leaflet of cellular membranes, primarily by phosphorylation of phosphatidylinositol by class II and class III phosphatidylinositol 3-kinases. The bulk of this lipid is found on the limiting and intraluminal membranes of endosomes, but it can also be detected in domains of phagosomes, autophagosome precursors, cytokinetic bridges, the plasma membrane and the nucleus. PtdIns3P controls cellular functions through recruitment of specific protein effectors, many of which contain FYVE or PX domains. Cellular processes known to be controlled by PtdIns3P and its effectors include endosomal fusion, sorting and motility, autophagy, cytokinesis, regulated exocytosis and signal transduction. Here we discuss how Ptdins3P is generated on specific cellular membranes, how its localizations and functions can be studied, and how its effectors serve to control cellular functions. Editor's suggested further reading in BioEssays: Phosphatidylinositol 4,5-bisphosphate: Targeted production and signaling Abstract How does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity? Abstract Phosphatidylinositol-3,4,5-trisphosphate: Tool of choice for class I PI 3-kinases Abstract Phosphatidylinositol-4-phosphate: The Golgi and beyond Abstract Phosphatidylinositol 3-phosphate (PtdIns3P) is generated on various cellular membranes by class II and III PI 3-kinases and functions by recruiting effectors that contain FYVE or PX domains. Cellular processes controlled by PtdIns3P and its effectors include endosomal fusion, sorting, and motility, autophagy, cytokinesis, regulated exocytosis and signal transduction.
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  • 74
    Publication Date: 2013-07-25
    Description: The contribution of inherited non-genetic factors to complex diseases is of great current interest. The ways in which mothers and fathers can affect their offspring's health clearly differ as a result of the intimate interactions between mother and offspring during pre- and postnatal life. There is, however, potential for some overlap in mechanisms, particularly epigenetic mechanisms. A small number of epidemiological studies and animal models have investigated the non-genetic contribution of the parents to offspring health. Discovering new mechanisms of disease inheritance is technically difficult, especially in genetically, socially and environmentally heterogeneous human populations. Therefore, rigorous experimental design, appropriate sample numbers and the use of high-throughput technologies are necessary to provide convincing evidence. Based on recent examples from the literature, here we propose several ways to improve human studies that aim to identify the underlying mechanisms of transgenerational inheritance of metabolic disease. Recommendations for improving the different steps of studies investigating mechanisms of parental programming
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  • 75
    Publication Date: 2013-07-06
    Description: We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long-range transcriptional regulation. Several observations suggest that TADs can indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied. It has been recently shown that chromosomes are segmented in a series of discrete Topologically Associating Domains, or TADs, which in mammals have an average size of 1 Megabase. Here we discuss how such an arrangement may provide a basis for domain-wide control of chromatin structure and transcriptional regulation.
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  • 76
    Publication Date: 2013-07-13
    Description: Sexually-selected exaggerated traits tend to be unusually reliable signals of individual condition, as their expression tends to be more sensitive to nutritional history and physiological circumstance than that of other phenotypes. As such, these traits are the foundation for many models of sexual selection and animal communication, such as “handicap” and “good genes” models. Exactly how expression of these traits is linked to the bearer's condition has been a central yet unresolved question, in part because the underlying physiological mechanisms regulating their development have remained largely unknown. Recent discoveries across animals as diverse as deer, beetles, and flies now implicate the widely conserved insulin-like signaling pathway, as a common physiological mechanism regulating condition-sensitive structures with extreme growth. This raises the exciting possibility that one highly conserved pathway may underlie the evolution of trait exaggeration in a multitude of sexually-selected signal traits across the animal kingdom. From the elaborate tails of peacocks to the enlarged head-horns of dung beetles, sexually-selected exaggerated traits are conspicuous and reliable signals of individual condition. How is the reliability and honesty of the signal maintained? We propose that co-option of the ancient and highly conserved insulin/insulin-like signaling pathway is the key.
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  • 77
    Publication Date: 2013-07-09
    Description: Large-scale characterization of the human microbiota has largely focused on Western adults, yet these populations may be uncharacteristic because of their diets and lifestyles. In particular, the rise of “Western diseases” may in part stem from reduced exposure to, or even loss of, microbes with which humans have coevolved. Here, we review beneficial microbes associated with pathogen resistance, highlighting the emerging role of complex microbial communities in protecting against disease. We discuss ways in which modern lifestyles and practices may deplete physiologically important microbiota, and explore prospects for reintroducing or encouraging the growth of beneficial microbes to promote the restoration of healthy microbial ecosystems. Exposure to microbes is known to train our immune system to recognize pathogens and promote host health. Here, we discuss how modern behaviors, including Cesarean sections, antibiotic use, and limited exposure to animals, might derail our microbiota from its ancestral trajectory, and discuss suggested methods to replenish beneficial human microbes.
