bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting low-k zeolite materials
Authors: Poloni Roberta , Kim Jihan
Published: January 2014

The IZA and the hypothetical pure-silica zeolite structures are investigated theoretically to identify optimal dielectric materials for semiconducting device applications.
Protein kinase networks that limit TLR signalling
Authors: Clark Kristopher
Published: January 2014

TLRs (Toll-like receptors) detect invading micro-organisms which triggers the production of pro-inflammatory mediators needed to combat infection. Although these signalling networks are required to protect the host against invading pathogens, dysregulation of TLR pathways contributes to the development of chronic inflammatory diseases and autoimmune disorders. Molecular mechanisms have therefore evolved to restrict the strength of TLR signalling. In the present review, I highlight recent advances in our understanding of the protein kinase networks required to suppress the innate immune response by negatively regulating TLR signalling and/or promoting the secretion of anti-inflammatory cytokines. I present my discoveries on the key roles of the IKK (inhibitor of nuclear factor κB kinase)-related kinases and the SIKs (salt-inducible kinases) in limiting innate immunity within the greater context of the field.
The translational machinery is an optimized molecular network that affects cellular homoeostasis and disease
Authors: Kazana Eleanna , von der Haar Tobias
Published: January 2014

Translation involves interactions between mRNAs, ribosomes, tRNAs and a host of translation factors. Emerging evidence on the eukaryotic translational machinery indicates that these factors are organized in a highly optimized network, in which the levels of the different factors are finely matched to each other. This optimal factor network is essential for producing proteomes that result in optimal fitness, and perturbations to the optimal network that significantly affect translational activity therefore result in non-optimal proteomes, fitness losses and disease. On the other hand, experimental evidence indicates that translation and cell growth are relatively robust to perturbations, and viability can be maintained even upon significant damage to individual translation factors. How the eukaryotic translational machinery is optimized, and how it can maintain optimization in the face of changing internal parameters, are open questions relevant to the interaction between translation and cellular disease states.
NF-κB and the cell cycle
Authors: Ledoux Adeline C. , Perkins Neil D.
Published: January 2014

The NF-κB (nuclear factor κB) transcription factor family is a pleiotropic regulator of many cellular pathways, providing a mechanism for the cell to respond to a wide variety of stimuli and environmental challenges. It is not surprising therefore that an important component of NF-κB's function includes regulation of the cell cycle. However, this aspect of its behaviour is often overlooked and receives less attention than its ability to induce inflammatory gene expression. In the present article, we provide an updated review of the current state of our knowledge about integration of NF-κB activity with cell cycle regulation, including newly characterized direct and indirect target genes in addition to the mechanisms through which NF-κB itself can be regulated by the cell cycle.
Regulating the level of intracellular hydrogen peroxide: the role of peroxiredoxin IV
Authors: Martin Rachel E. , Cao Zhenbo , Bulleid Neil J.
Published: January 2014

Hydrogen peroxide (H2O2) can act as a signalling molecule affecting the cell cycle as well as contributing towards the oxidative stress response. The primary target of this molecule is oxidation-sensitive cysteine residues in proteins such as protein tyrosine phosphatases. The cell has robust mechanisms to remove H2O2 that need to be regulated for H2O2 to react with and modify protein thiols. In particular, the family of peroxiredoxins are capable of the rapid removal of even trace amounts of this molecule. It has been suggested that the inactivation of peroxiredoxins by hyperoxidation may allow H2O2 levels to increase in cells and thereby modify critical thiol groups in proteins. We have been studying how the H2O2 produced during disulfide formation in the ER (endoplasmic reticulum) is metabolized and have shown that ER-resident peroxiredoxin IV not only can remove H2O2, but also contributes to de novo disulfide formation. In the present article, we review recent data on the structure and function of this enzyme as well as its sensitivity to hyperoxidation.
PARP inhibitors for anticancer therapy
Authors: Curtin Nicola
Published: January 2014

PARP-1 [poly(ADP-ribose) polymerase-1], which plays a key role in DNA repair, was discovered 50 years ago. PARPi (PARP inhibitors), originally made to probe the function of the enzyme, inhibit DNA repair and increase the potency of anticancer cytotoxic agents. PARPi of increasing potency were developed as chemo- and radio-sensitizers and first entered clinical trial in cancer patients in 2003. However, it was the revelation in 2005 that they were synthetically lethal in cells with DNA repair defects, found almost exclusively in some tumours, that led to a major interest in this class of drug. Several PARPi have entered clinical trials and show promising activity in breast, ovarian and other cancers associated with BRCA (breast cancer early-onset) mutations or other defects in homologous recombination DNA repair. It is likely that at least one of these will be licensed soon. The present review describes key events from the discovery to clinical application of PARPi.
New strategies for the treatment of ovarian cancer
Authors: Robinson Elizabeth , Fisher Natalie , Stamelos Vasileios , Redman Charles , Richardson Alan
Published: January 2014

