bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and treatment of heme depletion attributed to overexpression of a lineage of evolved P450 monooxygenases
Authors: Michener Joshua K. , Nielsen Jens , Smolke Christina D.
Published: November 2012

Recent advances in metabolic engineering have demonstrated that microbial biosynthesis can provide a viable alternative to chemical synthesis for the production of bulk and fine chemicals. Introduction of a new biosynthetic pathway typically requires the expression of multiple heterologous enzymes in the production host, which can impose stress on the host cell and, thereby, limit performance of the pathway. Unfortunately, analysis and treatment of the host stress response can be difficult, because there are many sources of stress that may interact in complex ways. We use a systems biological approach to analyze the stress imposed by expressing different enzyme variants from a lineage of soluble P450 monooxygenases, previously evolved for heterologous activity in
Saccharomyces cerevisiae
. Our analysis identifies patterns of stress imposed on the host by heterologous enzyme overexpression that are consistent across the evolutionary lineage, ultimately implicating heme depletion as the major stress. We show that the monooxygenase evolution, starting from conditions of either high or low stress, caused the cellular stress to converge to a common level. Overexpression of rate-limiting enzymes in the endogenous heme biosynthetic pathway alleviates the stress imposed by expression of the P450 monooxygenases and increases the enzymatic activity of the final evolved P450 by an additional 2.3-fold. Heme overexpression also increases the total activity of an endogenous cytosolic heme-containing catalase but not a heterologous P450 that is membrane-associated. This work demonstrates the utility of combining systems and synthetic biology to analyze and optimize heterologous enzyme expression.
Mechanistic insights into editing-site specificity of ADARs
Authors: Kuttan Ashani , Bass Brenda L.
Published: November 2012

Adenosine deaminases that act on RNA (ADARs) deaminate adenosines in dsRNA to produce inosines. ADARs are essential in mammals and are particularly important in the nervous system. Altered levels of adenosine-to-inosine (A-to-I) editing are observed in several diseases. The extent to which an adenosine is edited depends on sequence context. Human ADAR2 (hADAR2) has 5′ and 3′ neighbor preferences, but which amino acids mediate these preferences, and by what mechanism, is unknown. We performed a screen in yeast to identify mutations in the hADAR2 catalytic domain that allow editing of an adenosine within a disfavored triplet. Binding affinity, catalytic rate, base flipping, and preferences were monitored to understand the effects of the mutations on ADAR reactivity. Our data provide information on the amino acids that affect preferences and point to a conserved loop as being of key importance. Unexpectedly, our data suggest that hADAR2’s preferences derive from differential base flipping rather than from direct recognition of neighboring bases. Our studies set the stage for understanding the basis of altered editing levels in disease and for developing therapeutic reagents.
Phleboviruses encapsidate their genomes by sequestering RNA bases
Authors: Raymond Donald D. , Piper Mary E. , Gerrard Sonja R. , Skiniotis Georgios , Smith Janet L.
Published: November 2012

Rift Valley fever and Toscana viruses are human pathogens for which no effective therapeutics exist. These and other phleboviruses have segmented negative-sense RNA genomes that are sequestered by a nucleocapsid protein (N) to form ribonucleoprotein (RNP) complexes of irregular, asymmetric structure, previously uncharacterized at high resolution. N binds nonspecifically to single-stranded RNA with nanomolar affinity. Crystal structures of Rift Valley fever virus N-RNA complexes reconstituted with defined RNAs of different length capture tetrameric, pentameric and hexameric N-RNA multimers. All N-N subunit contacts are mediated by a highly flexible α-helical arm. Arm movement gives rise to the three multimers in the crystal structures and also explains the asymmetric architecture of the RNP. Despite the flexible association of subunits, the crystal structures reveal an invariant, monomeric RNP building block, consisting of the core of one N subunit, the arm of a neighboring N, and four RNA nucleotides with the flanking phosphates. Up to three additional RNA nucleotides bind between subunits. The monomeric building block is matched in size to the repeating unit in viral RNP, as visualized by electron microscopy. N sequesters four RNA bases in a narrow hydrophobic binding slot and has polar contacts only with the sugar-phosphate backbone, which faces the solvent. All RNA bases, whether in the binding slot or in the subunit interface, face the protein in a manner that is incompatible with base pairing or with “reading” by the viral polymerase.
Bone morphogenetic protein- and mating-dependent secretory cell growth and migration in the
Drosophila
accessory gland
Authors: Leiblich Aaron , Marsden Luke , Gandy Carina , Corrigan Laura , Jenkins Rachel , Hamdy Freddie , Wilson Clive
Published: November 2012

