ALBERT

Description: Publication date: Available online 7 September 2013 Source: FEBS Open Bio Author(s): Veronika Temml , Susanne Kuehnl , Daniela Schuster , Stefan Schwaiger , Hermann Stuppner , Dietmar Fuchs Mediterranean Carthamus tinctorius (Safflower) is used for treatment of inflammatory conditions and neuropsychiatric disorders. Recently C. tinctorius lignans arctigenin and trachelogenin but not matairesinol were described to interfere with the activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) in peripheral blood mononuclear cells in vitro . We examined a potential direct influence of compounds on IDO enzyme activity applying computational calculations based on 3D geometry of the compounds. The interaction pattern analysis and force field-based minimization was performed within LigandScout 3.03, the docking simulation with MOE 2011.10 using the X-ray crystal structure of IDO. Results confirm the possibility of an intense interaction of arctigenin and trachelogenin with the binding site of the enzyme, while matairesinol had no such effect.

Description: Publication date: Available online 7 September 2013 Source: FEBS Open Bio Author(s): Mitsuru Ishikawa , Jun Shiota , Yuta Ishibashi , Tomoyuki Hakamata , Shizuku Shoji , Mamoru Fukuchi , Masaaki Tsuda , Tomoaki Shirao , Yuko Sekino , Toshihisa Ohtsuka , Jay M. Baraban , Akiko Tabuchi Megakaryoblastic leukemia 1 (MKL1) is a member of the MKL family of serum response factor (SRF) coactivators. Here we have identified three rat MKL1 transcripts: two are homologues of mouse MKL1 transcripts, full-length MKL1 (FLMKL1) and basic, SAP, and coiled-coil domains (BSAC), the third is a novel transcript, M KL1- elo ngated d erivative of y ield (MELODY). These rat MKL1 transcripts are differentially expressed in a wide variety of tissues with highest levels in testis and brain. During brain development, these transcripts display differential patterns of expression. The FLMKL1 transcript encodes two isoforms that utilize distinct translation start sites. The longer form possesses three actin-binding RPXXXEL (RPEL) motifs and the shorter form, MKL1met only has two RPEL motifs. All four rat MKL1 isoforms, FLMKL1, BSAC, MKL1met and MELODY increased SRF-mediated transcription, but not CREB-mediated transcription. Accordingly, the differential expression of MKL1 isoforms may help fine-tune gene expression during brain development.

Description: Publication date: Available online 11 September 2013 Source: FEBS Open Bio Author(s): Gisele Castro , Maria Fernanda C. Areias , Lais Weissmann , Paula G.F. Quaresma , Carlos K. Katashima , Mario J.A. Saad , Patricia O. Prada Insulin acts in the hypothalamus, decreasing food intake (FI) by the IR/PI3K/Akt pathway. This pathway is impaired in obese animals and endoplasmic reticulum (ER) stress and low-grade inflammation are possible mechanisms involved in this impairment. Here, we highlighted the amygdala as an important brain region for FI regulation in response to insulin. This regulation was dependent on PI3K/AKT pathway similar to the hypothalamus. Insulin was able to decrease neuropeptide Y (NPY) and increase oxytocin mRNA levels in the amygdala via PI3K, which may contribute to hypophagia. Additionally, obese rats did not reduce FI in response to insulin and AKT phosphorylation was decreased in the amygdala, suggesting insulin resistance. Insulin resistance was associated with ER stress and low-grade inflammation in this brain region. The inhibition of ER stress with PBA reverses insulin action/signaling, decreases NPY and increases oxytocin mRNA levels in the amygdala from obese rats, suggesting that ER stress is probably one of the mechanisms that induce insulin resistance in the amygdala.

Description: We describe the structure, microstructure, and petrophysical properties of fault rocks from two normal fault zones formed in low-porosity turbiditic arkosic sandstones, in deep diagenesis conditions similar to those of deeply buried reservoirs. These fault rocks are characterized by a foliated fabric and quartz-calcite sealed veins, which formation resulted from the combination of the (1) pressure solution of quartz, (2) intense fracturing sealed by quartz and calcite cements, and (3) neoformation of synkinematic white micas derived from the alteration of feldspars and chlorite. Fluid inclusion microthermometry in quartz and calcite cements demonstrates fault activity at temperatures of 195°C to 268°C. Permeability measurements on plugs oriented parallel with the principal axes of the finite strain ellipsoid show that the Y axis (parallel with the foliation and veins) is the direction of highest permeability in the foliated sandstone (10 •2 md for Y against 10 •3 md for X, Z, and the protolith, measured at a confining pressure of 20 bars). Microstructural observations document the localization of the preferential fluid path between the phyllosilicate particles forming the foliation. Hence, the direction of highest permeability in these fault rocks would be parallel with the fault and subhorizontal, that is, perpendicular to the slickenlines representing the local slip direction on the fault surface. We suggest that a similar relationship between kinematic markers and fault rock permeability anisotropy may be found in other fault zone types (reverse or strike-slip) affecting feldspar-rich lithologies in deep diagenesis conditions.

Description: This work discusses concepts related to the occurrence of salt along weakness planes, such as faults and fractures, which resemble igneous intrusions and may result in peculiar seismic features. We suggest that mechanisms for the formation of these structures basically involve the creation of extensional faults (commonly associated with crestal collapse grabens), which are rotated and migrated to structural flanks by domation, creating interesting seismic features here referred to as halokinetic rotating faults. At the time of their formation, some of these faults may be incipiently intruded by salt as a way of relieving sporadic intense internal overpressure episodes in the salt body, by regional compression, and/or by buoyancy effects compensating the density difference between salt and surrounding sediments. The relatively low overburden pressure at the crest of the diapir and the original high dip angles of these fault planes favor salt intrusions near the diapir apex. The process may occur in several cycles along the salt dome evolution, creating several generations of salt apophyses positioned in the diapir apex and flanks, resulting in different dips and areas of extension. These intrusions sometimes resemble the branches of Christmas tree structures, which are commonly formed by extrusive mechanisms. Although well and seismic data point to the occurrence of salt along fault planes, we recognize that salt is not a low-viscosity fluid, and the mechanisms to allow its penetration along fault planes remain unknown. Some of the possible mechanisms, which are commonly associated with a later phase of regional compression, are discussed in this work. The implications for petroleum exploration may have been overlooked in the recent exploration campaigns in the deep-water regions of the Brazilian margin. Halokinetic rotating faults, when partially filled with salt, are sometimes responsible for common pitfalls observed in seismic and well data interpretation. When fault planes present subhorizontal dips and high reflectivity, caused by the presence of salt, they have been mistakenly interpreted as flatspots, a well-known seismic hydrocarbon indicator. When drilled and proved to correspond to thin evaporite intervals in well data, these salt apophyses have also been misinterpreted as younger localized evaporitic events overlying the main salt body.

Description: Publication date: Available online 12 September 2013 Source: Cell Reports Author(s): Debra A. Mayes , Tilat A. Rizvi , Haley Titus-Mitchell , Rachel Oberst , Georgianne M. Ciraolo , Charles V. Vorhees , Andrew P. Robinson , Stephen D. Miller , Jose A. Cancelas , Anat O. Stemmer-Rachamimov , Nancy Ratner Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1–NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients. Graphical abstract Teaser In this study, Ratner and colleagues show that altering intracellular signaling in oligodendrocytes affects brain astrocytes and blood vessels that together make up the blood-brain barrier. Increasing oligodendrocyte Ras-GTP, mimicking neurofibromatosis type 1 and Costello syndrome, disrupted astrocyte and endothelial cell tight junctions and gap junctions and caused a leaky blood-brain barrier. Exposure to a nitric oxide synthase inhibitor or an antioxidant reversed cellular phenotypes and behavioral hyperactivity. Thus, oligodendrocytes contribute to brain homeostasis, and antioxidant therapy may be beneficial when homeostasis is disrupted.

Description: Publication date: Available online 12 September 2013 Source: Cell Reports Author(s): Dalit Ben-Yosef , Francesca S. Boscolo , Hadar Amir , Mira Malcov , Ami Amit , Louise C. Laurent Given the association between mutational load and cancer, the observation that genetic aberrations are frequently found in human pluripotent stem cells (hPSCs) is of concern. Prior studies in human induced pluripotent stem cells (hiPSCs) have shown that deletions and regions of loss of heterozygosity (LOH) tend to arise during reprogramming and early culture, whereas duplications more frequently occur during long-term culture. For the corresponding experiments in human embryonic stem cells (hESCs), we studied two sets of hESC lines: one including the corresponding parental DNA and the other generated from single blastomeres from four sibling embryos. Here, we show that genetic aberrations observed in hESCs can originate during preimplantation embryo development and/or early derivation. These early aberrations are mainly deletions and LOH, whereas aberrations arising during long-term culture of hESCs are more frequently duplications. Our results highlight the importance of close monitoring of genomic integrity and the development of improved methods for derivation and culture of hPSCs. Graphical abstract Teaser Human embryonic stem cells (hESCs) are potential sources of cells for transplantation therapy. However, given the association between mutations and cancer, the frequency of genetic aberrations observed in hESCs is concerning. Using unique pedigrees of hESC lines, Laurent and colleagues now find that aberrations that occur during cell-line derivation are mainly deletions and loss of heterozygosity, whereas duplications arise more commonly during long-term culture. These results highlight the need for improved methods for derivation and culture that preserve the genetic integrity of hESCs.

Description: Publication date: Available online 12 September 2013 Source: Cell Reports Author(s): Jason Karpac , Benoit Biteau , Heinrich Jasper Loss of metabolic homeostasis is a hallmark of aging and is commonly characterized by the deregulation of adaptive signaling interactions that coordinate energy metabolism with dietary changes. The mechanisms driving age-related changes in these adaptive responses remain unclear. Here, we characterize the deregulation of an adaptive metabolic response and the development of metabolic dysfunction in the aging intestine of Drosophila . We find that activation of the insulin-responsive transcription factor Foxo in intestinal enterocytes is required to inhibit the expression of evolutionarily conserved lipases as part of a metabolic response to dietary changes. This adaptive mechanism becomes chronically activated in the aging intestine, mediated by changes in Jun-N-terminal kinase (JNK) signaling. Age-related chronic JNK/Foxo activation in enterocytes is deleterious, leading to sustained repression of intestinal lipase expression and the disruption of lipid homeostasis. Changes in the regulation of Foxo-mediated adaptive responses thus contribute to the age-associated breakdown of metabolic homeostasis. Graphical abstract Teaser Aging is associated with a loss of metabolic homeostasis, which is a risk factor for various human pathologies. Using Drosophila , Karpac, Biteau, and Jasper show that the transcription factor Foxo regulates intestinal lipid homeostasis as part of an adaptive response to dietary changes and that chronic intestinal activation of Foxo with age leads to the disruption of lipid metabolism. These results demonstrate that changes in the regulation of adaptive signaling mechanisms can contribute to the age-associated breakdown of metabolic homeostasis.

Description: Publication date: Available online 13 September 2013 Source: Geoscience Frontiers Author(s): K. Naganjaneyulu

Description: Publication date: Available online 17 September 2013 Source: FEBS Open Bio Author(s): Rasheda Sultana , Maria A. Theodoraki , Avrom J. Caplan The UBR1 ubiquitin ligase promotes degradation of proteins via the N-end rule and by another mechanism that detects a misfolded conformation. Although UBR1 was shown recently to act on protein kinases whose misfolding was promoted by inhibition of Hsp90, it was unknown whether this ubiquitin ligase targeted other client types of the chaperone. We analyzed the role of UBR1 in the degradation of nuclear receptors that are classical clients of Hsp90. Our results showed that UBR1 deletion results in impaired degradation of the glucocorticoid receptor and the androgen receptor but not the estrogen receptor α. These findings demonstrate specificity in the actions of the UBR1 ubiquitin ligase in the degradation of Hsp90 clients in the presence of small molecule inhibitors that promote client misfolding. Graphical abstract

Description: Publication date: Available online 19 September 2013 Source: Cell Reports Author(s): George E. Gentsch , Nick D.L. Owens , Stephen R. Martin , Paul Piccinelli , Tiago Faial , Matthew W.B. Trotter , Michael J. Gilchrist , James C. Smith The design of effective cell replacement therapies requires detailed knowledge of how embryonic stem cells form primary tissues, such as mesoderm or neurectoderm that later become skeletal muscle or nervous system. Members of the T-box transcription factor family are key in the formation of these primary tissues, but their underlying molecular activities are poorly understood. Here, we define in vivo genome-wide regulatory inputs of the T-box proteins Brachyury, Eomesodermin, and VegT, which together maintain neuromesodermal stem cells and determine their bipotential fates in frog embryos. These T-box proteins are all recruited to the same genomic recognition sites, from where they activate genes involved in stem cell maintenance and mesoderm formation while repressing neurogenic genes. Consequently, their loss causes embryos to form an oversized neural tube with no mesodermal derivatives. This collaboration between T-box family members thus ensures the continuous formation of correctly proportioned neural and mesodermal tissues in vertebrate embryos during axial elongation. Graphical abstract Teaser The development of effective cell replacement therapies requires detailed knowledge of how embryonic stem cells form primary tissues, such as mesoderm or neurectoderm that later become skeletal muscle or spinal cord. Gentsch, Smith, and colleagues now provide mechanistic insight into how T-box transcription factors regulate stem cells to form neural or mesodermal tissues. The authors show how this ensures the harmonious formation of spinal cord, muscle, and notochord as the vertebrate embryo elongates along its anteroposterior axis.

