ALBERT

Beschreibung: © The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Annual Review of Marine Science 9 (2017): 173-203, doi:10.1146/annurev-marine-010816-060733.

Beschreibung: The events that followed the Tohoku earthquake and tsunami on March 11, 2011, included the loss of power and overheating at the Fukushima Daiichi nuclear power plants, which led to extensive releases of radioactive gases, volatiles, and liquids, particularly to the coastal ocean. The fate of these radionuclides depends in large part on their oceanic geochemistry, physical processes, and biological uptake. Whereas radioactivity on land can be resampled and its distribution mapped, releases to the marine environment are harder to characterize owing to variability in ocean currents and the general challenges of sampling at sea. Five years later, it is appropriate to review what happened in terms of the sources, transport, and fate of these radionuclides in the ocean. In addition to the oceanic behavior of these contaminants, this review considers the potential health effects and societal impacts.

Beschreibung: K.B. was supported in part by the Gordon and Betty Moore Foundation and the Deerbrook Charitable Trust. P.M. was supported in part by the Generalitat de Catalunya through MERS (grant 2014 SGR 1356), the European Commission 7th Framework COMET-FRAME project (grant agreement 604974), and the Ministerio de Economía y Competitividad of Spain (project CTM2011-15152-E). S.C. was supported in part by the French program Investissement d'Avenir run by the National Research Agency (AMORAD project, grant ANR-11-RSNR-0002). D.O. was supported in part by the Center for Environmental Radioactivity (NFR Centers of Excellence grant 223268/F50). J.N.S. was supported in part by the Marine Environmental Observation, Prediction, and Response Network.

Beschreibung: Coeval changes in atmospheric CO2 and 14C contents during the last deglaciation are often attributed to ocean circulation changes that released carbon stored in the deep ocean during the Last Glacial Maximum (LGM). Work is being done to generate records that allow for the identification of the exact mechanisms leading to the accumulation and release of carbon from the oceanic reservoir, but these mechanisms are still the subject of debate. Here we present foraminifera 14C data from five cores in a transect across the Chilean continental margin between ~540 and ~3,100 m depth spanning the last 20,000 years. Our data reveal that during the LGM, waters at ~2,000 m were 50% to 80% more depleted in Δ14C than waters at ~1,500 m when compared to modern values, consistent with the hypothesis of a glacial deep ocean carbon reservoir that was isolated from the atmosphere. During the deglaciation, our intermediate water records reveal homogenization in the Δ14C values between ~800 and ~1,500 m from ~16.5–14.5 ka cal BP to ~14–12 ka cal BP, which we interpret as deeper penetration of Antarctic Intermediate Water. While many questions still remain, this process could aid the ventilation of the deep ocean at the beginning of the deglaciation, contributing to the observed ~40 ppm rise in atmospheric pCO2.

Beschreibung: The Arctic Ocean is known to be contaminated by various persistent organic pollutants (POPs). The Fram Strait, the only deepwater passage to the Arctic Ocean (from the Atlantic Ocean), represents an unquantified gateway for POPs fluxes into and out of the Arctic. Polyethylene passive samplers were deployed in vertical profiles in the Fram Strait and in air and surface water in the Canadian Archipelago to determine the concentrations, profiles, and mass fluxes of dissolved polychlorinated biphenyls (PCBs) and organochlorine pesticides. In the Fram Strait, higher concentrations of ΣPCBs (1.3–3.6 pg/L) and dichlorodiphenyltrichloroethanes (ΣDDTs, 5.2–9.1 pg/L) were observed in the deepwater masses (below 1,000 m), similar to nutrient-like vertical profiles. There was net southward transport of hexachlorobenzene and hexachlorocyclohexanes (ΣHCHs) of 0.70 and 14 Mg/year but a net northward transport of ΣPCBs at 0.16 Mg/year through the Fram Strait.

Beschreibung: Histones are a major component of chromatin, the nucleoprotein complex fundamental to regulating transcription, facilitating cell division, and maintaining genome integrity in almost all eukaryotes. In addition to canonical, replication-dependent histones, replication-independent histone variants exist in most eukaryotes. In recent years, steady progress has been made in understanding how histone variants assemble, their involvement in development, mitosis, transcription, and genome repair. In this review, we will focus on the localization of the major histone variants H3.3, CENP-A, H2A.Z, and macroH2A, as well as how these variants have evolved, their structural differences, and their functional significance in vivo.

Beschreibung: 4-Coumarate:CoA ligase (4CL) genes are critical for the biosynthesis of plant phenylpropanoids. Here we identified 20 4CL genes in the genomes of two desert poplars (Populus euphratica and P. pruinosa) and salt-sensitive congener (P. trichocarpa), but 12 in Salix suchowensis (Salix willow). Phylogenetic analyses clustered all Salicaceae 4CL genes into two clades, and one of them (corresponding to the 4CL-like clade from Arabidopsis) showed signals of adaptive evolution, with more genes retained in Populus than Salix and Arabidopsis. We also found that 4CL12 (in 4CL-like clade) showed positive selection along the two desert poplar lineages. Transcriptional profiling analyses indicated that the expression of 4CL2, 4CL11, and 4CL12 changed significantly in one or both desert poplars in response to salt stress compared to that of in P. trichocarpa. Our results suggest that the evolution of the 4CL genes may have contributed to the development of salt tolerance in the two desert poplars.

Beschreibung: In the last few decades, epigenetics has emerged as an exciting new field in development and disease, with a more recent focus towards cancer. Epigenetics has classically referred to heritable patterns of gene expression, primarily mediated through DNA methylation patterns. More recently, it has come to include the reversible chemical modification of histones and DNA that dictate gene expression patterns. Both the epigenetic up-regulation of oncogenes and downregulation of tumor suppressors have been shown to drive tumor development. Current clinical trials for cancer therapy include pharmacological inhibition of DNA methylation and histone deacetylation, with the aim of reversing these cancer-promoting epigenetic changes. However, the DNA methyltransferase and histone deacetylase inhibitors have met with less than promising results in the treatment of solid tumors. Regions of hypoxia are a common occurrence in solid tumors. Tumor hypoxia is associated with increased aggressiveness and therapy resistance, and importantly, hypoxic tumor cells have a distinct epigenetic profile. In this review, we provide a summary of the recent clinical trials using epigenetic drugs in solid tumors, discuss the hypoxia-induced epigenetic changes and highlight the importance of testing the epigenetic drugs for efficacy against the most aggressive hypoxic fraction of the tumor in future preclinical testing.

Beschreibung: The adiponectin gene (ADIPOQ) plays an important role in energy homeostasis. In this study five separate regions (regions 1 to 5) of ovine ADIPOQ were analysed using PCR-SSCP. Four different PCR-SSCP patterns (A1-D1, A2-D2) were detected in region-1 and region-2, respectively, with seven and six SNPs being revealed. In region-3, three different patterns (A3-C3) and three SNPs were observed. Two patterns (A4-B4, A5-B5) and two and one SNPs were observed in region-4 and region-5, respectively. In total, nineteen SNPs were detected, with five of them in the coding region and two (c.46T/C and c.515G/A) putatively resulting in amino acid changes (p.Tyr16His and p.Lys172Arg). In region-1, -2 and -3 of 316 sheep from eight New Zealand breeds, variants A1, A2 and A3 were the most common, although variant frequencies differed in the eight breeds. Across region-1 and region-3, nine haplotypes were identified and haplotypes A1-A3, A1-C3, B1-A3 and B1-C3 were most common. These results indicate that the ADIPOQ gene is polymorphic and suggest that further analysis is required to see if the variation in the gene is associated with animal production traits.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 139-166, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 477-507, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 167-205, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 207-231, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: In the future, Earth will be warmer, precipitation events will be more extreme, global mean sea level will rise, and many arid and semi-arid regions will be drier. Human modifications of landscapes will also occur at an accelerated rate as developed areas increase in size and population density. We now have gridded global forecasts, being continually improved, of the climatic and land-use changes (C&LUC) that are likely to occur in the coming decades. Aside from a few exceptions, however, consensus forecasts do not exist for how these C&LUC will likely impact Earth-surface processes and hazards. In some cases we have the tools to forecast the geomorphic responses to likely future C&LUC. Fully exploiting these models and utilizing these tools will require close collaboration among Earth-surface scientists and Earth-system modelers. This paper assesses the state-of-the-art tools and data that are being used or could be used to forecast changes in the state of Earth's surface as a result of likely future C&LUC. We also propose strategies for filling key knowledge gaps, emphasizing where additional basic research and/or collaboration across disciplines is necessary. The main body of the paper addresses cross-cutting issues, including the importance of nonlinear/threshold-dominated interactions among topography, vegetation, and sediment transport, as well as the importance of alternate stable states and extreme, rare events for understanding and forecasting Earth-surface response to C&LUC. Five supplements delve into different scales or process zones (global-scale assessments, and fluvial, aeolian, glacial/periglacial, and coastal process zones) in detail.