The paired male accessory glands of
Drosophila melanogaster
enhance sperm function, stimulate egg production, and reduce female receptivity to other males by releasing a complex mixture of glycoproteins from a secretory epithelium into seminal fluid. A small subpopulation of about 40 specialized secretory cells, called secondary cells, resides at the distal tip of each gland. We show that these cells grow via mechanisms promoted by mating. If aging males mate repeatedly, a subset of these cells delaminates from and migrates along the apical surface of the glandular epithelium toward the proximal end of the gland. Remarkably, these secretory cells can transfer to females with sperm during mating. The frequency of this event increases with age, so that more than 50% of triple-mated, 18-d-old males transfer secondary cells to females. Bone morphogenetic protein signaling specifically in secondary cells is needed to drive all of these processes and is required for the accessory gland to produce its normal effects on female postmating behavior in multiply mated males. We conclude that secondary cells are secretory cells with unusual migratory properties that can allow them to be transferred to females, and that these properties are a consequence of signaling that is required for secondary cells to maintain their normal reproductive functions as males age and mate.
Arrested demixing opens route to bigels
Authors: Varrato Francesco , Di Michele Lorenzo , Belushkin Maxim , Dorsaz Nicolas , Nathan Simon H. , Eiser Erika , Foffi Giuseppe
Published: November 2012

Understanding and, ultimately, controlling the properties of amorphous materials is one of the key goals of material science. Among the different amorphous structures, a very important role is played by colloidal gels. It has been only recently understood that colloidal gels are the result of the interplay between phase separation and arrest. When short-ranged attractive colloids are quenched into the phase-separating region, density fluctuations are arrested and this results in ramified amorphous space-spanning structures that are capable of sustaining mechanical stress. We present a mechanism of aggregation through arrested demixing in binary colloidal mixtures, which leads to the formation of a yet unexplored class of materials––bigels. This material is obtained by tuning interspecies interactions. Using a computer model, we investigate the phase behavior and the structural properties of these bigels. We show the topological similarities and the geometrical differences between these binary, interpenetrating, arrested structures and their well-known monodisperse counterparts, colloidal gels. Our findings are supported by confocal microscopy experiments performed on mixtures of DNA-coated colloids. The mechanism of bigel formation is a generalization of arrested phase separation and is therefore universal.
Functional and structural analysis of the human SLO3 pH- and voltage-gated K
+
channel
Authors: Leonetti Manuel D. , Yuan Peng , Hsiung Yichun , MacKinnon Roderick
Published: November 2012

The activation of eukaryotic SLO K
+
channels by intracellular cues, mediated by a cytoplasmic structure called the gating ring, is central to their physiological roles. SLO3 channels are exclusively expressed in mammalian sperm, where variations of intracellular pH are critical to cellular function. Previous studies primarily focused on the mouse SLO3 orthologue and revealed that, in murine sperm, SLO3 mediates a voltage- and alkalization-activated K
+
current essential to male fertility. Here we investigate the activation of the human SLO3 channel by intracellular pH at the functional and structural level. By using electrophysiology in a heterologous system, we show that human SLO3 opens upon intracellular pH increase and that its expression and functional properties are modulated by LRRC52, a testis-specific accessory subunit. We next present the crystal structure of the human SLO3 gating ring. Comparison with the known structures of the corresponding domain from SLO1, a Ca
2+
-activated homologue, suggests that the SLO3 gating ring structure may represent an open state. Together, these results present insights into the function of a protein expected to be critical for human reproduction and provide a framework to study the mechanism of pH gating in SLO3 channels.
Simultaneous, accurate measurement of the 3D position and orientation of single molecules
Authors: Backlund Mikael P. , Lew Matthew D. , Backer Adam S. , Sahl Steffen J. , Grover Ginni , Agrawal Anurag , Piestun Rafael , Moerner W. E.
Published: November 2012

Recently, single molecule-based superresolution fluorescence microscopy has surpassed the diffraction limit to improve resolution to the order of 20 nm or better. These methods typically use image fitting that assumes an isotropic emission pattern from the single emitters as well as control of the emitter concentration. However, anisotropic single-molecule emission patterns arise from the transition dipole when it is rotationally immobile, depending highly on the molecule’s 3D orientation and
z
position. Failure to account for this fact can lead to significant lateral (
x
,
y
) mislocalizations (up to ∼50–200 nm). This systematic error can cause distortions in the reconstructed images, which can translate into degraded resolution. Using parameters uniquely inherent in the double-lobed nature of the Double-Helix Point Spread Function, we account for such mislocalizations and simultaneously measure 3D molecular orientation and 3D position. Mislocalizations during an axial scan of a single molecule manifest themselves as an apparent lateral shift in its position, which causes the standard deviation (SD) of its lateral position to appear larger than the SD expected from photon shot noise. By correcting each localization based on an estimated orientation, we are able to improve SDs in lateral localization from ∼2× worse than photon-limited precision (48 vs. 25 nm) to within 5 nm of photon-limited precision. Furthermore, by averaging many estimations of orientation over different depths, we are able to improve from a lateral SD of 116 (∼4× worse than the photon-limited precision; 28 nm) to 34 nm (within 6 nm of the photon limit).
Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism
Authors: Gorbunova Vera , Hine Christopher , Tian Xiao , Ablaeva Julia , Gudkov Andrei V. , Nevo Eviatar , Seluanov Andrei
Published: November 2012