Description: Publication date: Available online 19 September 2013 Source: Cell Reports Author(s): Ivan Zanoni , Roberto Spreafico , Caterina Bodio , Marco Di Gioia , Clara Cigni , Achille Broggi , Tatiana Gorletta , Michele Caccia , Giuseppe Chirico , Laura Sironi , Maddalena Collini , Mario P. Colombo , Natalio Garbi , Francesca Granucci Natural killer (NK) cells have antitumor, antiviral, and antibacterial functions, and efforts are being made to manipulate them in immunotherapeutic approaches. However, their activation mechanisms remain poorly defined, particularly during bacterial infections. Here, we show that upon lipopolysaccharide or E. coli exposure, dendritic cells (DCs) produce three cytokines—interleukin 2 (IL-2), IL-18, and interferon β (IFN-β)—necessary and sufficient for NK cell activation. IFN-β enhances NK cell activation by inducing IL-15 and IL-15 receptor α not only in DCs but, surprisingly, also in NK cells. This process allows the transfer of IL-15 on NK cell surface and its cis presentation. cis -presented NK cell-derived and trans -presented DC-derived IL-15 contribute equally to optimal NK cell activation. Graphical abstract Teaser NK cells depend on IL-15 provided by accessory cells for their survival under steady-state conditions. It has long been believed that a similar requirement is applied to NK cell activation as well. Zanoni, Granucci, and colleagues now show that NK cells express IL-15 and IL-15Rα when stimulated by type I interferons. NK cells cis -present self-produced IL-15, and this is as important to NK cell activation as trans presentation of IL-15 by dendritic cells.

Description: Publication date: Available online 19 September 2013 Source: Cell Reports Author(s): Oren Ben-Ami , Dan Friedman , Dena Leshkowitz , Dalia Goldenberg , Kira Orlovsky , Niv Pencovich , Joseph Lotem , Amos Tanay , Yoram Groner The t(8;21) and inv(16) chromosomal aberrations generate the oncoproteins AML1-ETO (A-E) and CBFβ-SMMHC (C-S). The role of these oncoproteins in acute myeloid leukemia (AML) etiology has been well studied. Conversely, the function of native RUNX1 in promoting A-E- and C-S-mediated leukemias has remained elusive. We show that wild-type RUNX1 is required for the survival of t(8;21)-Kasumi-1 and inv(16)-ME-1 leukemic cells. RUNX1 knockdown in Kasumi-1 cells (Kasumi-1 RX1-KD ) attenuates the cell-cycle mitotic checkpoint, leading to apoptosis, whereas knockdown of A-E in Kasumi-1 RX1-KD rescues these cells. Mechanistically, a delicate RUNX1/A-E balance involving competition for common genomic sites that regulate RUNX1/A-E targets sustains the malignant cell phenotype. The broad medical significance of this leukemic cell addiction to native RUNX1 is underscored by clinical data showing that an active RUNX1 allele is usually preserved in both t(8;21) or inv(16) AML patients, whereas RUNX1 is frequently inactivated in other forms of leukemia. Thus, RUNX1 and its mitotic control targets are potential candidates for new therapeutic approaches. Graphical abstract Teaser The t(8;21) and inv(16) chimeric oncogenes are major etiological drivers of human acute myeloid leukemia. However, the function of native RUNX1 in these leukemias has remained unknown. Groner and colleagues demonstrate that expression of wild-type RUNX1 is essential for t(8;21) and inv(16) leukemogenesis. Reducing RUNX1 activity destines the leukemic cells for apoptosis. Importantly, an active RUNX1 allele is usually preserved in t(8;21) or inv(16) patients, whereas, in other leukemias, it is frequently inactivated, underscoring the significance of this leukemic cell addiction to RUNX1.

Description: Publication date: Available online 19 September 2013 Source: Cell Reports Author(s): Markus Reschke , John G. Clohessy , Nina Seitzer , Daniel P. Goldstein , Susanne B. Breitkopf , Daniel B. Schmolze , Ugo Ala , John M. Asara , Andrew H. Beck , Pier Paolo Pandolfi Increasing evidence points to an important role for the ribosome in the regulation of biological processes and as a target for deregulation in disease. Here, we describe a SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry approach to probing mammalian riboproteomes. Using a panel of cell lines, as well as genetic and pharmacological perturbations, we obtained a comparative characterization of the cellular riboproteome. This analysis identified a set of riboproteome components, consisting of a diverse array of proteins with a strong enrichment for RNA-binding proteins. Importantly, this global analysis uncovers a high incidence of genetic alterations to riboproteome components in cancer, with a distinct bias toward genetic amplification. We further validated association with polyribosomes for several riboproteome components and demonstrate that enrichment at the riboproteome can depend on cell type, genetics, or cellular stimulus. Our results have important implications for the understanding of how ribosomes function and provide a platform for uncovering regulators of translation. Graphical abstract Teaser Increasing evidence points to an important role for the ribosome in regulating biological processes and as a target in disease. Now, Pandolfi and colleagues use mass spectrometry to probe the mammalian riboproteome. They show that the riboproteome displays differential composition in cancer cells and contains an array of proteins, many of which are frequently amplified in cancer. These results have important implications for the understanding of how ribosomes function and provide a platform to broaden our understanding of translational regulation.

Description: The Cretaceous rocks of Florida have been recognized as potentially suitable reservoirs for geologic carbon dioxide (CO 2 ) sequestration. Specifically, the upper member of the Upper Cretaceous Lawson Formation, together with the lower part of the Paleocene Cedar Keys Formation, is presented here as a potential composite CO 2 storage reservoir that is mainly composed of porous dolostone sealed by thick anhydrites of the overlying middle Cedar Keys Formation. Many of the porous intervals within the Cedar Keys-Lawson storage reservoir display lateral continuity and have an average porosity range of 20%–30%. The estimated CO 2 storage capacity for the reservoir is approximately 97 billion t of CO 2 , which means the Lawson and Cedar Keys Formations composite reservoir could potentially support CO 2 sequestration for hundreds of large-scale power plants in the southeastern United States for their entire 40-yr lifespan. Because most of the previous research on the Lawson Formation is concentrated in north-central and northeastern Florida and southern Georgia, this study further characterizes the formation and its CO 2 sequestration potential in south-central and southern Florida.

Description: Publication date: Available online 19 September 2013 Source: Cell Reports Author(s): Shunqiang Li , Dong Shen , Jieya Shao , Robert Crowder , Wenbin Liu , Aleix Prat , Xiaping He , Shuying Liu , Jeremy Hoog , Charles Lu , Li Ding , Obi L. Griffith , Christopher Miller , Dave Larson , Robert S. Fulton , Michelle Harrison , Tom Mooney , Joshua F. McMichael , Jingqin Luo , Yu Tao , Rodrigo Goncalves , Christopher Schlosberg , Jeffrey F. Hiken , Laila Saied , Cesar Sanchez , Therese Giuntoli , Caroline Bumb , Crystal Cooper , Robert T. Kitchens , Austin Lin , Chanpheng Phommaly , Sherri R. Davies , Jin Zhang , Megha Shyam Kavuri , Donna McEachern , Yi Yu Dong , Cynthia Ma , Timothy Pluard , Michael Naughton , Ron Bose , Rama Suresh , Reida McDowell , Loren Michel , Rebecca Aft , William Gillanders , Katherine DeSchryver , Richard K. Wilson , Shaomeng Wang , Gordon B. Mills , Ana Gonzalez-Angulo , John R. Edwards , Christopher Maher , Charles M. Perou , Elaine R. Mardis , Matthew J. Ellis To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation. Graphical abstract Teaser In this study, Ellis and colleagues compare whole-tumor genomes from drug-resistant breast cancers with paired xenografts. Genomic fidelity upon transplantation was high for structural variants but variable at the single-nucleotide level. Therefore, tumor and xenograft whole-genome comparisons critically assess genetic drift and clonal representation. Additional analysis revealed ESR1 mutations, amplification, and translocations associated with endocrine resistance in lumenal xenografts. Sequenced patient-derived xenografts are an important resource for functional genomics and capture treatment-resistance etiologies that are not observed in standard cell lines.

Description: Geochemical reactions that may occur on CO 2 injection into a sandstone formation in Missouri (MO) were investigated by means of geochemical modeling. Five possible injection sites were considered: two in the northwestern part of the state, two in the northeastearn part, and one in the southwestern part. The Geochemist Workbench software was used to investigate solubility trapping and mineral precipitation. Modeling was performed for two periods: an injection period of 10 yr and a postinjection period where the reactions proceeded to equilibrium. The work presented substantial challenges. Among them are uncertainty in kinetic constants for the dissolution and precipitation of minerals on CO 2 injection. Model results include equilibrium values for CO 2 stored via solubility trapping ranging from 49-g CO 2 /kg free formation water in Northeast MO to 78-g CO 2 /kg free formation water for Southwest MO. Mineral trapping is significantly lower, between 2.6- and 18.4-g CO 2 /kg free formation water. The model shows siderite and dawsonite as the major carbonate minerals formed, in this order. On a volumetric basis, northwest MO sequestration values were slightly greater than those obtained for northeast MO because of the somewhat greater depth and higher injection pressure at the injection target (Lamotte Sandstone) at the northwestern sites. However, the greater thickness of the aquifer for the northeastern sites provided overall greater sequestration capacity. Greene County was altogether unfit for sequestration because of the low total dissolved solids value of the formation water.

Description: Publication date: Available online 26 September 2013 Source: Cell Reports Author(s): Jun Ding , Ursula Loizides-Mangold , Gianpaolo Rando , Vincent Zoete , Olivier Michielin , Janardan K. Reddy , Walter Wahli , Howard Riezman , Bernard Thorens Specific metabolic pathways are activated by different nutrients to adapt the organism to available resources. Although essential, these mechanisms are incompletely defined. Here, we report that medium-chain fatty acids contained in coconut oil, a major source of dietary fat, induce the liver ω-oxidation genes Cyp4a10 and Cyp4a14 to increase the production of dicarboxylic fatty acids. Furthermore, these activate all ω- and β-oxidation pathways through peroxisome proliferator activated receptor (PPAR) α and PPARγ, an activation loop normally kept under control by dicarboxylic fatty acid degradation by the peroxisomal enzyme L-PBE. Indeed, L-pbe −/− mice fed coconut oil overaccumulate dicarboxylic fatty acids, which activate all fatty acid oxidation pathways and lead to liver inflammation, fibrosis, and death. Thus, the correct homeostasis of dicarboxylic fatty acids is a means to regulate the efficient utilization of ingested medium-chain fatty acids, and its deregulation exemplifies the intricate relationship between impaired metabolism and inflammation. Graphical abstract Teaser Specific metabolic pathways are activated by different nutrients to adapt the organism to available resources. Riezman, Thorens, and colleagues find that mice lacking the peroxisomal L-bifunctional enzyme (L-pbe) die of liver failure when fed coconut oil but not lard. Medium-chain fatty acids in coconut oil induce the liver ω-oxidation to increase the production of dicarboxylic fatty acids (DCAs). Furthermore, these activate all ω- and β-oxidation pathways through peroxisome proliferator activated receptors, an activation loop normally fine tuned by L-PBE degrading DCAs. Their work demonstrates the physiological role of mouse L-PBE in hepatic adaptation to medium-chain fatty acids.

Description: Publication date: Available online 26 September 2013 Source: Cell Reports Author(s): Tae Kyung Kim , Jai-Yoon Sul , Henrik Helmfors , Ulo Langel , Junhyong Kim , James Eberwine Protein synthesis in neuronal dendrites underlies long-term memory formation in the brain. Local translation of reporter mRNAs has demonstrated translation in dendrites at focal points called translational hotspots. Various reports have shown that hundreds to thousands of mRNAs are localized to dendrites, yet the dynamics of translation of multiple dendritic mRNAs has remained elusive. Here, we show that the protein translational activities of two dendritically localized mRNAs are spatiotemporally complex but constrained by the translational hotspots in which they are colocalized. Cotransfection of glutamate receptor 2 (GluR2) and GluR4 mRNAs (engineered to encode different fluorescent proteins) into rat hippocampal neurons demonstrates a heterogeneous distribution of translational hotspots for the two mRNAs along dendrites. Stimulation with s -3,5-dihydroxy-phenylglycine modifies the translational dynamics of both of these RNAs in a complex saturable manner. These results suggest that the translational hotspot is a primary structural regulator of the simultaneous yet differential translation of multiple mRNAs in the neuronal dendrite. Graphical abstract Teaser Local translation of dendritic mRNAs plays a crucial role in synaptic plasticity and formation of long-term memory. However, the dynamics of simultaneous translation of multiple dendritic mRNAs has remained elusive. In this study, Eberwine and colleagues show that the translational activities of two dendritically localized mRNAs are spatiotemporally complex but constrained by the translational hotspots in which they are colocalized. The results suggest structural constraints and stochastic regulation of synaptic plasticity.

Description: Publication date: Available online 26 September 2013 Source: Cell Reports Author(s): Sara Ribeiro , Ilaria Napoli , Ian J. White , Simona Parrinello , Adrienne M. Flanagan , Ueli Suter , Luis F. Parada , Alison C. Lloyd Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC) origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs) are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1 −/− mSCs redifferentiate normally, whereas at the wound site Nf1 −/− mSCs give rise to neurofibromas in both Nf1 +/+ and Nf1 +/− backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas. Graphical abstract Teaser Neurofibromas are mixed-cell tumors of Schwann cell (SC) origin that arise upon loss of NF1. Here, Lloyd and colleagues show that adult myelinating SCs (mSCs) are insensitive to NF1 loss. However, when nerves are injured, NF1-deficient mSCs display opposing behavior along the wounded nerve, forming tumors at the injury site while redifferentiating normally along the rest of the nerve. This demonstrates that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury.