Ovarian cancer usually responds well to chemotherapy, but once the disease becomes resistant to chemotherapy, the treatment options available are inadequate. A number of strategies are currently undergoing clinical evaluation, among which angiogenesis and PARP [poly(ADP-ribose) polymerase] inhibitors appear promising. Pre-clinical studies have identified several potential new therapeutic strategies, and we review the potential for use of BH3 (Bcl-2 homology) mimetics, autotaxin inhibitors and statins to treat ovarian cancer.
Structural organization of signalling to and from IP3 receptors
Authors: Taylor Colin W. , Tovey Stephen C. , Rossi Ana M. , Lopez Sanjurjo Cristina I. , Prole David L. , Rahman Taufiq
Published: January 2014

In the 30 years since IP3 (inositol 1,4,5-trisphosphate) was first shown to release Ca2+ from intracellular stores, the importance of spatially organized interactions within IP3-regulated signalling pathways has been universally recognized. Recent evidence that addresses three different levels of the structural determinants of IP3-evoked Ca2+ signalling is described in the present review. High-resolution structures of the N-terminal region of the IP3R (IP3 receptor) have established that the two essential phosphate groups of IP3 bind to opposite sides of the IP3-binding site, pulling its two domains together. This conformational change is proposed to disrupt an interaction between adjacent subunits within the tetrameric IP3R that normally holds the channel in a closed state. Similar structural changes are thought to allow gating of ryanodine receptors. cAMP increases the sensitivity of IP3Rs and thereby potentiates the Ca2+ signals evoked by receptors that stimulate IP3 formation. We speculate that both IP3 and cAMP are delivered to IP3Rs within signalling junctions, wherein the associated IP3Rs are exposed to a saturating concentration of either messenger. The concentration-dependent effects of extracellular stimuli come from recruitment of junctions rather than from a graded increase in the activity of individual junctions. IP3Rs within ‘IP3 junctions’ respond directly to receptors that stimulate phospholipase C, whereas extra-junctional IP3Rs are exposed to suboptimal concentrations of IP3 and open only when they are sensitized by cAMP. These results highlight the importance of selective delivery of diffusible messengers to IP3Rs. The spatial organization of IP3Rs also allows them to direct Ca2+ to specific intracellular targets that include other IP3Rs, mitochondria and Ca2+-regulated channels and enzymes. IP3Rs also interact functionally with lysosomes because Ca2+ released by IP3Rs, but not that entering cells via store-operated Ca2+ entry pathways, is selectively accumulated by lysosomes. This Ca2+ uptake shapes the Ca2+ signals evoked by IP3 and it may regulate lysosomal behaviour.
Rho GTPase–phosphatidylinositol phosphate interplay in fungal cell polarity
Authors: Arkowitz Robert A. , Bassilana Martine
Published: January 2014

Rho G-proteins and phosphatidylinositol phosphates, which are important for exocytosis, endocytosis and cytoskeleton organization, are key regulators of polarized growth in a range of organisms. The aim of the present brief review is to highlight recent findings and their implications with respect to the functions and interplay between Rho G-proteins and phosphatidylinositol phosphates in highly polarized fungal filamentous growth.
Structure and function of RLIP76 (RalBP1): an intersection point between Ras and Rho signalling
Authors: Mott Helen R. , Owen Darerca
Published: January 2014

RLIP76 (Ral-interacting protein of 76 kDa) [also known as RalBP1 (Ral-binding protein 1)] is an effector for the Ral family small GTPases. RLIP76 has been implicated in a number of cell processes, including receptor-mediated endocytosis, cell migration, mitochondrial division and metabolite transport. RLIP76 has two recognizable domains in the centre of the protein sequence: a GAP (GTPase-activating protein) domain for the Rho family G-proteins and an RBD (Ral-binding domain). The remainder of RLIP76 has no discernable homology with other proteins. The RBD forms a simple coiled-coil of two α-helices, which interacts with RalB by binding to both of the nucleotide-sensitive ‘switch’ regions. Both of these RLIP76 helices are involved in the interaction with Ral, but the interhelix loop is left free. This is the location of one of the two ATP-binding sites that have been identified in RLIP76 and suggests that Ral interaction would not prevent ATP binding. The structure of the RhoGAP–RBD dyad shows that the two domains are fixed in their orientation by a relatively rigid linker. This domain arrangement allows the two domains to engage Rho family and Ral small G-proteins simultaneously at the membrane. This suggests that RLIP76 is a node for Rho and Ras family signalling.
AMPK: a cellular energy sensor primarily regulated by AMP
Authors: Gowans Graeme J. , Hardie D. Grahame
Published: January 2014

AMPK (AMP-activated protein kinase) is a cellular energy sensor that monitors the ratio of AMP/ATP, and possibly also ADP/ATP, inside cells. Once activated by falling cellular energy levels, it acts to restore energy homoeostasis by switching on catabolic pathways that generate ATP, while switching off anabolic pathways and other processes consuming ATP. AMPK is switched on by increases in AMP via three mechanisms, all of which are antagonized by ATP: (i) promotion of phosphorylation of Thr172 by upstream activating kinases; (ii) inhibition of dephosphorylation of Thr172 by phosphatases; and (iii) allosteric activation of the phosphorylated kinase. Recently, it has been proposed that the first two mechanisms are also triggered by ADP, which might be the physiological signal rather than AMP, and that the third mechanism may not be physiologically significant. We have re-evaluated these questions, and found that only mechanism (ii) is mimicked by ADP, and that ADP is also less potent than AMP, which we still believe to be the primary signal. We have also provided evidence that mechanism (iii), i.e. allosteric activation by AMP, is a quantitatively significant mechanism in intact cells.
cAMP signalling in the vasculature: the role of Epac (exchange protein directly activated by cAMP)
Authors: Roberts Owain Llŷr , Dart Caroline
Published: January 2014