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  • 78
    Publication Date: 2013-07-10
    Description: Whole genome sequencing and SNP genotyping arrays can paint strikingly different pictures of demographic history and natural selection. This is because genotyping arrays contain biased sets of pre-ascertained SNPs. In this short review, we use comparisons between high-coverage whole genome sequences of African hunter-gatherers and data from genotyping arrays to highlight how SNP ascertainment bias distorts population genetic inferences. Sample sizes and the populations in which SNPs are discovered affect the characteristics of observed variants. We find that SNPs on genotyping arrays tend to be older and present in multiple populations. In addition, genotyping arrays cause allele frequency distributions to be shifted towards intermediate frequency alleles, and estimates of linkage disequilibrium are modified. Since population genetic analyses depend on allele frequencies, it is imperative that researchers are aware of the effects of SNP ascertainment bias. With this in mind, we describe multiple ways to correct for SNP ascertainment bias. The specific genetic variants that are analyzed can have important implications for studies of population genetics. Using data from African hunter-gatherers, we demonstrate how high-coverage whole genome sequences and ascertained SNPs on genotyping arrays yield different results.
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  • 79
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    In: BioEssays
    Publication Date: 2013-07-16
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  • 80
    Publication Date: 2013-07-16
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  • 81
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    Wiley
    In: BioEssays
    Publication Date: 2013-07-16
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  • 82
    Publication Date: 2013-07-18
    Description: Phenotypic divergence among animal species may be due in part to species-specific (SS) regulation of gene expression by small, non-coding regulatory RNAs termed “microRNAs”. This phenomenon can be modulated by several variables. First, microRNA genes vary by their level of conservation, many of them being SS, or unique to a particular evolutionary lineage. Second, microRNA expression levels vary spatially and temporally in different species. Lastly, while microRNAs bind the 3′UTR of target genes in order to silence their expression, the binding sites themselves are often non-conserved. The variability of the miRNA-target paradigm between different species is thus multifactorial, and this paradigm has only just started to gain attention from researchers in various fields. Here we present and discuss recent findings regarding the characteristics and implications of SS microRNA regulation. Non-conserved microRNA repertoire, microRNA expression patterns, and their gene target binding sites, are likely to be key drivers of phenotypic differences among animal species. Here we present and discuss recent findings regarding these phenomena that form a complex species-specific microRNA regulation paradigm.
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  • 83
    Publication Date: 2013-05-14
    Description: Recently, the development of several strategies based on immunotherapy has raised hopes for a more promising way to treat cancer patients. Here, we describe how interleukin (IL)-10, a seemingly unlikely candidate, stimulates the immune system in a particularly efficacious way. IL-10, an omnipotent anti-inflammatory cytokine, delivers an equally potent immune stimulation in the context of CD8 + T cells and tumor immunity. By activation of tumor-resident, tumor-specific CD8 + T cells, pegylated IL-10 can induce rejection of large and metastasizing tumors in mice. Here, we summarize the mechanisms of action of IL-10, the reasons why the mechanisms may be crucial for the treatment of cancer patients, and the rationale for applying pegylated IL-10 in the clinic. Pegylated IL-10 induces several essential components for cancer immunity: expansion of tumor resident CD8 + T cells, expression of IFN-γ and cytotoxic enzymes in tumor resident CD8 + T cells and antigen presentation within the tumor. PEG-IL-10 treatment leads to tumor rejection and long lasting tumor immunity.
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  • 84
    Publication Date: 2013-04-12
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  • 85
    Publication Date: 2013-04-10
    Description: Enormous phylogenetic variation exists in the number and sizes of introns in protein-coding genes. Although some consideration has been given to the underlying role of the population-genetic environment in defining such patterns, the influence of the intracellular environment remains virtually unexplored. Drawing from observations on interactions between co-transcriptional processes involved in splicing and mRNA 3′-end formation, a mechanistic model is proposed for splice-site recognition that challenges the commonly accepted intron- and exon-definition models. Under the suggested model, splicing factors that outcompete 3′-end processing factors for access to intronic binding sites concurrently favor the recruitment of 3′-end processing factors at the pre-mRNA tail. This hypothesis sheds new light on observations such as the intron-mediated enhancement of gene expression and the negative correlation between intron length and levels of gene expression. We propose a scenario wherein factors that regulate pre-mRNA splicing and 3′-end formation compete for access to binding sites within introns and 3′ UTRs. Dynamic molecular tradeoffs determine the outcome of these antagonistic interactions and mediate the selection of exons and transcription termination sites.
