bluuebunny/crossref_metadata_2025 huggingface dataset:
ErbB4 reduces synaptic GABA
A
currents independent of its receptor tyrosine kinase activity
Authors: Mitchell Robert M. , Janssen Megan J. , Karavanova Irina , Vullhorst Detlef , Furth Katrina , Makusky Anthony , Markey Sanford P. , Buonanno Andres
Published: November 2013

Significance

We identify a mode of Neuregulin signaling through ErbB4, requiring the receptor but not its canonical tyrosine kinase activity, that selectively decreases fast synaptic GABA
A
currents on hippocampal interneurons. Neuregulin promotes the clustering and association of ErbB4 with α1-containing GABA receptors, and results in the selective internalization of α1-containing receptors via a mechanism that requires PKC activity and clathrin-dependent endocytosis. These findings emphasize the diverse modes of Neuregulin signaling that can regulate interneuron network activity and which may contribute to the pathophysiology of neuropsychiatric disorders and epilepsy.
Serotonin selectively enhances perception and sensory neural responses to stimuli generated by same-sex conspecifics
Authors: Deemyad Tara , Metzen Michael G. , Pan Yingzhou , Chacron Maurice J.
Published: November 2013

Significance

Serotonergic innervation of sensory areas is seen ubiquitously across species and systems, but its functional role remains unclear to this day. We used a systems level approach to investigate the functional role of serotonergic input onto electrosensory pyramidal neurons in the weakly electric fish
Apteronotus leptorhynchus
. We found that serotonin selectively improved neuronal responses to stimuli associated with same-sex conspecifics by inducing increased excitability and burst firing. Further, serotonin enhanced perception of these stimuli while simultaneously inhibiting aggressive behaviors. Our results provide the first evidence that the serotonergic system acts as a “shut up and listen” system, thereby favoring covert behavior after an aggressive encounter together with enhanced perception of stimuli associated with dominant conspecifics.
Gene product 0.4 increases bacteriophage T7 competitiveness by inhibiting host cell division
Authors: Kiro Ruth , Molshanski-Mor Shahar , Yosef Ido , Milam Sara L. , Erickson Harold P. , Qimron Udi
Published: November 2013

Significance

We have identified a phage-encoded inhibitor of the major cytoskeletal protein in bacterial division. The inhibition is shown to confer T7 bacteriophage with a significant growth advantage in dividing hosts. Our studies thus indicate a strategy in bacteriophages to maximize their progeny number by inhibiting escape of one of the daughter cells of an infected bacterium.
Synthetic lethality betweenCCNE1amplification and loss ofBRCA1
Authors: Etemadmoghadam Dariush , Weir Barbara A. , Au-Yeung George , Alsop Kathryn , Mitchell Gillian , George Joshy ,   Australian Ovarian Cancer Study Group, Davis Sally , D’Andrea Alan D. , Simpson Kaylene , Hahn William C. , Bowtell David D. L.
Published: November 2013

Significance

Women with high-grade serous ovarian cancer (HGSC) harboring Cyclin E1 (CCNE1) gene amplification generally face a poor clinical outcome. These tumors comprise a significant group of ∼20% of HGSCs that are not associated withBRCA1/2mutation and are unlikely to respond to standard cytotoxic or poly-ADP-ribose polymerase inhibitors. We identified a specific dependency onBRCA1and members of the ubiquitin pathway inCCNE1-amplified tumors. The requirement forBRCA1seems to account for the mutual exclusivity of mutations observed in primary tumors. We propose a unique therapeutic strategy involving inhibition of the proteasome and homologous recombination function with bortezomib. Our findings are likely to have relevance to the treatment of other tumor types withCCNE1amplification, including triple negative breast cancer.
Identifying external influences on global precipitation
Authors: Marvel Kate , Bonfils Céline
Published: November 2013

Significance

This study provides evidence that human activities are affecting precipitation over land and oceans. Anthropogenic increases in greenhouse gases and stratospheric ozone depletion are expected to lead to a latitudinal intensification and redistribution of global precipitation. However, detecting these mechanisms in the observational record is complicated by strong climate noise and model errors. We establish that the changes in land and ocean precipitation predicted by theory are indeed present in the observational record, that these changes are unlikely to arise purely due to natural climate variability, and that external influences, probably anthropogenic in origin, are responsible.
Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet
Authors: Buchanan Lauren E. , Dunkelberger Emily B. , Tran Huong Q. , Cheng Pin-Nan , Chiu Chi-Cheng , Cao Ping , Raleigh Daniel P. , de Pablo Juan J. , Nowick James S. , Zanni Martin T.
Published: November 2013

Significance

There is an enormous interest in the mechanism by which proteins misfold and aggregate into amyloid fibrils. Amyloid has been implicated in many human diseases, but the mechanism of aggregation is not understood. Intermediates have been postulated to play an important role in the process, but there have been very few direct measurements that provide specific structural details. The use of isotope labeling and 2D IR methods has allowed the characterization of a critical intermediate generated during amyloid formation by islet amyloid polypeptide, the peptide responsible for amyloid formation in type 2 diabetes. Identification of this intermediate provides a structural explanation for the lag phase and may explain why some species develop amyloid deposits of hIAPP while others do not.
Prefusion structure of syntaxin-1A suggests pathway for folding into neuronal
trans
-SNARE complex fusion intermediate
Authors: Liang Binyong , Kiessling Volker , Tamm Lukas K.
Published: November 2013