Beschreibung: Chromatin remodelers are key players in the regulation of chromatin accessibility and nucleosome positioning on the eukaryotic DNA, thereby essential for all DNA dependent biological processes. Thus, it is not surprising that upon of deregulation of those molecular machines healthy cells can turn into cancerous cells. Even though the remodeling enzymes are very abundant and a multitude of different enzymes and chromatin remodeling complexes exist in the cell, the particular remodeling complex with its specific nucleosome positioning features must be at the right place at the right time in order to ensure the proper regulation of the DNA dependent processes. To achieve this, chromatin remodeling complexes harbor protein domains that specifically read chromatin targeting signals, such as histone modifications, DNA sequence/structure, non-coding RNAs, histone variants or DNA bound interacting proteins. Recent studies reveal the interaction between non-coding RNAs and chromatin remodeling complexes showing importance of RNA in remodeling enzyme targeting, scaffolding and regulation. In this review, we summarize current understanding of chromatin remodeling enzyme targeting to chromatin and their role in cancer development.

Beschreibung: The thyroid gland is an important endocrine organ modulating development, growth, and metabolism, mainly by controlling the synthesis and secretion of thyroid hormones (THs). However, little is known about the pig thyroid transcriptome. Long non-coding RNAs (lncRNAs) regulate gene expression and play critical roles in many cellular processes. Yorkshire pigs have a higher growth rate but lower fat deposition than that of Jinhua pigs, and thus, these species are ideal models for studying growth and lipid metabolism. This study revealed higher levels of THs in the serum of Yorkshire pigs than in the serum of Jinhua pigs. By using Ribo-zero RNA sequencing—which can capture both polyA and non-polyA transcripts—the thyroid transcriptome of both breeds were analyzed and 22,435 known mRNAs were found to be expressed in the pig thyroid. In addition, 1189 novel mRNAs and 1018 candidate lncRNA transcripts were detected. Multiple TH-synthesis-related genes were identified among the 455 differentially-expressed known mRNAs, 37 novel mRNAs, and 52 lncRNA transcripts. Bioinformatics analysis revealed that differentially-expressed genes were enriched in the microtubule-based process, which contributes to THs secretion. Moreover, integrating analysis predicted 13 potential lncRNA-mRNA gene pairs. These data expanded the repertoire of porcine lncRNAs and mRNAs and contribute to understanding the possible molecular mechanisms involved in animal growth and lipid metabolism.

Beschreibung: Stratigraphy provides insights into the evolution and dynamics of the Earth System over its long history. With recent developments in Earth System science, changes in Earth System dynamics can now be observed directly and projected into the near future. An integration of the two approaches provides powerful insights into the nature and significance of contemporary changes to Earth. From both perspectives, the Earth has been pushed out of the Holocene Epoch by human activities, with the mid-20 th century a strong candidate for the start date of the Anthropocene, the proposed new epoch in Earth history. Here we explore two contrasting scenarios for the future of the Anthropocene, recognizing that the Earth System has already undergone a substantial transition away from the Holocene state. A rapid shift of societies towards the UN Sustainable Development Goals could stabilize the Earth System in a state with more intense interglacial conditions than in the late Quaternary climate regime and with little further biospheric change. In contrast, a continuation of the present Anthropocene trajectory of growing human pressures will likely lead to biotic impoverishment and a much warmer climate with a significant loss of polar ice.

Beschreibung: We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan.

Beschreibung: We determine the contribution of glacial isostatic adjustment (GIA) to future relative sea level change for the North American coastline between Newfoundland and Texas. We infer GIA model parameters using recently compiled and quality assessed databases of past sea-level changes, including new databases for the United States Gulf coast and Atlantic Canada. At 13 cities along this coastline, we estimate the GIA contribution to range from a few centimeters (e.g. 3[−1 − 9]cm, Miami) to a few decimeters (e.g. 18[12 − 22]cm, Halifax) for the period 2085-2100 relative to 2006-2015 (1- σ ranges given). We provide estimates of uncertainty in the GIA component using two different methods; the more conservative approach produces total ranges (1- σ confidence) that vary from 3to16cm for the cities considered. Contributions from ocean steric and dynamic changes as well as those from changes in land ice are also estimated to provide context for the GIA projections. When summing the contributions from all three processes at the 13 cities considered along this coastline, using median or best-estimate values, the GIA signal comprises ≈ 5 − 38 % of the total depending on the adopted climate forcing and location. The contributions from ocean dynamic/steric changes and ice mass loss are similar in amplitude but with spatial variation that approximately cancels, resulting in GIA dominating the net spatial variability north of 35 ∘ N).

Beschreibung: The literature on the costs of climate change often draws a link between climatic ‘tipping points’ and large economic shocks, frequently called ‘catastrophes’. The phrase ‘tipping points’ in this context can be misleading. In popular and social scientific discourse, ‘tipping points’ involve abrupt state changes. For some climatic ‘tipping points,’ the commitment to a state change may occur abruptly, but the change itself may be rate-limited and take centuries or longer to realize. Additionally, the connection between climatic ‘tipping points’ and economic losses is tenuous, though emerging empirical and process-model-based tools provide pathways for investigating it. We propose terminology to clarify the distinction between ‘tipping points’ in the popular sense, the critical thresholds exhibited by climatic and social ‘tipping elements,’ and ‘economic shocks’. The last may be associated with tipping elements, gradual climate change, or non-climatic triggers. We illustrate our proposed distinctions by surveying the literature on climatic tipping elements, climatically sensitive social tipping elements, and climate-economic shocks, and we propose a research agenda to advance the integrated assessment of all three.

Beschreibung: The United States Embassy in Beijing, China, released publicly a record of mass concentrations of particulate matter 2.5 µm and smaller in aerodynamic diameter (PM 2 .5 ) from April 2008 to the present measured with a Beta Attenuation Monitor (BAM). We compare these measurements with observations of particulate matter recorded at the Beijing Institute of Atmospheric Physics and observations of visibility recorded at the Beijing Capital International Airport (BCIA) to assess their value as a record of air quality in the greater Beijing metropolitan area. We find that the PM 2 .5 observations correlate well with the other observations of PM over the period January 1 st to February 1 st 2013 using a Tapered Element Oscillating Microbalance and an Aerosol Mass Spectrometer (AMS), and they exhibit a clear inverse correlation with visibility measured at BCIA. Using inverse visibility as a proxy of radiation extinction, we determine a dry mass extinction efficiency and a dependence of radiation extinction to relative humidity that is consistent with other studies of polluted urban environments. We deduce a strong degree of homogeneity of particulate pollution across the Beijing metropolitan region and conclude that the U.S. Embassy measurements are a reliable sample of this particulate pollution during periods of photochemical smog. The U.S. Embassy observations of PM 2 .5 appear to remain consistent throughout the available record and can serve as a useful dataset for studying future trends in particulate matter as China implements ambitious measures to improve air quality in the region.

Beschreibung: Duplication of bacterial chromosomes is initiated via the assembly of two replication forks at a single defined origin. Forks proceed bi-directionally until they fuse in a specialised termination area opposite the origin. This area is flanked by polar replication fork pause sites that allow forks to enter but not to leave. The precise function of this replication fork trap has remained enigmatic, as no obvious phenotypes have been associated with its inactivation. However, the fork trap becomes a serious problem to cells if the second fork is stalled at an impediment, as replication cannot be completed, suggesting that a significant evolutionary advantage for maintaining this chromosomal arrangement must exist. Recently, we demonstrated that head-on fusion of replication forks can trigger over-replication of the chromosome. This over-replication is normally prevented by a number of proteins including RecG helicase and 3’ exonucleases. However, even in the absence of these proteins it can be safely contained within the replication fork trap, highlighting that multiple systems might be involved in coordinating replication fork fusions. Here, we discuss whether considering the problems associated with head-on replication fork fusion events helps us to better understand the important role of the replication fork trap in cellular metabolism.

Beschreibung: The Hippo signalling pathway has recently emerged as an important regulator of cell apoptosis and proliferation with significant implications in human diseases. In mammals, the pathway contains the core kinases MST1/2, which phosphorylate and activate LATS1/2 kinases. The pro-apoptotic function of the MST/LATS signalling axis was previously linked to the Akt and ERK MAPK pathways, demonstrating that the Hippo pathway does not act alone but crosstalks with other signalling pathways to coordinate network dynamics and cellular outcomes. These crosstalks were characterised by a multitude of complex regulatory mechanisms involving competitive protein-protein interactions and phosphorylation mediated feedback loops. However, how these different mechanisms interplay in different cellular contexts to drive the context-specific network dynamics of Hippo-ERK signalling remains elusive. Using mathematical modelling and computational analysis, we uncovered that the Hippo-ERK network can generate highly diverse dynamical profiles that can be clustered into distinct dose-response patterns. For each pattern, we offered mechanistic explanation that defines when and how the observed phenomenon can arise. We demonstrated that Akt displays opposing, dose-dependent functions towards ERK, which are mediated by the balance between the Raf-1/MST2 protein interaction module and the LATS1 mediated feedback regulation. Moreover, Ras displays a multi-functional role and drives biphasic responses of both MST2 and ERK activities; which are critically governed by the competitive protein interaction between MST2 and Raf-1. Our study represents the first in-depth and systematic analysis of the Hippo-ERK network dynamics and provides a concrete foundation for future studies.