The second messenger cAMP plays a central role in mediating vascular smooth muscle relaxation in response to vasoactive transmitters and in strengthening endothelial cell–cell junctions that regulate the movement of solutes, cells and macromolecules between the blood and the surrounding tissue. The vasculature expresses three cAMP effector proteins: PKA (protein kinase A), CNG (cyclic-nucleotide-gated) ion channels, and the most recently discovered Epacs (exchange proteins directly activated by cAMP). Epacs are a family of GEFs (guanine-nucleotide-exchange factors) for the small Ras-related GTPases Rap1 and Rap2, and are being increasingly implicated as important mediators of cAMP signalling, both in their own right and in parallel with the prototypical cAMP target PKA. In the present paper, we review what is currently known about the role of Epac within blood vessels, particularly with regard to the regulation of vascular tone, endothelial barrier function and inflammation.
Structure, function and inhibition of the phosphoinositide 3-kinase p110α enzyme
Authors: Flanagan Jack U. , Shepherd Peter R.
Published: January 2014

The PI3K (phosphoinositide 3-kinase) p110α isoform is activated by oncogenic mutations in many cancers. This has stimulated intense interest in identifying inhibitors of the PI3K pathway as well as p110α-selective inhibitors, and understanding the mechanisms underlying activation by the oncogenic mutations. In the present article, we review recent progress in the structure and function of the p110α enzyme and two of its most common oncogenic mutations, the development of isoform-selective inhibitors, and p110α pharmacology.
Explorations of time and electrochemical potential: opportunities for fresh perspectives on signalling proteins
Authors: Butt Julea N.
Published: January 2014

Apoptosis is triggered by an accumulation of ROS (reactive oxygen species) produced by proteins of the mitochondrial respiratory chain. The levels of ROS are controlled by the activities of mitochondrial redox proteins such as glutaredoxin 2 that help to modulate the susceptibility of a cell to apoptosis. However, once downstream events have resulted in the release of cytochrome c to the cytosol, it is widely considered that cell death is inevitable. Cytochrome c may promote its own release from mitochondria through interactions with the mitochondrial phospholipid cardiolipin (diphosphatidylglycerol). In the present article, spectroelectrochemistry of the cardiolipin complex of cytochrome c and protein film electrochemistry of glutaredoxin 2 are reviewed to illustrate how electrochemical methods provide insight into the properties of signalling proteins.
Allosteric linkers in cAMP signalling
Authors: Akimoto Madoka , Moleschi Kody , Boulton Stephen , VanSchouwen Bryan , Selvaratnam Rajeevan , Taylor Susan S. , Melacini Giuseppe
Published: January 2014

Weak interactions mediated by dynamic linkers are key determinants of allosteric regulation in multidomain signalling proteins. However, the mechanisms of linker-dependent control have remained largely elusive. In the present article, we review an allosteric model introduced recently to explain how signalling proteins effectively sense and respond to weak interactions, such as those elicited by flexible linkers flanking globular domains. Central to this model is the idea that near degeneracy within the free energy landscape of conformational selection maximally amplifies the response to weak (~2RT), but conformation-selective interactions. The model was tested as proof of principle using the prototypical regulatory subunit (R) of protein kinase A and led to the unanticipated finding that dynamic linkers control kinase activation and inhibition by tuning the inhibitory pre-equilibrium of a minimally populated intermediate (apo R). A practical implication of the proposed model is a new strategy to design kinase inhibitors with enhanced potency through frustration-relieving mutations.
Dynamics of ezrin and EBP50 in regulating microvilli on the apical aspect of epithelial cells
Authors: Viswanatha Raghuvir , Bretscher Anthony , Garbett Damien
Published: January 2014

Microvilli are found on the apical surface of epithelial cells. Recent studies on the microvillar proteins ezrin and EBP50 (ezrin/radixin/moesin-binding phosphoprotein of 50 kDa) have revealed both the dynamics and the regulation of microvillar components, and how a dynamic ezrin phosphocycle is necessary to confine microvilli to the apical membrane. In the present review, we first summarize the background to allow us to place these advances in context.
Wideband microstrip rat‐race hybrid with via‐swap phase inverter
Authors: Mung S.W.Y. , Chan W.S.
Published: January 2014

A via‐swap 180° phase inverter on the slotted ground is presented. The phase inverter with a 90° line replaces the conventional 270° line built into the microstrip rat‐race hybrid. This results in a size reduction and the widening of the bandwidth. The experiments show that the proposed hybrid has a good performance from 1.5 to 2.5 GHz (fo = 2 GHz). The bandwidth is increased from 10 to 50% and a 43% size reduction is obtained compared with the conventional rat‐race hybrid.
Saving the Amazon? Sustainable Soy and the New Extractivism
Authors: Baletti Brenda
Published: January 2014