Significance

Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNAREs) are the key molecules that control fusion in intracellular vesicle traffic. A special case of vesicle-to-plasma membrane fusion is exocytosis of synaptic vesicles at the presynaptic membrane to release neurotransmitters into the synaptic cleft. Structures are known of postfusion SNARE complexes, including a famous four-helix bundle with parallel C-terminal transmembrane domains. However, prefusion structures and the structures of intermediate
trans
-SNARE complexes remain much more elusive. Using nuclear magnetic resonance, we have determined the prefusion structure of the lipid-bound t-SNARE syntaxin-1A, with its transmembrane domain, and confirmed its lipid interactions and conformational transitions on co-t-SNARE SNAP-25 binding by high-resolution interference contrast microscopy in lipid bilayers. We discuss how these structures and their folding into later SNARE complexes might drive membrane fusion.
Microphysical effects determine macrophysical response for aerosol impacts on deep convective clouds
Authors: Fan Jiwen , Leung L. Ruby , Rosenfeld Daniel , Chen Qian , Li Zhanqing , Zhang Jinqiang , Yan Hongru
Published: November 2013

Significance

Deep convective clouds (DCCs) play a key role in atmospheric circulation and the hydrological and energy cycle. How aerosol particles affect DCCs is poorly understood, making it difficult to understand current and future weather and climate. Our work showed that in addition to the invigoration of convection, which has been unanimously cited for explaining the observed results, the microphysical effects induced by aerosols are a fundamental reason for the observed increases in cloud fraction, cloud top height, and cloud thickness in the polluted environment, even when invigoration is absent. The finding calls for an augmented focus on understanding the changes in stratiform/anvils associated with convective life cycle.
Phosphorylation-dependent derepression by the response regulator HnoC in theShewanella oneidensisnitric oxide signaling network
Authors: Plate Lars , Marletta Michael A.
Published: November 2013

Significance

The majority of response regulators in bacterial two-component signaling systems function as transcription factors to induce changes in gene expression in response to an external stimulus. Phosphorylation typically promotes subunit oligomerization, which enhances DNA binding. Here we describe a response regulator, HnoC, with an unprecedented regulation mechanism. Unphosphorylated HnoC exists as a tetramer and associates tightly to DNA, whereas phosphorylation causes subunit dissociation and transcriptional derepression. HnoC is part of a multicomponent signaling network, which controls biofilm formation in response to nitric oxide, possibly as a defense mechanism against NO cytotoxicity. HnoC represses transcription of all of the genes in the NO-signaling network, thus creating a transcriptional feedback loop, which could further tune the signaling dynamics.
Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene
PRODH
Authors: Suntsova Maria , Gogvadze Elena V. , Salozhin Sergey , Gaifullin Nurshat , Eroshkin Fedor , Dmitriev Sergey E. , Martynova Natalia , Kulikov Kirill , Malakhova Galina , Tukhbatova Gulnur , Bolshakov Alexey P. , Ghilarov Dmitry , Garazha Andrew , Aliper Alexander , Cantor Charles R. , Solokhin Yuri , Roumiantsev Sergey , Balaban Pavel , Zhavoronkov Alex , Buzdin Anton
Published: November 2013

Significance

We identified a human-specific endogenous retroviral insert (hsERV) that acts as an enhancer for human
PRODH
, hsERV_PRODH.
PRODH
encodes proline dehydrogenase, which is involved in neuromediator synthesis in the CNS. We show that the hsERV_PRODH enhancer acts synergistically with the CpG island of
PRODH
and is regulated by methylation. We detected high
PRODH
expression in the hippocampus, which was correlated with the undermethylated state of this enhancer.
PRODH
regulatory elements provide neuron-specific transcription in hippocampal cells, and the mechanism of hsERV_PRODH enhancer activity involves the binding of transcriptional factor SOX2. Because
PRODH
is associated with several neurological disorders, we hypothesize that the human-specific regulation of
PRODH
by hsERV_PRODH may have played a role in human evolution by upregulating the expression of this important CNS-specific gene.
Comminution of solids caused by kinetic energy of high shear strain rate, with implications for impact, shock, and shale fracturing
Authors: Bažant Zdeněk P. , Caner Ferhun C.
Published: November 2013

Significance

Fragmentation, crushing, and pulverization of solids, referred to as comminution, has long been of keen interest for mining, tunneling, explosions, meteorite impact, missile impact, ground shock, terrorist attacks, and various industrial processes. Recently, interest surged in comminution of gas or oil shale as a way to enhance the permeability of shale mass by orders of magnitude. Particularly intriguing is a proposed, environmentally friendlier, alternative to hydraulic fracturing in which the fracturing would be achieved by shock waves from explosions or electrohydraulic pulsed arc in a horizontal borehole. The discharge of contaminated water would, in this case, be negligible. In all these problems the energy dissipation density is a key parameter to predict. Here a theory to do so is outlined.
Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo
Authors: Li Fubin , Ravetch Jeffrey V.
Published: November 2013