Beschreibung: Telomerase, regulated primarily by the transcription of its catalytic subunit telomerase reverse transcriptase (TERT), is critical for controlling cell proliferation and tissue homeostasis by maintaining telomere length. Although there is a high conservation between human and mouse TERT genes, the regulation of their transcription is significantly different in these two species. Whereas mTERT expression is widely detected in adult mice, hTERT is expressed at extremely low levels in most adult human tissues and cells. As a result, mice do not exhibit telomere-mediated replicative aging, but telomere shortening is a critical factor of human aging and its stabilization is essential for cancer development in humans. The chromatin environment and epigenetic modifications of the hTERT locus, the binding of transcriptional factors to its promoter, and recruitment of nucleosome modifying complexes all play essential roles in restricting its transcription in different cell types. In this review, we will discuss recent progress in understanding the molecular mechanisms of TERT regulation in human and mouse tissues and cells, and during cancer development.

Beschreibung: Chinese soft-shelled turtle (Pelodiscus sinensis) is commercially cultured in East and Southeast Asia for its nutritional and medicinal values. In this study, we identified interleukin-1β (IL-1β) from Chinese soft-shelled turtle. The full-length cDNA of Pelodiscus sinensis IL-1β (tIL-1β) consists of 1529 base pairs with an 831-base-pair open reading frame, encoding 277 amino acids. The guanine-cytosine (GC) content in the coding sequence and 3’ untranslated region of tIL-1β is considerably higher than that of other vertebrates. Its mRNA expression level increased significantly during Aeromonas hydrophila infection. The tIL-1β lacks the typical IL-1β-converting enzyme (ICE) cut site found in mammalian IL-1β, but still could be cleaved by turtle caspase-1. By mutating the potential cleavage sites, we identified aspartic acid (Asp/D) 130 as the ICE cut site in tIL-1β. The peptide truncated at D130 was expressed using the baculovirus expression system; its bioactivity is confirmed by the ability to induce cyclooxygenase-2 (COX-2) and tIL-1β itself in peripheral blood monocytes. In conclusion, we characterized IL-1β from Chinese soft-shelled turtle and identified its D130 as a non-typical ICE cut size.

Beschreibung: Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics.

Beschreibung: Climate change damages agriculture, causing deteriorating food security and increased malnutrition. Many studies have examined the role of distinct physical processes, but impacts have not been previously attributed to individual pollutants. Using a simple model incorporating process-level results from detailed models, here I show that although carbon dioxide (CO 2 ) is the largest driver of climate change, other drivers dominate agricultural yield changes. I calculate that anthropogenic emissions to date have decreased global agricultural yields by 9.5 ± 3.0%, with roughly 93% stemming from non-CO 2 emissions, including methane (-5.2 ± 1.7%) and halocarbons (-1.4 ± 0.4%). The differing impacts stem from atmospheric composition responses: CO 2 fertilizes crops, offsetting much of the loss induced by warming; halocarbons do not fertilize; methane leads to minimal fertilization but increases surface ozone which augments warming-induced losses. By the end of the century, strong CO 2 mitigation improves agricultural yields by ~3 ± 5%. In contrast, strong methane and hydrofluorocarbon mitigation improve yields by ~16 ± 5% and ~5 ± 4%, respectively. These are the first quantitative analyses to include climate, CO 2 and ozone simultaneously, and hence additional studies would be valuable. Nonetheless, as policy makers have leverage over pollutant emissions rather than isolated processes, the perspective presented here may be more useful for decision making than that in the prior work upon which this study builds. The results suggest that policies should target a broad portfolio of pollutant emissions in order to optimize mitigation of societal damages.

Beschreibung: The swine leukocyte antigens (SLAs) are the multigene families related to immune responses. Little is known about the effect of the DRA gene on diarrheal disease. This study reported the genetic diversity of the DRA gene in exons 1, 3 and 4 in 290 Chinese Yantai black pigs. No variation was identified in exon 3. In exon 1, three genotypes and two alleles were identified, generated by two single nucleotide polymorphisms (SNPs). In exon 4, there were eight genotypes and five alleles containing seven SNPs were detected with four SNPs being novel SNPs. The low polymorphism found in swine DRA is consistent with the concept that the DRA gene is highly conserved among all mammalian species. Statistical analyses indicated that the genotypes of exon 1 were not significantly associated with piglet diarrhea (p > 0.05); however, genotypes C4C4 (1.80 ± 0.33) and A4E4 (1.66 ± 0.25) of exon 4 were significantly susceptible to diarrhea (p 〈 0.01). These indicate that the particular genotypes of the DRA gene are susceptible to diarrheal disease, which provides valuable information for disease-resistance breeding in swine.

Beschreibung: Genome sequencing is now a common procedure, but prior to this, screening experiments using protein baits was one of the routinely used methods that, occasionally, allowed the identification of new gene products. One such experiment uncovered the gene product called willin/human Expanded/FRMD6. Initial characterization studies found that willin bound phospholipids and was strongly co-localised with actin. However, subsequently, willin was found to be the closest human sequence homologue of the Drosophila protein Expanded (Ex), sharing 60% homology with the Ex FERM domain. This in turn suggested, and then was proven that willin could activate the Hippo signalling pathway. This review describes the increasing body of knowledge about the actions of willin in a number of cellular functions related to cancer. However, like many gene products involved in aspects of cell signalling, a convincing direct role for willin in cancer remains tantalisingly elusive, at present.

Beschreibung: The accumulated evidence has pointed to a key role of telomerase in carcinogenesis. As a RNA-dependent DNA polymerase, telomerase synthesizes telomeric DNA at the end of linear chromosomes, and attenuates or prevents telomere erosion associated with cell divisions. By lengthening telomeres, telomerase extends cellular life-span or even induces immortalization. Consistent with its functional activity, telomerase is silent in most human normal somatic cells while active only in germ-line, stem and other highly proliferative cells. In contrast, telomerase activation widely occurs in human cancer and the enzymatic activity is detectable in up to 90% of malignancies. Recently, hotspot point mutations in the regulatory region of the telomerase reverse transcriptase (TERT) gene, encoding the core catalytic component of telomerase, was identified as a novel mechanism to activate telomerase in cancer. This review discusses the cancer-specific TERT promoter mutations and potential biological and clinical significances.

Beschreibung: Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches. Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a ‘mild’ integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis.

Beschreibung: An aquatic gastropod belonging to the family Neritidae, Clithon retropictus is listed as an endangered class II species in South Korea. The lack of information on its genomic background limits the ability to obtain functional data resources and inhibits informed conservation planning for this species. In the present study, the transcriptomic sequencing and de novo assembly of C. retropictus generated a total of 241,696,750 high-quality reads. These assembled to 282,838 unigenes with mean and N50 lengths of 736.9 and 1201 base pairs, respectively. Of these, 125,616 unigenes were subjected to annotation analysis with known proteins in Protostome DB, COG, GO, and KEGG protein databases (BLASTX; E ≤ 0.00001) and with known nucleotides in the Unigene database (BLASTN; E ≤ 0.00001). The GO analysis indicated that cellular process, cell, and catalytic activity are the predominant GO terms in the biological process, cellular component, and molecular function categories, respectively. In addition, 2093 unigenes were distributed in 107 different KEGG pathways. Furthermore, 49,280 simple sequence repeats were identified in the unigenes (>1 kilobase sequences). This is the first report on the identification of transcriptomic and microsatellite resources for C. retropictus, which opens up the possibility of exploring traits related to the adaptation and acclimatization of this species.

Beschreibung: Accessory replicative helicases aid the primary replicative helicase in duplicating protein-bound DNA, especially transcribed DNA. Recombination enzymes also aid genome duplication by facilitating the repair of DNA lesions via strand exchange and also processing of blocked fork DNA to generate structures onto which the replisome can be reloaded. There is significant interplay between accessory helicases and recombination enzymes in both bacteria and lower eukaryotes but how these replication repair systems interact to ensure efficient genome duplication remains unclear. Here, we demonstrate that the DNA content defects of Escherichia coli cells lacking the strand exchange protein RecA are driven primarily by conflicts between replication and transcription, as is the case in cells lacking the accessory helicase Rep. However, in contrast to Rep, neither RecA nor RecBCD, the helicase/exonuclease that loads RecA onto dsDNA ends, is important for maintaining rapid chromosome duplication. Furthermore, RecA and RecBCD together can sustain viability in the absence of accessory replicative helicases but only when transcriptional barriers to replication are suppressed by an RNA polymerase mutation. Our data indicate that the minimisation of replisome pausing by accessory helicases has a more significant impact on successful completion of chromosome duplication than recombination-directed fork repair.

