bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated Training for Aphasia: An Application of Part–Whole Learning to Treat Lexical Retrieval, Sentence Production, and Discourse-Level Communications in Three Cases of Nonfluent Aphasia
Authors: Milman Lisa , Vega-Mendoza Mariana , Clendenen Deanna
Published: March 2014

Purpose

The purpose of this study was to evaluate integrated training for aphasia (ITA), a multicomponent language-production treatment based on part–whole learning that systematically trains lexical retrieval, sentence production, and discourse-level communications. Specific research objectives were to evaluate acquisition of target structures, statistical parameters associated with learning variables, treatment generalization, and the efficacy of individual treatment components.

Method

ITA was administered to 3 individuals with nonfluent aphasia following a multiple-baseline, across-behaviors design. Effect size and correlational coefficients were computed to assess acquisition, generalization, and maintenance of target structures. Standardized tests and a treatment efficacy questionnaire were also completed.

Results

A significant treatment effect was found in 2 of the 3 participants. In addition, as is seen in normal skill acquisition, practice time and error rate were significantly correlated. All participants demonstrated evidence of generalization on standardized language measures. Only 1 participant improved, however, on the communication measures. Results of the treatment component analysis revealed significant differences in the perceived efficacy of individual therapy tasks.

Conclusions

Findings add to the evidence supporting multicomponent aphasia treatments, provide preliminary support for ITA and the application of a part–whole learning approach, and suggest that specific treatment components may contribute differentially to outcomes and generalization effects.

Supplemental Material

https://doi.org/10.23641/asha.6170210
Reconstruction of Irradiated Mandible after Segmental Resection of Osteoradionecrosis—A Technique Employing a Microvascular Latissimus Dorsi Flap and Subsequent Particulate Iliac Bone Grafting
Authors: Hillerup Soren , Elberg JensJorgen , Thorn JensJorgen , Andersen Mikael
Published: March 2014

The fibula osteocutaneous flap has revolutionized the options of mandibular segmental defect bridging in osteoradionecrosis (ORN). In selected cases, however, the fibula flap is not an option because of atherosclerosis or other features that compromise the vascularity of the lower leg and foot. The aim of this study is to present an alternative method of mandibular segmental reconstruction employing a latissimus dorsi (LD) flap and subsequent particulate iliac free bone graft reconstruction. In 15 patients with ORN, a mandibular segmental defect was bridged with a reconstruction plate, and the defect site was primed with a LD musculocutaneous flap wrapped around the reconstruction plate to bring in vascularized tissue and optimize healing conditions for a subsequent particulate iliac free bone graft reconstruction. The management of defect closure was successful in all 15 patients. Twelve patients had a subsequent bone grafting from the posterior ileum for repair of defects up to 14 cm length. Three patients had no bone graft for various reasons. In three patients dental rehabilitation was achieved with implant supported prosthodontic appliances. Ten patients met the success criteria of uneventful graft healing with restitution of osseous continuity, mandibular height, symmetry and function, and avoidance of reconstruction plate fracture.
Investigation of on-current degradation behavior induced by surface hydrolysis effect under negative gate bias stress in amorphous InGaZnO thin-film transistors
Authors: Liu Kuan-Hsien , Chang Ting-Chang , Chang Kuan-Chang , Tsai Tsung-Ming , Hsieh Tien-Yu , Chen Min-Chen , Yeh Bo-Liang , Chou Wu-Ching
Published: March 2014

This study investigates the electrical instability under negative gate bias stress (NGBS) induced by surface hydrolysis effect. Electrical characteristics exhibit instability for amorphous InGaZnO (a-IGZO) Thin Film Transistors (TFTs) under NGBS, in which on-current degradation and current crowding phenomenon can be observed. When the negative gate bias is applied on the TFT, hydrogen ions will dissociate from ZnO-H bonds and the dissociated hydrogen ions will cause electrical instability under NGBS. The ISE-Technology Computer Aided Design simulation tool and moisture partial pressure modulation measurement are utilized to clarify the anomalous degradation behavior.
Spatiotemporal focusing dynamics in plasmas at X-ray wavelength
Authors: Sharma A. , Tibai Z. , Hebling J. , Mishra S. K.
Published: March 2014

Using a finite curvature beam, we investigate here the spatiotemporal focusing dynamics of a laser pulse in plasmas at X-ray wavelength. We trace the dependence of curvature parameter on the focusing of laser pulse and recognize that the self-focusing in plasma is more intense for the X-ray laser pulse with curved wavefront than with flat wavefront. The simulation results demonstrate that spatiotemporal focusing dynamics in plasmas can be controlled with the appropriate choice of beam-plasma parameters to explore the high intensity effects in X-ray regime.
Getting a grip on the transverse motion in a Zeeman decelerator
Authors: Dulitz Katrin , Motsch Michael , Vanhaecke Nicolas , Softley Timothy P.
Published: March 2014