Significance

Agonistic antibodies targeting key TNF receptor (TNFR) molecules involved in antitumor responses have been demonstrated as potent antitumor therapies in preclinical studies. However, no effective agonistic anti-TNFR therapies have been successfully developed to date. In contrast, cytotoxic antitumor antibodies targeting tumor antigens or antagonistic antibodies blocking key inhibitory checkpoints are widely used in clinical settings. One explanation for this discrepancy has been recently provided by the finding that agonistic anti-TNFR antibodies have a previously unappreciated requirement for inhibitory Fcγ receptor FcγRIIB coengagement. Understanding the differential FcγRIIB coengagement requirement by different antibodies and the in vivo cross-linking function of FcγRIIB, as defined by this study, not only has implications for the development of potent agonistic anti-TNFR therapies but also for the understanding of TNFR activation mechanisms.
Déjà vu diplomacy: South Korea’s Middle East policy under Lee Myung-bak
Authors: Azad Shirzad
Published: November 2013

This paper probes major directions in South Korea’s Middle East foreign policy under the presidency of Lee Myung-bak, during a turbulent transitional period in the region. These include serious attempts to forge multifaceted and long-lasting connections with members of the Gulf Cooperation Council (GCC), efforts to penetrate Kurdistan’s energy and construction industries, and strategies to overcome the quandary of sanctions against Iran. Epitomized by the concept of ‘déjà vu diplomacy’, this study argues that Lee drew heavily on his previous experiences in the Middle East in a nostalgic sense of thrill and action, striving to foster Seoul’s policy goals and to extend the country’s increasing vested interests in the region. Drawing on international relations theory, this research also attributes the Lee administration’s achievements in the Middle East to a combination of both individual (statesman) and international system (structure) elements, with a greater emphasis on the former than on the latter. However, it in no way gainsays the overall contribution of the state bureaucracy as an ancillary component to other parameters.
Molecular interactions involved in proton-dependent gating in KcsA potassium channels
Authors: Posson David J. , Thompson Ameer N. , McCoy Jason G. , Nimigean Crina M.
Published: November 2013

The bacterial potassium channel KcsA is gated open by the binding of protons to amino acids on the intracellular side of the channel. We have identified, via channel mutagenesis and x-ray crystallography, two pH-sensing amino acids and a set of nearby residues involved in molecular interactions that influence gating. We found that the minimal mutation of one histidine (H25) and one glutamate (E118) near the cytoplasmic gate completely abolished pH-dependent gating. Mutation of nearby residues either alone or in pairs altered the channel’s response to pH. In addition, mutations of certain pairs of residues dramatically increased the energy barriers between the closed and open states. We proposed a Monod–Wyman–Changeux model for proton binding and pH-dependent gating in KcsA, where H25 is a “strong” sensor displaying a large shift in pKa between closed and open states, and E118 is a “weak” pH sensor. Modifying model parameters that are involved in either the intrinsic gating equilibrium or the pKa values of the pH-sensing residues was sufficient to capture the effects of all mutations.
Computing the invariant measure and the Lyapunov exponent for one-dimensional maps using a measure-preserving polynomial basis
Authors: Aston Philip , Junge Oliver
Published: November 2013

We consider a generalisation of Ulam’s method for approximating invariant densities of one-dimensional maps. Rather than use piecewise constant polynomials to approximate the density, we use polynomials of degree

n
n

which are defined by the requirement that they preserve the measure on

n
+
1

n+1

neighbouring subintervals. Over the whole interval, this results in a discontinuous piecewise polynomial approximation to the density. We prove error results where this approach is used to approximate smooth densities. We also consider the computation of the Lyapunov exponent using the polynomial density and show that the order of convergence is one order better than for the density itself. Together with using cubic polynomials in the density approximation, this yields a very efficient method for computing highly accurate estimates of the Lyapunov exponent. We illustrate the theoretical findings with some examples.
DNAJC13 mutations in Parkinson disease
Authors: Vilariño-Güell Carles , Rajput Alex , Milnerwood Austen J. , Shah Brinda , Szu-Tu Chelsea , Trinh Joanne , Yu Irene , Encarnacion Mary , Munsie Lise N. , Tapia Lucia , Gustavsson Emil K. , Chou Patrick , Tatarnikov Igor , Evans Daniel M. , Pishotta Frederick T. , Volta Mattia , Beccano-Kelly Dayne , Thompson Christina , Lin Michelle K. , Sherman Holly E. , Han Heather J. , Guenther Bruce L. , Wasserman Wyeth W. , Bernard Virginie , Ross Colin J. , Appel-Cresswell Silke , Stoessl A. Jon , Robinson Christopher A. , Dickson Dennis W. , Ross Owen A. , Wszolek Zbigniew K. , Aasly Jan O. , Wu Ruey-Meei , Hentati Faycal , Gibson Rachel A. , McPherson Peter S. , Girard Martine , Rajput Michele , Rajput Ali H. , Farrer Matthew J.
Published: November 2013