Beschreibung: High telomerase activity is detected in nearly all human cancers but most human cells are devoid of telomerase activity. There is well-documented evidence that reactivation of telomerase occurs during cellular transformation. In humans, tumors can rely in reactivation of telomerase or originate in a telomerase positive stem/progenitor cell, or rely in alternative lengthening of telomeres, a telomerase-independent telomere-length maintenance mechanism. In this review, we will focus on the telomerase positive tumors. In this context, the recent findings that telomerase reverse transcriptase (TERT) promoter mutations represent the most common non-coding mutations in human cancer have flared up the long-standing discussion whether cancer originates from telomerase positive stem cells or telomerase reactivation is a final step in cellular transformation. Here, we will discuss the pros and cons of both concepts in the context of telomere length-dependent and telomere length-independent functions of telomerase. Together, these observations may provoke a re-evaluation of telomere and telomerase based therapies, both in telomerase inhibition for cancer therapy and telomerase activation for tissue regeneration and anti-ageing strategies.

Beschreibung: Coastal responses to sea level rise (SLR) include inundation of wetlands, increased shoreline erosion, and increased flooding during storm events. Hydrodynamic parameters such as tidal ranges, tidal prisms, tidal asymmetries, increased flooding depths and inundation extents during storm events respond non-additively to SLR. Coastal morphology continually adapts towards equilibrium as sea levels rise, inducing changes in the landscape. Marshes may struggle to keep pace with SLR and rely on sediment accumulation and the availability of suitable uplands for migration. Whether hydrodynamic, morphologic or ecologic, the impacts of SLR are inter-related. To plan for changes under future sea levels, coastal managers need information and data regarding the potential effects of SLR to make informed decisions for managing human and natural communities. This review examines previous studies that have accounted for the dynamic, nonlinear responses of hydrodynamics, coastal morphology and marsh ecology to SLR by implementing more complex approaches rather than the simplistic “bathtub” approach. These studies provide an improved understanding of the dynamic effects of SLR on coastal environments and contribute to an overall paradigm shift in how coastal scientists and engineers approach modeling the effects of SLR, transitioning away from implementing the “bathtub” approach. However, it is recommended that future studies implement a synergetic approach that integrates the dynamic interactions between physical and ecological environments to better predict the impacts of SLR on coastal systems.

Beschreibung: Gene-set analysis has been proposed as a powerful tool to deal with the highly polygenic architecture of complex traits, as well as with the small effect sizes typically found in GWAS studies for complex traits. We developed a tool, Joint Association of Genetic variants (JAG), which can be applied to Genome Wide Association (GWA) data and tests for the joint effect of all single nucleotide polymorphisms (SNPs) located in a user-specified set of genes or biological pathway. JAG assigns SNPs to genes and incorporates self-contained and/or competitive tests for gene-set analysis. JAG uses permutation to evaluate gene-set significance, which implicitly controls for linkage disequilibrium, sample size, gene size, the number of SNPs per gene and the number of genes in the gene-set. We conducted a power analysis using the Wellcome Trust Case Control Consortium (WTCCC) Crohn’s disease data set and show that JAG correctly identifies validated gene-sets for Crohn’s disease and has more power than currently available tools for gene-set analysis. JAG is a powerful, novel tool for gene-set analysis, and can be freely downloaded from the CTG Lab website.

Beschreibung: The initiation of DNA replication is tightly regulated in order to ensure that the genome duplicates only once per cell cycle. In vertebrate cells, the unstable regulatory protein Geminin prevents a second round of DNA replication by inhibiting the essential replication factor Cdt1. Cdt1 recruits mini-chromosome maintenance complex (MCM2-7), the replication helicase, into the pre-replication complex (pre-RC) at origins of DNA replication. The mechanism by which Geminin inhibits MCM2-7 loading by Cdt1 is incompletely understood. The conventional model is that Geminin sterically hinders a direct physical interaction between Cdt1 and MCM2-7. Here, we describe an inactive missense mutant of Geminin, GemininAWA, which binds to Cdt1 with normal affinity yet is completely inactive as a replication inhibitor even when added in vast excess. In fact, GemininAWA can compete with GemininWT for binding to Cdt1 and prevent it from inhibiting DNA replication. GemininAWA does not inhibit the loading of MCM2-7 onto DNA in vivo, and in the presence of GemininAWA, nuclear DNA is massively over-replicated within a single S phase. We conclude that Geminin does not inhibit MCM loading by simple steric interference with a Cdt1-MCM2-7 interaction but instead works by a non-steric mechanism, possibly by inhibiting the histone acetyltransferase HBO1.

Beschreibung: Transport of messenger RNA (mRNA) from the nucleus to the cytoplasm is an essential step of eukaryotic gene expression. In the cell nucleus, a precursor mRNA undergoes a series of processing steps, including capping at the 5' ends, splicing and cleavage/polyadenylation at the 3' ends. During this process, the mRNA associates with a wide variety of proteins, forming a messenger ribonucleoprotein (mRNP) particle. Association with factors involved in nuclear export also occurs during transcription and processing, and thus nuclear export is fully integrated into mRNA maturation. The coupling between mRNA maturation and nuclear export is an important mechanism for providing only fully functional and competent mRNA to the cytoplasmic translational machinery, thereby ensuring accuracy and swiftness of gene expression. This review describes the molecular mechanism of nuclear mRNA export mediated by the principal transport factors, including Tap-p15 and the TREX complex.

Beschreibung: DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3.

Beschreibung: Genetic mosaics provide information about cellular lineages that is otherwise difficult to obtain, especially in humans. De novo mutations act as cell markers, allowing the tracing of developmental trajectories of all descendants of the cell in which the new mutation arises. De novo mutations may arise at any time during development but are relatively rare. They have usually been observed through medical ascertainment, when the mutation causes unusual clinical signs or symptoms. Mutational events can include aneuploidies, large chromosomal rearrangements, copy number variants, or point mutations. In this review we focus primarily on the analysis of point mutations and their utility in addressing questions of germ line versus somatic lineages. Genetic mosaics demonstrate that the germ line and soma diverge early in development, since there are many examples of combined somatic and germ line mosaicism for de novo mutations. The occurrence of simultaneous mosaicism in both the germ line and soma also shows that the germ line is not strictly clonal but arises from at least two, and possibly multiple, cells in the embryo with different ancestries. Whole genome or exome DNA sequencing technologies promise to expand the range of studies of genetic mosaics, as de novo mutations can now be identified through sequencing alone in the absence of a medical ascertainment. These technologies have been used to study mutation patterns in nuclear families and in monozygotic twins, and in animal model developmental studies, but not yet for extensive cell lineage studies in humans.

Beschreibung: ABSTRACT Predictions of coastal evolution driven by episodic and persistent processes associated with storms and relative sea-level rise (SLR) are required to test our understanding, evaluate our predictive capability, and to provide guidance for coastal management decisions. Previous work demonstrated that the spatial variability of long-term shoreline change can be predicted using observed SLR rates, tide range, wave height, coastal slope, and a characterization of the geomorphic setting. The shoreline is not sufficient to indicate which processes are important to causing shoreline change, such as overwash that depends on coastal dune elevations. Predicting dune height is intrinsically important to assessing future storm vulnerability. Here, we enhance shoreline-change predictions by including dune height as a variable in a statistical modeling approach. Dune height can also be used as an input variable, but it does not improve the shoreline-change prediction skill. Dune-height input does help to reduce prediction uncertainty. That is, by including dune height, the prediction is more precise but not more accurate. Comparing hindcast evaluations, better predictive skill was found when predicting dune height (0.8) compared to shoreline change (0.6). The skill depends on the level of detail of the model and we identify an optimized model that has high skill and minimal overfitting. The predictive model can be implemented with a range of forecast scenarios, and we illustrate the impacts of a higher future sea-level. This scenario shows that the shoreline change becomes increasingly erosional and more uncertain. Predicted dune heights are lower and the dune height uncertainty decreases.

Beschreibung: The response of runoff and sediment loading in the Apalachicola River under projected climate change scenarios and land use land cover (LULC) change is evaluated. A hydrologic model using the Soil Water Assessment Tool (SWAT) was developed for the Apalachicola region to simulate daily runoff and sediment load under present (circa 2000) and future conditions (2100) to understand how parameters respond over a seasonal time frame to changes in climate, LULC, and coupled climate / LULC. The Long Ashton Research Station-Weather Generator (LARS-WG) was used to downscale temperature and precipitation from three general circulation models (GCM), each under Intergovernmental Panel on Climate Change (IPCC) carbon emission scenarios A2, A1B, and B1. Projected 2100 LULC data provided by the United States Geological Survey (USGS) Earth Resources Observation and Science (EROS) Center was incorporated for each corresponding IPCC scenario. Results indicate climate change may induce seasonal shifts to both runoff and sediment loading. Changes in LULC showed more sediment load was associated with increased agriculture and urban areas and decreased forested regions. A nonlinear response for both runoff and sediment loading was observed by coupling climate and LULC change, suggesting both should be incorporated into hydrologic models when studying future conditions. The outcomes from this research can be used to better guide management practices and mitigation strategies.