Zeeman deceleration is an experimental technique in which inhomogeneous, time-dependent magnetic fields generated inside an array of solenoid coils are used to manipulate the velocity of a supersonic beam. A 12-stage Zeeman decelerator has been built and characterized using hydrogen atoms as a test system. The instrument has several original features including the possibility to replace each deceleration coil individually. In this article, we give a detailed description of the experimental setup, and illustrate its performance. We demonstrate that the overall acceptance in a Zeeman decelerator can be significantly increased with only minor changes to the setup itself. This is achieved by applying a rather low, anti-parallel magnetic field in one of the solenoid coils that forms a temporally varying quadrupole field, and improves particle confinement in the transverse direction. The results are reproduced by three-dimensional numerical particle trajectory simulations thus allowing for a rigorous analysis of the experimental data. The findings suggest the use of a modified coil configuration to improve transverse focusing during the deceleration process.
Effect of impingement surface roughness on the noise from impinging jets
Authors: Dhamanekar Abhijit , Srinivasan K.
Published: March 2014

This paper presents extensive acoustic measurements on jets impinging on surfaces of various surface roughness values. Besides surface roughness, the effects of nozzle-to-plate spacing distance and nozzle pressure ratio are also investigated. Turbulent mixing noise and tonal noise are explained using far-field wall-jet velocity and impingement region temperature fields. The results demonstrate that roughness of the impingement plate widens the staging region of impingement noise. In general, high speed jet impinging on a rough plate generates less noise compared to a smooth plate. When tones are removed from the spectra, it is found that acoustic power monotonically decreases with increasing surface roughness. Thermal imaging in the stagnation region indicates that whenever tones are present, the temperature at the stagnation region is high. Further, sound pressure directivity pattern of impingement noise is constructed by superimposing a wall-jet and a free jet in the appropriate orientations.
Elasticity of a soap film junction
Authors: Elias F. , Janiaud E. , Bacri J.-C. , Andreotti B.
Published: March 2014

We investigate the elasticity of an isolated, threefold junction of soap films (Plateau border), which displays static undulations when liquid rapidly flows into it. By analyzing the shape of the Plateau border (thickness R and transverse displacement) as a function of the liquid flow rate Q, we show experimentally and theoretically that the elasticity of the Plateau border is dominated by the bending of the soap films pulling on the Plateau border. In this asymptotic regime, the undulation wavelength obeys the scaling law ∼Q2 R−2 and the decay length ∼Q2 R−4.
Electrostatics of proteins in dielectric solvent continua. II. Hamiltonian reaction field dynamics
Authors: Bauer Sebastian , Tavan Paul , Mathias Gerald
Published: March 2014

In Paper I of this work [S. Bauer, G. Mathias, and P. Tavan, J. Chem. Phys. 140, 104102 (2014)] we have presented a reaction field (RF) method, which accurately solves the Poisson equation for proteins embedded in dielectric solvent continua at a computational effort comparable to that of polarizable molecular mechanics (MM) force fields. Building upon these results, here we suggest a method for linearly scaling Hamiltonian RF/MM molecular dynamics (MD) simulations, which we call “Hamiltonian dielectric solvent” (HADES). First, we derive analytical expressions for the RF forces acting on the solute atoms. These forces properly account for all those conditions, which have to be self-consistently fulfilled by RF quantities introduced in Paper I. Next we provide details on the implementation, i.e., we show how our RF approach is combined with a fast multipole method and how the self-consistency iterations are accelerated by the use of the so-called direct inversion in the iterative subspace. Finally we demonstrate that the method and its implementation enable Hamiltonian, i.e., energy and momentum conserving HADES-MD, and compare in a sample application on Ac-Ala-NHMe the HADES-MD free energy landscape at 300 K with that obtained in Paper I by scanning of configurations and with one obtained from an explicit solvent simulation.
Femtosecond laser ablation dynamics of fused silica extracted from oscillation of time-resolved reflectivity
Authors: Kumada Takayuki , Akagi Hiroshi , Itakura Ryuji , Otobe Tomohito , Yokoyama Atsushi
Published: March 2014

Femtosecond laser ablation dynamics of fused silica is examined via time-resolved reflectivity measurements. After optical breakdown was caused by irradiation of a pump pulse with fluence Fpump = 3.3–14.9 J/cm2, the reflectivity oscillated with a period of 63 ± 2 ps for a wavelength λ = 795 nm. The period was reduced by half for λ = 398 nm. We ascribe the oscillation to the interference between the probe pulses reflected from the front and rear surfaces of the photo-excited molten fused silica layer. The time-resolved reflectivity agrees closely with a model comprising a photo-excited layer which expands due to the formation of voids, and then separates into two parts, one of which is left on the sample surface and the other separated as a molten thin layer from the surface by the spallation mechanism. Such oscillations were not observed in the reflectivity of soda-lime glass. Whether the reflectivity oscillates or not probably depends on the layer viscosity while in a molten state. Since viscosity of the molten fused silica is several orders of magnitude higher than that of the soda-lime glass at the same temperature, fused silica forms a molten thin layer that reflects the probe pulse, whereas the soda-lime glass is fragmented into clusters.
Experimental evidence of intermittent chaos in a glow discharge plasma without external forcing and its numerical modelling
Authors: Ghosh S. , Kumar Shaw Pankaj , Sekar Iyengar A. N. , Janaki M. S. , Saha Debajyoti , Michael Wharton Alpha , Mitra Vramori
Published: March 2014