A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case–control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch–German–Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.
Molecular and immunological characterization of β′-component (Onc k 5), a major IgE-binding protein in chum salmon roe
Authors: Shimizu Yutaka , Kishimura Hideki , Kanno Gaku , Nakamura Atsushi , Adachi Reiko , Akiyama Hiroshi , Watanabe Kazuhiko , Hara Akihiko , Ebisawa Motohiro , Saeki Hiroki
Published: November 2013

Salmon roe has a high allergic potency and often causes anaphylaxis in Japan. The major allergic protein of salmon roe is β′-component, which is a 35kDa vitellogenin fragment consisting of two subunits. To elucidate structural information and immunological characteristics, β′-component and the subunit components were purified from chum salmon (Onchorhincus keta) roe and vitellogenin-encoding mRNA was used to prepare β′-component subunit-encoding cDNA. This was PCR-amplified, cloned and sequenced and the deduced amino acid sequence compared with partial sequences of β′-component obtained by peptide mapping. The recombinant β′-component subunit was produced by bacterial expression in Escherichia coli and its IgE-binding ability was measured by ELISA using the sera of a patient allergic to salmon roe. This was then compared with that of the native β′-component with and without carboxymethylation. Following successful cloning of the cDNA encoding the β′-component subunit, 170 amino acid residues were deduced and matched with the amino acid sequences of 121 and 88 residues in the 16kDa and 18kDa subunits, respectively. The sequences of both β′-component subunits were almost identical, and the predicted secondary structure of the β′-component showed a high content of β-pleated sheets and no α-helices. There was no difference in IgE-binding ability between the native and recombinant β′-component subunits at the same protein concentration, regardless of carboxymethylation. In conclusion, β′-component is a homodimer protein composed of two isoform subunits having the same level of IgE-binding ability and, therefore, allergenic identity.
Meteor showers on Earth from sungrazing comets
Authors: Sekhar A. , Asher D. J.
Published: November 2013

Sungrazing comets have always captured a lot of interest and curiosity among the general public as well as scientists since ancient times. The perihelion passage of comet C/2012 S1 (ISON) at the end of this year (on 2013 November 28) is an eagerly awaited event. In this work, we do a mathematical study to check whether meteoroids ejected from this comet during its journey around the Sun can produce spectacular meteor phenomena on Earth. Our calculations show that although the orbital elements of this comet are much more favourable than for most sungrazers to have its descending node near the Earth's orbit, even ejection velocities as high as 1 km s−1 do not induce sufficient nodal dispersion to bring meteoroids to Earth intersection during present times. A similar result applies to Newton's comet C/1680 V1 which has surprisingly similar orbital elements, although it is known to be a distinct comet from C/2012 S1. Our analysis also shows that for meteoroids ejected from all known sungrazing groups during recent epochs, only the Marsden family (with required ejection velocities of some hundreds of m s−1) can produce meteor phenomena during present times. In a broader sense, we indicate why we do not observe visually brilliant meteor showers from frequently observed sungrazers.
Evolution of transcriptional enhancers and animal diversity
Authors: Rubinstein Marcelo , de Souza Flávio S. J.
Published: November 2013

Deciphering the genetic bases that drive animal diversity is one of the major challenges of modern biology. Although four decades ago it was proposed that animal evolution was mainly driven by changes incis-regulatory DNA elements controlling gene expression rather than in protein-coding sequences, only now are powerful bioinformatics and experimental approaches available to accelerate studies into how the evolution of transcriptional enhancers contributes to novel forms and functions. In the introduction to this Theme Issue, we start by defining the general properties of transcriptional enhancers, such as modularity and the coexistence of tight sequence conservation with transcription factor-binding site shuffling as different mechanisms that maintain the enhancer grammar over evolutionary time. We discuss past and current methods used to identify cell-type-specific enhancers and provide examples of how enhancers originatede novo, change and are lost in particular lineages. We then focus in the central part of this Theme Issue on analysing examples of how the molecular evolution of enhancers may change form and function. Throughout this introduction, we present the main findings of the articles, reviews and perspectives contributed to this Theme Issue that together illustrate some of the great advances and current frontiers in the field.
Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution
Authors: Ramos Andrea I. , Barolo Scott
Published: November 2013

In the era of functional genomics, the role of transcription factor (TF)–DNA binding affinity is of increasing interest: for example, it has recently been proposed that low-affinity genomic binding events, though frequent, are functionally irrelevant. Here, we investigate the role of binding site affinity in the transcriptional interpretation of Hedgehog (Hh) morphogen gradients.We noted that enhancers of several Hh-responsiveDrosophilagenes have low predicted affinity for Ci, the Gli family TF that transduces Hh signalling in the fly. Contrary to our initial hypothesis, improving the affinity of Ci/Gli sites in enhancers ofdpp,winglessandstripe, by transplanting optimal sites from thepatchedgene, did not result in ectopic responses to Hh signalling. Instead, we found that these enhancers require low-affinity binding sites for normal activation in regions of relatively low signalling. When Ci/Gli sites in these enhancers were altered to improve their binding affinity, we observed patterning defects in the transcriptional response that are consistent with a switch from Ci-mediated activation to Ci-mediated repression. Synthetic transgenic reporters containing isolated Ci/Gli sites confirmed this finding in imaginal discs. We propose that the requirement for gene activation by Ci in the regions of low-to-moderate Hh signalling results in evolutionary pressure favouring weak binding sites in enhancers of certain Hh target genes.
A fast-evolving humanNPAS3enhancer gained reporter expression in the developing forebrain of transgenic mice
Authors: Kamm Gretel B. , López-Leal Rodrigo , Lorenzo Juan R. , Franchini Lucía F.
Published: November 2013