Most ‘progressive’ Latin American governments, which have come to power over the past decade or so, continue to rely on agriculture and resource extraction as the primary generators of wealth. Scholars argue that this ‘neoextractivism’ is made politically possible by directing some profits toward the funding of progressive social programs. The Brazilian Amazon's vast wealth of extractive resources and its large economically depressed population make it the emblematic site for neoextractivism. Its biodiversity and inhabited landscapes, however, mean that the neoextractive program encounters concerted resistance from the global environmental community as well as from traditional, indigenous, and migrant smallholders. In response, neoextractivism must deploy another form of progressivism—environmentalism. The author uses the case of agroindustrial soy production in the Brazilian Amazonian state of Pará to demonstrate how the emergence of environmental governance there facilitates neoextractivism by ‘greening’ it. Through an analysis of the mechanisms and effects of two programs, implemented through partnerships between nongovernmental organizations and corporations, to manage soy expansion into the Amazon, it is demonstrated that these programs have questionable environmental benefits at best and at worst work to reenforce the hegemony of international environmental organizations, to green the image of agri-business multinationals, and to destabilize strategies of resistance.
Estimation of Autoregressive Models with Two Types of Weak Spatial Dependence by Means of the W-Based and the Latent Variables Approach: Evidence from Monte Carlo Simulations
Authors: Liu An , Folmer Henk , Oud Johan H L
Published: January 2014

We evaluate by means of Monte Carlo simulations the W-based spatial autoregressive model and the structural equation model with latent variables (SEM) to handle two types of simultaneously occurring weak spatial dependence: (i) spillover from a hotspot, and (iia) spillover from first-order, queen contiguous neighbours, (iib) inverse-distance-related spatial units, (iic) the first three nearest neighbours. Although it is possible to account for several different types of weak spatial lag dependence by several different weights matrices, the W-based approach usually proceeds on the basis of a single weights matrix that is implicitly assumed to adequately capture all types of spatial dependence. SEM on the other hand has been developed to explicitly distinguish between different types of weak spatial dependence in a model. In addition, whereas conventional higher order spatial econometric models entail specification and parameter space definition problems, SEM spatial dependence models can be routinely specified and estimated. In this paper we briefly discuss the pitfalls of including several types of weak spatial lag dependence (and thus different W matrices) in a standard W-based lag model and how these problems are mitigated by the SEM approach. Furthermore, the single W-based and the SEM approach are compared by means of simulations in terms of bias and root mean squared error (RMSE) for different values of the spatial lag parameters, specifications of the weights matrices, and sample sizes. We also include in the comparison the W-based approach with spatial dependence accounted for by the two weights matrices used to generate the data: That is, the correctly specified model. The simulation results show that compared with the single W-based models, SEM frequently has smaller bias and RMSE. Furthermore, SEM even outperforms the correctly specified W-based models (based on the same two weights matrices used for data generation) in many cases. These trends increase when the values of the spatial lag parameters increase. The dominance of SEM also increases with sample size. Finally, SEM is more stable in terms of both bias and RMSE over various dimensions.
Permeability across a Metropolitan Area: Conceptualizing and Operationalizing a Macrolevel Crime Pattern Theory
Authors: Groff Elizabeth R , Taylor Ralph B , Elesh David B , McGovern Jennifer , Johnson Lallen
Published: January 2014

The intrametropolitan relationship between municipality-level physical environment and crime changes appears to have been overlooked by crime and environment researchers. The current effort focuses on permeability; suggests dynamics whereby permeability affects changing municipality-level crime patterns across a metropolitan area; selects and operationalizes theoretically appropriate permeability indicators; and links permeability to unexpected crime changes. Data are from 355 municipalities in the Philadelphia metropolitan area, and property and violent crime unexpected changes over two change periods are assessed. Three municipality-level indices reflecting internal and boundary permeability are developed that are internally consistent and cross reference in sensible ways with large-scale physical environment features of municipalities. Permeability indicators link as predicted with unexpected violent and property crime changes. This research provides a theoretical and empirical foundation for linking permeability to changing municipality-level crime rates across a metropolitan area.
Overcrowding and ‘Underoccupancy’ in Romania: A Case Study of Housing Inequality
Authors: Soaita Adriana Mihaela
Published: January 2014

This paper examines aspects of space consumption in two very different housing types: The communist mid-rise estates and postcommunist suburban self-built housing. Examining residents' perceptions in order to categorise space as overcrowded or underoccupied, the paper engages critically with the issue of the inefficient distribution of Romanian housing: that is, a considerable mismatch between dwelling and household size. The analysis documents the continued salience of overcrowding in the communist estates and, conversely, self-builders' satisfaction with the generous size of their new homes. Market forces permit various modes of residential mobility, but their likely outcome is growing housing inequality while any redistributive impact will remain insignificant unless policy incentives could facilitate conversion of underoccupied space into (social) renting housing. However, only a sustained delivery of larger and affordable new dwellings could alleviate overcrowding.
Political Ecologies of Electronic Waste: Uncertainty and Legitimacy in the Governance of E-Waste Geographies
Authors: Pickren Graham
Published: January 2014