Blind mole ratsSpalax(BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and resistance to cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this resistance, we examined the growth of BMR fibroblasts in vitro of the speciesSpalax judaeiandSpalax golani. BMR cells proliferated actively for 7–20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and cancer-resistant African mole rat,Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that cancer resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to cancer resistance of this subterranean mammal extremely adapted to life underground.
Formation of triple-helical structures by the 3′-end sequences of MALAT1 and MENβ noncoding RNAs
Authors: Brown Jessica A. , Valenstein Max L. , Yario Therese A. , Tycowski Kazimierz T. , Steitz Joan A.
Published: November 2012

Stability of the long noncoding-polyadenylated nuclear (PAN) RNA from Kaposi's sarcoma-associated herpesvirus is conferred by an expression and nuclear retention element (ENE). The ENE protects PAN RNA from a rapid deadenylation-dependent decay pathway via formation of a triple helix between the U-rich internal loop of the ENE and the 3′-poly(A) tail. Because viruses borrow molecular mechanisms from their hosts, we searched highly abundant human long-noncoding RNAs and identified putative ENE-like structures in metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and multiple endocrine neoplasia-β (MENβ) RNAs. Unlike the PAN ENE, the U-rich internal loops of both predicted cellular ENEs are interrupted by G and C nucleotides and reside upstream of genomically encoded A-rich tracts. We confirmed the ability of MALAT1 and MENβ sequences containing the predicted ENE and A-rich tract to increase the levels of an intronless β-globin reporter RNA. UV thermal denaturation profiles at different pH values support formation of a triple-helical structure composed of multiple U•A-U base triples and a single C•G-C base triple. Additional analyses of the MALAT1 ENE revealed that robust stabilization activity requires an intact triple helix, strong stems at the duplex-triplex junctions, a G-C base pair flanking the triplex to mediate potential A-minor interactions, and the 3′-terminal A of the A-rich tract to form a blunt-ended triplex lacking unpaired nucleotides at the duplex-triplex junction. These examples of triple-helical, ENE-like structures in cellular noncoding RNAs, are unique.
Non-cell-autonomous regulation of crucifer self-incompatibility by Auxin Response Factor ARF3
Authors: Tantikanjana Titima , Nasrallah June B.
Published: November 2012

In many angiosperms, outcrossing is enforced by genetic self-incompatibility (SI), which allows cells of the pistil to recognize and specifically inhibit “self” pollen. SI is often associated with increased stigma-anther separation, a morphological trait that promotes cross-pollen deposition on the stigma. However, the gene networks responsible for coordinate evolution of these complex outbreeding devices are not known. In self-incompatible members of the Brassicaceae (crucifers), the inhibition of “self”-pollen is triggered within the stigma epidermal cell by allele-specific interaction between two highly polymorphic proteins, the stigma-expressed
S
-locus receptor kinase (SRK) and its pollen coat-localized ligand, the S-locus cysteine-rich (SCR) protein. Using
Arabidopsis thaliana
plants that express SI as a result of transformation with a functional
SRK–SCR
gene pair, we identify Auxin Response Factor 3 (ARF3) as a mediator of cross-talk between SI signaling and pistil development. We show that ARF3, a regulator of pistil development that is expressed in the vascular tissue of the style, acts non-cell-autonomously to enhance the SI response and simultaneously down-regulate auxin responses in stigma epidermal cells, likely by regulating a mobile signal derived from the stylar vasculature. The inverse correlation we observed in stigma epidermal cells between the strength of SI and the levels of auxin inferred from activity of the auxin-responsive reporter
DR5::GUS
suggests that the dampening of auxin responses in the stigma epidermis promotes inhibition of “self” pollen in crucifer SI.
Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression
Authors: Luo Weibo , Chang Ryan , Zhong Jun , Pandey Akhilesh , Semenza Gregg L.
Published: November 2012

Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that play key roles in breast cancer biology. We hypothesized that interaction of HIF-1 with epigenetic regulators may increase HIF-1 transcriptional activity, and thereby promote breast cancer progression. We report that the histone demethylase jumonji domain containing protein 2C (JMJD2C) selectively interacts with HIF-1α, but not HIF-2α, and that HIF-1α mediates recruitment of JMJD2C to the hypoxia response elements of HIF-1 target genes. JMJD2C decreases trimethylation of histone H3 at lysine 9, and enhances HIF-1 binding to hypoxia response elements, thereby activating transcription of
BNIP3
,
LDHA
,
PDK1
, and
SLC2A1
, which encode proteins that are required for metabolic reprogramming, as well as
LOXL2
and
L1CAM
, which encode proteins that are required for lung metastasis. JMJD2C expression is significantly associated with expression of GLUT1, LDHA, PDK1, LOX, LOXL2, and L1CAM mRNA in human breast cancer biopsies. JMJD2C knockdown inhibits breast tumor growth and spontaneous metastasis to the lungs of mice following mammary fat pad injection. Taken together, these findings establish an important epigenetic mechanism that stimulates HIF-1–mediated transactivation of genes encoding proteins involved in metabolic reprogramming and lung metastasis in breast cancer.
Ubiquitin ligase RNF167 regulates AMPA receptor-mediated synaptic transmission
Authors: Lussier Marc P. , Herring Bruce E. , Nasu-Nishimura Yukiko , Neutzner Albert , Karbowski Mariusz , Youle Richard J. , Nicoll Roger A. , Roche Katherine W.
Published: November 2012

AMPA receptors (AMPARs) mediate the majority of fast excitatory neurotransmission, and their density at postsynaptic sites determines synaptic strength. Ubiquitination is a posttranslational modification that dynamically regulates the synaptic expression of many proteins. However, very few of the ubiquitinating enzymes implicated in the process have been identified. In a screen to identify transmembrane RING domain-containing E3 ubiquitin ligases that regulate surface expression of AMPARs, we identified RNF167. Predominantly lysosomal, a subpopulation of RNF167 is located on the surface of cultured neurons. Using a RING mutant RNF167 or a specific shRNA to eliminate endogenous RNF167, we demonstrate that AMPAR surface expression increases in hippocampal neurons with disrupted RNF167 activity and that RNF167 is involved in activity-dependent ubiquitination of AMPARs. In addition, RNF167 regulates synaptic AMPAR currents, whereas synaptic NMDAR currents are unaffected. Therefore, our study identifies RNF167 as a selective regulator of AMPAR-mediated neurotransmission and expands our understanding of how ubiquitination dynamically regulates excitatory synapses.
Dimerization of postsynaptic neuroligin drives synaptic assembly via transsynaptic clustering of neurexin
Authors: Shipman Seth L. , Nicoll Roger A.
Published: November 2012

The transsynaptic complex of neuroligin (NLGN) and neurexin forms a physical connection between pre- and postsynaptic neurons that occurs early in the course of new synapse assembly. Both neuroligin and neurexin have, indeed, been proposed to exhibit active, instructive roles in the formation of synapses. However, the process by which these instructive roles play out during synaptogenesis is not well understood. Here, we examine one aspect of postsynaptic neuroligin with regard to its synaptogenic properties: its basal state as a constitutive dimer. We show that dimerization is required for the synaptogenic properties of neuroligin and likely serves to induce presynaptic differentiation via a transsynaptic clustering of neurexin. Further, we introduce chemically inducible, exogenous dimerization domains to the neuroligin molecule, effectively bestowing chemical control of neuroligin dimerization. This allows us to identify the acute requirements of neuroligin dimerization by chemically manipulating the monomeric-to-dimeric conversion of neuroligin. Based on the results of the inducible dimerization experiments, we propose a model in which dimerized neuroligin induces the mechanical clustering of presynaptic molecules as part of a requisite step in the coordinated assembly of a chemical synapse.
Micro-syntax, macro-syntax, foregrounding and backgrounding in discourse
Authors: Cornish Francis
Published: November 2012

Adopting Berrendonner’s (1990, 2002) and Berrendonner et al.’s (forthcoming) distinction between “micro-syntax” and “macro-syntax”, as well as the orthogonal dichotomy between foregrounded and backgrounded discourse segments (cf. Khalil 2005), this paper aims to examine certain “non-canonical” interactions amongst these domains. In particular, it analyses instances where a potential referent is evoked within a highly presupposed, discursively backgrounded text segment, but where that referent is targeted via an “anadeictic” indexical expression and may be made into a discourse entity in its own right. This last-mentioned use is characteristic of discourse deixis, but not of anaphora as such. The paper also examines larger stretches of text, which relate to each other discursively in terms of “macro-syntax”. The overall aim is to characterise the limits of discourse-anaphoric reference as a function of the degree of backgrounding or foregrounding of the discourse units in terms of which the referent is determined and targeted.
Influence of relational and referential coherence on the distribution of coordinated verb-second clauses in German and Dutch
Authors: Stuyckens Geert
Published: November 2012