Description: Publication date: Available online 26 September 2013 Source: Cell Reports Author(s): Hui Zheng , Vibhor Gupta , Jeffrey Patterson-Fortin , Sabyasachi Bhattacharya , Kanstantsin Katlinski , Junmin Wu , Bentley Varghese , Christopher J. Carbone , Bernadette Aressy , Serge Y. Fuchs , Roger A. Greenberg Lysine63-linked ubiquitin (K63-Ub) chains represent a particular ubiquitin topology that mediates proteasome-independent signaling events. The deubiquitinating enzyme (DUB) BRCC36 segregates into distinct nuclear and cytoplasmic complexes that are specific for K63-Ub hydrolysis. RAP80 targets the five-member nuclear BRCC36 complex to K63-Ub chains at DNA double-strand breaks. The alternative four-member BRCC36 containing complex (BRISC) lacks a known targeting moiety. Here, we identify serine hydroxymethyltransferase (SHMT) as a previously unappreciated component that fulfills this function. SHMT directs BRISC activity at K63-Ub chains conjugated to the type 1 interferon (IFN) receptor chain 1 (IFNAR1). BRISC-SHMT2 complexes localize to and deubiquitinate actively engaged IFNAR1, thus limiting its K63-Ub-mediated internalization and lysosomal degradation. BRISC-deficient cells and mice exhibit attenuated responses to IFN and are protected from IFN-associated immunopathology. These studies reveal a mechanism of DUB regulation and suggest a therapeutic use of BRISC inhibitors for treating pathophysiological processes driven by elevated IFN responses. Graphical abstract Teaser Fuchs, Greenberg, and colleagues describe a deubiquitinating (DUB) enzyme complex consisting of an interaction between BRISC and SHMT enzymes. This lysine63-ubiquitin-specific DUB complex deubiquitinates the actively engaged type I interferon receptor, resulting in receptor stabilization and activation of interferon signaling pathways. BRISC-deficient cells and mice have attenuated interferon responses and are resistant to bacterial lipopolysaccharide. These findings suggest strategies for treating disease states that arise from elevated interferon signals.

Description: We present a new hypothesis for the Jurassic plate-tectonic evolution of the Gulf of Mexico basin and discuss how this evolution influenced Jurassic salt tectonics. Four interpretations, some based on new data, constrain the hypothesis. First, the limit of normal oceanic crust coincides with a landward-dipping basement ramp near the seaward end of the salt basin, which has been mapped on seismic data. Second, the deep salt in the deep-water Gulf of Mexico can be separated into provinces on the basis of position with respect to this ramp. Third, paleodepths in the postsalt sequence indicate that salt filled the Gulf of Mexico salt basin to near sea level. Fourth, seismic data show that postsalt sediments in the central Louann and the Yucatan salt basins exhibit large magnitudes of Late Jurassic salt-detached extension not balanced by equivalent salt-detached shortening. In our hypothesis, Callovian salt was deposited in preexisting crustal depressions on hyperextended continental and transitional crust. After salt deposition ended, rifting continued for another 7 to 12 m.y. before sea-floor spreading began. During this phase of postsalt crustal stretching, the salt and its overburden were extended by 100 to 250 km (62–155 mi), depending on location. Sea-floor spreading divided the northern Gulf of Mexico into two segments, separated by the northwest-trending Brazos transform. The eastern segment opened from east to west, leaving the Walker Ridge salient in the center of the basin as the final area to break apart. In some areas, salt flowed seaward onto new oceanic crust, first concordantly over the basement as a parautochthonous province, then climbing up over stratigraphically younger strata as an allochthonous province.

Description: Three aspects of basement structure and rift-related salt distribution have especially influenced the evolution of the deep-water northern Gulf of Mexico: (1) creation of a basement high (Toledo Bend flexure), separating a chain of interior basins from the central Louann salt basin, (2) segmentation of the central Louann salt basin by the Brazos transfer fault into eastern and central domains, and (3) salt provinces formed during basin opening. The Toledo Bend flexure was reactivated as a hinge during the Cenozoic uplift of the North American craton. This uplift triggered gravity gliding, forming fold belts in the seaward parts of the continental margin. The geometry of the Toledo Bend flexure influenced the position of these fold belts. The Brazos transfer fault separates the west sector of the study area from the central and east sectors. Most of the salt in the deep-water northern Gulf of Mexico lay in the central sector, which sourced most of the Sigsbee salt canopy. The western sector was narrower and was subdivided by the East Breaks basement high. Splitting the Callovian salt basin in two as the gulf opened created a southward-thinning wedge of salt at the seaward end of the northern Gulf of Mexico. We divide this wedge into a series of provinces on the basis of the geometry of the base of the deep salt. Original salt thickness influenced diapir location, the geometry of the Sigsbee canopy, the geometry and style of later compressional fold belts, and petroleum systems.

Description: Recent ultradeep exploration in the northern Gulf of Mexico has revealed a broad diffuse zone of salt-cored folding beneath the present continental shelf. This zone is a pillow fold belt, where salt pillows grew halokinetically and were then mildly shortened. Below the Louisiana shelf, a contractional early-to-late Miocene pillow fold belt is separated by a partly welded canopy from an overlying early Miocene–to–Pliocene extensional system. This anomalous juxtaposition raises two paradoxes: (1) Why was mid-Miocene shortening close to the Miocene shelf break, where extension is expected? and (2) Why did shortening below the canopy overlap in time with extension above the canopy? Coastal uplift can explain both paradoxes. Cenozoic uplift and exhumation of the north rim of the Gulf of Mexico created the observed coastal offlap and truncation around the rim. Uplift tilted the continental margin and overpowered the influence of the paleoshelf break, causing shortening much farther updip than before uplift. Physical models confirm that this hypothesis is mechanically sound. Our other models had two stacked detachments, each pinned in different locations. Because of this, deep shortening below the canopy was coeval with shallow extension above the canopy. The deep detachment was pinned far inland, equivalent to the uplifted continental interior. Extension above this deep detachment was partly balanced by shortening far downdip to form a pillow fold belt where a network of thrusts linked the squeezed pillows. In contrast, the shallow extensional system above the canopy was pinned farther seaward, equivalent to the upper continental slope.

Description: The process and mechanisms of secondary hydrocarbon migration in the Tazhong uplift, Tarim Basin, were investigated based on the analysis of the regional structure and by integrating geologic, hydrodynamic, and geochemical parameters. Parameters successfully analyzed included the fluid potential, fluid properties, production outputs, and diamantane index. The results indicated that hydrocarbons migrated into the Tazhong uplift from the northern part of the Manjiaer depression through a series of injection points (IPs) during four orogenies, that is, the early Caledonian (510 Ma), the late Caledonian (439 Ma), the late Hercynian–Indosinian (290 Ma), and the Yanshanian–Himalayan (208 Ma). A total of six IPs were identified at the intersections of the northeast-trending faults and the northwest-trending flower strike faults. The hydrocarbons migrated from the IPs into traps along regional trends from northwest to southeast and from northeast to southwest. The hydrocarbon migration process and patterns determined the distribution of hydrocarbon properties and production rates in the Tazhong uplift. With increasing distance from the IPs, daily hydrocarbon production decreases, and the hydrocarbons become progressively heavier and display lower gas:oil ratios.

Description: Determination of turbidite event magnitude and frequency remains subjective and difficult to define. This is because turbidite sedimentation events commonly include both sand and mud, with the mud component commonly excluded from bed thickness studies because of the inability to establish a genetic link to the turbidity current. Pelagic mudrock is defined as fine-grained marine sediment derived primarily from biogenic particles, whereas hemipelagic mudrock includes both biogenic and terrigenous particles. Unfortunately, these compositional definitions do not account for differences in depositional process. Scanning electron microscopy, field emission scanning electron microscopy, and x-ray diffraction analyses of 70 samples from El Rosario Formation outcrops (Baja California, Mexico) and core from the Woodford Shale (Oklahoma) illustrate this distinction. Furthermore, these laboratory measurements are calibrated to 192 outcrop samples to provide a robust method for field identification of clay fabric and mineralogy to define turbidite sedimentation units. Pelagites show organized layering of clay platelets, few flocculates, and a lower proportion of high-density minerals. Hemipelagites have disorganized and chaotic clay fabrics characterized by visible flocculates and contain a higher proportion of denser particles. There may also be a corresponding change in clay mineralogy, for example, smectite in pelagites versus kaolinite in hemipelagites. These results indicate a settling velocity greater than shear velocity in pelagites, whereas hemipelagites record the opposite condition. Turbidity currents support and suspend denser grains, generate disorganized and chaotic clay fabrics, and provide more time for flocculation. Discrimination between pelagites and hemipelagites has important implications in the determination of turbidite event frequency and magnitude, which affects vertical connectivity and continuity of sand, deposited from multipartite turbidity currents. In addition, distinction between pelagites and hemipelagites provides a better understanding of mudrock reservoir architecture.