The developmental brain geneNPAS3stands out as a hot spot in human evolution because it contains the largest number of human-specific, fast-evolving, conserved, non-coding elements. In this paper we studied 2xHAR142, one of these elements that is located in the fifth intron ofNPAS3.Using transgenic mice, we show that the mouse and chimp 2xHAR142 orthologues behave as transcriptional enhancers driving expression of the reporter genelacZto a similarNPAS3expression subdomain in the mouse central nervous system. Interestingly, the human 2xHAR142 orthologue driveslacZexpression to an extended expression pattern in the nervous system. Thus, molecular evolution of 2xHAR142 provides the first documented example of human-specific heterotopy in the forebrain promoted by a transcriptional enhancer and suggests that it may have contributed to assemble the unique properties of the human brain.
Beyond the ENCODE project: using genomics and epigenomics strategies to study enhancer evolution
Authors: Sakabe Noboru Jo , Nobrega Marcelo A.
Published: November 2013

The complex expression patterns observed for many genes are often regulated by distal transcription enhancers. Changes in the nucleotide sequences of enhancers may therefore lead to changes in gene expression, representing a central mechanism by which organisms evolve. With the development of the experimental technique of chromatin immunoprecipitation (ChIP), in which discrete regions of the genome bound by specific proteins can be identified, it is now possible to identify transcription factor binding events (putative
cis
-regulatory elements) in entire genomes. Comparing protein–DNA binding maps allows us, for the first time, to attempt to identify regulatory differences and infer global patterns of change in gene expression across species. Here, we review studies that used genome-wide ChIP to study the evolution of enhancers. The trend is one of high divergence of
cis
-regulatory elements between species, possibly compensated by extensive creation and loss of regulatory elements and rewiring of their target genes. We speculate on the meaning of the differences observed and discuss that although ChIP experiments identify the biochemical event of protein–DNA interaction, it cannot determine whether the event results in a biological function, and therefore more studies are required to establish the effect of divergence of binding events on species-specific gene expression.
Assessing constraints on the path of regulatory sequence evolution
Authors: Glassford William J. , Rebeiz Mark
Published: November 2013

Structural and functional constraints are known to play a major role in restricting the path of evolution of protein activities. However, constraints acting on evolving transcriptional regulatory sequences, e.g. enhancers, are largely unknown. Recently, we elucidated how a novel expression pattern of the
Neprilysin-1
(
Nep1
) gene in the optic lobe of
Drosophila santomea
evolved via co-option of existing enhancer activities.
Drosophila santomea
, which has diverged from
Drosophila yakuba
by approximately 400 000 years has accumulated four fixed mutations that each contribute to the full activity of this enhancer. Recreating and testing the optic lobe enhancer of the ancestor of
D. santomea
and
D. yakuba
revealed that the strong
D. santomea
enhancer activity evolved from a weak ancestral activity. Because each mutation on the path from the
D. yakuba/santomea
ancestor to modern-day
D. santomea
contributes to the newly derived optic lobe enhancer activity, we sought here to use this system to study the path of evolution of enhancer sequences. We inferred likely paths of evolution of this enhancer by observing the transcriptional output of all possible intermediate steps between the ancestral
D. yakuba/santomea
enhancer and the modern
D. santomea
enhancer. Many possible paths had epistatic and cooperative effects. Furthermore, we found that several paths significantly increased ectopic transcriptional activity or affected existing enhancer activities from which the novel activity was co-opted. We suggest that these attributes highlight constraints that guide the path of evolution of enhancers.
The structure and evolution ofcis-regulatory regions: theshavenbabystory
Authors: Stern David L. , Frankel Nicolás
Published: November 2013

In this paper, we provide a historical account of the contribution of a single line of research to our current understanding of the structure ofcis-regulatory regions and the genetic basis for morphological evolution. We revisit the experiments that shed light on the evolution of larval cuticular patterns within the genusDrosophilaand the evolution and structure of theshavenbabygene. We describe the experiments that led to the discovery that multiple genetic changes in thecis-regulatory region ofshavenbabycaused the loss of dorsal cuticular hairs (quaternary trichomes) in first instar larvae ofDrosophila sechellia. We also discuss the experiments that showed that the convergent loss of quaternary trichomes inD. sechelliaandDrosophila ezoanawas generated by parallel genetic changes in orthologous enhancers ofshavenbaby. We discuss the observation that multipleshavenbabyenhancers drive overlapping patterns of expression in the embryo and that these apparently redundant enhancers ensure robustshavenbabyexpression and trichome morphogenesis under stressful conditions. All together, these data, collected over 13 years, provide a fundamental case study in the fields of gene regulation and morphological evolution, and highlight the importance of prolonged, detailed studies of single genes.
Structure-aided prediction of mammalian transcription factor complexes in conserved non-coding elements
Authors: Guturu Harendra , Doxey Andrew C. , Wenger Aaron M. , Bejerano Gill
Published: November 2013