Geographers broadly, and political ecologists in particular, have been at the forefront of analyzing the progressive linking of Northern consumption practices with livelihoods elsewhere, problematizing the devolution that places ‘citizen-consumers’, NGOs, and corporate actors as key political agents of protecting workers and environments, promoting ‘ethical’ trade, and ‘greening’ economies through their purchasing choices. Utilizing empirical work on the development of certification and labeling schemes designed to ensure the safe recycling of used electronics, or e-wastes, across a global supply chain, this paper extends lessons learned from these critical analyses of consumer politics to ongoing debates about e-waste, trade, and recycling. I highlight the ambiguities and democratic deficits that emerge from promoting global environmental justice politics through market-driven disposal choices. I analyze the practices of representation through which NGOs and institutions produce e-waste as an object of regulation/commodification that is amenable to consumer action and argue that there is a disconnect between the abstractions necessary to sell ‘ethical’ e-waste recycling and the nuances of place-specific recycling practices. Like other fair trade schemes, certifications for ethical electronics recyclers rely upon narratives, such as environmental justice, that construct the e-waste problem in ways that render it governable, or ‘legible’ in Scott's sense. However, given the complexity of global commodity-networks like those for used electronics, these governing narratives rely on abstractions that oversimplify and rework the fetish of what e-waste is, where it goes, and how it should be managed. In unearthing both what labels do as well as the silences and ambiguities embedded within them, the limits and opportunities of consumer-driven waste politics come more clearly into view.
Role of general practice in the utilisation of the NSW Get Healthy Information and Coaching Service
Authors: O'Hara Blythe J. , Phongsavan Philayrath , Rissel Chris , Hardy Louise L. , Zander Alexis , Greenaway Mark , Bauman Adrian E.
Published: January 2014

A lifestyle-modification telephone-based service is delivered in New South Wales (NSW; the Get Healthy Information and Coaching Service (GHS)) as an important obesity-prevention, population-wide program. The present study examined referrals from general practitioners (GP) versus self-referral to the GHS in terms of risk profile and effectiveness of outcomes. The study used a pre–post test design to assess changes in outcomes within the setting of a telephone-based lifestyle-support service available to NSW adults (18+ years) who self-referred or were referred by their health practitioner and/or GP, and registered for the GHS between February 2009 and August 2013 (n = 22 183). The GHS has two service components: (1) the provision of an information kit (one off contact) on healthy eating, being physically active and achieving and/or maintaining a healthy weight; and (2) a 6-month coaching program that includes 10 telephone calls aimed at achieving and maintaining lifestyle-related goals. Sociodemographic characteristics, referral source and self-reported anthropometric (height, waist and waist circumference (WC)) and behavioural risk factor (physical activity and nutrition-related behaviours) data were collected at baseline and at 6 months. Analysis revealed that GPs effectively recruited hard-to-reach subtargets, as well as adults who are obese and have an increased WC risk. Participants in the GHS coaching program, irrespective of GHS referral source, reported a mean weight loss of –3.8 kg, a decrease in WC of –5.0 cm and increases in both fruit and vegetable consumption and physical activity. In conclusion, GPs have an important role in GHS uptake (through proactive referral or as an adjunct to practice-based interventions) because they can recruit those most at need and facilitate improvements in their patients’ risk factor profiles.
Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in
Escherichia coli
Authors: Egloff Pascal , Hillenbrand Matthias , Klenk Christoph , Batyuk Alexander , Heine Philipp , Balada Stefanie , Schlinkmann Karola M. , Scott Daniel J. , Schütz Marco , Plückthun Andreas
Published: January 2014

Significance

Only a tiny fraction (<2%) of the unique structures in the protein database correspond to membrane proteins, and only a few of these are of eukaryotic origin, representing potential drug targets. The difficulties in structure determination of these proteins are due to two specific complications, which are unique for membrane proteins: first, low expression levels and, second, the necessity for detergent micelles, which are often destabilizing as they mimic the hydrophobic membrane environment only poorly. We prove that directed evolution has the potential to overcome these problems by determining several structures of evolved eukaryotic G protein–coupled receptor variants. High functional expression levels and superior receptor stability in harsh detergents allowed us to gain deeper insights into this important receptor family.
EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding
Authors: Robichaux Michael A. , Chenaux George , Ho Hsin-Yi Henry , Soskis Michael J. , Dravis Christopher , Kwan Kenneth Y. , Šestan Nenad , Greenberg Michael Eldon , Henkemeyer Mark , Cowan Christopher W.
Published: January 2014

Significance

In this study, we report a critical role of EphB forward signaling in proper thalamocortical axon guidance. Moreover, our findings provide support for the controversial “handshake hypothesis,” which proposed that cofasciculation of specific thalamic and cortical axons controls proper cortical and thalamic interconnectivity. Finally, growing evidence suggests cortical synaptic connectivity and white matter tract development are abnormal in autism. The recent identification of a de novo
EPHB2
kinase domain mutation in an individual with autism suggests that a deficit in EphB forward signaling might result in abnormal brain wiring and enhanced risk for autism.
Comparing the Obvious: Interactional Characteristics of Staff in Acute Mental Health Nursing and Forensic Psychiatric Nursing
Authors: Gildberg FrederikA. , Bradley StephenK. , Hounsgaard Lise
Published: January 2014