Description: The Molasse deposits of the Central Eastern Alps are partly incorporated into a fold and thrust belt that recently has come into exploration focus. The structural style and timing of deformation varies significantly alongstrike. Regional three-dimensional seismic and well data interpretation indicate three different structural segments from east to west: (1) The Sierning imbricates have a decollement close to the base of the Molasse sequence and consist of varying numbers of thrust sheets alongstrike. Early Miocene shortening of the Molasse is at least 6.2 km (3.9 mi). Overthrusting of the internal Penninic and Helvetic wedge since the Oligocene accommodated at least 25 km (15.5 mi) of additional shortening. (2) The Regau segment is dominated by one to two small thrust sheets above a shallow detachment. This segment is dominated by overthrusting of the Alpine wedge. (3) The Perwang imbricates consist of an Oligocene wedge with complex deformed thrust sheets above a detachment horizon in Upper Cretaceous marls. Minimum shortening in the imbricates is 18.5 km (11.5 mi) with overthrusting 33.3 km (20.7 mi). All shortening estimates have an uncertainty of approximately 20% to 35%. The laterally varying thrust-belt architecture results from predeformational conditions (e.g., sediment thickness, mechanical stratigraphy, and basement dip). In the Sierning imbricates, hydrocarbon trap definition and charge issues are exploration risks. In the Regau segment, exploration is focused on the subthrust play. The Perwang imbricates have hydrocarbon shows but no economic discoveries. Charge and seal issues are the main risks. The petroleum systems in the context of the structural evolution are not yet fully understood.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Tamás Schauer , Petra C. Schwalie , Ava Handley , Carla E. Margulies , Paul Flicek , Andreas G. Ladurner Chromatin organization and gene activity are responsive to developmental and environmental cues. Although many genes are transcribed throughout development and across cell types, much of gene regulation is highly cell-type specific. To readily track chromatin features at the resolution of cell types within complex tissues, we developed and validated chromatin affinity purification from specific cell types by chromatin immunoprecipitation (CAST-ChIP), a broadly applicable biochemical procedure. RNA polymerase II (Pol II) CAST-ChIP identifies ∼1,500 neuronal and glia-specific genes in differentiated cells within the adult Drosophila brain. In contrast, the histone H2A.Z is distributed similarly across cell types and throughout development, marking cell-type-invariant Pol II-bound regions. Our study identifies H2A.Z as an active chromatin signature that is refractory to changes across cell fates. Thus, CAST-ChIP powerfully identifies cell-type-specific as well as cell-type-invariant chromatin states, enabling the systematic dissection of chromatin structure and gene regulation within complex tissues such as the brain. Graphical abstract Teaser Much gene regulation is cell-type specific, but there are few tools that allow the genome-wide tracking of chromatin features and transcriptional states at the resolution of cell types within complex tissues. Margulies, Flicek, Ladurner, and colleagues developed and validated CAST-ChIP, a biochemical procedure that profiles chromatin-associated proteins in cell types of the Drosophila brain. CAST-ChIP identified 1,500 neuron- and glia-specific genes and revealed that histone H2A.Z marks cell-type-invariant domains. CAST-ChIP enables the systematic dissection of gene regulation in cell types.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Per Nilsson , Krishnapriya Loganathan , Misaki Sekiguchi , Yukio Matsuba , Kelvin Hui , Satoshi Tsubuki , Motomasa Tanaka , Nobuhisa Iwata , Takashi Saito , Takaomi C. Saido Alzheimer’s disease (AD) is a neurodegenerative disease biochemically characterized by aberrant protein aggregation, including amyloid beta (Aβ) peptide accumulation. Protein aggregates in the cell are cleared by autophagy, a mechanism impaired in AD. To investigate the role of autophagy in Aβ pathology in vivo, we crossed amyloid precursor protein (APP) transgenic mice with mice lacking autophagy in excitatory forebrain neurons obtained by conditional knockout of autophagy-related protein 7. Remarkably, autophagy deficiency drastically reduced extracellular Aβ plaque burden. This reduction of Aβ plaque load was due to inhibition of Aβ secretion, which led to aberrant intraneuronal Aβ accumulation in the perinuclear region. Moreover, autophagy-deficiency-induced neurodegeneration was exacerbated by amyloidosis, which together severely impaired memory. Our results establish a function for autophagy in Aβ metabolism: autophagy influences secretion of Aβ to the extracellular space and thereby directly affects Aβ plaque formation, a pathological hallmark of AD. Graphical abstract Teaser In this study, Nilsson, Saido, and colleagues show that autophagy influences secretion of Alzheimer’s disease (AD) amyloid beta (Aβ) peptide. Autophagy deficiency, achieved by genetic deletion of autophagy-related gene 7 in excitatory neurons in mouse brain, reduced Aβ plaque load and caused intracellular Aβ accumulation. In addition, amyloidosis exacerbated autophagy-deficiency-induced neurodegeneration and caused severe memory impairment. Thus, autophagy has a key role in the two main characteristics of AD: intracellular Aβ accumulation and extracellular Aβ plaque formation.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Antonia Borovina , Brian Ciruna The role for cilia in establishing planar cell polarity (PCP) is contentious. Although knockdown of genes known to function in ciliogenesis has been reported to cause PCP-related morphogenesis defects in zebrafish, genetic mutations affecting intraflagellar transport (IFT) do not show PCP phenotypes despite the requirement for IFT in cilia formation. This discrepancy has been attributed to off-target effects of antisense morpholino oligonucleotide (MO) injection, confounding maternal effects in zygotic mutant embryos, or an inability to distinguish between cilia-dependent versus cilia-independent protein functions. To determine the role of cilia in PCP, we generated maternal + zygotic IFT88 (MZ ift88 ) mutant zebrafish embryos, which never form cilia. We clearly demonstrate that cilia are not required to establish PCP. Rather, IFT88 plays a cilia-independent role in controlling oriented cell divisions at gastrulation and neurulation. Our results have important implications for the interpretation of cilia gene function in normal development and in disease. Graphical abstract Teaser The role of cilia in establishing planar cell polarity (PCP) remains contentious, confounded by off-target effects of antisense morpholino oligonucleotide use, maternal effects in zygotic mutant backgrounds, and difficulties distinguishing between cilia-dependent versus cilia-independent protein function. Here, Borovina and Ciruna clearly demonstrate that PCP is established normally in cilia-deficient maternal-zygotic IFT88 mutant zebrafish. Furthermore, by analyzing morphogenic events that occur prior to cilia formation, they identify a cilia- and PCP-independent role for IFT88 in controlling polarized cell divisions.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Tian Xie , Wei Peng , Chuangye Yan , Jianping Wu , Xinqi Gong , Yigong Shi RIP3 is an essential upstream kinase in necroptosis. The pseudokinase MLKL functions as a substrate of RIP3 to mediate downstream signaling. The molecular mechanism by which RIP3 recognizes and phosphorylates MLKL remains unknown. Here, we report the crystal structures of the mouse RIP3 kinase domain, the MLKL kinase-like domain, and a binary complex between the two. Both RIP3 and MLKL adopt the canonical kinase fold. Free RIP3 exists in an active conformation, whereas MLKL-bound RIP3 is stabilized by AMP-PNP to adopt an inactive conformation. The formation of the RIP3-MLKL complex, involving their respective N- and C-lobes, is accompanied by pronounced conformational changes of the αC helix and activation loop in RIP3 and the corresponding structural elements in MLKL. RIP3-mediated MLKL phosphorylation, though important for downstream signaling, is dispensable for stable complex formation between RIP3 and MLKL. Our study serves as a framework for mechanistic understanding of RIP3-mediated necroptotic signaling. Graphical abstract Teaser RIP3 is an essential upstream kinase in necroptosis. The pseudokinase MLKL functions as a substrate of RIP3 to mediate downstream signaling. In this study, Shi and colleagues report the crystal structures of the mouse RIP3 kinase domain, the MLKL kinase-like domain, and a binary complex between the two, which reveals the structural basis of MLKL recognition by RIP3 and gives structural insights into RIP3-mediated necroptotic signaling. Their structural analysis serves as a framework for understanding RIP3-mediated necroptosis.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Albert Ribes-Zamora , Sandra M. Indiviglio , Ivana Mihalek , Christopher L. Williams , Alison A. Bertuch Telomeres are protected from nonhomologous end-joining (NHEJ) to avoid deleterious chromosome fusions, yet they associate with the Ku heterodimer that is principal in the classical NHEJ (c-NHEJ) pathway. T-loops have been proposed to inhibit Ku’s association with telomeric ends, thus inhibiting c-NHEJ; however, deficiencies in the t-loop model suggest additional mechanisms are in effect. We demonstrate that TRF2 interacts with Ku at telomeres and via residues in Ku70 helix 5 (α5), which are vital for NHEJ. We show that Ku’s interaction with a TRF2 mutant that induces telomeric fusions is significantly impaired. Additionally, we demonstrate that Ku70 α5 is required for Ku self-association in live cells, which can bridge DNA ends. Together, these findings lead us to propose a model in which telomeres are directly protected from c-NHEJ via TRF2 impeding Ku’s ability to synapse telomere ends. Graphical abstract Teaser The protection of chromosomal termini from fusions is an essential function of telomeres. Nonetheless, the Ku heterodimer, a factor required for nonhomologous end-joining (NHEJ), is associated with functional telomeres. In this study, Bertuch and colleagues show that the telomere end protection factor TRF2 interacts with a region of Ku required for NHEJ. They further show that this region promotes Ku-Ku interactions. These data lead the authors to propose a model for the protection of telomeres from NHEJ.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Hong Wu , Nikolas Mathioudakis , Boubou Diagouraga , Aiping Dong , Ludmila Dombrovski , Frédéric Baudat , Stephen Cusack , Bernard de Massy , Jan Kadlec PRDM9, a histone lysine methyltransferase, is a key determinant of the localization of meiotic recombination hot spots in humans and mice and the only vertebrate protein known to be involved in hybrid sterility. Here, we report the crystal structure of the PRDM9 methyltransferase domain in complex with a histone H3 peptide dimethylated on lysine 4 (H3K4me2) and S-adenosylhomocysteine (AdoHcy), which provides insights into the methyltransferase activity of PRDM proteins. We show that the genuine substrate of PRDM9 is histone H3 lysine 4 (H3K4) and that the enzyme possesses mono-, di-, and trimethylation activities. We also determined the crystal structure of PRDM9 in its autoinhibited state, which revealed a rearrangement of the substrate and cofactor binding sites by a concerted action of the pre-SET and post-SET domains, providing important insights into the regulatory mechanisms of histone lysine methyltransferase activity. Graphical abstract Teaser The histone methyltransferase PRDM9 is a key determinant of meiotic recombination hot spots in humans and mice and the only vertebrate protein known to be involved in hybrid sterility. In this study, de Massy, Kadlec, and colleagues analyzed PRDM9 substrate specificity and report the crystal structures of its methyltransferase domain in an autoinhibited state and in complex with an H3K4me2 peptide and AdoHcy. These data provide important insights into the regulatory mechanisms of histone lysine methyltransferase activity.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Gwynneth Thomas , Jenna L. Betters , Caleb C. Lord , Amanda L. Brown , Stephanie Marshall , Daniel Ferguson , Janet Sawyer , Matthew A. Davis , John T. Melchior , Lawrence C. Blume , Allyn C. Howlett , Pavlina T. Ivanova , Stephen B. Milne , David S. Myers , Irina Mrak , Vera Leber , Christoph Heier , Ulrike Taschler , Jacqueline L. Blankman , Benjamin F. Cravatt , Richard G. Lee , Rosanne M. Crooke , Mark J. Graham , Robert Zimmermann , H. Alex Brown , J. Mark Brown The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this, we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues in order to identify in vivo substrates and understand ABHD6’s role in energy metabolism. Here, we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high-fat-diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches, we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes. Graphical abstract Teaser Metabolic syndrome has become a leading health concern. Now, Brown and colleagues show that that serine hydrolase ABHD6 is a key driver of the metabolic syndrome and that inhibition of ABHD6 protects mice from high-fat-diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic and in vitro enzymology approaches, the authors show that ABHD6 is a promiscuous lipase that hydrolyzes monoacylglycerols and lysophospholipids and argue that ABHD6 inhibitors may hold therapeutic promise.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Kinyui Alice Lo , Adam Labadorf , Norman J. Kennedy , Myoung Sook Han , Yoon Sing Yap , Bryan Matthews , Xiaofeng Xin , Lei Sun , Roger J. Davis , Harvey F. Lodish , Ernest Fraenkel Diet-induced obesity (DIO) predisposes individuals to insulin resistance, and adipose tissue has a major role in the disease. Insulin resistance can be induced in cultured adipocytes by a variety of treatments, but what aspects of the in vivo responses are captured by these models remains unknown. We use global RNA sequencing to investigate changes induced by TNF-α, hypoxia, dexamethasone, high insulin, and a combination of TNF-α and hypoxia, comparing the results to the changes in white adipose tissue from DIO mice. We found that different in vitro models capture distinct features of DIO adipose insulin resistance, and a combined treatment of TNF-α and hypoxia is most able to mimic the in vivo changes. Using genome-wide DNase I hypersensitivity followed by sequencing, we further examined the transcriptional regulation of TNF-α-induced insulin resistance, and we found that C/EPBβ is a potential key regulator of adipose insulin resistance. Graphical abstract Teaser Obesity-related insulin resistance is an increasingly common medical problem. Lodish, Fraenkel, and colleagues examine in vitro models for adipose insulin resistance using next-generation sequencing to analyze mRNA levels and chromatin states. They demonstrate that common models capture dramatically different aspects of the in vivo changes, with a combined TNF-α-hypoxia treatment most able to mimic diet-induced obesity. Their approach reveals C/EPBβ as a potential regulator of adipose insulin resistance. AdipoSight, a web portal, provides access to their data and algorithms.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Ricardo Weinlich , Andrew Oberst , Christopher P. Dillon , Laura J. Janke , Sandra Milasta , John R. Lukens , Diego A. Rodriguez , Prajwal Gurung , Chandra Savage , Thirumala D. Kanneganti , Douglas R. Green Caspase-8 or cellular FLICE-like inhibitor protein (cFLIP) deficiency leads to embryonic lethality in mice due to defects in endothelial tissues. Caspase-8 −/− and receptor-interacting protein kinase-3 (RIPK3) −/− , but not cFLIP −/− and RIPK3 −/− , double-knockout animals develop normally, indicating that caspase-8 antagonizes the lethal effects of RIPK3 during development. Here, we show that the acute deletion of caspase-8 in the gut of adult mice induces enterocyte death, disruption of tissue homeostasis, and inflammation, resulting in sepsis and mortality. Likewise, acute deletion of caspase-8 in a focal region of the skin induces local keratinocyte death, tissue disruption, and inflammation. Strikingly, RIPK3 ablation rescues both phenotypes. However, acute loss of cFLIP in the skin produces a similar phenotype that is not rescued by RIPK3 ablation. TNF neutralization protects from either acute loss of caspase-8 or cFLIP. These results demonstrate that caspase-8-mediated suppression of RIPK3-induced death is required not only during development but also for adult homeostasis. Furthermore, RIPK3-dependent inflammation is dispensable for the skin phenotype. Graphical abstract Teaser In this study, Green and colleagues show that acute loss of caspase-8 in the gut or the skin can induce a TNF-dependent, RIPK3-mediated loss of tissue homeostasis and inflammation, demonstrating that RIPK3 function is tightly regulated in adult tissues. Strikingly, the authors show that loss of cFLIP in RIPK3-deficient background induces a similar phenotype, suggesting that loss of tissue barrier function, rather than the type of cell death (necroptosis or apoptosis), defines the onset of disease.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Todd C. Metzger , Imran S. Khan , James M. Gardner , Maria L. Mouchess , Kellsey P. Johannes , Anna K. Krawisz , Katarzyna M. Skrzypczynska , Mark S. Anderson Thymic epithelial cells in the medulla (mTECs) play a critical role in enforcing central tolerance through expression and presentation of tissue-specific antigens (TSAs) and deletion of autoreactive thymocytes. TSA expression requires autoimmune regulator (Aire), a transcriptional activator present in a subset of mTECs characterized by high CD80 and major histocompatibility complex II expression and a lack of potential for differentiation or proliferation. Here, using an Aire-DTR transgenic line, we show that short-term ablation specifically targets Aire + mTECs, which quickly undergo RANK-dependent recovery. Repeated ablation also affects Aire − mTECs, and using an inducible Aire-Cre fate-mapping system, we find that this results from the loss of a subset of mTECs that showed prior expression of Aire, maintains intermediate TSA expression, and preferentially migrates toward the center of the medulla. These results clearly identify a distinct stage of mTEC development and underscore the diversity of mTECs that play a key role in maintaining tolerance. Graphical abstract Teaser In this study, Anderson and colleagues investigate the recovery and developmental potential of Aire + thymic epithelial cells (TECs), a cell population with unique roles in limiting self-reactivity of developing T cells. The authors find that this population is capable of rapid recovery following targeted ablation and that such ablation leads to loss of tolerance to self. The authors also find that Aire + TECs progress to a terminal Aire − stage, which may have a unique role in driving central tolerance.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Anastazja Grabarz , Josée Guirouilh-Barbat , Aurélia Barascu , Gaëlle Pennarun , Diane Genet , Emilie Rass , Susanne M. Germann , Pascale Bertrand , Ian D. Hickson , Bernard S. Lopez The choice of the appropriate double-strand break (DSB) repair pathway is essential for the maintenance of genomic stability. Here, we show that the Bloom syndrome gene product, BLM, counteracts CtIP/MRE11-dependent long-range deletions (>200 bp) generated by alternative end-joining (A-EJ). BLM represses A-EJ in an epistatic manner with 53BP1 and RIF1 and is required for ionizing-radiation-induced 53BP1 focus assembly. Conversely, in the absence of 53BP1 or RIF1, BLM promotes formation of A-EJ long deletions, consistent with a role for BLM in DSB end resection. These data highlight a dual role for BLM that influences the DSB repair pathway choi (1) protection against CtIP/MRE11 long-range deletions associated with A-EJ and (2) promotion of DNA resection. These antagonist roles can be regulated, according to cell-cycle stage, by interacting partners such as 53BP1 and TopIII, to avoid unscheduled resection that might jeopardize genome integrity. Graphical abstract Teaser The choice of the appropriate double-strand break (DSB) repair pathway is essential for the maintenance of genomic stability. Here, Lopez and colleagues show a dual role for the Bloom syndrome gene product, BLM, that influences the DSB repair pathway choice in two ways: (1) protection against long-range deletions associated with DSB end-joining and (2) promotion of DNA resection. These antagonistic roles can be regulated, according to cell-cycle stage, by interacting partners, to avoid unscheduled resection that might jeopardize genome integrity.

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Samantha B. Foley , Zacariah L. Hildenbrand , Abigail A. Soyombo , Jeffery A. Magee , Yipin Wu , Katherine I. Oravecz-Wilson , Theodora S. Ross Chronic myeloid leukemia (CML) and some acute lymphoblastic leukemias are characterized by the t(9;22) chromosome, which encodes the BCR/ABL oncogene. Multiple mouse models of CML express BCR/ABL at high levels from non- Bcr promoters, resulting in the development of leukemias. In contrast, a significant fraction of healthy humans have been found to have BCR/ABL-positive hematopoietic cells. To bridge the gap between the information derived from current mouse models and nonleukemic humans with the BCR/ABL oncogene, we generated a knockin model with BCR/ABL p210 expressed from the Bcr locus. Unlike previous models, expression of BCR/ABL from the knockin allele did not induce leukemia. BCR/ABL mutant cells did exhibit favorable bone marrow engraftment compared to control cells. These data suggest that BCR/ABL expression alone is insufficient to induce disease. This model allows for inducible spatial and temporal control of BCR/ABL expression for analysis of early steps in the pathogenesis of BCR/ABL-expressing leukemias. Graphical abstract Teaser In this study, Ross and colleagues show that when the BCR/ABL oncogene is placed in the mouse genome as a single-copy knockin mutation, the mice, like some humans with the BCR/ABL mutation, are leukemia free. The combination of this BCR/ABL allele with an AML1/ETO knockin allele led to myeloid neoplasia. This mouse mutation will aid in understanding BCR/ABL-associated predisease, which many predict is the precursor to florid chronic myeloid leukemia.