Mapping the DNA-binding preferences of transcription factor (TF) complexes is critical for deciphering the functions of
cis
-regulatory elements. Here, we developed a computational method that compares co-occurring motif spacings in conserved versus unconserved regions of the human genome to detect evolutionarily constrained binding sites of rigid TF complexes. Structural data were used to estimate TF complex physical plausibility, explore overlapping motif arrangements seldom tackled by non-structure-aware methods, and generate and analyse three-dimensional models of the predicted complexes bound to DNA. Using this approach, we predicted 422 physically realistic TF complex motifs at 18% false discovery rate, the majority of which (326, 77%) contain some sequence overlap between binding sites. The set of mostly novel complexes is enriched in known composite motifs, predictive of binding site configurations in TF–TF–DNA crystal structures, and supported by ChIP-seq datasets. Structural modelling revealed three cooperativity mechanisms: direct protein–protein interactions, potentially indirect interactions and ‘through-DNA’ interactions. Indeed, 38% of the predicted complexes were found to contain four or more bases in which TF pairs appear to synergize through overlapping binding to the same DNA base pairs in opposite grooves or strands. Our TF complex and associated binding site predictions are available as a web resource at
http://bejerano.stanford.edu/complex
.
Anaerostipes rhamnosivorans sp. nov., a human intestinal, butyrate-forming bacterium
Authors: Bui Thi Phuong Nam , de Vos Willem M. , Plugge Caroline M.
Published: November 2013

A novel butyrate-producing bacterium, strain 1y-2T, was isolated from a stool sample of a 1-year-old, healthy Dutch infant. The isolate was obtained by using lactate and acetate as sources of carbon and energy. The strain was Gram-variable, strictly anaerobic and spore-forming and formed curly rod-shaped cells that fermented glucose into butyrate, lactate, formate and acetate as main products. The DNA G+C content of the strain was 44.5 mol% and its major cellular fatty acids were C12 : 0, iso-C19 : 1 I and C16 : 0. Strain 1y-2T was related to

Anaerostipes caccae

DSM 14662T based on 16S rRNA gene sequence analysis, with 3 % divergence, but hybridization studies of their genomic DNA revealed only 33 % relatedness. Moreover, strain 1y-2T showed marked physiological and biochemical differences from known species of the genus

Anaerostipes

. Based on phylogenetic, chemotypic and phenotypic criteria, we propose that strain 1y-2T should be classified in the genus

Anaerostipes

within a novel species, Anaerostipes rhamnosivorans sp. nov. The type strain is 1y-2T ( = DSM 26241T = KCTC 15316T).
Antibacterial activity of moxifloxacin on bacteria associated with periodontitis within a biofilm
Authors: Tsaousoglou Phoebus , Nietzsche Sandor , Cachovan Georg , Sculean Anton , Eick Sigrun
Published: November 2013

The activity of moxifloxacin was compared with ofloxacin and doxycycline against bacteria associated with periodontitis within a biofilm (single strain and mixed population) in vitro. MICs and minimal bactericidal concentrations (MBCs) of moxifloxacin, ofloxacin and doxycyline were determined against single strains and mixed populations in a planktonic state. Single-species biofilms of two Porphyromonas gingivalis and two Aggregatibacter actinomycetemcomitans strains and a multispecies biofilm consisting of 12 species were formed for 3 days. The minimal biofilm eradication concentrations (MBECs) were determined after exposing the biofilms to the antibacterials (0.002–512 µg ml−1) for 18 h, addition of nutrient broth for 3 days and subsequent subcultivation. Photographs were taken using confocal laser-scanning microscopy and scanning electron microscopy. The MICs and MBCs did not differ between ofloxacin and moxifloxacin against A. actinomycetemcomitans, whilst moxifloxacin was more active than the other tested antibacterials against anaerobes and the mixed population. The single-species biofilms were eradicated by moderate concentrations of the antibacterials, and the lowest MBECs were always found for moxifloxacin (2–8 µg ml−1). MBECs against the multispecies biofilms were 128, >512 and >512 µg ml−1 for moxifloxacin, ofloxacin and doxycycline, respectively. In summary, moxifloxacin in a topical formulation may have potential as an adjunct to mechanical removal of the biofilms.
Recovering Root System Traits Using Image Analysis Exemplified by Two-Dimensional Neutron Radiography Images of Lupine
Authors: Leitner Daniel , Felderer Bernd , Vontobel Peter , Schnepf Andrea
Published: November 2013