Intermittent chaos was observed in a glow discharge plasma as the system evolved from regular type of relaxation oscillations (of larger amplitude) to an irregular type of oscillations (of smaller amplitude) as the discharge voltage was increased. Floating potential fluctuations were analyzed by different statistical and spectral methods. Features like a gradual change in the normal variance of the interpeak time intervals, a dip in the skewness, and a hump in the kurtosis with variation in the control parameter have been seen, which are strongly indicative of intermittent behavior in the system. Detailed analysis also suggests that the intrinsic noise level in the experiment increases with the increasing discharge voltage. An attempt has been made to model the experimental observations by a second order nonlinear ordinary differential equation derived from the fluid equations for an unmagnetized plasma. Though the experiment had no external forcing, it was conjectured that the intrinsic noise in the experiment could be playing a vital role in the dynamics of the system. Hence, a constant bias and noise as forcing terms were included in the model. Results from the theoretical model are in close qualitative agreement with the experimental results.
Low-frequency spatial wave manipulation via phononic crystals with relaxed cell symmetry
Authors: Celli Paolo , Gonella Stefano
Published: March 2014

Phononic crystals enjoy unique wave manipulation capabilities enabled by their periodic topologies. On one hand, they feature frequency-dependent directivity, which allows directional propagation of selected modes even at low frequencies. However, the stellar nature of the propagation patterns and the inability to induce single-beam focusing represent significant limitations of this functionality. On the other hand, one can realize waveguides by defecting the periodic structure of a crystal operating in bandgap mode along some desired path. Waveguides of this type are only activated in the relatively high and narrow frequency bands corresponding to total bandgaps, which limits their potential technological applications. In this work, we introduce a class of phononic crystals with relaxed cell symmetry and we exploit symmetry relaxation of a population of auxiliary microstructural elements to achieve spatial manipulation of elastic waves at very low frequencies, in the range of existence of the acoustic modes. By this approach, we achieve focusing without modifying the default static properties of the medium and by invoking mechanisms that are well suited to envision adaptive configurations for semi-active wave control.
Investigation of leakage current paths in n-GaN by conductive atomic force microscopy
Authors: Kim Bumho , Moon Daeyoung , Joo Kisu , Oh Sewoung , Lee Young Kuk , Park Yongjo , Nanishi Yasushi , Yoon Euijoon
Published: March 2014

We have investigated electrical characteristics of leakage current paths in n-GaN layer grown by metal-organic chemical vapor deposition with conductive-atomic force microscopy (C-AFM). The C-AFM mapping shows two kinds of leakage current paths existing in the n-GaN layer: open-core dislocation and pure screw dislocation. From the localized I-V curves measured by C-AFM, we confirmed that the open-core screw dislocation shows more significant leakage current. We explained these results in terms of a modified Schottky band model based on donor states formed by oxygen segregation at the {10−10} sidewall of the open-core screw dislocation.
Utilisation of general practitioner services and achievement of guideline targets by people with diabetes who joined a peer-support program in Victoria, Australia
Authors: Rawal Lal B. , Wolfe Rory , Joyce Catherine , Riddell Michaela , Dunbar James A. , Li Hang , Oldenburg Brian
Published: March 2014

This paper describes the use of general practitioner (GP) services and achievement of guideline targets by 285 adults with type 2 diabetes in urban and regional areas of Victoria, Australia. Anthropometric and biomedical measures and responses to a self-administered questionnaire were collected. Findings indicate that almost all participants had visited a GP and had had their hypoglycated haemoglobin (HbA1c) measured in the past 6 months; less than one-third had visited a practice nurse. Fifty per cent achieved a HbA1c target of ≤7.0%; 40%, a total cholesterol ≤4.00 mmol/L; 39%, BP Systolic ≤130 mmHg; 51%, BP Diastolic ≤80 mmHg; 15%, body mass index ≤25 kg/m2; and 34% reported a moderately intense level of physical activity, that is, ≥30 min, 5 days a week. However, 39% of individuals achieved at least two targets and 18% achieved at least three of these guideline targets. Regional participants were more likely to report having a management plan and having visited a practice nurse, but they were less likely to have visited other health professionals. Therefore, a more sustained effort that also includes collaborative care approaches is required to improve the management of diabetes in Australia.
VipD is a Rab5-activated phospholipase A
1
that protects
Legionella pneumophila
from endosomal fusion
Authors: Gaspar Andrew H. , Machner Matthias P.
Published: March 2014

Significance

The pathogen
Legionella pneumophila
replicates within human alveolar macrophages, causing a potentially fatal pneumonia known as Legionnaires’ disease. We identified that the effector protein VipD, which is injected into infected cells by
L. pneumophila
, localizes to degradative host organelles called endosomes. There, VipD binds to the endosomal regulator Rab5, an event that triggers the hydrolytic phospholipase A
1
activity in VipD, which causes the removal of the lipid phosphatidylinositol 3-phosphate. Without this key lipid, endosomes can no longer execute their function and
L. pneumophila
is protected from their harmful effect. Our finding opens new avenues for the development of therapeutics that interfere with the activation of VipD and with endosomal avoidance by
L. pneumophila
.
Role of substrate unbinding in Michaelis–Menten enzymatic reactions
Authors: Reuveni Shlomi , Urbakh Michael , Klafter Joseph
Published: March 2014