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  • 86
    Publication Date: 2013-04-25
    Description: Plants move in very different ways and for different reasons, but some active carnivorous plants perform extraordinary motion: Their snap-, catapult- and suction traps perform very fast and spectacular motions to catch their prey after receiving mechanical stimuli. Numerous investigations have led to deeper insights into the physiology and biomechanics of these trapping devices, but they are far from being fully understood. We review concisely how plant movements are classified and how they follow principles that bring together speed, actuation and architecture of the moving organ. In particular, we describe and discuss how carnivorous plants manage to execute fast motion. We address open questions and assess the prospects for future studies investigating potential universal mechanisms that could be the basis of key characteristic features in plant movement such as stimulus transduction, post-stimulatory mechanical answers, and organ formation. Carnivorous plants like the Venus' flytrap make use of mechanical tricks to speed up their traps. We review the interaction of plant organ dimension, movement speed and type of actuation as a biophysical principle, and discuss promising key aspects for future studies.
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  • 87
    Publication Date: 2013-04-25
    Description: The discovery of a stable latent reservoir for HIV-1 in resting memory CD4 + T cells provides a mechanism for lifelong persistence of HIV-1. The long-lived latently infected cells persist in spite of prolonged highly active antiretroviral therapy and present a major barrier to a cure of HIV-1 infection. In this review, we discuss the current understanding of HIV-1 persistence and latent viral infection in the context of effective antiretroviral therapy and the recent progress in purging latent viral reservoirs. Recent studies demonstrate that reactivation of latent HIV-1 is a promising strategy for the depletion of these viral reservoirs. A thorough evaluation of the anti-latency activity of drug candidates should include the measurement of changes in intracellular viral RNA, plasma virus levels, and the size of latent viral reservoirs, as well as potential adverse effects. Currently, there are several technical barriers to the evaluation of anti-latency drugs in vivo. We also discuss these challenging issues that remain unresolved. A stable latent reservoir for HIV-1 in resting memory CD4 + T cells presents a major barrier to a cure of HIV-1 infection. This paper summarizes the recent progress in purging the latent reservoir and discusses the challenging issues that remain unresolved.
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  • 88
    Publication Date: 2013-04-30
    Description: High-throughput genomic technologies are revolutionizing human genetics. So far the focus has been on the 1.5% of the genome, which is coding, in spite of the fact that the great majority of genomic variants fall outside the coding regions. Recent efforts to annotate the non-coding sequence show that over 80% of the genome is biochemically active. The genome is divided into regulatory domains consisting of sequence regions that enhance and/or silence the expression of nearby genes and are, in some cases, separated by boundaries with insulator activity. In this paper, we review the recent advances in the identification of variations that influence gene regulation and their consequences for human disease. We hypothesize that structural variations outside of the coding genome can interfere with normal gene regulation by disrupting the regulatory landscape. Therefore, the regulatory landscape of the genome has also to be taken into consideration when investigating the pathology of human disease. The ENCODE data indicate that over 80% of the genome is biochemically active. The regulatory landscape of the genome is divided into topological domains containing cis-regulatory elements: enhancers, silencers, and insulators. Non-coding CNVs and mutations have to be taken into consideration for the investigation of human disease.
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  • 89
    Publication Date: 2013-04-30
    Description: In vitro reconstitution assays are commonly used to study biological membrane fusion. However, to date, most ensemble and single-vesicle experiments involving SNARE proteins have been performed only with lipid-mixing, but not content-mixing indicators. Through simultaneous detection of lipid and small content-mixing indicators, we found that lipid mixing often occurs seconds prior to content mixing, or without any content mixing at all, during a 50-seconds observation period, for Ca 2+ -triggered fusion with SNAREs, full-length synaptotagmin-1, and complexin. Our results illustrate the caveats of commonly used bulk lipid-mixing fusion experiments. We recommend that proteoliposome fusion experiments should always employ content-mixing indicators in addition to, or in place of, lipid-mixing indicators. In vitro reconstitution assays are commonly used to study molecular mechanism of SNARE-mediated membrane fusion. The large difference between lipid and content mixing observed from single vesicle-vesicle assay simultaneously monitoring both lipid and content exchange, calls into question proteoliposome assays that only rely on lipid-mixing reporters to assess fast fusion.