Root system traits are important in view of current challenges such as sustainable crop production with reduced fertilizer input or in resource-limited environments. We present a novel approach for recovering root architectural parameters based on image-analysis techniques. It is based on a graph representation of the segmented and skeletonized image of the root system, where individual roots are tracked in a fully automated way. Using a dynamic root architecture model for deciding whether a specific path in the graph is likely to represent a root helps to distinguish root overlaps from branches and favors the analysis of root development over a sequence of images. After the root tracking step, global traits such as topological characteristics as well as root architectural parameters are computed. Analysis of neutron radiographic root system images of lupine (Lupinus albus) grown in mesocosms filled with sandy soil results in a set of root architectural parameters. They are used to simulate the dynamic development of the root system and to compute the corresponding root length densities in the mesocosm. The graph representation of the root system provides global information about connectivity inside the graph. The underlying root growth model helps to determine which path inside the graph is most likely for a given root. This facilitates the systematic investigation of root architectural traits, in particular with respect to the parameterization of dynamic root architecture models.
4-Oxo-N-phenyl-4H-chromene-2-carboxamide and of a new polymorph of 7-methoxy-4-oxo-N-p-tolyl-4H-chromene-2-carboxamide and its hemihydrate
Authors: Reis Joana , Gaspar Alexandra , Borges Fernanda , Gomes Ligia R. , Low John Nicolson
Published: November 2013

4-Oxo-N-phenyl-4H-chromene-2-carboxamide, C16H11NO3, crystallizes in the space groupP21/nand its derivative 7-methoxy-4-oxo-N-p-tolyl-4H-chromene-2-carboxamide, C18H15NO4, forms two polymorphs which crystallize in the space groupsP21/candP\overline{1}. The structures have ananti-rotamer conformation about the C—N bond; however, the amide O atom can be eithertrans- orcis-related to the O atom of the pyran ring. The latter compound also crystallizes as a hemihydrate, C18H15NO4·0.5H2O, in the space groupC2/c. This compound has a similar structure to that of the unsolvated compound.
N′-Benzoyl-5-methyl-1,3-diphenyl-1H-pyrazole-4-carbohydrazide
Authors: Chandra  , Srikantamurthy N. , Kumar Shamantha , Doreswamy B. H. , Umesha K. B. , Mahendra M.
Published: November 2013

In the title compound, C24H20N4O2, the pyrazole ring makes dihedral angles of 47.57 (10)° and 30.56 (11)° with its N-bound and C-bound phenyl groups, respectively. The C—N—N—C group that links the two carbonyls has a torsion angle of 81.5 (2)°. The torsion angles between the carbonyl groups and their adjacent pyrazole and phenyl rings are 125.89 (19) and 164.22 (17)°, respectively. In the crystal, pairs of molecules are linked by N—H...O hydrogen bonds intoR22(10) ring motifs, which in turn link to form chains that propagate parallel to thec-axis direction.
(3aR,8bR)-3a,8b-Dihydroxy-2-methylsulfanyl-3-nitro-1-phenyl-1,8b-dihydroindeno[1,2-b]pyrrol-4(3aH)-one
Authors: Nagalakshmi R. A. , Suresh J. , Jeyachandran V. , Kumar R. Ranjith , Lakshman P. L. Nilantha
Published: November 2013

In the title compound, C18H14N2O5, the pyrrolidine ring adopts a shallow envelope conformation, with the C atom bearing the OH group (and remote from the N atom) displaced by 0.257 (2) Å from the other atoms. The cyclopentane ring has a twisted conformation about the C—C bond bearing one =O and one —OH grouping. The dihedral angle between the five-membered rings (all atoms) is 65.54 (9)° and the OH groups lie to the same side of the ring-junction. The molecular structure features a weak intramolecular O—H...O bond and a possible C—H...π interaction. In the crystal, the molecules are linked into [010] chains by O—H...O hydrogen bonds. Weak C—H...O bonds connect the chains into (100) sheets.
6-Chloro-N-(pyridin-4-ylmethyl)pyridine-3-sulfonamide
Authors: Suchetan Parameshwar Adimoole , Mohan Revanasiddappa Nadigar , Vijithkumar  , Palakshamurthy Bandrehalli Siddagangaiah , Sreenivasa Swamy
Published: November 2013

In the title sulfonamide derivative, C11H10ClN3O2S, the dihedral angle between the pyridine rings is 46.85 (12)°. The N atom of the chloropyridine ring isantito the N—H bond. In the crystal, molecules are linked through N—H...N hydrogen bonds into zigzag chains parallel to [001] with aC(7) graph-set motif.
Hexaaquanickel(II) dihydrogen hypodiphosphate
Authors: Gjikaj Mimoza , Wu Peng , Pook Niels-Patrick
Published: November 2013

The asymmetric unit of the title compound, [Ni(H2O)6](H2P2O6), contains one-half of the hexaaquanickel(II) cation and one-half of the dihydrogen hypodiphosphate anion. In the complex cation, the Ni2+atom is located on an inversion center and has an octahedral coordination sphere. The P—P distance in the centrosymmetric anion is 2.1853 (7) Å. In the crystal, discrete [Ni(H2O)6]2+cations and (H2P2O6)2−anions are stacked in columns parallel to thecaxis and are linked into a three-dimensional network by medium-strength O—H...O hydrogen bonds.
Human herpesvirus‐6A gQ1 and gQ2 are critical for human CD46 usage
Authors: Jasirwan Chyntia , Furusawa Yoshikazu , Tang Huamin , Maeki Takahiro , Mori Yasuko
Published: November 2013