Description: Bassem El Zoghbi, Rafael Estevez, and Christian Olagnon Intergranular slow crack growth in zirconia polycrystal is described with a cohesive zone model that simulate mechanically the reaction-rupture mechanism underlying stress and environmentally assisted failure. A 2D polycrystal is considered with cohesive surfaces inserted along the grain boundarie ... [Theor. Appl. Mech. Lett. 3 , 051001 (2013)] published Tue Sep 10, 2013 .

Description: Long Li, Jizeng Wang, and Youhe Zhou This study intends to investigate how the elasticity of a bacterial phage can affect the process of DNA packaging and ejection. For this purpose, we propose a unified continuum and statistical mechanics model by taking into account the effects of DNA bending deformation, electrostatic repulsion be ... [Theor. Appl. Mech. Lett. 3 , 054003 (2013)] published Tue Sep 10, 2013 .

Description: Ahmad Sedaghat and Mohammad Ali Badri In this study, a flow solver was developed based on the governing RANS equations of compressible flows and was further extended to include the effects of electromagnetic forces namely Lorentz forces. Lorentz forces may be added as a source term in the governing fluid flow equations. Numerical stud ... [Theor. Appl. Mech. Lett. 3 , 052003 (2013)] published Tue Sep 10, 2013 .

Description: Meie Li, Chao Jin, and Jinxiong Zhou Hydrogel can swell to many times of its dry volume, resulting in large deformation which is vital for its function. The swelling process is regulated by many physical and chemical mechanisms, and can, to some extent, be fairly described by the poroelasticity theory. Implementation of the poroelast ... [Theor. Appl. Mech. Lett. 3 , 054009 (2013)] published Tue Sep 10, 2013 .

Description: Chaofeng Lü, Wen Chen, and Jinxiong Zhou et al. Abstract not available. [Theor. Appl. Mech. Lett. 3 , 054001 (2013)] published Sun Sep 01, 2013 .

Description: Wenxiang Xu, Huisu Chen, and Wen Chen When interfacial layers are viewed as a separate phase, the interface thickness plays an essential role in assessing physico-mechanical properties of particulate materials. However, the interface thickness from sectional analysis is often overestimated, due to the irregularity of surface textures ... [Theor. Appl. Mech. Lett. 3 , 054008 (2013)] published Tue Sep 10, 2013 .

Description: Yu Wan, Quanshui Zheng, and Zhiping Xu Nano-particle capture is a key process in filtration, separation, and biomedical applications. Here we explored the mechanisms of soft particle capture using nanofiber networks. We identified possible states of the capture process, which are defined by their structural and material parameters. By ... [Theor. Appl. Mech. Lett. 3 , 054002 (2013)] published Tue Sep 10, 2013 .

Description: Ke-Qing Xia The system of turbulent thermal convection is introduced. Progresses in recent decades in the four major areas of research in turbulent convection are briefly reviewed. Some of the recent trends of the field are then discussed, which also serve to point out that the future directions in this impor ... [Theor. Appl. Mech. Lett. 3 , 052001 (2013)] published Tue Sep 10, 2013 .

Description: Quartz is the principal framework mineral in clastic sediment reservoirs. In a frontier basin with sparse wells, the source of quartz in sandstones may be a predictor of the availability of medium- to coarse-grained quartz sand from plutonic sources, likely to provide good reservoirs. The Scotian Basin, offshore eastern Canada, was used to test this hypothesis because of its well-understood provenance history and geographic variability in known medium- to coarse-grained reservoir sandstones. The sources of detrital quartz in fine-grained sandstones were determined using hot-cathode cathodoluminescence (CL), supplemented by other petrographic techniques. The CL color shift for different quartz types was calibrated against the CL properties of representative source rocks in the hinterland, because generalizations in the literature do not precisely match our basin-specific observations. Grain size of sandstone exerts a strong control over quartz type, with plutonic-hypabyssal quartz and high-grade metamorphic quartz more abundant in coarse-grained sandstones and low-grade metamorphic quartz more abundant in fine-grained sandstones. Nevertheless, the analysis of fine-grained sandstones shows that plutonic-hypabyssal quartz is more abundant in fine-grained sandstones of the Sable subbasin than in those of the Abenaki subbasin. The abundance of plutonic-hypabyssal quartz correlates with the abundance of medium- to coarse-grained sandstone reservoirs in the Sable subbasin. This study suggests that, in frontier basins, the abundance of plutonic-hypabyssal quartz in fine-grained sandstones can be used as an indicator of available medium- to coarse-grained sandstone reservoir.

Description: The three-dimensional (3-D) geometry of fractures and fault-related dolomite is difficult to access with classical subsurface prospection tools. Therefore, we have investigated an outcrop to improve the subsurface prediction for complex dolomite bodies. This outcrop is located in the Etoile massif (southeastern France) within a fault-bend anticline. The sedimentary units are of Upper Triassic to lower Barremian age. The fold results from the Pyreneo-Provençal shortening during the Late Cretaceous to the Eocene. The anticline hosts three types of dolomite bodies: (1a) massive dolomite of middle to late Oxfordian age, (1b) syndepositional stratabound dolomite of Tithonian age, and (2) isolated dolomite bodies associated with fractures and faults. Large-scale geometries of fault-related dolomite bodies have been modeled in 3-D. The 3-D geometries of these bodies show diapir-, finger- and wall-like structures. These bodies are located close to the main thrusts, in strata of middle Oxfordian to early Barremian age and are linked to the compressive fold-bending phase during the Late Cretaceous. Fault-related dolomitization occurred because of magnesium removal from the hydraulic brecciation and the pressure solution of type 1 dolomite with overpressured fluids. These fluids flushed upward along the main thrust and laterally by following the reservoir property contrasts in the host rocks. Fault-related dolomite bodies are either spread far apart from faults in grainy limestones with good initial reservoir properties or are restricted to fault vicinity in muddy limestones with poor initial reservoir properties. The study of the structural and stratigraphic framework was essential in the understanding of the dolomitization process.

Description: Publication date: Available online 12 September 2013 Source: Cell Reports Author(s): Ke Zhao , Juan Du , Xue Han , John L. Goodier , Peng Li , Xiaohong Zhou , Wei Wei , Sean L. Evans , Linzhang Li , Wenyan Zhang , Ling E. Cheung , Guanjun Wang , Haig H. Kazazian Jr. , Xiao-Fang Yu Long interspersed elements 1 (LINE-1) occupy at least 17% of the human genome and are its only active autonomous retrotransposons. However, the host factors that regulate LINE-1 retrotransposition are not fully understood. Here, we demonstrate that the Aicardi-Goutières syndrome gene product SAMHD1, recently revealed to be an inhibitor of HIV/simian immunodeficiency virus (SIV) infectivity and neutralized by the viral Vpx protein, is also a potent regulator of LINE-1 and LINE-1-mediated Alu/SVA retrotransposition. We also found that mutant SAMHD1s of Aicardi-Goutières syndrome patients are defective in LINE-1 inhibition. Several domains of SAMHD1 are critical for LINE-1 regulation. SAMHD1 inhibits LINE-1 retrotransposition in dividing cells. An enzymatic active site mutant SAMHD1 maintained substantial anti-LINE-1 activity. SAMHD1 inhibits ORF2p-mediated LINE-1 reverse transcription in isolated LINE-1 ribonucleoproteins by reducing ORF2p level. Thus, SAMHD1 may be a cellular regulator of LINE-1 activity that is conserved in mammals. Graphical abstract Teaser Long interspersed elements 1 (LINE-1) are active autonomous retrotransposons that occupy 17% of the human genome. The host factors that regulate LINE-1 retrotransposition are not fully understood. In this study, Yu and colleagues show that the Aicardi-Goutières syndrome (AGS) gene product, SAMHD1, is a potent regulator of LINE-1 retrotransposition. SAMHD1 mutants linked to AGS are defective in LINE-1 inhibition. Although SAMHD1 has also recently been shown to suppress HIV-1, the authors find that suppression of LINE-1 occurs through a distinct mechanism.

Description: Publication date: Available online 12 September 2013 Source: Cell Reports Author(s): Runsheng He , Ning Huang , Yitian Bao , Haining Zhou , Junlin Teng , Jianguo Chen During interphase, centrosomes are connected by a proteinaceous linker between the proximal ends of the centrioles, which is important for the centrosomes to function as a single microtubule-organizing center. However, the composition and regulation of centrosomal linker remain largely unknown. Here, we show that LRRC45 is a centrosome linker that localizes at the proximal ends of the centrioles and forms fiber-like structures between them. Depletion of LRRC45 results in centrosome splitting during interphase. Moreover, LRRC45 interacts with both C-Nap1 and rootletin and is phosphorylated by Nek2A at S661 during mitosis. After phosphorylation, both LRRC45 centrosomal localization and fiber-like structures are significantly reduced, which subsequently leads to centrosome separation. Thus, LRRC45 is a critical component of the proteinaceous linker between two centrioles and is required for centrosome cohesion. Graphical abstract Teaser During interphase, the centrosomes are connected by a loose proteinaceous linker. Here, Teng, Chen, and colleagues identify LRRC45 as a centrosome linker required for centrosome cohesion. It is recruited by C-Nap1 at the proximal ends of the centrioles and forms fiber-like structures, together with rootletin. Also, LRRC45 is phosphorylated by Nek2A, which induces centrosome separation during mitosis. These findings facilitate a better understanding of the composition and regulation of centrosome linkers.

Description: Publication date: Available online 12 September 2013 Source: Cell Reports Author(s): Ying Tan , Dinghui Yu , Germain U. Busto , Curtis Wilson , Ronald L. Davis Wnt signaling regulates synaptic plasticity and neurogenesis in the adult nervous system, suggesting a potential role in behavioral processes. Here, we probed the requirement for Wnt signaling during olfactory memory formation in Drosophila using an inducible RNAi approach. Interfering with β-catenin expression in adult mushroom body neurons specifically impaired long-term memory (LTM) without altering short-term memory. The impairment was reversible, being rescued by expression of a wild-type β-catenin transgene, and correlated with disruption of a cellular LTM trace. Inhibition of wingless , a Wnt ligand, and arrow , a Wnt coreceptor, also impaired LTM. Wingless expression in wild-type flies was transiently elevated in the brain after LTM conditioning. Thus, inhibiting three key components of the Wnt signaling pathway in adult mushroom bodies impairs LTM, indicating that this pathway mechanistically underlies this specific form of memory. Graphical abstract Teaser Wnt signaling is crucial for many aspects of embryonic development, including cell proliferation, cell movement, and cell-fate decisions. In this report, Davis and colleagues show that Wnt signaling is required for the formation of protein-synthesis-dependent, long-term memory. Using RNAi approaches that target Wnt signaling components in the adult fly mushroom body, they show that knockdown of the Wnt ligand wingless , the Wnt coreceptor arrow , and the effector molecule β-catenin all impair the formation of long-term behavioral memory as well as a cellular memory trace representing this form of memory.

Description: Publication date: Available online 19 September 2013 Source: FEBS Open Bio Author(s): Wei Chi , Xiaoni Gan , Wuhan Xiao , Wen Wang , Shunping He Hypoxia-inducible factor (HIF) is a crucial regulator of cellular and systemic responses to low oxygen levels. Here we firstly cloned three HIF-α isoforms from the basal branches of Osteichthyes and used computational tools to characterize the molecular change underlying the functional divergence of HIF-α isoforms in different lineages. Only the HIF-1α and HIF-2α in African lungfish and amphibians were found under positive selection. HIF-1α and -2α were less functionally divergent in basal ray-finned fish than in teleosts, and showed conserved but different transcriptional activity toward specific target genes.

Description: Publication date: Available online 19 September 2013 Source: Cell Reports Author(s): Hongxia Zhao , Alphée Michelot , Essi V. Koskela , Vadym Tkach , Dimitrios Stamou , David G. Drubin , Pekka Lappalainen Bin-Amphiphysin-Rvs (BAR) domain proteins are central regulators of many cellular processes involving membrane dynamics. BAR domains sculpt phosphoinositide-rich membranes to generate membrane protrusions or invaginations. Here, we report that, in addition to regulating membrane geometry, BAR domains can generate extremely stable lipid microdomains by “freezing” phosphoinositide dynamics. This is a general feature of BAR domains, because the yeast endocytic BAR and Fes/CIP4 homology BAR (F-BAR) domains, the inverse BAR domain of Pinkbar, and the eisosomal BAR protein Lsp1 induced phosphoinositide clustering and halted lipid diffusion, despite differences in mechanisms of membrane interactions. Lsp1 displays comparable low diffusion rates in vitro and in vivo, suggesting that BAR domain proteins also generate stable phosphoinositide microdomains in cells. These results uncover a conserved role for BAR superfamily proteins in regulating lipid dynamics within membranes. Stable microdomains induced by BAR domain scaffolds and specific lipids can generate phase boundaries and diffusion barriers, which may have profound impacts on diverse cellular processes. Graphical abstract Teaser Bin-Amphiphysin-Rvs (BAR) domain superfamily proteins are central membrane-sculpting proteins in all eukaryote cells. Here, Lappalainen and colleagues demonstrate that BAR domain scaffolds not only bend membranes but also affect lipid distribution and dynamics by dramatically inhibiting the lateral diffusion of phosphoinositides. The extremely stable BAR domain-induced phosphoinositide microdomains can generate lipid phase boundaries and diffusion barriers, which are likely to have profound impacts on a wide variety of cellular processes, including endocytosis.