This paper investigates, from the point of view of role and reference grammar, the formal and the functional side of SLF (‘subject gap in finite/frontal clauses’) coordination on the basis of a bidirectional parallel German-Dutch corpus. The main research question is how relational and referential coherence are mapped to the syntactic structure of SLF and coordination constructions alternating with it. A typology of the alternative constructions is proposed. Since both relational and referential coherence at the discourse level, as well as the nexus types at the syntax level, are composed of more or less prominent states of affairs, the paper defines a relative concept of prominence on both these grammar levels and examines whether and, if so, how this concept influences the mapping between discursive and syntactic structure. In particular, it looks at absolute and relative frequencies so as to find potential trends in this mapping. There is a tendency that the more prominent the discursive states of affairs are, the more syntactically prominent the chosen coordination alternative is. The states of affairs linked by the interclausal coherence relation seem to affect the distribution of the coordination alternatives both in German and in Dutch. The state of affairs expressed by the information-structural status of the first subject seems to affect at least the distribution of two types. To a certain extent, both German and Dutch strive to iconically map discursive to syntactic prominence.
Some thoughts on “noting” in Language Management Theory and beyond
Authors: Nekvapil Jiří
Published: November 2012

This paper analyses how “noting” has been conceptualized in the Language Management Framework originating in the work of Neustupný and Jernudd. It deals with the influence of the cognitivist concept of “noticing” as used in the theories of Second Language Acquisition and instead proposes to assume the discursive approach of “noting” inspired by Discursive Psychology and Conversation Analysis. It pays attention to the formulations and concrete words which people use to express that they “noted” a phenomenon (be it linguistic, communicative or socio-cultural). Finally, it addresses micro-macro-linkage in the framework, namely, how “noting” of everyday speakers connects to management acts performed by experts in institutions.
Noting as revealed by “checking” in second language interactions
Authors: Sherman Tamah
Published: November 2012

This paper uses Language Management Theory (LMT) to explore situations in which non-native speakers of a language explicitly reveal that they have noted a potential linguistic deviation. This can be paraphrased as the concept of “checking”, identifiable through the use of question intonation for the trouble source item, phrases such as “is that right?”, or the offering of alternative words or forms. This process is explored in Czech conversations between native speakers and American missionaries. In the analysis, two major points are made: 1) There is a limit to the types of deviations which are noted in this way, as checking is mainly done in cases of potential lexical and morphological deviations, and 2) In order for this strategy to be realized, there must be an appropriate categorial context for its execution, particularly in regard to the categories that speakers assign (or do not assign) to one another situationally, such as “non-native speaker” or “language expert”. In this way, simple management can be directly connected to organized management in that missionaries learning a foreign language are instructed to utilize their interlocutors as “language experts”. The paper also considers methodological tools for LMT analysts to uncover the fact that noting has occurred.
Chinese teachers’ use of humour in coping with stress
Authors: Wu Joseph , Chan Raymond M. C.
Published: November 2012

The purpose of this study was to examine the mentality of Chinese teachers regarding their use of humour in coping with stress. Specifically, the study investigated their frequency of use of humour in coping with stress as compared to other coping styles and their perceptions about the relationship of humour with other coping styles. Data were collected from a sample of 789 Chinese teachers holding teaching posts at local Hong Kong secondary schools. Based on responses made to the COPE questionnaire, there was evidence that Chinese teachers had a lower frequency of use of humour as compared to other coping styles. As suggested by the results of a factor analysis, there was a perception among Chinese teachers that the use of humour was related more closely to escaping and/or avoidance as coping strategies, but more differentiable from problem‐focused/task‐oriented and emotional/social coping. It is interesting to find that the results of our study echoed those of a previous crosscultural comparison between Chinese and Canadian university students, in which the Chinese university students reported less use of humour in coping with stress than did their Canadian counterparts. These results have provided some empirical support for the notion that “humor has been traditionally given little respect in Chinese culture mainly due to the Confucian emphasis on keeping proper manners in social interactions” (Yue, 2010, p. 403). As teachers in Chinese societies are regarded as persons who are full of wisdom and capable of problem‐solving, it is expected that they should act as role models to their students. These social expectations on Chinese teachers could further mould their perceptions on the use of humour in coping with stress.
Violent Female Offending: An Exploration of Repeat and One-Time Offending
Authors: Mahoney AdamLouis , Karatzias Thanos
Published: November 2012

There has been an increased focus on understanding the factors that may be predictive of violent recidivism among female offenders. Previous research has indicated that repeat and one-time violent female offenders have very different profiles. All female prisoners incarcerated for a violent offense in Scotland over a two-month period ( n = 87) were compared on a range of demographic, offending, behavioral and mental health variables. Multivariate regression analysis revealed a lack of ‘spousal’ relationships and early onset of violent offending were significant predictor variables that distinguished the recidivist subgroup (explaining 68.2% of variance). Difficulties with intimate relationships are, however, noted for both subgroups.
Use of Measures of Cognitive Effort and Feigned Psychiatric Symptoms with Pretrial Forensic Psychiatric Patients
Authors: Green Debbie , Rosenfeld Barry , Belfi Brian , Rohlehr Lia , Pierson Ashley
Published: November 2012