Significance

Enzymes are biological catalysts vital to all life processes, and the quest to determine their inner workings continues to attract and fascinate scientists over a broad range of disciplines. With the advent of high-resolution methods of single-molecule spectroscopy, it is now possible to directly observe and manipulate the behavior of individual enzymes in the course of a chemical reaction. Chemistry at the single-molecule level is, however, inherently stochastic and, at times, extremely unintuitive. In this paper, we explain why, and under what circumstances, an increase in the rate at which an enzyme unproductively departs from a bound substrate will—unexpectedly—lead to an acceleration in the rate of product formation. The far-reaching implications of this effect are discussed.
Out-of-body–induced hippocampal amnesia
Authors: Bergouignan Loretxu , Nyberg Lars , Ehrsson H. Henrik
Published: March 2014

Significance

Transformation of experiences into long-term memory is a remarkable capability. However, some experiences are so extreme that they are not translated into coherent or lasting memories. Clinical reports suggest that one potential mechanism for memory disturbance could be “dissociative experiences,” in which events are experienced in a distance from the body (out-of-body). Here, we experimentally induced an illusory out-of-body experience on healthy participants while they were experiencing life events. Remarkably, participants had an episodic impairment for events encoded out-of-body. Out-of-body encoding specifically impacted the activation of the left posterior hippocampus during retrieval. These findings establish that hippocampus-based episodic memory depends on the perception of the world from within one's own body, and that a dissociative experience during encoding blocks the memory-forming mechanism.
Binding of the histone chaperone ASF1 to the CBP bromodomain promotes histone acetylation
Authors: Das Chandrima , Roy Siddhartha , Namjoshi Sarita , Malarkey Christopher S. , Jones David N. M. , Kutateladze Tatiana G. , Churchill Mair E. A. , Tyler Jessica K.
Published: March 2014

Significance

The Creb-binding protein (CBP) transcriptional coactivator contains a histone acetyl transferase domain and a bromodomain. Bromodomains bind to acetylated lysines, and their function as previously understood was limited to mediating recruitment to chromatin via binding to acetylated proteins. Here we show that the acetyl lysine-binding activity of the CBP bromodomain has unexpected roles in CBP-mediated acetylation of nonchromatin bound histones, and we show that the interaction between a bromodomain and acetyl lysine is stimulated by autoacetylation. Furthermore, we find that the histone chaperone anti-silencing function 1 binds to the bromodomain of CBP to present free histones correctly for efficient acetylation. Through a combination of structural, biochemical, and cell-based analyses, these studies enhance our understanding of bromodomain function and regulation.
Latent luciferase activity in the fruit fly revealed by a synthetic luciferin
Authors: Mofford David M. , Reddy Gadarla Randheer , Miller Stephen C.
Published: March 2014

Significance

Few organisms are capable of glowing in the dark. Perhaps the best known example is the firefly, a beetle that can emit flashes of yellow-green light when the small molecule
d
-luciferin is oxidized by the enzyme firefly luciferase. Here we show that a homologous enzyme in fruit flies is also capable of bioluminescence, but only when treated with a rigid synthetic analog of
d
-luciferin. The discovery of hidden luciferase activity in a nonluminescent insect suggests that the inherent chemistry required for bioluminescence is more common than previously thought, and that the evolution of new enzymatic activities can be directed by the appearance of a new substrate even in the absence of mutation.
Exchange of ADP with ATP in the CII ATPase domain promotes autophosphorylation of cyanobacterial clock protein KaiC
Authors: Nishiwaki-Ohkawa Taeko , Kitayama Yohko , Ochiai Erika , Kondo Takao
Published: March 2014

Significance

The circadian clock protein KaiC cyclically phosphorylates and dephosphorylates itself with a periodicity of ∼24 h. Unlike the reactions mediated by conventional protein phosphatases, dephosphorylation of KaiC occurs via reversal of the phosphorylation reaction. This unusual mechanism suggests that the KaiC phosphorylation rhythm is sustained by periodic shifts in the equilibrium of the reversible autophosphorylation reaction, the molecular basis of which has never been elucidated. In this study, we found that KaiA promoted the forward reaction by stimulating exchange of KaiC-bound ADP for exogenous ATP. KaiB inhibited KaiA, promoting retention of KaiC-bound ADP, and thereby facilitating the reverse reaction. We propose that KaiA and KaiB sustain the circadian oscillation by regulating this reversible reaction at the level of substrate availability.
Structural polymorphism in the N-terminal oligomerization domain of NPM1
Authors: Mitrea Diana M. , Grace Christy R. , Buljan Marija , Yun Mi-Kyung , Pytel Nicholas J. , Satumba John , Nourse Amanda , Park Cheon-Gil , Madan Babu M. , White Stephen W. , Kriwacki Richard W.
Published: March 2014