Beschreibung: This work outlines a dynamic modeling framework to examine the effects of global climate change, and sea level rise (SLR) in particular, on tropical cyclone-driven storm surge inundation. The methodology, applied across the northern Gulf of Mexico, adapts a present day large-domain, high resolution, tide, wind-wave, and hurricane storm surge model to characterize the potential outlook of the coastal landscape under four SLR scenarios for the year 2100. The modifications include shoreline and barrier island morphology, marsh migration, and land use land cover change. Hydrodynamics of ten historic hurricanes were simulated through each of the five model configurations (present day and four SLR scenarios). Under SLR, the total inundated land area increased by 87% and developed and agricultural lands by 138% and 189%, respectively. Peak surge increased by as much as 1 m above the applied SLR in some areas, and other regions were subject to a reduction in peak surge, with respect to the applied SLR, indicating a nonlinear response. Analysis of time-series water surface elevation suggests the interaction between SLR and storm surge is nonlinear in time; SLR increased the time of inundation and caused an earlier arrival of the peak surge, which cannot be addressed using a static (“bathtub”) modeling framework. This work supports the paradigm shift to using a dynamic modeling framework to examine the effects of global climate change on coastal inundation. The outcomes have broad implications and ultimately support a better holistic understanding of the coastal system and aid restoration and long-term coastal sustainability.

Beschreibung: This study examines the integrated influence of sea level rise (SLR) and future morphology on tidal hydrodynamics along the Northern Gulf of Mexico (NGOM) coast including seven embayments and three ecologically and economically significant estuaries. A large-domain hydrodynamic model was used to simulate astronomic tides for present and future conditions (circa 2050 and 2100). Future conditions were simulated by imposing four SLR scenarios to alter hydrodynamic boundary conditions and updating shoreline position and dune heights using a probabilistic model that is coupled to SLR. Under the highest SLR scenario, tidal amplitudes within the bays increased as much as 67% (10.0 cm) due to increases in the inlet-cross-sectional area. Changes in harmonic constituent phases indicated tidal propagation was faster in the future scenarios within most of the bays. Maximum tidal velocities increased in all of the bays, especially in Grand Bay where velocities doubled under the highest SLR scenario. In addition, the ratio of the maximum flood to maximum ebb velocity decreased in the future scenarios (i.e., currents became more ebb dominant) by as much as 26% and 39% in Weeks Bay and Apalachicola, respectively. In Grand Bay, the flood-ebb ratio increased (i.e., currents became more flood dominant) by 25% under the lower SLR scenarios, but decreased by 16% under the higher SLR as a result of the offshore barrier islands being overtopped, which altered the tidal prism. Results from this study can inform future storm surge and ecological assessments of SLR, and improve monitoring and management decisions within the NGOM.

Beschreibung: Water vapor is the most important greenhouse gas in the atmosphere although changes in carbon dioxide constitute the “control knob” for surface temperatures. While the latter fact is well recognized, resulting in extensive spaceborne and ground based measurement programs for carbon dioxide [et~al.(1996), Chin, and Whorf, et~al.(2009), Suto, Nakajima, and Hamazaki, et~al.(2014), Cai, Yang, Zheng, Duan, and Lu], the need for an accurate characterization of the long-term changes in upper tropospheric and lower stratospheric (UTLS) water vapor has not yet resulted in sufficiently extensive long-term international measurement programs (although first steps have been taken). Here we argue for the implementation of a, long-term balloon-borne measurement program for UTLS water vapor covering the entire globe that likely will have to be sustained for hundreds of years.

Beschreibung: This paper analyzes multi-year records of solar flux and climate data from two solar power sites in Vermont. We show the interannual differences of temperature, wind, panel solar flux, electrical power production and cloud cover. Power production has a linear relation to a dimensionless measure of the transmission of sunlight through the cloud field. The difference between panel and air temperatures reaches 24°C with high solar flux and low windspeed. High panel temperatures that occur in summer with low windspeeds and clear skies can reduce power production by as much as 13%. The intercomparison of two sites 63 km apart shows that while temperature is highly correlated on daily (R 2 =0.98) and hourly (R 2 =0.94) timescales, the correlation of panel solar flux drops markedly from daily (R 2 =0.86) to hourly (R 2 =0.63) timescales. Minimum temperatures change little with cloud cover, but the diurnal temperature range shows a nearly linear increase with falling cloud cover to 16°C under nearly clear skies, similar to results from the Canadian Prairies. The availability of these new solar and climate datasets allows local student groups, here a Rutland High School team, to explore the coupled relationships between climate, clouds and renewable power production. As our society makes major changes in our energy infrastructure in response to climate change, it is important that we accelerate the technical education of high school students using real-world data. Citation: Betts, A.K., J. Hamilton, S. Ligon and A.M. Mahar (2015), Integrating solar energy and climate research into science education. Submitted to Earth's Future, 2015EF000315.

Beschreibung: Words are integral to thinking and communicating. Words also carry old baggage. The Anthropocene necessitates new thinking and communication at the human-nature interface. Words like progress, natural, and thresholds are pervasive in both scientific and policy discourse, but carry baggage that will likely slow understanding of the Anthropocene and appropriate adaptation. The dynamic systems thinking with emergent properties of ecology needs to replace the efficiency and growth framework of economics. Diversity and resilience are productive and less historically burdened words.

Beschreibung: Mitogen‐activated protein kinase kinase kinase (MAPKKK) is a component of the MAPK cascade pathway that plays an important role in plant growth, development, and response to abiotic stress, the functions of which have been well characterized in several plant species, such as Arabidopsis, rice, and maize. In this study, we performed genome‐wide and systemic bioinformatics analysis of MAPKKK family genes in Medicago truncatula. In total, there were 73 MAPKKK family members identified by search of homologs, and they were classified into three subfamilies, MEKK, ZIK, and RAF. Based on the genomic duplication function, 72 MtMAPKKK genes were located throughout all chromosomes, but they cluster in different chromosomes. Using microarray data and high‐throughput sequencing‐data, we assessed their expression profiles in growth and development processes; these results provided evidence for exploring their important functions in developmental regulation, especially in the nodulation process. Furthermore, we investigated their expression in abiotic stresses by RNA‐seq, which confirmed their critical roles in signal transduction and regulation processes under stress. In summary, our genome‐wide, systemic characterization and expressional analysis of MtMAPKKK genes will provide insights that will be useful for characterizing the molecular functions of these genes in M. truncatula.

Beschreibung: The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in both, including the plant homeodomain finger protein 6 (PHF6) gene. Indeed, germline mutations in PHF6 are the cause of the Börjeson–Forssman–Lehmann X-linked intellectual disability syndrome (BFLS), while somatic PHF6 mutations have been identified in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function. In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus. Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis.

Beschreibung: Centromeric protein A (CENP-A) is the epigenetic determinant of centromeres. This protein has been shown to be adaptively evolving in a number of animal and plant species. In a previous communication we were able to demonstrate that signs of adaptive evolution were detected in the comparison of CENP-A sequences from three percid fish species. In this study we isolated the CENP-A gene from eight additional species from the Percidae family. With these sequences and those previously obtained, we carried out a more robust statistical analysis of codon specific positive selection in CENP-A coding sequences of eleven percid species. We were able to demonstrate that at least two amino acid positions within the N-terminal tail are under strong positive selection and that one of these positions is potentially a substrate for phosphorylation. While nonsynonymous substitutions were detected in the histone fold domain, these were not statistically supported as resulting from positive selection.

Beschreibung: Dynamic structural properties of chromatin play an essential role in defining cell identity and function. Transcription factors and chromatin modifiers establish and maintain cell states through alteration of DNA accessibility and histone modifications. This activity is focused at both gene-proximal promoter regions and distally located regulatory elements. In the three-dimensional space of the nucleus, distal elements are localized in close physical proximity to the gene-proximal regulatory sequences through the formation of chromatin loops. These looping features in the genome are highly dynamic as embryonic stem cells differentiate and commit to specific lineages, and throughout reprogramming as differentiated cells reacquire pluripotency. Identifying these functional distal regulatory regions in the genome provides insight into the regulatory processes governing early mammalian development and guidance for improving the protocols that generate induced pluripotent cells.

Beschreibung: Paternally expressed Insulin-like Growth Factor II (IGF2) encodes a gene whose protein product functions as a potent growth mitogen. Overexpression of IGF2 has been implicated in a wide number of disorders and diseases. IGF2 is regulated in part by differential methylation of the two parentally derived alleles. The differentially methylated region (DMR) located upstream of the imprinted promoters of IGF2 exhibits plasticity under environmental stress and is hypomethylated in several types of cancer. Through bisulfite pyrosequencing and confirmation by nucleotide sequencing, we discovered a CpG to CpC transversion that results in hypomethylation of one of the three CpGs comprising this DMR. The presence of the polymorphism introduces a genetic rather than an environmentally-driven epigenetic source of hypomethylation that is additive to non-genetic sources.