This article reports on and compares two separate studies of the interactional characteristics of forensic mental health staff and acute mental health staff as they interact with inpatients, respectively. Both studies were conducted using participant observation, along with informal and formal interviews. Findings show that both acute and forensic mental health nursing practice is characterized by two overriding themes; ‘trust and relationship-enabling care’ and ‘behavior and perception-corrective care.’ The comparison of the two studies shows no major differences in the characteristics of staff interactions with patients or in the overall meanings ascribed by staff in the different practice settings.
Use of Clove Oil and Eugenol to Anesthetize Fingerling Shabut Barbus grypus
Authors: Öğretmen Fatih , Gölbaşi Selami , Inanan Burak E , Kizak Volkan , Kayim Murathan
Published: January 2014

In this study, the efficacy of four doses of clove oil and eugenol were compared to sedate fingerling Shabut Barbus grypus to various stages of sedation and recovery. The results from the present study indicated that effective concentrations were at 50 μL/L for eugenol (induction time: 58 ± 8 s; recovery time: 199 ± 15 s [mean ± SD]) and clove oil (induction time: 76 ± 6 s; recovery time: 161 ± 34 s). The induction times decreased significantly with the increasing concentrations of clove oil and eugenol, while recovery times increased with increasing concentrations of anesthetic (P < 0.05). Exposure of fish to 75 or 100 μL/L clove oil or to 50, 75, or 100 μL/L eugenol resulted in mean induction times ≤ 1 min. Fish did not become fully sedated within 3 min when treated with 25 μL/L clove oil. Other concentrations of both anesthetics, fish reached to full induction at ≤ 3 min and recovered from anesthesia ≤ 5 min. Our results showed the clove oil and eugenol are effective anesthetics for fingerling Shabut when used at concentrations of 50–100 μL/L.
Effects of Dietary Nutrient Composition on Compensatory Growth of Juvenile Blunt Snout Bream Megalobrama amblycephala
Authors: Lu Kang-Le , Li Xiang-Fei , Wang Li-Na , Zhang Chun-Nuan , Liu Wen-Bin
Published: January 2014

A feeding trial was conducted to evaluate the influences of dietary nutrient composition on the compensatory growth of Blunt Snout Bream Megalobrama amblycephala. Three diets were tested: a control, a high-protein (HP), and a high-protein and carbohydrate (HPC) diet. Each of the three diets was fed to Blunt Snout Bream (initially weight, 24 ± 0.50 g) for 60 d using either satiation feeding (in which fish were fed daily) or restricted feeding (no feeding for 3 d followed by feeding for the next 12 d). The weight gain of fish fed the HP and HPC diets was significantly higher than that of fish fed the control diet. In addition, restricted feeding led to significantly less weight gain than daily feeding with the control and HP diets. However, there was no significant difference between the two feeding regimes in the weight gain of fish fed the HPC diet. The feed conversion ratio of fish fed the control diet was significantly higher than that of fish fed the HP and HPC diets. Moreover, the ratio was significantly lower with restricted feeding than with satiation feeding. Whole-body composition was not significantly different among treatments. Fish subjected to the restricted feeding regime had an elevated hepatosomatic index compared with fish fed to satiation. On the whole, the HPC diet could improve the compensatory growth of fish without altering their whole-body composition, and compensatory growth has the advantage of improving feed efficiency and nutrient retention.
Optimizing Soybean Meal Levels in Alternative Diets for Pond-Raised Hybrid Catfish
Authors: Li Menghe H , Robinson Edwin H , Bosworth Brian G , Oberle Daniel F , Lucas Penelope M
Published: January 2014

We evaluated decreasing soybean meal levels by the use of a combination of cottonseed meal and corn germ meal for pond-raised hybrid catfish (Channel Catfish Ictalurus punctatus×Blue Catfish I. furcatus). Five 28% protein diets containing 40, 30, 25, 20, 15% of soybean meal were formulated based on digestible nutrients and energy to meet or exceed all known nutrient requirements of Channel Catfish. Fingerling hybrid catfish with a mean initial weight of 25.1 g/fish were stocked into 25, earthen ponds (0.04 ha) at a rate of 14,826 fish/ha. Fish were fed once daily to apparent satiation over a 184-d growing season. Reducing soybean meal levels from 40% to 15% in the diet by the use of a combination of cottonseed meal and corn germ meal did not significantly affect total amount of diet fed, gross yield, weight gain, and survival of hybrid catfish by ANOVA or regression analyses. However, feed conversion ratio was significantly higher in fish fed diets containing ≤30% soybean meal than those fed the control diet (40% soybean meal) and feed conversion ratio increased linearly as soybean meal levels decreased. Hybrid catfish fed diets containing 20% and 15% soybean meal had significantly lower carcass yield than fish fed the control diet. Fish fed the diet containing 15% soybean meal also had significantly lower fillet yield. Regression analyses show that both carcass and fillet yields decreased linearly with decreasing soybean meal levels in the diet. No significant differences were observed for fillet protein, fat, and moisture levels among fish fed the diets containing various levels of soybean meal. A 28% protein diet containing 25% soybean meal appears to support maximum growth of hybrid catfish without marked impact on feed conversion ratio and processed yield.
Economic Feasibility of an In-Pond Raceway System for Commercial Catfish Production in West Alabama
Authors: Brown Travis W , Hanson Terrill R , Chappell Jesse A , Boyd Claude E , Wilson Dean S
Published: January 2014

