bluuebunny/crossref_metadata_2025 huggingface dataset:
SATP (YaaH), a succinate–acetate transporter protein in Escherichia coli
Authors: Sá-Pessoa Joana , Paiva Sandra , Ribas David , Silva Inês Jesus , Viegas Sandra Cristina , Arraiano Cecília Maria , Casal Margarida
Published: July 2013

In the present paper we describe a new carboxylic acid transporter in Escherichia coli encoded by the gene yaaH. In contrast to what had been described for other YaaH family members, the E. coli transporter is highly specific for acetic acid (a monocarboxylate) and for succinic acid (a dicarboxylate), with affinity constants at pH 6.0 of 1.24±0.13 mM for acetic acid and 1.18±0.10 mM for succinic acid. In glucose-grown cells the ΔyaaH mutant is compromised for the uptake of both labelled acetic and succinic acids. YaaH, together with ActP, described previously as an acetate transporter, affect the use of acetic acid as sole carbon and energy source. Both genes have to be deleted simultaneously to abolish acetate transport. The uptake of acetate and succinate was restored when yaaH was expressed in trans in ΔyaaH ΔactP cells. We also demonstrate the critical role of YaaH amino acid residues Leu131 and Ala164 on the enhanced ability to transport lactate. Owing to its functional role in acetate and succinate uptake we propose its assignment as SatP: the Succinate–Acetate Transporter Protein.
A slender tract of glycine residues is required for translocation of the VP2 protein N-terminal domain through the parvovirus MVM capsid channel to initiate infection
Authors: Castellanos Milagros , Pérez Rebeca , Rodríguez-Huete Alicia , Grueso Esther , Almendral José M. , Mateu Mauricio G.
Published: July 2013

Viruses constitute paradigms to study conformational dynamics in biomacromolecular assemblies. Infection by the parvovirus MVM (minute virus of mice) requires a conformational rearrangement that involves the intracellular externalization through capsid channels of the 2Nt (N-terminal region of VP2). We have investigated the role in this process of conserved glycine residues in an extended glycine-rich tract located immediately after 2Nt. Based on the virus structure, residues with hydrophobic side chains of increasing volume were substituted for glycine residues 31 or 33. Mutations had no effect on capsid assembly or stability, but inhibited virus infectivity. All mutations, except those to alanine residues which had minor effects, impaired 2Nt externalization in nuclear maturing virions and in purified virions, to an extent that correlated with the side chain size. Different biochemical and biophysical analyses were consistent with this result. Importantly, all of the tested glycine residue replacements impaired the capacity of the virion to initiate infection, at ratios correlating with their restrictive effects on 2Nt externalization. Thus small residues within the evolutionarily conserved glycine-rich tract facilitate 2Nt externalization through the capsid channel, as required by this virus to initiate cell entry. The results demonstrate the exquisite dependence on geometric constraints of a biologically relevant translocation event in a biomolecular complex.
The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling
Authors: Chandor-Proust Alexia , Bibby Jaclyn , Régent-Kloeckner Myriam , Roux Jessica , Guittard-Crilat Emilie , Poupardin Rodolphe , Riaz Muhammad Asam , Paine Mark , Dauphin-Villemant Chantal , Reynaud Stéphane , David Jean-Philippe
Published: July 2013

The resistance of mosquitoes to chemical insecticides is threatening vector control programmes worldwide. Cytochrome P450 monooxygenases (CYPs) are known to play a major role in insecticide resistance, allowing resistant insects to metabolize insecticides at a higher rate. Among them, members of the mosquito CYP6Z subfamily, like Aedes aegypti CYP6Z8 and its Anopheles gambiae orthologue CYP6Z2, have been frequently associated with pyrethroid resistance. However, their role in the pyrethroid degradation pathway remains unclear. In the present study, we created a genetically modified yeast strain overexpressing Ae. aegypti cytochrome P450 reductase and CYP6Z8, thereby producing the first mosquito P450–CPR (NADPH-cytochrome P450-reductase) complex in a yeast recombinant system. The results of the present study show that: (i) CYP6Z8 metabolizes PBAlc (3-phenoxybenzoic alcohol) and PBAld (3-phenoxybenzaldehyde), common pyrethroid metabolites produced by carboxylesterases, producing PBA (3-phenoxybenzoic acid); (ii) CYP6Z8 transcription is induced by PBAlc, PBAld and PBA; (iii) An. gambiae CYP6Z2 metabolizes PBAlc and PBAld in the same way; (iv) PBA is the major metabolite produced in vivo and is excreted without further modification; and (v) in silico modelling of substrate–enzyme interactions supports a similar role of other mosquito CYP6Zs in pyrethroid degradation. By playing a pivotal role in the degradation of pyrethroid insecticides, mosquito CYP6Zs thus represent good targets for mosquito-resistance management strategies.
Neuroprotective effect of Danshensu derivatives as anti-ischaemia agents on SH-SY5Y cells and rat brain
Authors: Seetapun Sunisa , Yaoling Jia , Wang Yang , Zhu Yi Zhun
Published: July 2013