Beschreibung: Sponges are an ancient metazoan group with broad ecological, evolutionary, and biotechnological importance. As in other marine invertebrates with a biphasic life cycle, the developing sponge undergoes a significant morphological, physiological, and ecological transformation during settlement and metamorphosis. In this study, we compare new transcriptome datasets for three life cycle stages of the red sponge (Mycale phyllophila) to test whether gene expression (as in the model poriferan, Amphimedon queenslandica) also varies more after settlement and metamorphosis. In contrast to A. queenslandica, we find that the transcriptome of M. phyllophila changes more during the earlier pre-competent larva/post-larva transition that spans these defining events. We also find that this transition is marked by a greater frequency of significantly up-regulated Gene Ontology terms including those for morphogenesis, differentiation, and development and that the transcriptomes of its pre-competent larvae and adult are distinct. The life cycle transcriptome variation between M. phyllophila and A. queenslandica may be due to their long separate evolutionary histories and corresponding differences in developmental rates and timing. This study now calls for new transcriptome datasets of M. phyllophila and other sponges, which will allow for tests of the generality of our life cycle expression differences and for the greater exploitation of poriferans in both basic and applied research.

Beschreibung: Though climate models exhibit broadly similar agreement on key long-term trends, they have significant temporal and spatial differences due to inter-model variability. Such variability should be considered when using climate models to project the future marine Arctic. Here we present multiple scenarios of 21 st -century Arctic marine access as driven by sea ice output from 10 CMIP5 models known to represent well the historical trend and climatology of Arctic sea ice. Optimal vessel transits from North America and Europe to the Bering Strait are estimated for two periods representing early-century (2011–2035) and mid-century (2036–2060) conditions under two forcing scenarios (RCP 4.5/8.5), assuming Polar Class 6 and open-water vessels with medium and no ice-breaking capability, respectively. Results illustrate that projected shipping viability of the Northern Sea Route (NSR) and Northwest Passage (NWP) depends critically on model choice. The eastern Arctic will remain the most reliably accessible marine space for trans-Arctic shipping by mid-century, while outcomes for the NWP are particularly model-dependent. Omitting three models (GFDL-CM3, MIROC-ESM-CHEM, MPI-ESM-MR), our results would indicate minimal NWP potential even for routes from North America. Furthermore, the relative importance of the NSR will diminish over time as the number of viable central Arctic routes increases gradually toward mid-century. Compared to vessel class, climate forcing plays a minor role. These findings reveal the importance of model choice in devising projections for strategic planning by governments, environmental agencies, and the global maritime industry.

Beschreibung: Objective: The manuscript investigates the relation between adiponectin gene (ADIPOQ) polymorphisms and type 2 diabetes mellitus (T2DM) in a Chinese population. Methods: We designed a case-control study involving 340 normal glucose tolerant (NGT) subjects and 340 type 2 diabetes patients. Three SNPs (rs182052, rs1501299, and rs7627128) were genotyped by TaqMan methods. Results: We found that rs7627128, rs1501299 and rs182052 were significantly associated with T2DM. Haplotypes analysis indicated that the frequency of the haplotypes A-A-T was frequent in T2DM patients (OR = 2.10; 95%CI: 1.44–2.90; p 〈 0.001), but G-A-T was more frequent in the control group than in the T2DM group (OR = 0.66; 95%CI: 0.54–0.81; p 〈 0.001). Conclusion: The ADIPOQ genetic polymorphisms were associated with type 2 diabetes in a Chinese population.

Beschreibung: Malignant pleural mesothelioma (MPM) is a cancer associated with exposure to asbestos fibers, which accumulate in the pleural space, damage tissue and stimulate regeneration. Hedgehog signaling is a pathway important during embryonic mesothelium development and is inactivated in adult mesothelium. The pathway is reactivated in some MPM patients with poor clinical outcome, mainly mediated by the expression of the ligands. Nevertheless, mutations in components of the pathway have been observed in a few cases. Data from different MPM animal models and primary culture suggest that both autocrine and paracrine Hedgehog signaling are important to maintain tumor growth. Drugs inhibiting the pathway at the level of the smoothened receptor (Smo) or glioma-associated protein transcription factors (Gli) have been used mostly in experimental models. For clinical development, biomarkers are necessary for the selection of patients who can benefit from Hedgehog signaling inhibition.

Beschreibung: Polycomb group (PcG) proteins contribute to the formation and maintenance of a specific repressive chromatin state that prevents the expression of genes in a particular space and time. Polycomb repressive complexes (PRCs) consist of several PcG proteins with specific regulatory or catalytic properties. PRCs are recruited to thousands of target genes, and various recruitment factors, including DNA-binding proteins and non-coding RNAs, are involved in the targeting. PcG proteins contribute to a multitude of biological processes by altering chromatin features at different scales. PcG proteins mediate both biochemical modifications of histone tails and biophysical modifications (e.g., chromatin fiber compaction and three-dimensional (3D) chromatin conformation). Here, we review the role of PcG proteins in nuclear architecture, describing their impact on the structure of the chromatin fiber, on chromatin interactions, and on the spatial organization of the genome in nuclei. Although little is known about the role of plant PcG proteins in nuclear organization, much is known in the animal field, and we highlight similarities and differences in the roles of PcG proteins in 3D gene regulation in plants and animals.

Beschreibung: Despite numerous studies implicating Alu repeat elements in various diseases, there is sparse information available with respect to the potential functional and biological roles of the repeat elements in Type 1 diabetes (T1D). Therefore, we performed a genome-wide sequence analysis of T1D candidate genes to identify embedded Alu elements within these genes. We observed significant enrichment of Alu elements within the T1D genes (p-value 〈 10e−16), which highlights their importance in T1D. Functional annotation of T1D genes harboring Alus revealed significant enrichment for immune-mediated processes (p-value 〈 10e−6). We also identified eight T1D genes harboring inverted Alus (IRAlus) within their 3' untranslated regions (UTRs) that are known to regulate the expression of host mRNAs by generating double stranded RNA duplexes. Our in silico analysis predicted the formation of duplex structures by IRAlus within the 3'UTRs of T1D genes. We propose that IRAlus might be involved in regulating the expression levels of the host T1D genes.

Beschreibung: The contribution of chromatin dynamics to the regulation of human disease-associated loci such as the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been the focus of intensive experimentation for many years. Recent technological advances in the analysis of transcriptional mechanisms across the entire human genome have greatly facilitated these studies. In this review we describe the complex machinery of tissue-specific regulation of CFTR expression, and put earlier observations in context by incorporating them into datasets generated by the most recent genomics methods. Though the gene promoter is required for CFTR expression, cell-type specific regulatory elements are located elsewhere in the gene and in flanking intergenic regions. Probably within its own topological domain established by the architectural proteins CTCF and cohesin, the CFTR locus utilizes chromatin dynamics to remodel nucleosomes, recruit cell-selective transcription factors, and activate intronic enhancers. These cis-acting elements are then brought to the gene promoter by chromatin looping mechanisms, which establish long-range interactions across the locus. Despite its complexity, the CFTR locus provides a paradigm for elucidating the critical role of chromatin dynamics in the transcription of individual human genes.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 431-458, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 459-476, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 541-569, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Successful climate change mitigation will involve not only technological innovation, but innovation in how we understand the societal and individual behaviors that shape the demand for energy services. Traditionally, individual energy behaviors have been described as a function of utility optimization and behavioral economics, with price restructuring as the dominant policy lever. Previous research at the macro-level has identified economic activity, power generation and technology, and economic role as significant factors that shape energy use. However, most demand models lack basic contextual information on how dominant social phenomenon, the changing demographics of cities, and the socio-cultural setting within which people operate, affect energy decisions and use patterns. Here we use high-quality Suomi-NPP VIIRS nighttime environmental products to: (1) observe aggregate human behavior through variations in energy service demand patterns during the Christmas and New Year's season and the Holy Month of Ramadan; and (2) demonstrate that patterns in energy behaviors closely track socio-cultural boundaries at the country, city, and district-level. These findings indicate that energy decision-making and demand is a socio-cultural process as well as an economic process, often involving a combination of individual price-based incentives and societal-level factors. While nighttime satellite imagery has been used to map regional energy infrastructure distribution, tracking daily dynamic lighting demand at three major scales of urbanization is novel. This methodology can enrich research on the relative importance of drivers of energy demand and conservation behaviors at fine scales. Our initial results demonstrate the importance of seating energy demand frameworks in a social context.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 233-271, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 29-77, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 105-138, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 1-27, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 273-298, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 405-429, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 593-622, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 299-331, May 2015, ISSN 0084-6597, eISSN 1545-4495.

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Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 571-592, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Annual Review of Earth and Planetary Sciences Volume 43, Page 509-540, May 2015, ISSN 0084-6597, eISSN 1545-4495.