This study examined the classification accuracy of measures of cognitive effort, as well as the impact of estimated IQ and psychiatric symptoms on these measures in a sample of hospitalized pretrial criminal defendants. A criterion-groups design was used to classify patients into those suspected of feigning ( n = 25) and those believed to be genuinely mentally ill ( n = 93). The Test of Memory Malingering (TOMM), Dot Counting Test (DCT), and Rey Fifteen-Item Memory Test (RMT) were roughly comparable to the SIRS-2 in classifying patient groups but the Validity Indicator Profile (VIP) Verbal subscale was not. Several measures of cognitive effort increased detection of suspected feigning over the SIRS-2 alone. However, among genuinely mentally ill psychiatric patients, level of estimated intelligence was significantly associated with scores on each of the measures of cognitive effort ( r s = .38 to .65), with false positive rates in excess of 30% for patients with estimated intelligence in the Extremely Low range. Performance on measures of cognitive effort was only modestly associated with types, but not total severity of psychiatric symptoms. Implications for the assessment of feigning in clinical settings are discussed.
An Analysis of General Public and Professional's Attitudes about Mental Health Courts: Predictors of a Positive Perspective
Authors: McDougall Ainslie , Campbell MaryAnn , Smith Teresa , Burbridge Angela , Doucette Naomi , Canales DonaldoD.
Published: November 2012

Little research has been conducted on the public perception of mental health courts (MHCs) despite its potential to influence government support and funding. To measure public and professionals’ opinions about MHCs, self-report attitude measures were administered online to members of the general public ( n = 272) and professional groups with previous employment-related exposure to persons with mental health issues ( n = 237). Over 86% of the professional exposure sample had positive attitudes towards MHCs, whereas only 4% reported negative opinions. Approximately 70% of professionals supported government funding for a MHC in their community and 57% agreed even if this led to a tax increase. The public sample was also generally positive in their opinions, and only 3% reported negative opinions. Approximately 80% of public sample reported that they would support or strongly support government funding for a MHC in their community, and 58% would support it even if it led to a tax increase. Positive attitudes were predicted by prior knowledge of MHCs, older age, exposure to mental-health coursework, psychological openness, positive help-seeking attitudes, and positive attitudes towards mental illness in general. These patterns were similar, but varying in degree, for those with and without employment-related exposure to mental illness. Education about the effect of a specific MHC led to significant changes in the proportion of favourable opinions. Thus, public perception of MHCs ranged from neutral to positive and can be enhanced through education.
Taking Stock and Taking Steps: The Case for an Adolescent Version of the Short-Term Assessment of Risk and Treatability
Authors: Viljoen JodiL. , Cruise KeithR. , Nicholls ToniaL. , Desmarais SarahL. , Webster ChristopherD.
Published: November 2012

The field of violence risk assessment has matured considerably, possibly advancing beyond its own adolescence. At this point in the field's evolution, it is more important than ever for the development of any new device to be accompanied by a strong rationale and the capacity to provide a unique contribution. With this issue in mind, we first take stock of the field of adolescent risk assessment in order to describe the rapid progress that this field has made, as well as the gaps that led us to adapt the Short-Term Assessment of Risk and Treatability (START; Webster, Martin, Brink, Nicholls, & Desmarais, 2009) for use with adolescents. We view the Short-Term Assessment of Risk and Treatability: Adolescent Version (START:AV; Nicholls, Viljoen, Cruise, Desmarais, & Webster, 2010; Viljoen, Cruise, Nicholls, Desmarais, & Webster, in progress) as complementing other risk measures in four primary ways: 1) rather than focusing solely on violence risk, it examines broader adverse outcomes to which some adolescents are vulnerable (including self-harm, suicide, victimization, substance abuse, unauthorized leave, self-neglect, general offending); 2) it places a balanced emphasis on adolescents’ strengths and vulnerabilities; 3) it focuses on dynamic factors that are relevant to short-term assessment, risk management, and treatment planning; and 4) it is designed for both mental health and justice populations.