Novel Danshensu derivatives (3–8) were designed and synthesized to improve bioactivity based on the strategy of ‘medicinal chemical hybridization’. Our previous studies indicated that these compounds exhibited noticeable cardioprotective activities. Here, we investigate whether these novel Danshensu derivatives exert neuroprotective activities. An in vitro study revealed that these compounds could increase cell viability and reduce LDH (lactate dehydrogenase) leakage. Moreover, Danshensu-cysteine derivative compounds 6 and 8 could significantly inhibit lipid peroxidation of cell membrane and regulate the expression of apoptosis-related protein (Bcl-2, Bax and caspase 3). An in vivo study demonstrated that treatment with compound 6 at 30 mg/kg markedly decreased the infarct volume of MCAO (middle cerebral artery occlusion) insulted rat brain. Furthermore, treatment with compound 6 showed the antioxidant capacity by increasing the activity of SOD (superoxide dismutase) and GPx (glutathione peroxidase) and decreasing the level of MDA (malondialdehyde) and the ROS (reactive oxygen species) production significantly. These results suggested that these novel conjugates exert significant neuroprotective effects as anti-ischaemia agents and those with high potential merit further investigation.
Characterization of the complex formed between a potent neutralizing ovine-derived polyclonal anti-TNFα Fab fragment and human TNFα
Authors: Abbott W. Mark , Snow Melanie , Eckersley Sonia , Renshaw Jonathan , Davies Gareth , Norman Richard A. , Ceuppens Peter , Slootstra Jerry , Benschop Joris J. , Hamuro Yoshitomo , Lee Jessica E. , Newham Peter
Published: July 2013

TNFα (tumour necrosis factor α) is an early mediator in the systemic inflammatory response to infection and is therefore a therapeutic target in sepsis. AZD9773 is an ovine-derived, polyclonal anti-TNFα Fab fragment derived from a pool of serum and currently being developed as a treatment for severe sepsis and septic shock. In the present study, we show that although AZD9773 has a modest affinity for TNFα in a binding assay, the Ki in a cell-based assay is approximately four orders of magnitude lower. We show using SEC (size exclusion chromatography) that the maximum size of the complex between AZD9773 and TNFα is consistent with approximately 12 Fabs binding to one TNFα trimer. A number of approaches were taken to map the epitopes recognized by AZD9773. These revealed that a number of different regions on TNFα are involved in binding to the polyclonal Fab. The data suggest that there are probably three epitopes per monomer that are responsible for most of the inhibition by AZD9773 and that all three can be occupied at the same time in the complex. We conclude that AZD9773 is clearly demonstrated to bind to multiple epitopes on TNFα and suggest that the polyclonal nature may account, at least in part, for the very high potency observed in cell-based assays.
Deleted in breast cancer-1 (DBC-1) in the interface between metabolism, aging and cancer
Authors: Chini Eduardo Nunes , Chini Claudia C. S. , Nin Veronica , Escande Carlos
Published: July 2013

DBC1 (deleted in breast cancer-1) is a nuclear protein that regulates cellular metabolism. Since alteration in cellular metabolism have been proposed to be the emerging ‘hallmark’ of cancer, it is possible that DBC1 may be implicated in the regulation of cancer cell energy metabolism. However, at this point any role of DBC1 in cancer is only speculative. In this review, we will discuss the new developments in DBC1 research, its molecular structure, regulatory roles and implication in metabolism, aging and cancer.
The potential of molecular markers to improve interventions through the natural history of oesophageal squamous cell carcinoma
Authors: da Costa Nathalia Meireles , Soares Lima Sheila Coelho , de Almeida Simão Tatiana , Ribeiro Pinto Luis Felipe
Published: July 2013

EC (oesophageal cancer) is one of the ten most frequent and fatal tumours worldwide and ESCC (oesophageal squamous cell carcinoma) accounts for about 80% of the cases. The first symptoms of ESCC arise late during the progression of the disease and, therefore, the diagnosis is usually done in advanced stages. This leads to an inefficient treatment and consequently to a poor prognosis. Thus, a comprehensive knowledge of ESCC biology is of major importance to identify risk factors, especially in high-incidence areas and biomarkers which could enable ESCC prevention and interventions throughout the natural history of the disease. In this review, we present the current knowledge regarding ESCC aetiology as well as the different genetic and epigenetic alterations already described in this tumour. We also discuss how these alterations could be used to anticipate ESCC diagnosis as well as how they can help improving treatment. A molecular natural history of the disease is proposed pointing out potential markers that may improve interventions at different points of ESCC development. Only when the different layers of complexity behind this tumour are elucidated, it will be possible to successfully perform prevention at different levels.
The formation and phase transition of vortex domain structures in ferroelectric nanodots: First-principles-based simulations
Authors: Liu J. Y. , Chen W. J. , Wang B. , Zheng Yue
Published: July 2013

Effects of size and hydrostatic pressure on the formation of vortex domain structures (VDSs) in ferroelectric nanodots under the open circuit condition have been simulated using the effective Hamiltonian method. Our calculations indicate promising controllability of VDS in the nanodots. Interestingly, it is found that the VDS holds rhombohedral at various sizes and pressures. Furthermore, the paraelectric-ferrotoroidic phase transition temperature (TFD) is very sensitive to size and pressure, manifesting with near linear relationships in most investigated range. At high pressure range, we found that the TFD-pressure curves become nonlinear. It indicates that the traditional Landau potentials with polarization-strain coupling term up to ∼Pε2 are not sufficient to describe the high pressure effect and the expansion coefficients should be modified as pressure dependent.
Communication: Some critical features of the potential energy surface for the Cl + H2O → HCl + OH forward and reverse reactions
Authors: Guo Yundong , Zhang Meiling , Xie Yaoming , Schaefer Henry F.
Published: July 2013