Beschreibung: Topoisomerase 2 (Top2) is an essential enzyme responsible for manipulating DNA topology during replication, transcription, chromosome organization and chromosome segregation. It acts by nicking both strands of DNA and then passes another DNA molecule through the break. The 5′ end of each nick is covalently linked to the tyrosine in the active center of each of the two subunits of Top2 (Top2cc). In this configuration, the two sides of the nicked DNA are held together by the strong protein-protein interactions between the two subunits of Top2, allowing the nicks to be faithfully resealed in situ. Top2ccs are normally transient, but can be trapped by cancer drugs, such as etoposide, and subsequently processed into DSBs in cells. If not properly repaired, these DSBs would lead to genome instability and cell death. Here, I review the current understanding of the mechanisms by which DSBs are induced by etoposide, the unique features of such DSBs and how they are repaired. Implications for the improvement of cancer therapy will be discussed.

Beschreibung: In replication-limited cells of Bacillus subtilis, Mfd is mutagenic at highly transcribed regions, even in the absence of bulky DNA lesions. However, the mechanism leading to increased mutagenesis through Mfd remains currently unknown. Here, we report that Mfd may promote mutagenesis in nutritionally stressed B. subtilis cells by coordinating error-prone repair events mediated by UvrA, MutY and PolI. Using a point-mutated gene conferring leucine auxotrophy as a genetic marker, it was found that the absence of UvrA reduced the Leu+ revertants and that a second mutation in mfd reduced mutagenesis further. Moreover, the mfd and polA mutants presented low but similar reversion frequencies compared to the parental strain. These results suggest that Mfd promotes mutagenic events that required the participation of NER pathway and PolI. Remarkably, this Mfd-dependent mutagenic pathway was found to be epistatic onto MutY; however, whereas the MutY-dependent Leu+ reversions required Mfd, a direct interaction between these proteins was not apparent. In summary, our results support the concept that Mfd promotes mutagenesis in starved B. subtilis cells by coordinating both known and previously unknown Mfd-associated repair pathways. These mutagenic processes bias the production of genetic diversity towards highly transcribed regions in the genome.

Beschreibung: The family Mactridae is composed of a diverse group of marine organisms, commonly known as trough shells or surf clams, which illustrate a global distribution. Although this family includes some of the most fished and cultured bivalve species, their chromosomes are poorly studied. In this work, we analyzed the chromosomes of Spisula solida, Spisula subtruncata and Mactra stultorum by means of fluorochrome staining, C-banding and fluorescent in situ hybridization using 28S ribosomal DNA (rDNA), 5S rDNA, H3 histone gene and telomeric probes. All three trough shells presented 2n = 38 chromosomes but different karyotype compositions. As happens in most bivalves, GC-rich regions were limited to the nucleolus organizing regions in Spisula solida. In contrast, many GC-rich heterochromatic bands were detected in both Spisula subtruncata and Mactra stultorum. Although the three trough shells presented single 5S rDNA and H3 histone gene clusters, their chromosomal locations differed. Regarding major rDNA clusters, while Spisula subtruncata presented a single cluster, both Spisula solida and Mactra stultorum showed two. No evidence of intercalary telomeric signals was detected in these species. The molecular cytogenetic characterization of these taxa will contribute to understanding the role played by chromosome changes in the evolution of trough shells.

Beschreibung: Long non-coding transcripts from telomeres, called telomeric repeat-containing RNA (TERRA), were identified as blocking telomerase activity (TA), a telomere maintenance mechanism (TMM), in tumors. We expressed recombinant TERRA transcripts in tumor cell lines with TA and with alternative lengthening of telomeres (ALT) to study effects on TMM and cell growth. Adeno- and lentivirus constructs (AV and LV) were established for transient and stable expression of approximately 130 units of telomere hexanucleotide repeats under control of cytomegalovirus (CMV) and human RNase P RNA H1 (hH1) promoters with and without polyadenylation, respectively. Six human tumor cell lines either using telomerase or ALT were infected and analyzed for TA levels. Pre-infection cells using telomerase had 1%–3% of the TERRA expression levels of ALT cells. AV and LV expression of recombinant TERRA in telomerase positive cells showed a 1.3–2.6 fold increase in TERRA levels, and a decrease in TA of 25%–58%. Dominant-negative or small hairpin RNA (shRNA) viral expression against human telomerase reverse transcriptase (hTERT) results in senescence, not induced by TERRA expression. Population doubling time, cell viability and TL (telomere length) were not impacted by ectopic TERRA expression. Clonal growth was reduced by TERRA expression in TA but not ALT cell lines. ALT cells were not affected by treatments applied. Established cell models and tools may be used to better understand the role of TERRA in the cell, especially for targeting telomerase.

Beschreibung: Recombinational repair processes multiple types of DNA lesions. Though best understood in the repair of DNA breaks, recombinational repair is intimately linked to other situations encountered during replication. As DNA strands are decorated with many types of blocks that impede the replication machinery, a great number of genomic regions cannot be duplicated without the help of recombinational repair. This replication-associated recombinational repair employs both the core recombination proteins used for DNA break repair and the specialized factors that couple replication with repair. Studies from multiple organisms have provided insights into the roles of these specialized factors, with the findings in budding yeast being advanced through use of powerful genetics and methods for detecting DNA replication and repair intermediates. In this review, we summarize recent progress made in this organism, ranging from our understanding of the classical template switch mechanisms to gap filling and replication fork regression pathways. As many of the protein factors and biological principles uncovered in budding yeast are conserved in higher eukaryotes, these findings are crucial for stimulating studies in more complex organisms.

Beschreibung: Mounting evidence indicates that alternate DNA structures, which deviate from normal double helical DNA, form in vivo and influence cellular processes such as replication and transcription. However, our understanding of how the cellular machinery deals with unusual DNA structures such as G-quadruplexes (G4), triplexes, or hairpins is only beginning to emerge. New advances in the field implicate a direct role of the Fanconi Anemia Group J (FANCJ) helicase, which is linked to a hereditary chromosomal instability disorder and important for cancer suppression, in replication past unusual DNA obstacles. This work sets the stage for significant progress in dissecting the molecular mechanisms whereby replication perturbation by abnormal DNA structures leads to genomic instability. In this review, we focus on FANCJ and its role to enable efficient DNA replication when the fork encounters vastly abundant naturally occurring DNA obstacles, which may have implications for targeting rapidly dividing cancer cells.

Beschreibung: Fragile X syndrome (FXS) is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP), the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO) mice, the factors released by astrocytes are still unclear. We cultured wild type (WT) cortical neurons in astrocyte-conditioned medium (ACM) from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA) levels using high-performance liquid chromatography (HPLC). The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T) expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB), a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment.

Beschreibung: Embryonic stem cells and induced pluripotent stem cells have the ability to maintain their telomere length via expression of an enzymatic complex called telomerase. Similarly, more than 85%–90% of cancer cells are found to upregulate the expression of telomerase, conferring them with the potential to proliferate indefinitely. Telomerase Reverse Transcriptase (TERT), the catalytic subunit of telomerase holoenzyme, is the rate-limiting factor in reconstituting telomerase activity in vivo. To date, the expression and function of the human Telomerase Reverse Transcriptase (hTERT) gene are known to be regulated at various molecular levels (including genetic, mRNA, protein and subcellular localization) by a number of diverse factors. Among these means of regulation, transcription modulation is the most important, as evident in its tight regulation in cancer cell survival as well as pluripotent stem cell maintenance and differentiation. Here, we discuss how hTERT gene transcription is regulated, mainly focusing on the contribution of trans-acting factors such as transcription factors and epigenetic modifiers, as well as genetic alterations in hTERT proximal promoter.

Beschreibung: Combined Bisulfite Restriction Analysis (COBRA) quantifies DNA methylation at a specific locus. It does so via digestion of PCR amplicons produced from bisulfite-treated DNA, using a restriction enzyme that contains a cytosine within its recognition sequence, such as TaqI. Here, we introduce COBRA-seq, a genome wide reduced methylome method that requires minimal DNA input (0.1–1.0 mg) and can either use PCR or linear amplification to amplify the sequencing library. Variants of COBRA-seq can be used to explore CpG-depleted as well as CpG-rich regions in vertebrate DNA. The choice of enzyme influences enrichment for specific genomic features, such as CpG-rich promoters and CpG islands, or enrichment for less CpG dense regions such as enhancers. COBRA-seq coupled with linear amplification has the additional advantage of reduced PCR bias by producing full length fragments at high abundance. Unlike other reduced representative methylome methods, COBRA-seq has great flexibility in the choice of enzyme and can be multiplexed and tuned, to reduce sequencing costs and to interrogate different numbers of sites. Moreover, COBRA-seq is applicable to non-model organisms without the reference genome and compatible with the investigation of non-CpG methylation by using restriction enzymes containing CpA, CpT, and CpC in their recognition site.

Beschreibung: Substance abuse has an enormous impact on economic and quality of life measures throughout the world. In more developed countries, overutilization of the most common forms of substances of abuse, alcohol and tobacco, is addressed primarily through prevention of substance use initiation and secondarily through the treatment of those with substance abuse or dependence. In general, these therapeutic approaches to substance abuse are deemed effective. However, there is a broad consensus that the development of additional tools to aid diagnosis, prioritize treatment selection and monitor treatment response could have substantial impact on the effectiveness of both substance use prevention and treatment. The recent demonstrations by a number of groups that substance use exposure is associated with robust changes in DNA methylation signatures of peripheral blood cells suggests the possibility that methylation assessments of blood or saliva could find broad clinical applications. In this article, we review recent progress in epigenetic approaches to substance use assessment with a particular emphasis on smoking (and alcohol) related applications. In addition, we highlight areas, such as the epigenetics of psychostimulant, opioid and cannabis abuse, which are markedly understudied and could benefit from intensified collaborative efforts to define epigenetic biomarkers of abuse and dependence.