Based on genetic and antigenic differences and on their cell tropism, human herpes virus‐6 (HHV‐6) has been classified into two variants, HHV‐6A and HHV‐6B. Recently, these variants were re‐classified as two different species. The HHV‐6A glycoprotein complex, gH/gL/gQ1/gQ2 binds to its cellular receptor, CD46; however, the corresponding complex in HHV‐6B rarely binds to CD46. To determine which viral molecules in the glycoprotein complex determine HHV‐6A‐CD46 binding, each molecule of the HHV‐6A complex (i.e., gH, gL, gQ1, or gQ2) was replaced with the corresponding HHV‐6B molecule, and the ability of the replaced protein to be incorporated into the complex and the ability of the complex to bind CD46 were examined. It was found that when all four glycoproteins were expressed, they were able to form a tetrameric complex. However, a complex formed by HHV‐6A gH/gL/gQ1/gQ2 complexes replaced with HHV‐6B gQ1 or gQ2 scarcely bind CD46, whereas HHV‐6A complexes in which gH or gL was replaced with the HHV‐6B molecules did bind it. These results indicate that HHV‐6A gQ1 and gQ2 play an important role in CD46 binding.
Testing the roles of competition, facilitation and stochasticity on community structure in a species‐rich assemblage
Authors: Martorell Carlos , Freckleton Robert P.
Published: November 2013

There is an ongoing debate about whether communities are closely integrated and bound together via interactions such as competition or facilitation, or are disintegrated and dominated by chance. We still lack community‐wide data on the intensities of interactions and randomness, and measurements of their impacts on community structure.

Using a long‐term data set, we sought to measure the effects of interactions and stochasticity in structuring a highly diverse (>100 species) semi‐arid grassland plant community, testing for positive and negative interactions at different stages of population growth of all species.

During the colonization of new patches, most species were facilitated or inhibited by several others. These opposite effects can potentially have a large effect on species abundances, but they were correlated and cancelled out at the community level. Nevertheless, competition during colonization was strong enough to cause poor competitors to have small population sizes.

The subsequent phase of population growth (increase and subsequent change in numbers within occupied patches) was mainly driven by intraspecific density dependence, and we found little evidence for interspecific interactions.

Model results showed that stochasticity and recurrent colonization of transient, favourable patches maintained diversity, keeping poor competitors from becoming extinct.

Synthesis: Our results, taken together with recent studies on tropical forests, suggest that weak interactions among established plants may be a general phenomenon, but that local interactions during colonization are important drivers of community composition. Most of the variance in species abundance in our community was explained by intraspecific competition and stochasticity, with interspecific interactions playing a minor role due to their overall weakness, interaction changes over ontogeny, and the cancellation of opposite‐sign interactions when all the species in the community are considered. Despite this, some species were rare seemingly because they cannot withstand interspecific competition. Thus, to untangle the effects of interactions on community structure, future research should focus on interactions occurring at different phases of population growth and on whole communities.
Deliberation and Opinion Change: Evidence from a Deliberative Mini‐public inFinland
Authors: Himmelroos Staffan , Christensen Henrik Serup
Published: November 2013

A number of studies examining the effects of deliberative citizen forums have found that citizens taking part in deliberative processes experience changes in their policy attitudes. However, it remains unclear why these opinion changes occur, since most studies pay little attention to the communicative exchange that is expected to cause the observed changes. Within deliberative theory, there is an expectation that reasonable individuals should be amenable to changing their preferences as a result of the reflection induced by the deliberative process. However, apart from a few recent studies, there has been little empirical research that directly examines how the quality of the communication affects opinion change. This article fills this gap by examining what factors help explain the opinion changes that occur in citizen deliberation. To do this, the article uses data from a mini‐public organized in Turku, Finland, concerning the use of nuclear power. First, the extent and nature of the opinion changes that occurred as a result of the deliberation are established. Following this, the article examines the explanatory powers of a number of potential explanations: deliberative reasoning, sociodemographic inequalities and issue awareness. The results suggest that both deliberative reasoning and issue awareness are significant predictors, meaning there is no single explanation for opinion changes.
Risk Selection into Consumer‐Directed Health Plans: An Analysis of Family Choices within Large Employers
Authors: McDevitt Roland D. , Haviland Amelia M. , Lore Ryan , Laudenberger Laura , Eisenberg Matthew , Sood Neeraj
Published: November 2013

Objective

To identify the degree of selection into consumer‐directed health plans (CDHPs) versus traditional plans over time, and factors that influence choice and temper risk selection.

Data Sources/Study Setting

Sixteen large employers offering both CDHP and traditional plans during the 2004–2007 period, more than 200,000 families.

Study Design

We model CDHP choice with logistic regression; predictors include risk scores, in addition to family, choice setting, and plan characteristics. Additional models stratify by account type or single enrollee versus family.

Data Collection/Extraction Methods

Risk scores, family characteristics, and enrollment decisions are derived from medical claims and enrollment files. Interviews with human resources executives provide additional data.

Principal Findings

CDHP risk scores were 74 percent of traditional plan scores in the first year, and this difference declined over time. Employer contributions to accounts and employee premium savings fostered CDHP enrollment and reduced risk selection. Having to make an active choice of plan increased CDHP enrollment but also increased risk selection. Risk selection was greater for singles than families and did not differ between HRA and HSA‐based CDHPs.

Conclusions

Risk selection was not severe and it was well managed. Employers have effective methods to encourage CDHP enrollment and temper selection against traditional plans.