Significance

Nucleophosmin (NPM1) is a multifunctional protein with critical roles in ribosome biogenesis, centrosome duplication, and tumor suppression. Despite the established importance of NPM1 as a tumor marker and potential drug target, little is currently known about the molecular mechanisms that govern its various functions. Our manuscript describes that the N-terminal domain of NPM1 (Npm-N) exhibits phosphorylation-dependent structural polymorphism along a broad conformational landscape between two extreme states: a stable, folded pentamer and a globally disordered monomer. We propose that phosphorylation-induced “regulated unfolding” of Npm-N provides a means to modulate NPM1 function and subcellular localization. Our findings will drive future structure-based studies on the roles of regulated unfolding in NPM1 biology and will provide a foundation for NPM1-targeted anticancer drug development.
Expanding the detectable HLA peptide repertoire using electron-transfer/higher-energy collision dissociation (EThcD)
Authors: Mommen Geert P. M. , Frese Christian K. , Meiring Hugo D. , van Gaans-van den Brink Jacqueline , de Jong Ad P. J. M. , van Els Cécile A. C. M. , Heck Albert J. R.
Published: March 2014

Significance

The surface presentation of peptides by human leukocyte antigen (HLA) class I molecules is essential for adaptive immune responses against pathogens and tumors. To date, the repertoire of HLA class I peptides remains largely unexplored, although their identity could lead to new targets for vaccine development or cancer immunotherapy. Here, we demonstrate that recent developments in mass spectrometry (MS)-based sequencing technology can expand the detectable peptide repertoire to an unprecedented depth, revealing unique features in the antigen presentation machinery. Our data include a variety of posttranslational modifications for which evidence is accumulating that they play important roles in human diseases. Hence, next-generation MS-based sequencing can make the important step into the discovery of disease-related HLA class I antigens.
Neandertal clavicle length
Authors: Trinkaus Erik , Holliday Trenton W. , Auerbach Benjamin M.
Published: March 2014

Significance

Neandertal clavicle length, relative to that of modern humans, has long been considered distinctive. It has been invoked with respect to their ecogeographic body proportions, thoracic shape, scapular posture and biomechanics, temporal labyrinthine shape, and ancient DNA, as well as their trait polarities and phylogenetic status. Appropriate scaling of clavicle length to estimated body mass reveals that there is a consistent pattern of clavicle length to body mass proportions across early and recent modern humans, Neandertals, and probably most of the genus
Homo
. It is the relative abbreviation of Neandertal humeri, a reflection of ecogeographical body proportions and population history, that distinguishes the Neandertals from many modern humans. It is therefore inappropriate to use Neandertal clavicular length to assess their biology and evolutionary relationships.
Episodic simulation and episodic memory can increase intentions to help others
Authors: Gaesser Brendan , Schacter Daniel L.
Published: March 2014

Significance

Humans are readily willing to help individuals in need, in part because they can adopt the thoughts and feelings of others. Here, we provide evidence of an additional mechanism facilitating empathic responses. Our experiments revealed that, when presented with a situation depicting another person’s plight, participants who imagined an event in which they help the person (episodic simulation) or remembered a related past event of actually helping others (episodic memory) showed increased prosocial intentions. The findings reported here provide a starting point for research that could be used to develop new strategies targeted at episodic mechanisms for promoting empathy, as well as to guide research that attempts to characterize and improve empathic deficits in patient populations.
Protective role of miR-155 in breast cancer through
RAD51
targeting impairs homologous recombination after irradiation
Authors: Gasparini Pierluigi , Lovat Francesca , Fassan Matteo , Casadei Lucia , Cascione Luciano , Jacob Naduparambil K. , Carasi Stefania , Palmieri Dario , Costinean Stefan , Shapiro Charles L. , Huebner Kay , Croce Carlo M.
Published: March 2014

Significance

Cell survival after DNA damage relies on DNA repair, the abrogation of which causes genomic instability and development of cancer. DNA double-strand breaks are lesions induced by ionizing radiation (IR) and can be efficiently repaired by DNA homologous recombination, a system that requires RAD51 recombinase (RAD51). Here we show that overexpression of miR-155 in human breast cancer cells reduces the levels of RAD51 and affects the cellular response to IR. High miR-155 levels were associated with lower RAD51 expression and with better overall survival of patients in a large series of triple-negative breast cancers. Testing triple-negative breast cancer patients for miR-155 expression may be a useful prognostic tool to identify who will benefit from an IR-based therapeutic approach.
Trust and argumentation in multi-agent systems
Authors: Koster Andrew
Published: March 2014

This survey is the first to review the combination of computational trust and argumentation. The combination of the two approaches seems like a natural match, with the two areas tackling different aspects of reasoning in an uncertain, social environment. We discuss the different areas of research and describe the approaches taken so far, analysing both how they address the problems and the challenges that are unaddressed.
Cyclin B–Cdk1 inhibits protein phosphatase PP2A-B55 via a Greatwall kinase–independent mechanism
Authors: Okumura Eiichi , Morita Atsushi , Wakai Mizuho , Mochida Satoru , Hara Masatoshi , Kishimoto Takeo
Published: March 2014