Beschreibung: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. MDS is frequently associated with deletions on chromosome 5q as well as aberrant DNA methylation patterns including hypermethylation of key tumor suppressors. We have previously shown that hypermethylation and silencing of the non-coding RNA VTRNA2-1 are correlated with poor outcomes in acute myeloid leukemia patients. In this study, we find that VTRNA1-2 and VTRNA1-3, both located on chromosome 5q, can be regulated and silenced by promoter DNA methylation, and that the hypomethylating agent 5-aza-2-deoxycytidine causes reactivation these genes. In normal hematopoiesis, we find that vault RNAs (vtRNAs) show differential methylation between various hematopoietic cell populations, indicating that allele-specific methylation events may occur during hematopoiesis. In addition, we show that VTRNA1-3 promoter hypermethylation is frequent in lower risk MDS patients and is associated with a decreased overall survival.

Beschreibung: Despite advances in our understanding of the processes driving contemporary sea level rise, the stability of the Antarctic ice sheets and their contribution to sea level under projected future warming remains uncertain due to the influence of strong ice-climate feedbacks. Disentangling these feedbacks is key to reducing uncertainty. Here we present a series of climate system model simulations that explore the potential effects of increased West Antarctic Ice Sheet (WAIS) meltwater flux on Southern Ocean dynamics. We project future changes driven by sectors of the WAIS, delivering spatially and temporally variable meltwater flux into the Amundsen, Ross and Weddell embayments over future centuries. Focusing on the Amundsen Sea sector of the WAIS over the next 200 years, we demonstrate that the enhanced meltwater flux rapidly stratifies surface waters, resulting in a significant decrease in the rate of Antarctic Bottom Water (AABW) formation. This triggers rapid pervasive ocean warming (〉1°C) at depth due to advection from the original site(s) of meltwater input. The greatest warming predicted along sectors of the ice sheet that are highly sensitized to ocean forcing, creating a feedback loop that could enhance basal ice shelf melting and grounding line retreat. Given that we do not include the effects of rising CO 2 - predicted to further reduce AABW formation - our experiments highlight the urgent need to develop a new generation of fully-coupled ice sheet climate models, that include feedback mechanisms such as this, to reduce uncertainty in climate and sea level projections.

Beschreibung: Codon usage bias, which exists in many genomes, is mainly determined by mutation and selection. To elucidate the genetic features and evolutionary history of herbaceous peony (Paeonia lactiflora), a well-known symbol of prosperity in China, we examined synonymous codon usage in 24,216 reconstructed genes from the P. lactiflora transcriptome. The mean GC content was 44.4%, indicating that the nucleotide content of P. lactiflora genes is slightly AT rich and GC poor. The P. lactiflora genome has a wide range of GC3 (GC content at the third synonymous codon position) distribution, with a significant correlation between GC12 and GC3. ENC (effective number of codons) analysis suggested that mutational bias played a major role in shaping codon usage. Parity Rule 2 (PR2) analysis revealed that GC and AU were not used proportionally. We identified 22 “optimal codons”, most ending with an A or U. Our results suggested that nucleotide composition mutation bias and translational selection were the main driving factors of codon usage bias in P. lactiflora. These results lay the foundation for exploring the evolutionary mechanisms and heterologous expression of functionally-important proteins in P. lactiflora.

Beschreibung: Variations in porin proteins are common in Gram-negative pathogens. Altered or absent porins reduce access of polar antibiotics across the outer membrane and can thus contribute to antibiotic resistance. Reduced permeability has a cost however, in lowering access to nutrients. This trade-off between permeability and nutritional competence is the source of considerable natural variation in porin gate-keeping. Mutational changes in this trade-off are frequently selected, so susceptibility to detergents and antibiotics is polymorphic in environmental isolates as well as pathogens. Understanding the mechanism, costs and heterogeneity of antibiotic exclusion by porins will be crucial in combating Gram negative infections.

Beschreibung: We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts of the epigenetic machinery. We discuss the effect of DNA promoter methylation and of transcriptional activity in the context of mutated epigenetic modifiers such as EZH2 and MLL2. As another mechanism, we studied the coupling between the energy metabolism and epigenetics via metabolites that act as cofactors of JmjC-type demethylases. Our study results suggest that Burkitt’s lymphoma and diffuse large B-cell Lymphoma differ by an imbalance of repressive and poised promoters, which is governed predominantly by the activity of methyltransferases and the underrepresentation of demethylases in this regulation. The data further suggest that coupling of epigenetics with the energy metabolism can also be an important factor in lymphomagenesis in the absence of direct mutations of genes in metabolic pathways. Understanding of epigenetic deregulation in lymphoma and possibly in cancers in general must go beyond simple schemes using only a few modes of regulation.

Beschreibung: Epigenetics contributes to molecular mechanisms leading to tumor cell transformation and systemic progression of cancer. However, the dynamics of epigenetic remodeling during metastasis remains unexplored. In this context, circulating tumor cells (CTCs) might enable a direct insight into epigenetic mechanisms relevant for metastasis by providing direct access to systemic cancer. CTCs can be used as prognostic markers in cancer patients and are regarded as potential metastatic precursor cells. However, despite substantial technical progress, the detection and molecular characterization of CTCs remain challenging, in particular the analysis of DNA methylation. As recent studies have started to address the epigenetic state of CTCs, we discuss here the potential of such investigations to elucidate mechanisms of metastasis and to develop tumor biomarkers.

Beschreibung: In pigs, successful embryo implantation is an important guarantee for producing litter size, and early embryonic loss occurring on day 12–30 of gestation critically affects the potential litter size. The implantation process is regulated by the expression of numerous genes, so comprehensive analysis of the endometrium is necessary. In this study, RNA sequencing (RNA-Seq) technology is used to analyze endometrial tissues during early pregnancy. We investigated the changes of gene expression between three stages (day 12, 18, and 25) by multiple comparisons. There were 1557, 8951, and 2345 differentially expressed genes (DEGs) revealed between the different periods of implantation. We selected several genes for validation by the use of quantitative real-time RT-PCR. Bioinformatic analysis of differentially expressed genes in the endometrium revealed a number of biological processes and pathways potentially involved in embryo implantation in the pig, most noticeably cell proliferation, regulation of immune response, interaction of cytokine-cytokine receptors, and cell adhesion. These results showed that specific gene expression patterns reflect the different functions of the endometrium in three stages (maternal recognition, conceptus attachment, and embryo implantation). This study identified comprehensive transcriptomic profile in the porcine endometrium and thus could be a foundation for targeted studies of genes and pathways potentially involved in abnormal endometrial receptivity and embryo loss in early pregnancy.

Beschreibung: Myrosinase, which is present in cruciferous plant species, plays an important role in the hydrolysis of glycosides such as glucosinolates and is involved in plant defense. Brassicaceae myrosinases are diverse although they share common ancestry, and structural knowledge about myrosinases from cabbage (Brassica oleracea) was needed. To address this, we constructed a three-dimensional model structure of myrosinase based on Sinapis alba structures using Iterative Threading ASSEmbly Refinement server (I-TASSER) webserver, and refined model coordinates were evaluated with ProQ and Verify3D. The resulting model was predicted with β/α fold, ten conserved N-glycosylation sites, and three disulfide bridges. In addition, this model shared features with the known Sinapis alba myrosinase structure. To obtain a better understanding of myrosinase–sinigrin interaction, the refined model was docked using Autodock Vina with crucial key amino acids. The key nucleophile residues GLN207 and GLU427 were found to interact with sinigrin to form a hydrogen bond. Further, 20-ns molecular dynamics simulation was performed to examine myrosinase–sinigrin complex stability, revealing that residue GLU207 maintained its hydrogen bond stability throughout the entire simulation and structural orientation was similar to that of the docked state. This conceptual model should be useful for understanding the structural features of myrosinase and their binding orientation with sinigrin.

Beschreibung: Clostridium difficile is well recognized as the leading cause of antibiotic-associated diarrhea, having a significant impact in both health-care and community settings. Central to predisposition to C. difficile infection is disruption of the gut microbiome by antibiotics. Being a Gram-positive anaerobe, C. difficile is intrinsically resistant to a number of antibiotics. Mobile elements encoding antibiotic resistance determinants have also been characterized in this pathogen. While resistance to antibiotics currently used to treat C. difficile infection has not yet been detected, it may be only a matter of time before this occurs, as has been seen with other bacterial pathogens. This review will discuss C. difficile disease pathogenesis, the impact of antibiotic use on inducing disease susceptibility, and the role of antibiotic resistance and mobile elements in C. difficile epidemiology.