Our objective was to improve profitability of catfish farming by demonstrating methods to achieve high levels of survival, feed performance, and efficiency in a commercial farm setting. During 2007, a commercial-scale in-pond raceway system (IPRS) was constructed in a 6.0-acre earthen pond on a catfish farm in west Alabama. The IPRS consisted of six raceways, each stocked with uniform-sized Channel Catfish Ictalurus punctatus or hybrid catfish (Channel Catfish × Blue Catfish I. furcatus). Co-cultured fish species (Paddlefish Polyodon spathula and Nile Tilapia Oreochromis niloticus) were stocked and harvested in the outside area of the pond containing the IPRS. Results from the 2008 production season were used to project 12 months of production from stocking either Channel Catfish or hybrid catfish in the IPRS. In addition, Channel Catfish production in traditional ponds was monitored from 2005 to 2009 on the same farm (∼430 water-acres). The 8-month IPRS results were compared with (1) the 12-month average production from the traditional farm and (2) the 12-month projected production in the IPRS. Variable and fixed costs to produce catfish were US0.71 and 0.14 per pound, respectively, in the IPRS during the 8-month study; 0.78 and 0.05 per pound for the 12-month average performance of the traditional farm; 0.74 and 0.19 per pound for 12-month projected Channel Catfish production; and 0.64 and 0.11 per pound for 12-month projected hybrid catfish production. Income above variable costs and net returns to land from using the IPRS increased when co-cultured species were included in the economic analysis. Our results showed that the IPRS can be efficient at producing catfish and co-cultured species, although the energy input per pound was greater than that for the traditional farm. Additional studies using the IPRS for fish production are underway to verify our initial research results.
The depletion of F1subunit ε in yeast leads to an uncoupled respiratory phenotype that is rescued by mutations in the proton-translocating subunits of F0
Authors: Tetaud Emmanuel , Godard François , Giraud Marie-France , Ackerman Sharon H. , di Rago Jean-Paul
Published: January 2014

The central stalk of the ATP synthase is an elongated hetero-oligomeric structure providing a physical connection between the catalytic sites in F1and the proton translocation channel in F0for energy transduction between the two subdomains. The shape of the central stalk and relevance to energy coupling are essentially the same in ATP synthases from all forms of life, yet the protein composition of this domain changed during evolution of the mitochondrial enzyme from a two- to a three-subunit structure (γ, δ, ε). Whereas the mitochondrial γ- and δ-subunits are homologues of the bacterial central stalk proteins, the deliberate addition of subunit ε is poorly understood. Here we report that down-regulation of the gene (ATP15) encoding the ε-subunit rapidly leads to lethal F0-mediated proton leaks through the membrane because of the loss of stability of the ATP synthase. The ε-subunit is thus essential for oxidative phosphorylation. Moreover, mutations in F0subunits a and c, which slow the proton translocation rate, are identified that prevent ε-deficient ATP synthases from dissipating the electrochemical potential. Cumulatively our data lead us to propose that the ε-subunit evolved to permit operation of the central stalk under the torque imposed at the normal speed of proton movement through mitochondrial F0.
Borg5 is required for angiogenesis by regulating persistent directional migration of the cardiac microvascular endothelial cells
Authors: Liu Zhonghua , Vong Queenie P. , Liu Chengyu , Zheng Yixian
Published: January 2014

The microvasculature is important for vertebrate organ development and homeostasis. However, the molecular mechanism of microvascular angiogenesis remains incompletely understood. Through studying Borg5 (Binder of the Rho GTPase 5), which belongs to a family of poorly understood effector proteins of the Cdc42 GTPase, we uncover a role for Borg5 in microvascular angiogenesis. Deletion of Borg5 in mice results in defects in retinal and cardiac microvasculature as well as heart development. Borg5 promotes angiogenesis by regulating persistent directional migration of the endothelial cells (ECs). In primary mouse cardiac ECs (MCECs), Borg5 associates with septins in the perinuclear region and colocalizes with actomyosin fibers. Both Borg5 deletion and septin 7 knockdown lead to a disruption of the perinuclear actomyosin and persistent directional migration. Our findings suggest that Borg5 and septin cytoskeleton spatially control actomyosin activity to ensure persistent directional migration of MCECs and efficient microvascular angiogenesis. Our studies reported here should offer a new avenue to further investigate the functions of Borg5, septin, and actomyosin in the microvasculature in the context of development and disease.
Mitotic regulation of fungal cell-to-cell connectivity through septal pores involves the NIMA kinase
Authors: Shen Kuo-Fang , Osmani Aysha H. , Govindaraghavan Meera , Osmani Stephen A.
Published: January 2014