Description: Publication date: Available online 25 September 2013 Source: FEBS Open Bio Author(s): Michal Slutzki , Maroor K. Jobby , Seth Chitayat , Alon Karpol , Bareket Dassa , Yoav Barak , Raphael Lamed , Steven P. Smith , Edward A. Bayer The cellulosome is a large extracellular multi-enzyme complex that facilitates the efficient hydrolysis and degradation of crystalline cellulosic substrates. During the course of our studies on the cellulosome of the rumen bacterium Ruminococcus flavefaciens, we focused on the critical ScaA dockerin (ScaADoc), the unique dockerin that incorporates the primary enzyme-integrating ScaA scaffoldin into the cohesin-bearing ScaB adaptor scaffoldin. In the absence of a high-resolution structure of the ScaADoc module, we generated a computational model, and, upon its analysis, we were surprised to discover a putative stacking interaction between an N-terminal Trp and a C-terminal Pro, which we termed intramolecular clasp. In order to verify the existence of such an interaction, these residues were mutated to alanine. Circular dichroism spectroscopy, intrinsic tryptophan and ANS fluorescence, and NMR spectroscopy indicated that mutation of these residues has a destabilizing effect on the functional integrity of the Ca 2+ -bound form of ScaADoc. Analysis of recently determined dockerin structures from other species revealed the presence of other well-defined intramolecular clasps, which consist of different types of interactions between selected residues at the dockerin termini. We propose that this thematic interaction may represent a major distinctive structural feature of the dockerin module. Graphical abstract

Description: Publication date: 26 September 2013 Source: Cell Reports, Volume 4, Issue 6 Author(s): Steffi Oesterreich , Adam M. Brufsky , Nancy E. Davidson In this issue of Cell Reports , Li et al. show that the analysis of genetic changes in patient-derived xenografts can reveal crucial details of tumor evolution, such as the emergence of functional estrogen receptor mutations in endocrine-resistant breast cancer.

Description: Publication date: Available online 26 September 2013 Source: Cell Reports Author(s): Lingjie Li , Bo Liu , Orly L. Wapinski , Miao-Chih Tsai , Kun Qu , Jiajing Zhang , Jeff C. Carlson , Meihong Lin , Fengqin Fang , Rajnish A. Gupta , Jill A. Helms , Howard Y. Chang Long noncoding RNAs (lncRNAs) are thought to be prevalent regulators of gene expression, but the consequences of lncRNA inactivation in vivo are mostly unknown. Here, we show that targeted deletion of mouse Hotair lncRNA leads to derepression of hundreds of genes, resulting in homeotic transformation of the spine and malformation of metacarpal-carpal bones. RNA sequencing and conditional inactivation reveal an ongoing requirement of Hotair to repress HoxD genes and several imprinted loci such as Dlk1-Meg3 and Igf2-H19 without affecting imprinting choice. Hotair binds to both Polycomb repressive complex 2, which methylates histone H3 at lysine 27 (H3K27), and Lsd1 complex, which demethylates histone H3 at lysine 4 (H3K4) in vivo. Hotair inactivation causes H3K4me3 gain and, to a lesser extent, H3K27me3 loss at target genes. These results reveal the function and mechanisms of Hotair lncRNA in enforcing a silent chromatin state at Hox and additional genes. Graphical abstract Teaser A targeted and conditional knockout of the lncRNA, Hotair , is now presented by Chang and colleagues. The authors find that Hotair disruption causes homeotic transformation and skeletal malformation during mouse development. Hotair knockout leads to derepression of multiple genes, including HoxD and several imprinted genes. Furthermore, Hotair interacts with PRC2 and LSD1, and Hotair deletion altered chromatin states at specific targets.

Description: Publication date: Available online 26 September 2013 Source: Cell Reports Author(s): Saskia Delpretti , Thomas Montavon , Marion Leleu , Elisabeth Joye , Athanasia Tzika , Michel Milinkovitch , Denis Duboule Hox genes are required for the development of the intestinal cecum, a major organ of plant-eating species. We have analyzed the transcriptional regulation of Hoxd genes in cecal buds and show that they are controlled by a series of enhancers located in a gene desert flanking the HoxD cluster. The start site of two opposite long noncoding RNAs (lncRNAs), Hotdog and Twin of Hotdog , selectively contacts the expressed Hoxd genes in the framework of a topological domain, coinciding with robust transcription of these genes during cecum budding. Both lncRNAs are specifically transcribed in the cecum, albeit bearing no detectable function in trans . Hedgehogs have kept this regulatory potential despite the absence of the cecum, suggesting that these mechanisms are used in other developmental situations. In this context, we discuss the implementation of a common “budding toolkit” between the cecum and the limbs. Graphical abstract Teaser The intestinal cecum is a major organ for plant-eating species. Duboule and colleagues report that a series of enhancers, along with the Hotdog lncRNA, selectively contact a subset of HoxD genes and form a 3D regulatory structure, which coincides with a topological domain and elicits robust transcription. Hedgehogs have kept this regulatory potential despite absence of the cecum, suggesting that these mechanisms are part of a common “budding toolkit” also used during limb bud development.

Description: Publication date: Available online 26 September 2013 Source: Cell Reports Author(s): Inna Shcherbakova , Aaron A. Hoskins , Larry J. Friedman , Victor Serebrov , Ivan R. Corrêa Jr. , Ming-Qun Xu , Jeff Gelles , Melissa J. Moore Removal of introns from nascent transcripts (pre-mRNAs) by the spliceosome is an essential step in eukaryotic gene expression. Previous studies have suggested that the earliest steps in spliceosome assembly in yeast are highly ordered and the stable recruitment of U1 small nuclear ribonucleoprotein particle (snRNP) to the 5′ splice site necessarily precedes recruitment of U2 snRNP to the branch site to form the “prespliceosome.” Here, using colocalization single-molecule spectroscopy to follow initial spliceosome assembly on eight different S. cerevisiae pre-mRNAs, we demonstrate that active yeast spliceosomes can form by both U1-first and U2-first pathways. Both assembly pathways yield prespliceosomes functionally equivalent for subsequent U5⋅U4/U6 tri-snRNP recruitment and for intron excision. Although fractional flux through the two pathways varies on different introns, both are operational on all introns studied. Thus, multiple pathways exist for assembling functional spliceosomes. These observations provide insight into the mechanisms of cross-intron coordination of initial spliceosome assembly. Graphical abstract Teaser Intron excision by the spliceosome is an essential process in eukaryotic gene expression. Gelles, Moore, and colleagues use single-molecule colocalization to monitor early spliceosome assembly events in yeast whole-cell extract. They demonstrate that pre-mRNAs can initiate the formation of functional spliceosomes by first binding either U1 or U2 snRNP. This branched pathway has important implications for mechanisms of cross-intron coordination during early spliceosome assembly.

Description: Publication date: Available online 26 September 2013 Source: Cell Reports Author(s): Naif Zaman , Lei Li , Maria Luz Jaramillo , Zhanpeng Sun , Chabane Tibiche , Myriam Banville , Catherine Collins , Mark Trifiro , Miltiadis Paliouras , Andre Nantel , Maureen O’Connor-McCourt , Edwin Wang Individual cancer cells carry a bewildering number of distinct genomic alterations (e.g., copy number variations and mutations), making it a challenge to uncover genomic-driven mechanisms governing tumorigenesis. Here, we performed exome sequencing on several breast cancer cell lines that represent two subtypes, luminal and basal. We integrated these sequencing data and functional RNAi screening data (for the identification of genes that are essential for cell proliferation and survival) onto a human signaling network. Two subtype-specific networks that potentially represent core-signaling mechanisms underlying tumorigenesis were identified. Within both networks, we found that genes were differentially affected in different cell lines; i.e., in some cell lines a gene was identified through RNAi screening, whereas in others it was genomically altered. Interestingly, we found that highly connected network genes could be used to correctly classify breast tumors into subtypes on the basis of genomic alterations. Further, the networks effectively predicted subtype-specific drug targets, which were experimentally validated. Graphical abstract Teaser In this study, Wang and colleagues examine cancer genome sequencing data in a framework of a signaling network integrated with genome-wide RNAi knockdown information. They show that cancer cell survival network genes recurrently switch roles, between essential and cancer driving, among cancer subtypes. Mutations and copy number variations driving tumorigenesis are selected to be convergent onto cell survival networks. Genomic alterations of cancer cell survival subtype-specific network genes successfully predicted cancer subtype-specific drug targets and accurately classified cancer subtypes.

Description: Publication date: Available online 27 September 2013 Source: Cell Reports Author(s): Elizabeth Garner , Yonghwan Kim , Francis P. Lach , Molly C. Kottemann , Agata Smogorzewska Holliday junctions (HJs), the DNA intermediates of homologous recombination, need to be faithfully processed in order to preserve genome integrity. In human cells, the BLM helicase complex promotes nonnucleolytic dissolution of double HJs. In vitro, HJs may be nucleolytically processed by MUS81-EME1, GEN1, and SLX4-SLX1. Here, we exploit human SLX4 -null cells to examine the requirements for HJ resolution in vivo. Lack of BLM and SLX4 or GEN1 and SLX4 is synthetically lethal in the absence of exogenous DNA damage, and lethality is a consequence of dysfunctional mitosis proceeding in the presence of unprocessed HJs. Thus, GEN1 activity cannot be substituted for the SLX4-associated nucleases, and one of the HJ resolvase activities, either of those associated with SLX4 or with GEN1, is required for cell viability, even in the presence of BLM. In vivo HJ resolution depends on both SLX4-associated MUS81-EME1 and SLX1, suggesting that they are acting in concert in the context of SLX4. Graphical abstract Teaser The requirements for Holliday junction (HJ) processing in human mitotic cells are now dissected by Smogorzewska and colleagues. The authors demonstrate that nuclease-mediated resolution of HJs, provided by SLX4-associated nucleases and GEN1, is a requirement for cell viability rather than a backup pathway for nonnucleolytic dissolution. When HJs do not get processed, dramatic chromosomal abnormalities appear and cells cannot complete division. The study also finds that two SLX4-associated nucleases, MUS81-EME1 and SLX1, are necessary for HJ resolution.

Description: Publication date: Available online 29 September 2013 Source: FEBS Open Bio Author(s): Chantel N. Jensen , Sohail T. Ali , Michael J. Allen , Gideon Grogan The flavoprotein monooxygenase (FPMO) from Stenotrophomonas maltophilia (SMFMO, Uniprot: B2FLR2) catalyses the asymmetric oxidation of thioethers and is unusual amongst FPMOs in its ability to use the non-phosphorylated cofactor NADH, as well as NADPH, for the reduction of the FAD coenzyme. In order to explore the basis for cofactor promiscuity, structure-guided mutation of two residues in the cofactor binding site, Gln193 and His194, in SMFMO were performed in an attempt to imitate the cofactor binding site of the NADPH-dependent FMO from Methylophaga aminisulfidivorans sp. SK1 (mFMO), in which structurally homologous residues Arg234 and Thr235 bind the NADPH 2’-ribose phosphate. Mutation of His194 to threonine proved most significant, with a switch in specificity from NADH to NADPH [( k cat / K m NADH)/ k cat / K m NADPH) from 1.5:1 to 1:3.5, mostly as a result of a reduced K m for NADPH of approximately seven-fold in the His194Thr mutant. The structure of the Gln193Arg/His194Thr mutant revealed no substantial changes in the backbone of the enzyme or orientation of side chains resulting from mutation. Mutation of Phe52, in the vicinity of FAD, and which in mFMO is an asparagine thought to be responsible for flavin hydroperoxide stabilisation, is, in SMFMO, a determinant of enantioselectivity in sulfoxidation. Mutation of Phe52 to valine resulted in a mutant that transformed para -tolyl methyl sulfide into the ( S )-sulfoxide with 32% e.e., compared to 25% ( R )- for the wild type. These results shed further light both on the cofactor specificity of FPMOs, and their determinants of enantioselectivity, with a view to informing engineering studies of FPMOs in the future.

Description: Publication date: Available online 30 September 2013 Source: FEBS Open Bio Author(s): Yoshichika Taira , Yuki Okegawa , Kazuhiko Sugimoto , Masato Abe , Hideto Miyoshi , Toshiharu Shikanai Antimycin A 3 (AA) is used as an inhibitor of cyclic electron transport around photosystem I. However, the high concentrations of AA that are needed for inhibition have secondary effects, even in chloroplasts. Here, we screened for chemicals that inhibited ferredoxin-dependent plastoquinone reduction in ruptured chloroplasts at lower concentrations than those required for AA. We identified two AA-like compounds: AAL1 and AAL2. AAL1 likely shares an inhibitory site with AA, most probably in the PGR5–PGRL1 protein complex, and enhances O 2 evolution in photosystem II, most likely via an uncoupler-like effect. AAL1 and AAL2 are unlikely to penetrate intact leaves. In ruptured chloroplasts, AALs are superior to AA as inhibitors of cyclic electron transport.

Description: An interpretation of geologic structure at King Sound in the Canning Basin was completed using airborne gravity gradient, magnetic, and seismic data. During the Late Devonian and Mississippian periods, the elevated part of the basement in the north was rimmed by carbonate reefs and redeposited carbonate debris, whereas in the south, siliciclastic submarine fans and turbidites were deposited along the margin of the basement in a deep-marine environment. Three principal lithologic units were identified from the vertical gravity gradient ( G DD ) in the basin: (1) the Fairfield Group carbonates of high density are interpreted to be the source of prominent positive gravity anomalies; (2) forereef debris and carbonate clastics reworked from carbonates higher up the slope or from the carbonate platform are interpreted to be the source of medium-density responses; and (3) turbidites, debris flows, and associated clastic basinal sequences of low density are interpreted to be the source of prominent negative gravity anomalies. Depth slices of G DD indicate the channelized nature of turbidite flows. In the lower section of the basin, intrasedimentary intrusives were identified from magnetic, G DD , seismic, and well data. Depth to magnetic basement calculation indicates that the surface of the Archean to Paleoproterozoic basement ranges from 3200 to 130 m (10,499–427 ft) below sea level. The northwest- and northeast-oriented south-dipping faults cut the basement and propagate upward into the sediments. A three-dimensional geologic model constructed for King Sound satisfies all known geologic constraints and is consistent with the gravity, magnetic, seismic, and well data.