Entry into M phase is governed by cyclin B–Cdk1, which undergoes both an initial activation and subsequent autoregulatory activation. A key part of the autoregulatory activation is the cyclin B–Cdk1–dependent inhibition of the protein phosphatase 2A (PP2A)–B55, which antagonizes cyclin B–Cdk1. Greatwall kinase (Gwl) is believed to be essential for the autoregulatory activation because Gwl is activated downstream of cyclin B–Cdk1 to phosphorylate and activate α-endosulfine (Ensa)/Arpp19, an inhibitor of PP2A-B55. However, cyclin B–Cdk1 becomes fully activated in some conditions lacking Gwl, yet how this is accomplished remains unclear. We show here that cyclin B–Cdk1 can directly phosphorylate Arpp19 on a different conserved site, resulting in inhibition of PP2A-B55. Importantly, this novel bypass is sufficient for cyclin B–Cdk1 autoregulatory activation. Gwl-dependent phosphorylation of Arpp19 is nonetheless necessary for downstream mitotic progression because chromosomes fail to segregate properly in the absence of Gwl. Such a biphasic regulation of Arpp19 results in different levels of PP2A-B55 inhibition and hence might govern its different cellular roles.
Kruppel-like factor 4 attenuates osteoblast formation, function, and cross talk with osteoclasts
Authors: Kim Jung Ha , Kim Kabsun , Youn Bang Ung , Lee Jongwon , Kim Inyoung , Shin Hong-In , Akiyama Haruhiko , Choi Yongwon , Kim Nacksung
Published: March 2014

Osteoblasts not only control bone formation but also support osteoclast differentiation. Here we show the involvement of Kruppel-like factor 4 (KLF4) in the differentiation of osteoclasts and osteoblasts. KLF4 was down-regulated by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) in osteoblasts. Overexpression of KLF4 in osteoblasts attenuated 1,25(OH)2D3-induced osteoclast differentiation in co-culture of mouse bone marrow cells and osteoblasts through the down-regulation of receptor activator of nuclear factor κB ligand (RANKL) expression. Direct binding of KLF4 to the RANKL promoter repressed 1,25(OH)2D3-induced RANKL expression by preventing vitamin D receptor from binding to the RANKL promoter region. In contrast, ectopic overexpression of KLF4 in osteoblasts attenuated osteoblast differentiation and mineralization. KLF4 interacted directly with Runx2 and inhibited the expression of its target genes. Moreover, mice with conditional knockout of KLF4 in osteoblasts showed markedly increased bone mass caused by enhanced bone formation despite increased osteoclast activity. Thus, our data suggest that KLF4 controls bone homeostasis by negatively regulating both osteoclast and osteoblast differentiation.
Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia
Authors: Järås Marcus , Miller Peter G. , Chu Lisa P. , Puram Rishi V. , Fink Emma C. , Schneider Rebekka K. , Al-Shahrour Fatima , Peña Pablo , Breyfogle L. Jordan , Hartwell Kimberly A. , McConkey Marie E. , Cowley Glenn S. , Root David E. , Kharas Michael G. , Mullally Ann , Ebert Benjamin L.
Published: March 2014

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML.
Quasi-conformal deformations of nonlinearizable germs
Authors: Biswas Kingshook
Published: March 2014

Let

f
(
z
)
=

e

2
π
i
α

z
+
O
(

z
2

)
,
α
∈

R

f(z) = e^{2\pi i \alpha }z + O(z^2), \alpha \in \mathbb {R}

, be a germ of a holomorphic diffeomorphism in

C

\mathbb {C}

. For

α
\alpha

rational and

f
f

of infinite order, the space of conformal conjugacy classes of germs topologically conjugate to

f
f

is parametrized by the Ecalle-Voronin invariants (and in particular is infinite-dimensional). When

α
\alpha

is irrational and

f
f

is nonlinearizable it is not known whether

f
f

admits quasi-conformal deformations. We show that if

f
f

has a sequence of repelling periodic orbits converging to the fixed point, then

f
f

embeds into an infinite-dimensional family of quasi-conformally conjugate germs, no two of which are conformally conjugate.
Depth of factors of square free monomial ideals
Authors: Popescu Dorin
Published: March 2014

Let

I
I

be an ideal of a polynomial algebra over a field generated by

r
r

square free monomials of degree

d
d

. If

r
r

is bigger than (or equal to, if

I
I

is not principal) the number of square free monomials of

I
I

of degree

d
+
1

d+1

, then

d
e
p
t
h

S

I
=
d

\mathrm {depth}_SI= d

. Let

J
⊊
I

J\subsetneq I

,

J
≠
0

J\not =0

be generated by square free monomials of degree

≥
d
+
1

\geq d+1

. If

r
r

is bigger than the number of square free monomials of

I
∖
J

I\setminus J

of degree

d
+
1

d+1

or, more generally, the Stanley depth of

I

/

J

I/J

is

d
d

, then

d
e
p
t
h

S

I

/

J
=
d

\mathrm {depth}_SI/J= d

. In particular, Stanley’s Conjecture holds in these cases.
Improved heat tolerance in air drives the recurrent evolution of air-breathing
Authors: Giomi Folco , Fusi Marco , Barausse Alberto , Mostert Bruce , Pörtner Hans-Otto , Cannicci Stefano
Published: March 2014