The forward and reverse reactions Cl + H2O → HCl + OH are very important in atmospheric chemistry. The entrance complex, transition state, and exit complex for the endothermic reaction Cl + H2O → HCl + OH have been studied using the CCSD(T) method with the correlation consistent basis sets through cc-pVQZ. The vibrational frequencies and the zero-point vibrational energies of the five stationary points for the reaction are reported and compared to the limited available experimental results. Contrary to the valence isoelectronic F + H2O system, the Cl + H2O reaction is endothermic by 18.4 kcal/mol. The two potential energy surfaces found to be radically different. The Cl + H2O entrance complex is found to lie 3.5 kcal/mol below the separated reactants. The classical barrier height for the title reaction is predicted to be 20.8 kcal/mol. The exit complex is bound by 3.7 kcal/mol relative to separated products. From the atmospherically important Cl + OH side, there is a small classical barrier of 2.4 kcal/mol.
Post-fire response variability in Mediterranean Basin tree species in Portugal
Authors: Catry Filipe X. , Pausas Juli G. , Moreira Francisco , Fernandes Paulo M. , Rego Francisco
Published: July 2013

Fire is the most important natural disturbance driving vegetation dynamics in the Mediterranean Basin. However, studies relating fire-induced tree responses to both fire severity and plant traits are still scarce in this region. We aimed to investigate such relationships further and to develop simple models that could help improve forest management in these fire-prone ecosystems. We compiled data from 16 fire sites in different regions and used models to relate post-fire responses of 4155 trees from 14 species with fire severity indicators and tree characteristics. The influence of several spatiotemporal factors at the site level was also considered. Results showed that pine mortality was usually high and mainly determined by fire severity, whereas plant traits played a minor role. In contrast, mortality of broadleaved trees was usually low, even for high-severity fire, but most trees were top-killed. Stem mortality increased with fire severity and decreased with bark thickness and tree size. The models for predicting individual mortality of pines and stem mortality of broadleaves showed very good performance, including when validated against independent datasets. Our results suggest that it is possible to accurately predict the most common post-fire responses of Mediterranean species based on simple fire and tree characteristics.
Advertisements impact the physiological efficacy of a branded drug
Authors: Kamenica Emir , Naclerio Robert , Malani Anup
Published: July 2013

We conducted randomized clinical trials to examine the impact of direct-to-consumer advertisements on the efficacy of a branded drug. We compared the objectively measured, physiological effect of Claritin (Merck & Co.), a leading antihistamine medication, across subjects randomized to watch a movie spliced with advertisements for Claritin or advertisements for Zyrtec (McNeil), a competitor antihistamine. Among subjects who test negative for common allergies, exposure to Claritin advertisements rather than Zyrtec advertisements increases the efficacy of Claritin. We conclude that branded drugs can interact with exposure to television advertisements.
Synthesizing cognition in neuromorphic electronic systems
Authors: Neftci Emre , Binas Jonathan , Rutishauser Ueli , Chicca Elisabetta , Indiveri Giacomo , Douglas Rodney J.
Published: July 2013

Significance

Neuromorphic emulations express the dynamics of neural systems in analogous electronic circuits, offering a distributed, low-power technology for constructing intelligent systems. However, neuromorphic circuits are inherently imprecise and noisy, and there has been no systematic method for configuring reliable behavioral dynamics on these substrates. We describe such a method, which is able to install simple cognitive behavior on the neuromorphic substrate. Our approach casts light on the general question of how the neuronal circuits of the brain, and also future neuromorphic technologies, could implement cognitive behavior in a principled manner.
Inverse Gillespie for inferring stochastic reaction mechanisms from intermittent samples
Authors: Chattopadhyay Ishanu , Kuchina Anna , Süel Gürol M. , Lipson Hod
Published: July 2013

Gillespie stochastic simulation is used extensively to investigate stochastic phenomena in many fields, ranging from chemistry to biology to ecology. The inverse problem, however, has remained largely unsolved: How to reconstruct the underlying reactions de novo from sparse observations. A key challenge is that often only aggregate concentrations, proportional to the population numbers, are observable intermittently. We discovered that under specific assumptions, the set of relative population updates in phase space forms a convex polytope whose vertices are indicative of the dominant underlying reactions. We demonstrate the validity of this simple principle by reconstructing stochastic models (reaction structure plus propensities) from a variety of simulated and experimental systems, where hundreds and even thousands of reactions may be occurring in between observations. In some cases, the inferred models provide mechanistic insight. This principle can lead to the understanding of a broad range of phenomena, from molecular biology to population ecology.
Agent-based Bayesian approach to monitoring the progress of invasive species eradication programs
Authors: Keith Jonathan M. , Spring Daniel
Published: July 2013