Intercellular bridges are a conserved feature of multicellular organisms. In multicellular fungi, cells are connected directly via intercellular bridges called septal pores. Using Aspergillus nidulans, we demonstrate for the first time that septal pores are regulated to be opened during interphase but closed during mitosis. Septal pore–associated proteins display dynamic cell cycle–regulated locations at mature septa. Of importance, the mitotic NIMA kinase locates to forming septa and surprisingly then remains at septa throughout interphase. However, during mitosis, when NIMA transiently locates to nuclei to promote mitosis, its levels at septa drop. A model is proposed in which NIMA helps keep septal pores open during interphase and then closed when it is removed from them during mitosis. In support of this hypothesis, NIMA inactivation is shown to promote interphase septal pore closing. Because NIMA triggers nuclear pore complex opening during mitosis, our findings suggest that common cell cycle regulatory mechanisms might control septal pores and nuclear pores such that they are opened and closed out of phase to each other during cell cycle progression. The study provides insights into how and why cytoplasmically connected Aspergillus cells maintain mitotic autonomy.
h5vc: scalable nucleotide tallies with HDF5
Authors: Pyl Paul Theodor , Gehring Julian , Fischer Bernd , Huber Wolfgang
Published: January 2014

Summary: As applications of genome sequencing, including exomes and whole genomes, are expanding, there is a need for analysis tools that are scalable to large sets of samples and/or ultra-deep coverage. Many current tool chains are based on the widely used file formats BAM and VCF or VCF-derivatives. However, for some desirable analyses, data management with these formats creates substantial implementation overhead, and much time is spent parsing files and collating data. We observe that a tally data structure, i.e. the table of counts of nucleotides × samples × strands × genomic positions, provides a reasonable intermediate level of abstraction for many genomics analyses, including single nucleotide variant (SNV) and InDel calling, copy-number estimation and mutation spectrum analysis. Here we present h5vc, a data structure and associated software for managing tallies. The software contains functionality for creating tallies from BAM files, flexible and scalable data visualization, data quality assessment, computing statistics relevant to variant calling and other applications. Through the simplicity of its API, we envision making low-level analysis of large sets of genome sequencing data accessible to a wider range of researchers.

Availability and implementation: The package h5vc for the statistical environment R is available through the Bioconductor project. The HDF5 system is used as the core of our implementation.

Contact:  pyl@embl.de or whuber@embl.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data
Authors: Bollen Sander , Leddin Mathias , Andrade-Navarro Miguel A. , Mah Nancy
Published: January 2014

Summary: The current methods available to detect chromosomal abnormalities from DNA microarray expression data are cumbersome and inflexible. CAFE has been developed to alleviate these issues. It is implemented as an R package that analyzes Affymetrix *.CEL files and comes with flexible plotting functions, easing visualization of chromosomal abnormalities.

Availability and implementation: CAFE is available from https://bitbucket.org/cob87icW6z/cafe/ as both source and compiled packages for Linux and Windows. It is released under the GPL version 3 license. CAFE will also be freely available from Bioconductor.

Contact:  sander.h.bollen@gmail.com or nancy.mah@mdc-berlin.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Reference-free cell mixture adjustments in analysis of DNA methylation data
Authors: Houseman Eugene Andres , Molitor John , Marsit Carmen J.
Published: January 2014

Motivation: Recently there has been increasing interest in the effects of cell mixture on the measurement of DNA methylation, specifically the extent to which small perturbations in cell mixture proportions can register as changes in DNA methylation. A recently published set of statistical methods exploits this association to infer changes in cell mixture proportions, and these methods are presently being applied to adjust for cell mixture effect in the context of epigenome-wide association studies. However, these adjustments require the existence of reference datasets, which may be laborious or expensive to collect. For some tissues such as placenta, saliva, adipose or tumor tissue, the relevant underlying cell types may not be known.

Results: We propose a method for conducting epigenome-wide association studies analysis when a reference dataset is unavailable, including a bootstrap method for estimating standard errors. We demonstrate via simulation study and several real data analyses that our proposed method can perform as well as or better than methods that make explicit use of reference datasets. In particular, it may adjust for detailed cell type differences that may be unavailable even in existing reference datasets.

Availability and implementation: Software is available in the R package RefFreeEWAS. Data for three of four examples were obtained from Gene Expression Omnibus (GEO), accession numbers GSE37008, GSE42861 and GSE30601, while reference data were obtained from GEO accession number GSE39981.

Contact:  andres.houseman@oregonstate.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies
Authors: Stamatakis Alexandros
Published: January 2014

Motivation: Phylogenies are increasingly used in all fields of medical and biological research. Moreover, because of the next-generation sequencing revolution, datasets used for conducting phylogenetic analyses grow at an unprecedented pace. RAxML (Randomized Axelerated Maximum Likelihood) is a popular program for phylogenetic analyses of large datasets under maximum likelihood. Since the last RAxML paper in 2006, it has been continuously maintained and extended to accommodate the increasingly growing input datasets and to serve the needs of the user community.

Results: I present some of the most notable new features and extensions of RAxML, such as a substantial extension of substitution models and supported data types, the introduction of SSE3, AVX and AVX2 vector intrinsics, techniques for reducing the memory requirements of the code and a plethora of operations for conducting post-analyses on sets of trees. In addition, an up-to-date 50-page user manual covering all new RAxML options is available.

Availability and implementation: The code is available under GNU GPL at https://github.com/stamatak/standard-RAxML.

Contact:  alexandros.stamatakis@h-its.org

Supplementary information:  Supplementary data are available at Bioinformatics online.