We describe the developmentally-informed approach we took in the adaptation of the START for adolescents, and outline future steps for the continuing validation and refinement of the START:AV.
Distinct functions of chloroplast FtsZ1 and FtsZ2 in Z-ring structure and remodeling
Authors: TerBush Allan D. , Osteryoung Katherine W.
Published: November 2012

FtsZ, a cytoskeletal GTPase, forms a contractile ring for cell division in bacteria and chloroplast division in plants. Whereas bacterial Z rings are composed of a single FtsZ, those in chloroplasts contain two distinct FtsZ proteins, FtsZ1 and FtsZ2, whose functional relationship is poorly understood. We expressed fluorescently tagged FtsZ1 and FtsZ2 in fission yeast to investigate their intrinsic assembly and dynamic properties. FtsZ1 and FtsZ2 formed filaments with differing morphologies when expressed separately. FRAP showed that FtsZ2 filaments were less dynamic than FtsZ1 filaments and that GTPase activity was essential for FtsZ2 filament turnover but may not be solely responsible for FtsZ1 turnover. When coexpressed, the proteins colocalized, consistent with coassembly, but exhibited an FtsZ2-like morphology. However, FtsZ1 increased FtsZ2 exchange into coassembled filaments. Our findings suggest that FtsZ2 is the primary determinant of chloroplast Z-ring structure, whereas FtsZ1 facilitates Z-ring remodeling. We also demonstrate that ARC3, a regulator of chloroplast Z-ring positioning, functions as an FtsZ1 assembly inhibitor.
Procontractile G protein–mediated signaling pathways antagonistically regulate smooth muscle differentiation in vascular remodeling
Authors: Althoff Till F. , Juárez Julián Albarrán , Troidl Kerstin , Tang Cong , Wang Shengpeng , Wirth Angela , Takefuji Mikito , Wettschureck Nina , Offermanns Stefan
Published: November 2012

Vascular smooth muscle (Sm) cells (VSMCs) are highly plastic. Their differentiation state can be regulated by serum response factor (SRF), which activates genes involved in Sm differentiation and proliferation by recruiting cofactors, such as members of the myocardin family and ternary complex factors (TCFs), respectively. However, the extracellular cues and upstream signaling mechanisms regulating SRF-dependent VSMC differentiation under in vivo conditions are poorly understood. In this study, we show that the procontractile signaling pathways mediated by the G proteins G12/G13 and Gq/G11 antagonistically regulate VSMC plasticity in different models of vascular remodeling. In mice lacking Gα12/Gα13 or their effector, the RhoGEF protein LARG, RhoA-dependent SRF-regulation was blocked and down-regulation of VSMC differentiation marker genes was enhanced. This was accompanied by an excessive vascular remodeling and exacerbation of atherosclerosis. In contrast, Sm-specific Gαq/Gα11 deficiency blocked activation of extracellular signal-regulated kinase 1/2 and the TCF Elk-1, resulting in a reduced VSMC dedifferentiation in response to flow cessation or vascular injury. These data show that the balanced activity of both G protein–mediated pathways in VSMCs is required for an appropriate vessel remodeling response in vascular diseases and suggest new approaches to modulate Sm differentiation in vascular pathologies.
Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
Authors: Kim Jungsu , Eltorai Adam E.M. , Jiang Hong , Liao Fan , Verghese Philip B. , Kim Jaekwang , Stewart Floy R. , Basak Jacob M. , Holtzman David M.
Published: November 2012

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
Near-field interactions in electric inductive–capacitive resonators for metamaterials
Authors: Withayachumnankul Withawat , Fumeaux Christophe , Abbott Derek
Published: November 2012

Near-field interactions in an array of electric inductive–capacitive (ELC) resonators are investigated analytically, numerically and experimentally. The measurement and simulation results show that inter-cell coupling plays an important role in determining the response of metamaterials. A quasistatic dipole–dipole interaction model, together with a Lagrangian formalism, quantitatively explains the interplay between the electric and magnetic couplings in the resonator array. Depending on the alignment of the resonators, the couplings can cause resonance shifting and/or splitting. The knowledge obtained from this study is crucial in designing metamaterials with ELC resonators.
The manipulation of an unstarting supersonic flow by plasma actuator
Authors: Im S , Do H , Cappelli M A
Published: November 2012

The manipulation of an unstarting supersonic flow is demonstrated using a dielectric barrier discharge (DBD). Experiments are carried out in a Mach 4.7 model inlet flow. Flow features, such as boundary layers and shockwaves at low freestream static pressure (1 kPa) and temperature (60 K) are visualized with Rayleigh scattering from condensed CO2 particles. Flow unstart, initiated by mass injection, is studied for three model inlet flow configurations, distinguished by the initial conditions (untripped or tripped, plasma actuated or not) of the boundary layers. Unstart in the presence of thick, tripped boundary layers is characterized by the formation of an oblique unstart shock just upstream of a separating and propagating boundary layer. The presence of plasma actuation of this tripped boundary layer seems to arrest the boundary layer separation and leads to the formation of a quasi-stationary pseudo-shock, delaying unstart. The flow generated with DBD actuation is more characteristic of what is seen when unstart is generated in a model flow in which thin boundary layers grow naturally. Planar laser Rayleigh scattering visualizations suggest that the DBD actuation thins the tripped boundary layer over the exposed electrode region.
Emission measurements from planar arrays of porous ionic liquid ion sources
Authors: Courtney Daniel G , Li Hanqing Q , Lozano Paulo
Published: November 2012