Description: The evolution of porosity in shales with increasing maturity was examined in a suite of five New Albany Shale samples spanning a maturity range from immature (vitrinite reflectance, R o 0.35%) to postmature (R o 1.41%). Devonian to lower Mississippian New Albany Shale samples from the Illinois Basin used in this study contain marine type II kerogen having total organic carbon contents from 1.2 to 13.0 wt. %. Organic petrology, CO 2 and N 2 low-pressure adsorption, and mercury intrusion capillary pressure techniques were used to quantify pore volumes, pore sizes, and pore-size distributions. Increasing maturity of the New Albany Shale is paralleled by many changes in the characteristics of porosity. The total porosity of 9.1 vol. % in immature New Albany Shale decreases to 1.5 vol. % in the late mature sample, whereas total pore volumes decrease from 0.0365 to 0.0059 cm 3 /g in the same sequence. Reversing the trend at even higher maturity, the postmature New Albany Shale exhibits higher porosity and larger total pore volumes compared to the late mature sample. With increasing maturity, changes in total porosity and total pore volumes are accompanied by changes in pore-size distributions and relative proportions of micropores, mesopores, and macropores. Porosity-related variances are directly related to differences in the amount and character of the organic matter and mineralogical composition, but maturity exerts the dominant control upon these characteristics. We conclude that organic matter transformation due to hydrocarbon generation and migration is a pivotal cause of the observed porosity differences.

Description: In this case study, we used simulated seismic data from outcrops on Svalbard to analyze what seismic facies are composed of, what the dominating factors in forming the facies are, and which consequences this has for the interpretation results. Seismic facies analyses can be used to interpret environmental setting, depositional processes, and lithology. Here, we found that noise is the most important factor in forming the seismic facies. Noise is defined as all reflections that cannot be ascribed directly to the reservoir model. Effects from overburden and processing dominated, and the low-frequency content of the seismic section complicated the seismic facies analyses. The main reason for this is that the analysis relies heavily on identified internal patterns and low-angle terminations. Such patterns and terminations are easily created by the seismic method itself, by overburden effects, and by artifacts generated when processing the data. External form, strong amplitudes, and continuous reflections are robust seismic observations, whereas the internal pattern and terminations are commonly deceptive. Identification of boundaries based on predefined patterns of terminations does not work here, and uncritical use of seismic facies analysis in this interpretation case will create wrong reservoir models. Because of the size of the outcrops, the results from this analysis are relevant for reservoir-scale seismic interpretation and detailed interpretation for prospect evaluation in mature basins. For seismic interpretation at a more regional scale, it is probably less relevant.

Description: The Ordovician carbonate platform at the Yijianfang outcrop of the Bachu uplift region in the western Tarim Basin contains four types of genetic facies associations developed in the calciclastic slope-fan depositional system: an olistostrome zone, fan channels, lobes, and a marginal slope. The olistostrome zone is characterized by olistoliths and slump fans, whereas the fan channels and lobes are further divided into proximal and distal facies. The marginal slope deposits constitute the background sedimentation in which the calciclastic slope fans are intercalated. From proximal to distal parts of the fan channels and lobes, their scale gradually becomes smaller, and the size and sorting of grains become finer and better, respectively. Analysis of the stratigraphic framework indicates that the fans formed in the lower strata of the Upper Ordovician Lianglitage Formation in four high-frequency sequences (i.e., Pss1–Pss4). Field paleocurrent measurements indicate northeast-southwest depositional strike for the early platform margin of the Lianglitage Formation. Sediments in the calciclastic slope fans were derived from the platform margin, and evolution of the calciclastic slope fans was generally progradational from Pss1 to Pss2 and then continuously retrogradational from Pss2 to Pss4. The calciclastic slope fans in the outcrop area are not reservoir-prone rocks, but interpretation on these fans can provide useful information about potential hydrocarbon reservoirs along the platform margin. The P -wave velocity, S -wave velocity, and density variations in each genetic facies may be used to identify the subsurface calciclastic slope-fan depositional system.

Description: Haiping Tian, Shaoqiong Yang, and Lu Cheng et al. Experiments were conducted in a water tunnel by tomographic time-resolved particle image velocimetry (Tomo-TRPIV). The Reynolds number Reθ is 2 460 on the base of momentum thickness. According to the physical mechanism of the stretch and compression of multi-scale vortex structures in the wall-bou ... [Theor. Appl. Mech. Lett. 3 , 052002 (2013)] published Tue Sep 10, 2013 .

Description: Junjie Sheng, Hualing Chen, and Lei Liu et al. Viscoelasticity and temperature can significantly affect the performance of a dielectric elastomer. In the current study, we use a thermodynamic model to describe the effect of temperature and viscoelasticity on the electromechanical response undergoing a cyclic electric load by taking into accoun ... [Theor. Appl. Mech. Lett. 3 , 054005 (2013)] published Tue Sep 10, 2013 .

Description: Fengchao Wang and Hengan Wu Spreading of nanofluids on solid substrate was studied via molecular dynamics simulations. Simulation models for two immiscible fluids (oil and water based nanofluids) confined in a slit between two planar solid walls were set up. The influence of the volume concentration of the nanoparticles on t ... [Theor. Appl. Mech. Lett. 3 , 054006 (2013)] published Tue Sep 10, 2013 .

Description: Xiang He, Pengfei Wang, and Guoyou Huang et al. Indentation is a simple and nondestructive method to measure the mechanical properties of soft materials, such as hydrogels, elastomers and soft tissues. In this work, we have developed a micro-indentation system with high-precision to measure the mechanical properties of soft materials, where the ... [Theor. Appl. Mech. Lett. 3 , 054004 (2013)] published Tue Sep 10, 2013 .

Description: Junshi Zhang, Hualing Chen, and Junjie Sheng et al. In this paper, we present a modified model describing the constitutive relation of viscoelastic dielectric elastomer (DE). The uniform uniaxial tension-recovery experiment was carried out at different stretching rates. Based on Yeoh hyper-elastic model, model-fitting approach is put forward to obt ... [Theor. Appl. Mech. Lett. 3 , 054011 (2013)] published Tue Sep 10, 2013 .

Description: Yugang Tang, Ying Liu, and Qingshan Yang Considering the effects of osmotic pressure, elastic bending, Maxwell pressure, surface tension, as well as flexo-electric and dielectric properties of phospholipid membrane, the shape equation for sphere vesicle in alternation (AC) electric field is derived based on the liquid crystal model by mi ... [Theor. Appl. Mech. Lett. 3 , 054010 (2013)] published Tue Sep 10, 2013 .

Description: Jianying Hu, Yuhao He, and Jincheng Lei et al. In periodic cellular structures, novel pattern transformations are triggered by a reversible elastic instability under the axial compression. Based on the deformation-triggered new pattern, periodic cellular structures can achieve special mechanical properties. In this paper, the designed architec ... [Theor. Appl. Mech. Lett. 3 , 054007 (2013)] published Tue Sep 10, 2013 .

Description: Abdessattar Abdelkefi and Mehdi Ghommem Wing flapping and morphing can be very beneficial to managing the weight of micro air vehicles through coupling the aerodynamic forces with stability and control. In this letter, harvesting energy from the wing morphing is studied to power cameras, sensors, or communication devices of micro air ve ... [Theor. Appl. Mech. Lett. 3 , 052004 (2013)] published Tue Sep 10, 2013 .

Description: Shabram Sadeghi Esfahlani, Hassan Shirvani, and Sunny Nwaubani et al. Structural optimization for crashworthiness criteria is of particular significance especially at early stage of design. The comparative study of Kriging and radial basis function network (RBFN) was performed in order to improve the crashworthiness effects of honeycomb. Improving the crashworthines ... [Theor. Appl. Mech. Lett. 3 , 031002 (2013)] published Fri May 10, 2013 .

Description: Guyue Jiao and Ruojing Zhang The erythrocytes play an important role in the human body. The healthy erythrocytes can undergo extremely large deformation while passing through small capillaries. Their infection by Malaria Plasmodium falcipurum (P.f.) will lead to capillary blockage and blood flow obstruction. Many experimental ... [Theor. Appl. Mech. Lett. 3 , 034001 (2013)] published Fri May 10, 2013 .

Description: Su Yean Teh, Hock Lye Koh, and Donald L. DeAngelis et al. Predicting potential changes in groundwater salinity in low-lying coastal regions due to climate change is important, where coastal vegetation is abundant, succession competition between halophytes and glycophytes plays a significant role in the salinity budget. Sea level rise enhances salinity in ... [Theor. Appl. Mech. Lett. 3 , 032001 (2013)] published Fri May 10, 2013 .

Description: Publication date: Available online 6 June 2013 Source: Cell Reports Author(s): Guillaume Diss , Alexandre K. Dubé , Joël Boutin , Isabelle Gagnon-Arsenault , Christian R. Landry Cells contain many important protein complexes involved in performing and regulating structural, metabolic, and signaling functions. One major challenge in cell biology is to elucidate the organization and mechanisms of robustness of these complexes in vivo. We developed a systematic approach to study structural dependencies within complexes in living cells by deleting subunits and measuring pairwise interactions among other components. We used our methodology to perturb two conserved eukaryotic complexes: the retromer and the nuclear pore complex. Our results identify subunits that are critical for the assembly of these complexes, reveal their structural architecture and uncover…, and uncover mechanisms by which protein interactions are modulated. Our results also show that paralogous proteins play a key role in the robustness of protein complexes and shape their assembly landscape. Our approach paves the way for studying the response of protein interactomes to mutations and enhances our understanding of genotype-phenotype maps. Graphical abstract

Description: Publication date: Available online 6 June 2013 Source: Cell Reports Author(s): Christopher R. Faehnle , Elad Elkayam , Astrid D. Haase , Gregory J. Hannon , Leemor Joshua-Tor Argonautes are the central protein component in small RNA silencing pathways. Of the four human Argonautes (hAgo1–hAgo4) only hAgo2 is an active slicer. We determined the structure of hAgo1 bound to endogenous copurified RNAs to 1.75 Å resolution and hAgo1 loaded with let-7 microRNA to 2.1 Å. Both structures are strikingly similar to the structures of hAgo2. A conserved catalytic tetrad within the PIWI domain of hAgo2 is required for its slicing activity. Completion of the tetrad, combined with a mutation on a loop adjacent to the active site of hAgo1, results in slicer activity that is substantially enhanced by swapping in the N domain of hAgo2. hAgo3, with an intact tetrad, becomes an active slicer by swapping the N domain of hAgo2 without additional mutations. Intriguingly, the elements that make Argonaute an active slicer involve a sophisticated interplay between the active site and more distant regions of the enzyme. Graphical abstract

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Quanxi Zhang , Jingjing Tian , Yunlong Bai , Zhenhua Yang , Huifang Zhang , Ziqiang Meng The present study was designed to investigate the mechanisms underlying the effects of SO2 on functions of the isolated perfused hearts in rats. The results suggest that both SO2 and SO2 derivatives (sulfite: bisulfite, 3:1, M/M) elicited a negative inotropic effect. At high concentrations, the effects of SO2 or its derivatives on heart functions might be related to the increasing of reactive oxygen species (ROS) contents and decreasing of ATPase activities as well as the potentially damaging effects on the hearts; while at low concentrations, SO2 or its derivatives might modulate heart functions mainly through the NO signal transduction pathway.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Lei Li , Xinqiang Shen , Yunlong Wang , Hang Jiang , Mei Jiang The toxicity effects of Alexandriurn minuturn and Gymnodiniurn on the embryonic development of Sparus macrocephalus were tested through the toxicological experiments about hatching spawns and developing larvae of Sparus macrocephalus . Alexandriurn minuturn and Gymnodiniurn solution was diluted into three groups (about 3000cell/ml, 1500cell/ml, 500cell/ml). The results showed that the hatch of the spawns was sensitive to both kinds of the algae. And the toxicity results from Alexandriurn minuturn were inferior to that from Gymnodiniurn . The test of larvae 96-LC50 showed that, larvae was more susceptible to the Gymnodiniurn and produced certain resistance to the toxicity of the algae. Both the Alexandriurn minuturn and Gymnodiniurn restrained body length and weight increase as well as ATPase and GSH-PX enzyme activities of the larvae, while restrain from Gymnodiniurn was stronger. In conclusion, the effects on growth and development of Sparus macrocephalus spawns and larvae resulted from Gymnodiniurn was much higher than that from Alexandriurn minuturn .