The transition to air-breathing by formerly aquatic species has occurred repeatedly and independently in fish, crabs and other animal phyla, but the proximate drivers of this key innovation remain a long-standing puzzle in evolutionary biology. Most studies attribute the onset of air-breathing to the repeated occurrence of aquatic hypoxia; however, this hypothesis leaves the current geographical distribution of the 300 genera of air-breathing crabs unexplained. Here, we show that their occurrence is mainly related to high environmental temperatures in the tropics. We also demonstrate in an amphibious crab that the reduced cost of oxygen supply in air extends aerobic performance to higher temperatures and thus widens the animal's thermal niche. These findings suggest that high water temperature as a driver consistently explains the numerous times air-breathing has evolved. The data also indicate a central role for oxygen- and capacity-limited thermal tolerance not only in shaping sensitivity to current climate change but also in underpinning the climate-dependent evolution of animals, in this case the evolution of air-breathing.
Constructing molecular structures on periodic superstructure of graphene/Ru(0001)
Authors: Li Geng , Huang Li , Xu Wenyan , Que Yande , Zhang Yi , Lu Jianchen , Du Shixuan , Liu Yunqi , Gao Hong-Jun
Published: March 2014

We review the way to fabricate large-scale, high-quality and single crystalline graphene epitaxially grown on Ru(0001) substrate. A moiré pattern of the graphene/Ru(0001) is formed due to the lattice mismatch between graphene and Ru(0001). This superstructure gives rise to surface charge redistribution and could behave as an ordered quantum dot array, which results in a perfect template to guide the assembly of organic molecular structures. Molecules, for example iron phthalocyanine and C
60
, on this template show how the molecule–substrate interaction makes different superstructures. These results show the possibility of constructing ordered molecular structures on graphene/Ru(0001), which is helpful for practical applications in the future.
Predicting premature termination with alliance at sessions 1 and 3: an exploratory study
Authors: Yoo Hana , Bartle‐Haring Suzanne , Gangamma Rashmi
Published: March 2014

Research has demonstrated that the therapeutic alliance is associated with termination status and treatment outcomes regardless of therapy models and the number of people involved in the treatment. Compared to individual therapy, however, relatively less attention has been paid to the therapeutic alliance as a predictor of premature termination of couple and family therapy. In the current study, videotape recordings of two samples of couples in therapy – one in the first session and the other in the third session – were analysed to examine the association between the therapeutic alliance and termination status. A total of 34 videotapes were analysed in this exploratory study. All the tapes were rated for the therapeutic alliance using the Vanderbilt therapeutic alliance scale, which allowed observers to code behaviour and interactions between couples and their therapist. The results of this study, though preliminary, suggested that the therapeutic alliance measured at the first session was more predictive of premature termination than was the alliance at the third session, which somewhat challenges findings from studies of individual psychotherapy.

Practitioner points

Assessing the therapeutic alliance in the first couple therapy session may be more important in predicting later premature termination than in the third session.

In particular, new therapists in training may need to pay special attention to their alliance with clients from the very beginning of therapy.
A Springtime Journey to the Soviet Union: Postwar Planning and Policy Mobilities through the Iron Curtain
Authors: Cook Ian R. , Ward Stephen V. , Ward Kevin
Published: March 2014

This article builds upon a relatively small but growing literature in geography, planning and cognate disciplines that seeks to understand the variegated geographies and histories of policy mobilities. The article uses a case study of an exchange trip between town planners in the Soviet Union and the UK between 1957 and 1958. It focuses on the experiences of the British planners in the Soviet Union and sets the tour within the wider context of a fluctuating and sometimes turbulent history of Anglo‐Soviet politics, travels and connections. In doing this, the article makes three arguments: first, there is much to be gained by bringing together the geography‐dominated policy mobilities literature with that on exchanges and visits by architects, engineers and planners. Secondly, the greater sensitivity to the histories of policy mobilities allows contemporary studies to be contextualized in the longer history of organized learning between different urban professions. Thirdly, despite the long history of policy mobilities, what differentiates the current era from previous eras is the prominent ‘knowledge intermediary’ roles now played by consultancies and think tanks. As the article will demonstrate, it was branches of government and professional bodies, rather than consultancies and think tanks, that tended to dominate such roles previously.
Monitoring temporal change of bird communities with dissimilarity acoustic indices
Authors: Lellouch Laurent , Pavoine Sandrine , Jiguet Frédéric , Glotin Hervé , Sueur Jérôme
Published: March 2014

A part of biodiversity assessment and monitoring consists in the estimation and track of the changes in species composition and abundance of animal communities. Such a task requires an important sampling over a broad‐scale time that is difficult to reach with classical survey methods. Acoustics may offer an alternative to usual techniques by recording the sound produced by vocal animals. Animal species that use sound for communication (sing and/or call) establish an acoustic community when they sing at the same time and at a particular place. The estimation of the acoustic community dynamics could provide indirect cues on what drives changes in community composition and species abundance.

Here, new methods were developed to estimate the changes in bird communities recorded at three woodland temperate sites in France. Both field recordings and simulated data were used to test whether acoustic dissimilarity indices can be used to estimate changes in the composition of the community. Four dissimilarity indices found in the literature, and a new one named Dcf were tested on auditory spectra after transformation to the Mel scale, rather than on classical Fourier frequency spectra. All indices were compared with each other and with compositional indices.

The results show that bird communities occurring at the three sites were dynamic with changes of composition with time. Dissimilarities computed on simulated acoustic communities were correlated with compositional dissimilarity but those computed on field‐recorded communities could not be considered as faithful estimators of community composition variations. However, the indices indicate important dates in community changes around mid‐April that were also seen in the composition dynamics.