Eradication of an invasive species can provide significant environmental, economic, and social benefits, but eradication programs often fail. Constant and careful monitoring improves the chance of success, but an invasion may seem to be in decline even when it is expanding in abundance or spatial extent. Determining whether an invasion is in decline is a challenging inference problem for two reasons. First, it is typically infeasible to regularly survey the entire infested region owing to high cost. Second, surveillance methods are imperfect and fail to detect some individuals. These two factors also make it difficult to determine why an eradication program is failing. Agent-based methods enable inferences to be made about the locations of undiscovered individuals over time to identify trends in invader abundance and spatial extent. We develop an agent-based Bayesian method and apply it to Australia’s largest eradication program: the campaign to eradicate the red imported fire ant (
Solenopsis invicta
) from Brisbane. The invasion was deemed to be almost eradicated in 2004 but our analyses indicate that its geographic range continued to expand despite a sharp decline in number of nests. We also show that eradication would probably have been achieved with a relatively small increase in the area searched and treated. Our results demonstrate the importance of inferring temporal and spatial trends in ongoing invasions. The method can handle incomplete observations and takes into account the effects of human intervention. It has the potential to transform eradication practices.
Pattern reorganization occurs independently of cell division during
Drosophila
wing disc regeneration in situ
Authors: Díaz-García Sandra , Baonza Antonio
Published: July 2013

One of the most intriguing problems in developmental biology is how an organism can replace missing organs or portions of its body after injury. This capacity, known as regeneration, is conserved across different phyla. The imaginal discs of
Drosophila melanogaster
provide a particularly well-characterized model for analyzing regeneration. We have developed a unique method to study organ regeneration under physiological conditions using the imaginal discs of
Drosophila
. Using this method, we revisited different aspects of organ regeneration. The results presented in this report suggest that during the initial stages of regeneration, different processes occur, including wound healing, a temporary loss of markers of cell-fate commitment, and pattern reorganization. We present evidence indicating that all of these processes occur even when cell division has been arrested. Our data also suggested that Wingless is not required during the early stages of disc regeneration.
Role of methyl-induced polarization in ion binding
Authors: Rossi Mariana , Tkatchenko Alexandre , Rempe Susan B. , Varma Sameer
Published: July 2013

The chemical property of methyl groups that renders them indispensable to biomolecules is their hydrophobicity. Quantum mechanical studies undertaken here to understand the effect of point substitutions on potassium (K-) channels illustrate quantitatively how methyl-induced polarization also contributes to biomolecular function. K- channels regulate transmembrane salt concentration gradients by transporting K
+
ions selectively. One of the K
+
binding sites in the channel’s selectivity filter, the S4 site, also binds Ba
2+
ions, which blocks K
+
transport. This inhibitory property of Ba
2+
ions has been vital in understanding K-channel mechanism. In most K-channels, the S4 site is composed of four threonine amino acids. The K channels that carry serine instead of threonine are significantly less susceptible to Ba
2+
block and have reduced stabilities. We find that these differences can be explained by the lower polarizability of serine compared with threonine, because serine carries one less branched methyl group than threonine. A T→S substitution in the S4 site reduces its polarizability, which, in turn, reduces ion binding by several kilocalories per mole. Although the loss in binding affinity is high for Ba
2+
, the loss in K
+
binding affinity is also significant thermodynamically, which reduces channel stability. These results highlight, in general, how biomolecular function can rely on the polarization induced by methyl groups, especially those that are proximal to charged moieties, including ions, titratable amino acids, sulfates, phosphates, and nucleotides.
Large Pt anomaly in the Greenland ice core points to a cataclysm at the onset of Younger Dryas
Authors: Petaev Michail I. , Huang Shichun , Jacobsen Stein B. , Zindler Alan
Published: July 2013

One explanation of the abrupt cooling episode known as the Younger Dryas (YD) is a cosmic impact or airburst at the YD boundary (YDB) that triggered cooling and resulted in other calamities, including the disappearance of the Clovis culture and the extinction of many large mammal species. We tested the YDB impact hypothesis by analyzing ice samples from the Greenland Ice Sheet Project 2 (GISP2) ice core across the Bølling-Allerød/YD boundary for major and trace elements. We found a large Pt anomaly at the YDB, not accompanied by a prominent Ir anomaly, with the Pt/Ir ratios at the Pt peak exceeding those in known terrestrial and extraterrestrial materials. Whereas the highly fractionated Pt/Ir ratio rules out mantle or chondritic sources of the Pt anomaly, it does not allow positive identification of the source. Circumstantial evidence such as very high, superchondritic Pt/Al ratios associated with the Pt anomaly and its timing, different from other major events recorded on the GISP2 ice core such as well-understood sulfate spikes caused by volcanic activity and the ammonium and nitrate spike due to the biomass destruction, hints for an extraterrestrial source of Pt. Such a source could have been a highly differentiated object like an Ir-poor iron meteorite that is unlikely to result in an airburst or trigger wide wildfires proposed by the YDB impact hypothesis.
Convergence of auxin and gibberellin signaling on the regulation of the GATA transcription factors
GNC
and
GNL
in
Arabidopsis thaliana
Authors: Richter René , Behringer Carina , Zourelidou Melina , Schwechheimer Claus
Published: July 2013