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Xiaodong Ding , Shirong Zhang , Shuyi Li , Xinrong Liao , Rongping Wang To test the hypothesis that exogenous silicon (Si) would mediate the detoxification of Chromium (Cr) on pakchoi ( Brassica Chinensis L.) growing in Cr-contaminated soil, a pot experiment that 0, 50, 100 and 200 mg·kg -1 Cr (Na 2 Cr 2 O 7 2H 2 O) were supplied to soil together with 0, 0.5, 1.0 and 1.5 g·kg-1 Si (Na2SiO3) for 48 days, was studied. Results showed that supplying Si improved the growth of pakchoi in low Cr level. However, the shoot dry weight decreased with the increasing Si supplied in high Cr level. Compared with under non-Cr stress, the application of Si significantly increased the activities of POD, SOD and CAT of pakchoi under excess Cr. However, antioxidant enzymes activities displayed no difference under three Cr levels supplied. Shoot Cr accumulation decreased, while root Cr concentration increased, which was ascribed to the formation of precipitation-bound, “organic matter bound” Cr and the reduction of exchangeable-bound Cr fractions in the soil. Furthermore, the rhizosphere soil pH increased with Si level under either Cr level, suggesting that exogenous Si would induce the alkalization in the rhizosphere mediated detoxification of Cr on pakchoi by promoting the formation of precipitation-bound, organic matter bound Cr in Cr-contaminated soil, thereby probably decreasing Cr uptake from Cr-contaminated soil. These results proved direct evidence that Si played a mediated role, which decreased Cr uptake and improved the stabilization of Cr in Cr- contaminated soil.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Shuyi Li , Shirong Zhang , Xiaodong Ding , Xinrong Liao , Rongping Wang A field experiment of foliar application of silicon sol, cerium sol and silicon-cerium composite sol of different concentrations on Lettuce in field mildly combined Cd/Pb contaminated soil, was conducted to study effects of the application on yield, quality, antioxidant enzymes (SOD, POD) activities and Cd/Pb absorption, and hence to determine optimum concentration of the silicon sols and cerium sols to be sprayed for relieving toxicity of Cd/Pb. Results showed that spraying silicon and cerium sols could promote growth of Lettuce, increase contents of vitamin C and soluble sugar, and reduce nitrite content, enhance activities of SOD and POD, and inhibit the absorption of Cd/Pb and decrease the content and accumulation of Cd/Pb in shoots and roots, and reduce the risk of Cd/Pb to human body through food chain, while spraying silicon-cerium composite sol of 0.50 g·kg -1 silicon sols (SiO2) and 0.20 g·kg -1 cerium sols (CeO 2 ) was the most significant in effect.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Fayun Li , Guoqiang Wu , Shui Hu , Zhiping Fan , Qun Gao The negative effect of deicing salt on surface water have been reported by a number of studies, but there is a lack of knowledge about the effects of deicing salt on the growth behavior and the change of biochemical composition of algal Chlorella vulgaris ( C. vulgaris ). Algal were cultured at different concentration of deicing salt, algal cell densities, chlorophyll (a), protein and polysaccharides contents were measured. The results of this work showed that deicing salt had statistically significant inhibitory effects ( P 〈0.01) on the cell growth of algae, and the best-fit predictive equation of algal cell densities ( D algal, algal cells m/l) versus concentration of deicing salt ( C salt, g/l) after 7- day culture in this experiment was presented as a quadratic equation with C salt being the independent variable and D algal being the dependent variable (R 2 =0.944, P 〈0.01). The contents of chlorophyll (a) in C. vulgaris cell exposed to different concentrations of deicing salt suggested that the chlorophyll (a) content significantly decreased ( P 〈0.05) with the concentration of deicing salt higher than 4 g/l. Deicing salts also caused the trend of proteins contents decrease in C. vulgaris cells, and significantly increased ( P 〈0.05) the contents of polysaccharides in algae cell at 2 g/l deicing salt, however, the change of that was not significantly affected at deicing salt concentrations higher than 2 g/l.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Zhenhua Yang , Yuexia Zhang , Quanxi Zhang , Tianxing Pei , Ziqiang Meng A number of studies on sulfur dioxide (SO 2 ) in toxicology and pharmacology have been reported, however spectral properties of SO 2 and its derivatives were seldom investigated. We investigated the absorption spectra of SO 2 , sodium sulfite (Na 2 SO 3 ), sodium bisulfite (NaHSO3) and sodium metabisulfite (Na 2 S 2 O 5 ) in aqueous solution. In the meanwhile, the effects of HCl on spectral properties of SO 2 and its derivatives were also investigated. We found that gaseous SO 2 in ethanol, n-butyl-alcohol and glycerol had a characteristic absorption peak at 276 nm. Na 2 S 2 O 5 and NaHSO 3 exhibited an absorption peak at 257 nm. Absorption of SO 2 at 276 nm was strongly enhanced in the presence of HCl. NaHSO3, Na 2 SO 3 and Na 2 S 2 O 5 also exhibited absorption at 276 nm with the addition of HCl, which was enhanced with the increase of HCl concentration. Importantly, two conclusions have been reached on the basis of our results. First, we attributed the absorbing power of SO 2 to SO 2 molecule, rather than hydrated sulfur dioxide. Second, absorption of SO 2 strongly enhanced by HCl at 276 nm was due to H + , instead of the formation of a complex SO 2 Cl-. Primary studies also indicated that NaHSO 3 and Na 2 S 2 O5 with HCl had a similar effect as SO 2 did in rat thoracic aortic rings, which prompted us believe that NaHSO3 and Na2S2O5 with HCl may be acted as a donor of SO2 in biology and other area.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Yuexia Zhang , Zhenhua Yang , Dan Guo , Hong Geng , Chuan Dong In the study, we present the results of thermodynamic simulation of CaSO4 water-salt systems containing Ca 2+ , Mg 2+ , Na + , K + and HCO - 3 at 37°C. The results showed that the solubility of CaSO phase increased with increasing NaCl as wells as KCl concentration in the range of 0.0 to 2.0 M and 0.0 to 1.0 M, respectively. Remarkably, enhanced effect of MgCl 2 on the solubility of CaSO 4 phase was much larger than that of KCl or NaCl. The only exception was CaCl 2 , which was found to reduce solubility value of CaSO4 in aqueous solution at 37°C with the increase of CaCl 2 concentration. Also, the solubility of CaSO4 phase in mixed salt solutions was investigated at 37°C. The common ion effect was the main factor on the solubility of CaSO 4 in the mixed salts solution. Furthermore, CaSO 4 solubility was reduced by small amounts of NaHCO 3 in mixed solutions. These studies are of relevance in the estimating the changes of various salts in blood plasma and production of salt with low impurities of Ca2+ and SO 4 2- ions, as well as estimating oceanic-containing CaSO 4 uptake of CO 2 .

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Huimin Zhao , Hongtao Wang , Xie Quan , Feng Tan Tetracycline (TC), a widely used broad spectrum antibiotic, is excreted to environment seriously. Because of its harmful effects, it is essential to establish an effective method for TC determintation. In this work, we fabricated an electrochemical sensor for TC detection based on molecularly imprinted technique. The molecularly imprinted polymer was thermalpolymerized on Ti substrate electrodeposited with micro-nano Pt cluster (MIP-Pt/Ti). The linear range was in a TC concentration range from 0.1 to 10 mg L-1, and the detection limit was 0.026 mg L-1 (S/N = 3). The current change of TC on MIP-Pt/Ti electrode was 10 and 14 times than that of CTC and CAP, respectively. The results indicated that this electrochemical sensor exhibited good sensitivity and selectivity for TC.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Hongbo Xu , Wanping Zhang , Xiaoshun Zhang , Jing Wang , Jian Wang A new cloud point extraction procedure was established for the simultaneous preconcentration and determination of cobalt(II), nickel(II), and copper(II) ions in water samples. After complexation with 2-(5-bromo-2-pyridylazo)-5- (diethylamino) phenol (5-Br-PADAP), the analytes could be competitively extracted in a surfactant octylphenoxy polyethoxyethanol (TritonX-114), prior to determination by flame atomic absorption spectrometry (FAAS). The effects of pH, the concentrations of chelating agent and surfactant, equilibration temperature and time, sample volume, etc on CPE were studied. The preconcentration factor obtained was 25 and the limits of detection (DL) obtained for cobalt(II), nickel(II), and copper(II) were 2.4, 1.7 and 1.5 ng·mL−1, respectively. Standard reference material of poplar leaf (GBW 07604) was analyzed by the proposed methods, giving results of cobalt(II), nickel(II), and copper(II) found contents in consistency with the standard values. The presented preconcentration procedure was successfully applied to determination cobalt(II), nickel(II), and copper(II) in water samples.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Duanping Xu , Changjian Gu , Xiao Chen Humic acid (HA) was isolated from lignite. Flocculent HA was made and used to adsorb and remove dye acid red 3R from aqueous solution. The adsorption experiments were carried out in a batch process to observe the effect of various parameters such as contact time, dose of flocculent HA, ionic strength (NaCl) as well as adsorption kinetics and isotherm. Results showed that adsorption of acid red 3R on flocculent HA could reach equilibrium at less than 180 min. The adsorption kinetics obeyed the pseudo-second order model (R2=0.994). The adsorption was described with Freundlich equation on the basis of value of regression coefficient (R2=0.984). The removal rate of the dye increased with the increase of the dose of flocculent HA, while it decreased with the addition of NaCl in the aqueous solution. These suggested that the adsorption mechanism was the electrostatic attraction, to form hydrogen bonds, and van der waals’ force between molecules of HA and acid red 3R. Conclusion was made that flocculent HA isolated from lignite could be used as an adsorbent to remove the dye from aqueous solution.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Shouliang Huo , Zhuoshi He , Jing Su , Beidou Xi , Chaowei Zhu Artificial neural network (ANN), a data driven modeling approach, is proposed to predict the water quality indicators of Lake Fuxian, the deepest lake of southwest China. To determine the non-linear relationships between the water quality factors and the eutrophication indicators, several ANN models was chosen for the investigation. A commonly used back-propagation neural network model was used to relate the key factors that influence a number of water quality indicators such as dissolved oxygen (DO), total phosphorus (TP), chlorophyll-a (Chl-a), and secchi disk depth (SD) in Lake Fuxian. The measured data were fed to the input layer, representing forcing functions to control the in- lake bio-chemical processes. Eutrophication indicators such as DO, TN, Chl-a and SD were represented in the output layers. The results indicated that the back-propagation neural network model performs good in ten months prediction and the neural network is able to predict these indicators with reasonable accuracy. This study also suggested that the neural network is a valuable tool for lake management.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Yiran Du , Bo Gao , Huaidong Zhou , Xinxin Ju , Hong Hao , Shuhua Yin Due to the continuous urbanization and industrialization in many countries of the world, heavy metals are continuously emitted into the terrestrial environment and pose a great threat on human health. A detailed study was conducted to determine the concentrations of six heavy metals (Cr, Ni, Cu, Zn, Cd and Pb) in road dusts in urban parks of Beijing, and assessed the health risk of these metals for local people. The dust samples were collected from 13 different urban parks in Beijing, China. The health risk was assessed using Hazard Quotient ( HQ ) and Health Index ( HI ). The results show that the average concentrations of Cr, Ni, Cu, Zn, Cd, Pb in the dust samples are 69.33, 25.97, 72.13, 219.20 0.64 and 201.82 mg/kg, respectively. The concentrations of Cu, Zn, Cd and Pb were much higher than those in the background value of Chinese soil. The assessment of health risk indicated that there were mainly three exposure pathways for people: ingestion, dermal contact and inhalation. The main exposure pathway of heavy metals to both children and adults is ingestion. The values of HQ and HI are lower than the safe level (=1), indicating no health risk exists in present condition. Meanwhile, the HI value for children is higher than that for adults, indicating that children have higher potential health risk than adults in Beijing parks.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Juan Chen , Yuanbo Xie , Wei Li Energy consumption leads to air pollution, which is a great threat to residents’ health. According to the requirements of energy and environment during “12th Five Year” period in Beijing, this paper set two different energy-constraint scenarios, applying an integrated energy-environment-health model to quantitatively evaluate Beijing's residents’ health damage caused by energy consumption. The results showed that: compared with low-constraint scenario, up to 2015, the high-constraint scenario can reduce totally 6501 cases of mortality, in which 1200 cases are related to SO2; 2489 cases are related to NOX; 1693 cases are related to PM10; 1119 cases are related to PM2.5. Therefore restricting energy consumption and improving energy structure are conductive to the reduction of atmospheric pollutants and the protection of population health.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Shuming Ma , Shushen Zhang , Yu Chen , Hongbo Zheng To meet the practical deficiency in the management of major environmental risk source, one of key issues in environmental management, especially in China, a major environmental risk source management system was developed based on the technology of ArcGIS Engine, .NET, and Oracle. The system used a C / S structure. Three function modules were designed. They are basic environmental information management module, enterprise risk source reporting module and risk source audit & management module. The system was applied to Da Gushan Peninsula, China.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Yuan Qin , Yi Wang , Huiqiong Wang , Jinsuo Gao , Zhenping Qu The dynamic adsorption/desorption behavior of VOCs (C7H8) was evaluated for mesoporous SBA-15 silicas with four kinds of morphologies and pore sizes on a fixed bed unit. The SBA-15 silica with interconnected rodlike morphology exhibited exceptionally good breakthrough behavior, a higher adsorption capacity, and better desorption performance for toluene. The large dynamic VOC capacity of the interconnected rodlike silica was attributed to the pore system of the micropores and mesopore size, group-togethering rods which can aggregate to enhance the ability of adsorption, together with the smoother surface.

Description: Publication date: 2013 Source: Procedia Environmental Sciences, Volume 18 Author(s): Yaxin Su , Liming Ren , Wenyi Deng Waste tire powder was used to reduce NO emission by reburning and burnout in a two-stage furnace with simulated flue gas. Ceramic tubes were used as the flow reactor. The reburning temperature was 1150 °C and burnout temperature was 1250 °C respectively. The simulated flue gas consisted 16.8% vol. CO2, 1.95% vol. O2, and 0.05% and 0.08% vol. NO in a helium base. 4 kinds of ashes were used to abate the reburning intermediate products, HCN and NH3 in order to improve the final NO reduction efficiency after burnout. Resutls showed that waste tire was very good reburning fuel. More than 95% NO reduction efficiency was achieved after reburning of waste tire when the stoichiometric ratio for reburning, SR2, was 0.9. When waste tire powder was mixed with lignite ash collected by baghouse at power plant and used as reburning fuel, the final NO reduction efficiency after reburning and burnout was as high as 86%, which was very close to that of natural gas. Further test showed that lignite ash could effectively reduce HCN and NH3 during reburning. The present research demonstrated that waste tire is a very effective reburning fuel.

Description: Publication date: Available online 11 June 2013 Source: FEBS Open Bio Author(s): Jun Kawaguchi , Kumino Maejima , Hiroyuki Kuroiwa , Masumi Taki The introduction of non-natural amino acids at the N-terminus of peptides/proteins using leucyl/phenylalanyl-tRNA-protein transferase (L/F-transferase) is a useful technique for protein engineering. To accelerate the chemoenzymatic reaction, here we systematically optimized the N-terminal penultimate residue of the acceptor peptide. Positively charged, small, or hydrophilic amino acids at this position show positive effects for the reaction. Kinetic analysis of peptides possessing different penultimate residues suggests that the side chain of the residue affects peptide-binding affinity towards the L/F-transferase. These findings also provide biological insight into the effect of the penultimate amino acid on substrate specificity of natural proteins to be degraded via the N-end rule pathway. Graphical abstract

Description: Heng Ren and Xiyun Lu A vortex ring impacting a three-dimensional circular cylinder is studied using large eddy simulation (LES) for a Reynolds number Re = 4×104 based on the initial translation speed and diameter of the vortex ring. We have investigated the evolution of vortical structures and identified three typical ... [Theor. Appl. Mech. Lett. 3 , 032007 (2013)] published Fri May 10, 2013 .