Acoustic dissimilarity indices failed to track accurately changes in species composition of the bird communities. However, these indices, which are easy to compute, still provide information on the acoustic dynamics of bird community. Acoustics might not be considered as a proxy of compositional diversity but rather as another facet of animal diversity that needs to be studied and preserved on its own.
Cognitive deficits in youth with familial and clinical high risk to psychosis: a systematic review and meta‐analysis
Authors: Bora E. , Lin A. , Wood S. J. , Yung A. R. , McGorry P. D. , Pantelis C.
Published: March 2014

Objective

It is likely that cognitive deficits are vulnerability markers for developing schizophrenia, as these deficits are already well‐established findings in first‐episode psychosis. Studies at‐risk adolescents and young adults are likely to provide information about cognitive deficits that predate the onset of the illness.

Method

We conducted meta‐analyses of studies comparing familial‐high risk (FHR) or ultra‐high risk (UHR; n = 2113) and healthy controls (n = 1748) in youth studies in which the mean age was between 15 and 29.

Results

Compared with controls, high risk subjects were impaired in each domain in both UHR (d = 0.34–0.71) and FHR (d = 0.24–0.81). Heterogeneity of effect sizes across studies was modest, increasing confidence to the findings of the current meta‐analysis (I2 = 0–0.18%). In both risk paradigms, co‐occurrence of genetic risk with attenuated symptoms was associated with more severe cognitive dysfunction. In UHR, later transition to psychosis was associated with more severe cognitive deficits in all domains (d = 0.31–0.49) except sustained attention. However, cognitive impairment has a limited capacity to predict the outcome of high‐risk patients.

Conclusion

Cognitive deficits are already evident in adolescents and young adults who have familial or clinical risk for psychosis. Longitudinal developmental studies are important to reveal timing and trajectory of emergence of such deficits.
Improving reproductive long‐term prognosis for women with a first ectopic pregnancy. A national controlled follow‐up study
Authors: Egerup Pia , Kårhus Line Lund , Skovlund Charlotte Wessel , Lidegaard Øjvind
Published: March 2014

Objective

To describe developments in reproductive long‐term prognosis in women with a first ectopic pregnancy as compared with two control cohorts.

Design

Controlled cohort study.

Setting

Data were collected from four national Danish registries.

Population

All Danish women of reproductive age (15–49 years) through the period 1977–2009 and all reproductive outcomes in these women.

Methods

Data were collected from four national Danish registries. Three cohorts of women with a first recorded ectopic pregnancy during the periods 1980–84, 1985–89, and 1990–94, were compared with age‐matched controls with a first miscarriage and a first induced abortion and followed for 15 years for all further pregnancy outcomes.

Main outcome measures

Pregnancy outcomes included deliveries, miscarriages, induced abortions and ectopic pregnancies.

Results

The birth rate for women with a first ectopic pregnancy increased significantly through the three cohorts from 85 to 122 deliveries/100 women during the follow‐up period. The risk of miscarriages also increased over time, whereas the risk of further ectopic pregnancies remained unchanged at 22–24 events/100 women. Compared to women with a first miscarriage, the rate ratio for deliveries increased from 0.59 (95% CI 0.56–0.63) to 0.71 (95% CI 0.68–0.75) over the time covering the three cohorts.

Conclusion

The long‐term delivery rate among women with a first ectopic pregnancy has improved significantly over time.
Evaluating the functional net value of pharmacologic agents in treating irritable bowel syndrome
Authors: Shah E. , Pimentel M.
Published: March 2014

Background

The recent FDA provisional endpoint incorporates a one‐tailed measure of improvement for IBS based on the underlying motility complaint. However, motility exists along a spectrum. Patients may experience diarrhoea resulting from therapy for their constipation‐predominant IBS (IBS‐C) or constipation during treatment for diarrhoea‐predominant IBS (IBS‐D), but still meet a unidirectional motility‐based FDA endpoint.

Aim

To weigh the reported efficacy of existing therapies based on patient‐reported outcomes with negative intestinal side effects in controlled clinical trial data.

Methods

We analysed the difference between ‘attributable risk’ of efficacy based on number needed to treat (NNT) in the literature and percentage of adverse events (AE) of opposite intestinal complaints in placebo‐controlled trials identified through a literature search of IBS trials. This calculation was coined ‘functional net value’ (FNV) or net benefit of the given drug.

Results

For treating IBS‐C, lubiprostone caused diarrhoea in excess of placebo in 3.9% of patients, leading to a FNV of 3.9 percentage units. Linaclotide caused diarrhoea in 15.3% resulting in negative FNV (−1.0 percentage unit). For IBS‐D, alosetron and tricyclic anti‐depressants caused constipation among a respective 16.9% and 13.0% resulting in a FNV of −3.6 and −0.5 percentage units. Among all therapies, only rifaximin did not cause the adverse event opposite the underlying motility complaint and the drug only had benefit, not detriment.

Conclusions

Functional net value (FNV) offers a method of evaluating the net benefit of a drug in IBS. Most IBS treatments have a negative effect on IBS that exceeds the benefits.