Plant growth is regulated by a complex network of signaling events. Points of convergence for the signaling cross-talk between the phytohormones auxin and gibberellin (GA), which partly control overlapping processes during plant development, are largely unknown. At the cellular level, auxin responses are controlled by members of the AUXIN RESPONSE FACTOR (ARF) family of transcription factors as well as AUXIN/INDOLE-3-ACETIC ACID INDUCIBLE (AUX/IAA) proteins that repress the activity of at least a subset of ARFs. Here, we show that the two paralogous GATA transcription factors
GATA, NITRATE-INDUCIBLE, CARBON-METABOLISM INVOLVED
(
GNC
) and
GNC-LIKE
(
GNL
)/
CYTOKININ-RESPONSIVE GATA FACTOR1
(
CGA1
) are direct and critical transcription targets downstream from ARF2 in the control of greening, flowering time, and senescence. Mutants deficient in the synthesis or signaling of the phytohormone GA are also impaired in greening, flowering, and senescence, and interestingly,
GNC
and
GNL
were previously identified as important transcription targets of the GA signaling pathway. In line with a critical regulatory role for
GNC
and
GNL
downstream from both auxin and GA signaling, we show here that the constitutive activation of GA signaling is sufficient to suppress
arf2
mutant phenotypes through repression of
GNC
and
GNL
. In addition, we show that GA promotes ARF2 protein abundance through a translation-dependent mechanism that could serve to override the autoinhibitory negative feedback regulation of ARF2 on its own transcription and thereby further promote GA signaling.
Bottlenose dolphins can use learned vocal labels to address each other
Authors: King Stephanie L. , Janik Vincent M.
Published: July 2013

In animal communication research, vocal labeling refers to incidents in which an animal consistently uses a specific acoustic signal when presented with a specific object or class of objects. Labeling with learned signals is a foundation of human language but is notably rare in nonhuman communication systems. In natural animal systems, labeling often occurs with signals that are not influenced by learning, such as in alarm and food calling. There is a suggestion, however, that some species use learned signals to label conspecific individuals in their own communication system when mimicking individually distinctive calls. Bottlenose dolphins (
Tursiops truncatus
) are a promising animal for exploration in this area because they are capable of vocal production learning and can learn to use arbitrary signals to report the presence or absence of objects. Bottlenose dolphins develop their own unique identity signal, the signature whistle. This whistle encodes individual identity independently of voice features. The copying of signature whistles may therefore allow animals to label or address one another. Here, we show that wild bottlenose dolphins respond to hearing a copy of their own signature whistle by calling back. Animals did not respond to whistles that were not their own signature. This study provides compelling evidence that a dolphin’s learned identity signal is used as a label when addressing conspecifics. Bottlenose dolphins therefore appear to be unique as nonhuman mammals to use learned signals as individually specific labels for different social companions in their own natural communication system.
Recent burning of boreal forests exceeds fire regime limits of the past 10,000 years
Authors: Kelly Ryan , Chipman Melissa L. , Higuera Philip E. , Stefanova Ivanka , Brubaker Linda B. , Hu Feng Sheng
Published: July 2013

Wildfire activity in boreal forests is anticipated to increase dramatically, with far-reaching ecological and socioeconomic consequences. Paleorecords are indispensible for elucidating boreal fire regime dynamics under changing climate, because fire return intervals and successional cycles in these ecosystems occur over decadal to centennial timescales. We present charcoal records from 14 lakes in the Yukon Flats of interior Alaska, one of the most flammable ecoregions of the boreal forest biome, to infer causes and consequences of fire regime change over the past 10,000 y. Strong correspondence between charcoal-inferred and observational fire records shows the fidelity of sedimentary charcoal records as archives of past fire regimes. Fire frequency and area burned increased ∼6,000–3,000 y ago, probably as a result of elevated landscape flammability associated with increased
Picea mariana
in the regional vegetation. During the Medieval Climate Anomaly (MCA; ∼1,000–500 cal B.P.), the period most similar to recent decades, warm and dry climatic conditions resulted in peak biomass burning, but severe fires favored less-flammable deciduous vegetation, such that fire frequency remained relatively stationary. These results suggest that boreal forests can sustain high-severity fire regimes for centuries under warm and dry conditions, with vegetation feedbacks modulating climate–fire linkages. The apparent limit to MCA burning has been surpassed by the regional fire regime of recent decades, which is characterized by exceptionally high fire frequency and biomass burning. This extreme combination suggests a transition to a unique regime of unprecedented fire activity. However, vegetation dynamics similar to feedbacks that occurred during the MCA may stabilize the fire regime, despite additional warming.
Nucleosome maps of the human cytomegalovirus genome reveal a temporal switch in chromatin organization linked to a major IE protein
Authors: Zalckvar Einat , Paulus Christina , Tillo Desiree , Asbach-Nitzsche Alexandra , Lubling Yaniv , Winterling Carla , Strieder Nicholas , Mücke Katrin , Goodrum Felicia , Segal Eran , Nevels Michael
Published: July 2013