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  • 90
    Publication Date: 2013-04-30
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  • 91
    Publication Date: 2013-05-03
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  • 92
    Publication Date: 2013-03-13
    Description: The secretory pathway delivers proteins synthesized at the rough endoplasmic reticulum (RER) to various subcellular locations via the Golgi apparatus. Currently, efforts are focused on understanding the molecular machineries driving individual processes at the RER and Golgi that package, modify and transport proteins. However, studies are routinely performed using non-dividing cells. This obscures the critical issue of how the secretory pathway is affected by cell division. Indeed, several studies have indicated that protein trafficking is down-regulated during mitosis. Moreover, the RER and Golgi apparatus exhibit gross reorganization in mitosis. Here I provide a relatively neglected perspective of how the mitotic cyclin-dependent kinase (CDK1) could regulate various stages of the secretory pathway. I highlight several aspects of the mitotic control of protein trafficking that remain unresolved and suggest that further studies on how the mitotic CDK1 influences the secretory pathway are necessary to obtain a deeper understanding of protein transport. The molecular details of protein trafficking in interphase cells are well-studied. Here I highlight interesting data showing down-regulation of protein trafficking at various levels in mitosis by CDK1. I propose that a deeper understanding of the secretory pathway could emerge from studies with a perspective from the cell division cycle.
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  • 93
    Publication Date: 2013-03-12
    Description: Polyglutamine (polyQ) diseases are genetically inherited neurodegenerative disorders. They are caused by mutations that result in polyQ expansions of particular proteins. Mutant proteins form intranuclear aggregates, induce cytotoxicity and cause neuronal cell death. Protein interaction data suggest that polyQ regions modulate interactions between coiled-coil (CC) domains. In the case of the polyQ disease spinocerebellar ataxia type-1 (SCA1), interacting proteins with CC domains further enhance aggregation and toxicity of mutant ataxin-1 (ATXN1). Here, we suggest that CC partners interacting with the polyQ region of a mutant protein, increase its aggregation while partners that interact with a different region reduce the formation of aggregates. Computational analysis of genetic screens revealed that CC-rich proteins are highly enriched among genes that enhance pathogenicity of polyQ proteins, supporting our hypothesis. We therefore suggest that blocking interactions between mutant polyQ proteins and their CC partners might constitute a promising preventive strategy against neurodegeneration. Editor's suggested further reading in BioEssays: Binding of amyloid peptides to domain-swapped dimers of other amyloid-forming proteins may prevent their neurotoxicity Abstract Active conversion to the prion state as a molecular switch for cellular adaptation to environmental stress Abstract Toxic polyQ proteins form beta-sheet aggregates (A). A partner with a coiled-coil (CC) conformation interacting with the toxic protein at its polyQ domain, enhances aggregation (B). On the contrary, a non-CC partner that interacts with the toxic protein at a different domain than its polyQ, suppresses protein aggregation (B).
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  • 94
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    In: BioEssays
    Publication Date: 2013-03-15
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  • 95
    Publication Date: 2013-03-15
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  • 96
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    Wiley
    In: BioEssays
    Publication Date: 2013-03-15
    Description: The various consequences of jumping: How mammalian transposons can differentially influence gene expression and function . Transposable elements (TEs) make up a large fraction of mammalian genomes. On pages 397–407 , Akagi, Li and Symer discuss how these elements can exert wide-ranging biological impacts by variably affecting and disrupting gene expression, regulation, structure and function. Both germline and somatic mobilization of TEs can occur, potentially contributing to genetic diversity both between individuals in mammalian populations, and within individuals' tissues and cells. The authors discuss various factors that can influence the wide-ranging functional impacts of ongoing, endogenous transposition in mammals. Cover art by Anthony Baker (Medical Visuals, Health Sciences Library, The Ohio State University).
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  • 97
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    In: BioEssays
    Publication Date: 2013-03-15
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  • 98
    Publication Date: 2013-03-15
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  • 99
    Publication Date: 2013-05-03
    Description: Stress associated proteins (SAPs), novel A20/AN1 zinc-finger domain-containing proteins, are fast emerging as potential candidates for biotechnological approaches in order to improve abiotic stress tolerance in plants – the ultimate aim of which is crop-yield protection. Until relatively recently, such proteins had only been identified in humans, where they had been shown to be key regulators of innate immunity. Their phylogenetic relationship and recruitment of diverse protein domains reflect an architectural and mechanistic diversity. Emerging evidence suggests that SAPs may act as ubiquitin ligase, redox sensor, and regulator of gene expression during stress. Here, we evaluate the new knowledge on SAPs with a view to understand their mechanism of action. Furthermore, we set an agenda for investigating hitherto unexplored roles of these proteins. Stress associated proteins (SAPs) are novel A20/AN1 zinc-finger proteins of plants showing phylogenetic relationship with their homologs in animals. They help protect crop-yield loss due to stress by acting as ubiquitin ligase, redox sensor, and regulator of gene expression. Also, they are known regulators of innate immunity in animals.
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  • 100
    Publication Date: 2013-05-16
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