We present current emission measurements from arrays of 480 porous ionic liquid ion source emitters for applications in space propulsion and in the processing and analysis of materials. The emitters are fabricated with a top-down approach from 10 × 10 × 1 mm3 bulk porous nickel and are housed within a microetched silicon frame and stainless-steel aperture-matching extraction grids. Measurements of emitted and collected currents are reported using two ionic liquids (ILs), EMI-BF4 and EMI-Im. Total beam currents up to about 400 µA can be sustained through passive feeding with IL fed from the rear of the bulk porous substrate. These currents are in agreement with previous work where currents of about 1 µA were observed from single emitters. Ion transparencies as high as 0.95 are achieved with manually assembled grids. Current emission displays reasonable symmetry between polarities, although slight differences could yield to the accumulation of one type of ion in the source leading to electrochemical reactions despite voltage alternation. Strong current decays with time and evidence of surface contamination reinforce this hypothesis. Future work should address this issue through closed-loop control of charge emission.
Experimental results with an optimized magnetic field configuration for JET breakdown
Authors: Albanese R. , Maviglia F. , Lomas P.J. , Manzanares A. , Mattei M. , Neto A. , Rimini F.G. , de Vries P.C.
Published: November 2012

Experiments and modelling have been carried out to optimize the magnetic field null during breakdown at JET. Such optimization may prove to be essential for reliable plasma initiation at low voltages, e.g. in ITER where the value of the electric field available will be limited to 0.33 V m−1.

A two-dimensional FEM electromagnetic model has been employed to predict the stray field configuration during JET breakdown. This model includes the active poloidal field circuits, a description of the passive structure and the JET magnetic circuit. In particular, the model includes the gap at the top of the iron circuit (but not at the bottom), which introduces a perturbing field, with radial and vertical components, not previously considered. A number of experiments were run using the optimized magnetic null configuration, allowing one to achieve a more robust breakdown at a low electric field. The model calculation to adjust the magnetic null position was validated using the recordings from a fast visible camera. The optimized position and dynamics of the plasma start lead to a smoother behaviour of the JET radial field control system, far from the amplifier limits. Finally, an important indication was obtained on the precision needed for the active current measurements during the low electric field breakdown relevant from the perspective of the ITER real-time acquisition system.
On the first moment of the symmetric-square 𝐿-function
Authors: Sun Qingfeng
Published: November 2012

We improve the error term in the asymptotic formula for the twisted first moment of the symmetric-square

L
L

-function on the critical line.
The Economics of Health and Vitamin Consumption
Authors: Schroeter Christiane , Anders Sven , Carlson Andrea
Published: November 2012

We estimate the impact of vitamin supplement intake, lifestyle, health indicators, food culture, and demographics on diet quality outcomes as measured by the Healthy Eating Index–2005 (HEI). Our data consists of U.S. adults who participated in the 2003–2004 National Health and Nutrition Examination Survey. Alternative instrumental variable estimators explicitly address issues of endogeneity and complex sample design. Our empirical analysis demonstrates that diet quality is strongly interrelated with food culture. We suggest that vitamin consumption serves as another marker for healthy eating. This finding emphasizes the need to employ economic modeling when developing public policy to reduce obesity.
LOGICOIL—multi-state prediction of coiled-coil oligomeric state
Authors: Vincent Thomas L. , Green Peter J. , Woolfson Derek N.
Published: November 2012

Motivation: The coiled coil is a ubiquitous α-helical protein-structure domain that directs and facilitates protein–protein interactions in a wide variety of biological processes. At the protein-sequence level, the coiled coil is readily recognized via a conspicuous heptad repeat of hydrophobic and polar residues. However, structurally coiled coils are more complicated, existing in a wide range of oligomer states and topologies. As a consequence, predicting these various states from sequence remains an unmet challenge.

Results: This work introduces LOGICOIL, the first algorithm to address the problem of predicting multiple coiled-coil oligomeric states from protein-sequence information alone. By covering >90% of the known coiled-coil structures, LOGICOIL is a net improvement compared with other existing methods, which achieve a predictive coverage of ∼31% of this population. This leap in predictive power offers better opportunities for genome-scale analysis, and analyses of coiled-coil containing protein assemblies.

Availability: LOGICOIL is available via a web-interface at http://coiledcoils.chm.bris.ac.uk/LOGICOIL. Source code, training sets and supporting information can be downloaded from the same site.

Contact:  D.N.Woolfson@bristol.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.