Human CMV (hCMV) establishes lifelong infections in most of us, causing developmental defects in human embryos and life-threatening disease in immunocompromised individuals. During productive infection, the viral >230,000-bp dsDNA genome is expressed widely and in a temporal cascade. The hCMV genome does not carry histones when encapsidated but has been proposed to form nucleosomes after release into the host cell nucleus. Here, we present hCMV genome-wide nucleosome occupancy and nascent transcript maps during infection of permissive human primary cells. We show that nucleosomes occupy nuclear viral DNA in a nonrandom and highly predictable fashion. At early times of infection, nucleosomes associate with the hCMV genome largely according to their intrinsic DNA sequence preferences, indicating that initial nucleosome formation is genetically encoded in the virus. However, as infection proceeds to the late phase, nucleosomes redistribute extensively to establish patterns mostly determined by nongenetic factors. We propose that these factors include key regulators of viral gene expression encoded at the hCMV major immediate-early (IE) locus. Indeed, mutant virus genomes deficient for IE1 expression exhibit globally increased nucleosome loads and reduced nucleosome dynamics compared with WT genomes. The temporal nucleosome occupancy differences between IE1-deficient and WT viruses correlate inversely with changes in the pattern of viral nascent and total transcript accumulation. These results provide a framework of spatial and temporal nucleosome organization across the genome of a major human pathogen and suggest that an hCMV major IE protein governs overall viral chromatin structure and function.
Structural and functional insight into an unexpectedly selective
N
-methyltransferase involved in plantazolicin biosynthesis
Authors: Lee Jaeheon , Hao Yue , Blair Patricia M. , Melby Joel O. , Agarwal Vinayak , Burkhart Brandon J. , Nair Satish K. , Mitchell Douglas A.
Published: July 2013

Plantazolicin (PZN), a polyheterocyclic,
N

α

,N

α

-dimethylarginine–containing antibiotic, harbors remarkably specific bactericidal activity toward strains of
Bacillus anthracis
, the causative agent of anthrax. Previous studies demonstrated that genetic deletion of the
S
-adenosyl-
l
-methionine–dependent methyltransferase from the PZN biosynthetic gene cluster results in the formation of desmethylPZN, which is devoid of antibiotic activity. Here we describe the in vitro reconstitution, mutational analysis, and X-ray crystallographic structure of the PZN methyltransferase. Unlike all other known small molecule methyltransferases, which act upon diverse substrates in vitro, the PZN methyltransferase is uncharacteristically limited in substrate scope and functions only on desmethylPZN and close derivatives. The crystal structures of two related PZN methyltransferases, solved to 1.75 Å (
Bacillus amyloliquefaciens
) and 2.0 Å (
Bacillus pumilus
), reveal a deep, narrow cavity, putatively functioning as the binding site for desmethylPZN. The narrowness of this cavity provides a framework for understanding the molecular basis of the extreme substrate selectivity. Analysis of a panel of point mutations to the methyltransferase from
B. amyloliquefaciens
allowed the identification of residues of structural and catalytic importance. These findings further our understanding of one set of orthologous enzymes involved in thiazole/oxazole-modified microcin biosynthesis, a rapidly growing sector of natural products research.
Pds5 promotes and protects cohesin acetylation
Authors: Chan Kok-Lung , Gligoris Thomas , Upcher William , Kato Yuki , Shirahige Katsuhiko , Nasmyth Kim , Beckouët Frédéric
Published: July 2013

Cohesin’s Smc1 and Smc3 subunits form V-shaped heterodimers, the nucleotide binding domains (NBDs) of which bind the C- and N-terminal domains, respectively, of the α-kleisin subunit, forming a large tripartite ring within in which sister DNAs are entrapped, and thereby held together (sister chromatid cohesion). During replication, establishment of stable cohesion is dependent on Eco1-mediated acetylation of Smc3’s NBD, which is thought to prevent dissociation of α-kleisin from Smc3, thereby locking shut a “DNA exit gate.” How Scc3 and Pds5, regulatory subunits bound to α-kleisin, regulate cohesion establishment and maintenance is poorly understood. We show here that by binding to α-kleisin adjacent to its Smc3 nucleotide binding N-terminal domain, Pds5 not only promotes cohesin’s release from chromatin but also mediates de novo acetylation of Smc3 by Eco1 during S phase and subsequently prevents de-acetylation by the deacetylase Hos1/HDAC8. By first promoting cohesin’s release from chromosomes and subsequently creating and guarding the chemical modification responsible for blocking release, Pds5 enables chromosomal cohesin to switch during S phase from a state of high turnover to one capable of tenaciously holding sister chromatids together for extended periods of time, a duality that has hitherto complicated analysis of this versatile cohesin subunit.
Homologous 2′,5′-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity
Authors: Zhang Rong , Jha Babal K. , Ogden Kristen M. , Dong Beihua , Zhao Ling , Elliott Ruth , Patton John T. , Silverman Robert H. , Weiss Susan R.
Published: July 2013

Efficient and productive virus infection often requires viral countermeasures that block innate immunity. The IFN-inducible 2′,5′-oligoadenylate (2-5A) synthetases (OASs) and ribonuclease (RNase) L are components of a potent host antiviral pathway. We previously showed that murine coronavirus (MHV) accessory protein ns2, a 2H phosphoesterase superfamily member, is a phosphodiesterase (PDE) that cleaves 2-5A, thereby preventing activation of RNase L. The PDE activity of ns2 is required for MHV replication in macrophages and for hepatitis. Here, we show that group A rotavirus (RVA), an important cause of acute gastroenteritis in children worldwide, encodes a similar PDE. The RVA PDE forms the carboxy-terminal domain of the minor core protein VP3 (VP3-CTD) and shares sequence and predicted structural homology with ns2, including two catalytic HxT/S motifs. Bacterially expressed VP3-CTD exhibited 2′,5′-PDE activity, which cleaved 2-5A in vitro. In addition, VP3-CTD expressed transiently in mammalian cells depleted 2-5A levels induced by OAS activation with poly(rI):poly(rC), preventing RNase L activation. In the context of recombinant chimeric MHV expressing inactive ns2, VP3-CTD restored the ability of the virus to replicate efficiently in macrophages or in the livers of infected mice, whereas mutant viruses expressing inactive VP3-CTD (H718A or H798R) were attenuated. In addition, chimeric viruses expressing either active ns2 or VP3-CTD, but not nonfunctional equivalents, were able to protect ribosomal RNA from RNase L–mediated degradation. Thus, VP3-CTD is a 2′,5′-PDE able to functionally substitute for ns2 in MHV infection. Remarkably, therefore, two disparate RNA viruses encode proteins with homologous 2′,5′-PDEs that antagonize activation of innate immunity.
Adult pallium transcriptomes surprise in not reflecting predicted homologies across diverse chicken and mouse pallial sectors
Authors: Belgard T. Grant , Montiel Juan F. , Wang Wei Zhi , García-Moreno Fernando , Margulies Elliott H. , Ponting Chris P. , Molnár Zoltán
Published: July 2013

The thorniest problem in comparative neurobiology is the identification of the particular brain region of birds and reptiles that corresponds to the mammalian neocortex [Butler AB, Reiner A, Karten HJ (2011)
Ann N Y Acad Sci
1225:14–27; Wang Y, Brzozowska-Prechtl A, Karten HJ (2010)
Proc Natl Acad Sci USA
107(28):12676–12681]. We explored which genes are actively transcribed in the regions of controversial ancestry in a representative bird (chicken) and mammal (mouse) at adult stages. We conducted four analyses comparing the expression patterns of their 5,130 most highly expressed one-to-one orthologous genes that considered global patterns of expression specificity, strong gene markers, and coexpression networks. Our study demonstrates transcriptomic divergence, plausible convergence, and, in two exceptional cases, conservation between specialized avian and mammalian telencephalic regions. This large-scale study potentially resolves the complex relationship between developmental homology and functional characteristics on the molecular level and settles long-standing evolutionary debates.
Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2–mediated suppression of mTORC1
Authors: Tripathi Durga N. , Chowdhury Rajdeep , Trudel Laura J. , Tee Andrew R. , Slack Rebecca S. , Walker Cheryl Lyn , Wogan Gerald N.
Published: July 2013

Significance

NO exposure triggered an ATM-mediated damage response in breast cancer cells involving activation of the LKB1 and TSC2 tumor suppressors, repression of mTORC1, ULK phosphorylation, and increased autophagic flux. The associated loss of cell viability indicates that autophagy can function as a cytotoxic response to nitrosative stress in tumor cells. Collectively, the data identify a nitrosative-stress signaling pathway that regulates autophagy. A more comprehensive understanding of signaling pathways regulating autophagy holds promise for developing new therapeutic approaches compromising prosurvival autophagic pathways that enable tumor cells to evade therapy, or promoting prodeath autophagic pathways that kill cancer cells.
Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance
Authors: Priceman Saul J. , Kujawski Maciej , Shen Shudan , Cherryholmes Gregory A. , Lee Heehyoung , Zhang Chunyan , Kruper Laura , Mortimer Joanne , Jove Richard , Riggs Arthur D. , Yu Hua
Published: July 2013

Dysregulated inflammation in adipose tissue, marked by increased proinflammatory T-cell accumulation and reduced regulatory T cells (Tregs), contributes to obesity-associated insulin resistance. The molecular mechanisms underlying T-cell-mediated inflammation in adipose tissue remain largely unknown, however. Here we show a crucial role for signal transducer and activator of transcription 3 (Stat3) in T cells in skewing adaptive immunity in visceral adipose tissue (VAT), thereby contributing to diet-induced obesity (DIO) and insulin resistance. Stat3 activity is elevated in obese VAT and in VAT-resident T cells. Functional ablation of
Stat3
in T cells reduces DIO, improves insulin sensitivity and glucose tolerance, and suppresses VAT inflammation. Importantly,
Stat3
ablation reverses the high Th1/Treg ratio in VAT of DIO mice that is likely secondary to elevated IL-6 production, leading in turn to suppression of Tregs. In addition, Stat3 in T cells in DIO mice affects adipose tissue macrophage accumulation and M2 phenotype. Our study identifies Stat3 in VAT-resident T cells as an important mediator and direct target for regulating adipose tissue inflammation, DIO, and its associated metabolic dysfunctions.
Resilience of river flow regimes
Authors: Botter Gianluca , Basso Stefano , Rodriguez-Iturbe Ignacio , Rinaldo Andrea
Published: July 2013

Landscape and climate alterations foreshadow global-scale shifts of river flow regimes. However, a theory that identifies the range of foreseen impacts on streamflows resulting from inhomogeneous forcings and sensitivity gradients across diverse regimes is lacking. Here, we derive a measurable index embedding climate and landscape attributes (the ratio of the mean interarrival of streamflow-producing rainfall events and the mean catchment response time) that discriminates erratic regimes with enhanced intraseasonal streamflow variability from persistent regimes endowed with regular flow patterns. Theoretical and empirical data show that erratic hydrological regimes typical of rivers with low mean discharges are resilient in that they hold a reduced sensitivity to climate fluctuations. The distinction between erratic and persistent regimes provides a robust framework for characterizing the hydrology of freshwater ecosystems and improving water management strategies in times of global change.
Shear stress activation of nuclear receptor PXR in endothelial detoxification
Authors: Wang Xiaohong , Fang Xi , Zhou Jing , Chen Zhen , Zhao Beilei , Xiao Lei , Liu Ao , Li Yi-Shuan J. , Shyy John Y.-J. , Guan Youfei , Chien Shu , Wang Nanping
Published: July 2013

Endothelial cells (ECs) are constantly exposed to xenobiotics and endobiotics or their metabolites, which perturb EC function, as well as to shear stress, which plays a crucial role in vascular homeostasis. Pregnane X receptor (PXR) is a nuclear receptor and a key regulator of the detoxification of xeno- and endobiotics. Here we show that laminar shear stress (LSS), the atheroprotective flow, activates PXR in ECs, whereas oscillatory shear stress, the atheroprone flow, suppresses PXR. LSS activation of PXR in cultured ECs led to the increased expression of a PXR target gene, multidrug resistance 1 (MDR1). An in vivo study using rats showed that the expression of MDR1 was significantly higher in the endothelium from the descending thoracic aorta, where flow is mostly laminar, than from the inner curvature of aortic arch, where flow is disturbed. Functionally, LSS-activated PXR protects ECs from apoptosis triggered by doxorubicin via the induction of MDR1 and other detoxification genes. PXR also suppressed the expression of proinflammatory adhesion molecules and monocyte adhesion in response to TNF-α and lipopolysaccharide. Overexpression of a constitutively active PXR in rat carotid arteries potently attenuated proinflammatory responses. In addition, cDNA microarray revealed a large number of the PXR-activated endothelial genes whose products are responsible for major steps of detoxification, including phase I and II metabolizing enzymes and transporters. These detoxification genes in ECs are induced by LSS in ECs in a PXR-dependent manner. In conclusion, our results indicate that PXR represents a flow-activated detoxification system to protect ECs against damage by xeno- and endobiotics.
Withholding and pursuit in the development of skills in interaction and language
Authors: Filipi Anna
Published: July 2013

Withholding and pursuit are well-documented phenomena in talk between adults and in talk with children. They have been described as working to perform various functions that emerge locally between speakers in a variety of interactional contexts both in ordinary conversation and in institutional talk.In this paper I explore further the actions of pursuit and withholding in interaction between parents and their very young children, first described in Filipi (2003, 2009) by going beyond description and by examining how these features might be implicated in learning. Longitudinal change is thus a focus of the analysis. Examples of talk are drawn from one child aged from 11 to 24 months interacting with members of her family.Applying the microanalytic approach of Conversation Analysis, the study reports four contexts in which pursuit emerges as an important resource. They are pursuit relevant to sequence structure, linguistic pursuit, pursuit of understanding and pursuit of a particular response token. Analysis shows that while the adults orient to the need to move the action forward, particularly observable in the Summons/Response adjacency pair, withholding of completion can occur at any time in order for parent and child to work on particular skills. Finally, I argue that the micro details of the actions of withholding and pursuit provide a particularly useful lens with which to observe the dynamic qualities of asymmetry. Keywords: parent child interaction; Conversation Analysis; language development; asymmetry; withholding; pursuit
Educating attention
Authors: Nomikou Iris , Rohlfing Katharina J. , Szufnarowska Joanna
Published: July 2013

In a longitudinal naturalistic study, we observed German mothers interacting with their infants when they were 3 and 6 months old. Pursuing the idea that infants’ attention is socialized in everyday interactions, we explored whether eye contact is reinforced selectively by behavioral modification in the input provided to infants. Applying a microanalytical approach focusing on the sequential organization of interaction, we explored how the mother draws the infant’s attention to herself and how she tries to maintain attention when the infant is looking at her. Results showed that eye contact is reinforced by specific infant-directed practices: interrogatives and conversational openings, multimodal stimulation, repetition, and imitation. In addition, these practices are contingent on the infant’s own behavior. By comparing the two data points (3 and 6 months), we showed how the education of attention evolves hand-in-hand with the developing capacities of the infant. Keywords: multimodal input; eye contact; interactional adaptation; ecology of attention; social learning
The Sociopolitical Culture of Iranian Baloch Elites
Authors: Taheri Ahmad Reza
Published: July 2013

The paper consists of six parts. The first part discusses the major reasons for the presence of a conventional sociopolitical Baloch culture in Iran. The second part presents a profile of the Iranian Baloch elites, dividing them into four major groups: the Sunni clerics or molavis, tribal chiefs, the educated, and the wealthy. The third discusses the challenging relationship which exists among the Baloch elites. The fourth describes the elites' attitudes towards the Baloch society's norms. The fifth determines the elites' orientation towards state and politics. And finally the paper ends with conclusions.
Circumcision: what should parents and states do? An essay
Authors: Banai Ayelet
Published: July 2013

In May 2012, the district court in Cologne found that male circumcision was unlawful in Germany. The law has since changed, but the ethical question remains: should parents circumcise their sons? Should states try to stop them? In this essay, I examine seven arguments for circumcision applicable to Jewish parents.