bluuebunny/crossref_metadata_2025 huggingface dataset:
MYBL2 is a substrate of GSK3-like kinase BIN2 and acts as a corepressor of BES1 in brassinosteroid signaling pathway in
Arabidopsis
Authors: Ye Huaxun , Li Lei , Guo Hongqing , Yin Yanhai
Published: November 2012

Plant steroid hormones, brassinosteroids (BRs), play important roles in plants. BRs regulate the expression of several thousand genes, half of which are induced and the other half repressed by the hormone. BRs signal through plasma membrane-localized receptor kinase brassinosteroid-insensitive 1 (BRI1), BRI1-associated receptor kinase (BAK1), and several intermediates to regulate the protein levels, cellular localizations, and/or DNA binding of BRI1–EMS suppressor 1 (BES1)/brassinazole-resistant 1 (BZR1) family transcription factors. Although BES1 is known to interact with other transcription factors, histone-modifying enzymes, and transcription elongation factors to activate BR-induced genes, how BES1 mediates the BR-repressed gene expression is not known. Here, we show that BES1 interacts with myeloblastosis family transcription factor-like 2 (MYBL2), a transcription repressor, to down-regulate BR-repressed gene expression. The loss-of-function
mybl2
mutant enhances the phenotype of a weak allele of
bri1
and suppresses the constitutive BR-response phenotype of
bes1-D
. The results suggest that suppression of BR-repressed gene expression is required for optimal BR response. Moreover, MYBL2 is a substrate of glycogen synthase kinase 3 (GSK3)-like kinase brassinosteroid-insensitive 2 (BIN2), which has been well established as a negative regulator in the BR pathway by phosphorylating and inhibiting the functions of BES1/BZR1. Unlike BIN2 phosphorylation of BES1/BZR1 leading to protein degradation, BIN2 phosphorylation stabilizes MYBL2. Such dual role of phosphorylation has also been reported in WNT signaling pathway in which GSK3 phosphorylation destabilizes β-catenin and stabilizes Axin, a scaffolding protein facilitating the phosphorylation of β-catenin by GSK3. Our results thus establish the mechanisms for BR-repressed gene expression and the integration of BR signaling and BR transcriptional network.
Connexin45 modulates the proliferation of transit-amplifying precursor cells in the mouse subventricular zone
Authors: Khodosevich Konstantin , Zuccotti Annalisa , Kreuzberg Maria M. , Le Magueresse Corentin , Frank Marina , Willecke Klaus , Monyer Hannah
Published: November 2012

Connexins have been implicated in the regulation of precursor cell migration and proliferation during embryonic development of the mammalian brain. However, their function in postnatal neurogenesis is unclear. Here we demonstrate that connexin (Cx) 45 is expressed in transit-amplifying cells and neuroblasts in the postnatal subventricular zone (SVZ) and modulated the proliferation of SVZ-derived precursor cells in vivo. Thus, overexpression of Cx45 by retroviral injections increased the proliferation of Mash-1–positive transit-amplifying precursor cells in the SVZ. Conversely, conditional deletion of
Cx45
in precursor cells decreased proliferation. Finally, we established that Cx45 positively influences cell cycle reentry via ATP signaling that involves intracellular calcium stores and ERK1/2 signaling.
AtWRKY15 perturbation abolishes the mitochondrial stress response that steers osmotic stress tolerance in
Arabidopsis
Authors: Vanderauwera Sandy , Vandenbroucke Korneel , Inzé Annelies , van de Cotte Brigitte , Mühlenbock Per , De Rycke Riet , Naouar Naïra , Van Gaever Tim , Van Montagu Marc C. E. , Van Breusegem Frank
Published: November 2012

Environmental stresses adversely affect plant growth and development. A common theme within these adverse conditions is the perturbation of reactive oxygen species (ROS) homeostasis. Here, we demonstrate that the ROS-inducible
Arabidopsis thaliana
WRKY15 transcription factor (AtWRKY15) modulates plant growth and salt/osmotic stress responses. By transcriptome profiling, a divergent stress response was identified in transgenic
WRKY15
-overexpressing plants that linked a stimulated endoplasmic reticulum-to-nucleus communication to a disrupted mitochondrial stress response under salt-stress conditions. We show that mitochondrial calcium-flux sensing might be important for regulating an active mitochondrial retrograde signaling and launching an appropriate defense response to confer salt-stress tolerance.
Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking
Authors: Lee Samuel M. , Chin Lih-Shen , Li Lian
Published: November 2012

Mutations in small integral membrane protein of lysosome/late endosome (SIMPLE) cause autosomal dominant, Charcot-Marie-Tooth disease (CMT) type 1C. The cellular function of SIMPLE is unknown and the pathogenic mechanism of SIMPLE mutations remains elusive. Here, we report that SIMPLE interacted and colocalized with endosomal sorting complex required for transport (ESCRT) components STAM1, Hrs, and TSG101 on early endosomes and functioned with the ESCRT machinery in the control of endosome-to-lysosome trafficking. Our analyses revealed that SIMPLE was required for efficient recruitment of ESCRT components to endosomal membranes and for regulating endosomal trafficking and signaling attenuation of ErbB receptors. We found that the ability of SIMPLE to regulate ErbB trafficking and signaling was impaired by CMT-linked SIMPLE mutations via a loss-of-function, dominant-negative mechanism, resulting in prolonged activation of ERK1/2 signaling. Our findings indicate a function of SIMPLE as a regulator of endosomal trafficking and provide evidence linking dysregulated endosomal trafficking to CMT pathogenesis.
MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β2-adrenergic receptors
Authors: Han Sang-oh , Xiao Kunhong , Kim Jihee , Wu Jiao-Hui , Wisler James W. , Nakamura Nobuhiro , Freedman Neil J. , Shenoy Sudha K.
Published: November 2012

Lysosomal degradation of ubiquitinated β2-adrenergic receptors (β2ARs) serves as a major mechanism of long-term desensitization in response to prolonged agonist stimulation. Surprisingly, the βAR antagonist carvedilol also induced ubiquitination and lysosomal trafficking of both endogenously expressed β2ARs in vascular smooth muscle cells (VSMCs) and overexpressed Flag-β2ARs in HEK-293 cells. Carvedilol prevented β2AR recycling, blocked recruitment of Nedd4 E3 ligase, and promoted the dissociation of the deubiquitinases USP20 and USP33. Using proteomics approaches (liquid chromatography–tandem mass spectrometry), we identified that the E3 ligase MARCH2 interacted with carvedilol-bound β2AR. The association of MARCH2 with internalized β2ARs was stabilized by carvedilol and did not involve β-arrestin. Small interfering RNA–mediated down-regulation of MARCH2 ablated carvedilol-induced ubiquitination, endocytosis, and degradation of endogenous β2ARs in VSMCs. These findings strongly suggest that specific ligands recruit distinct E3 ligase machineries to activated cell surface receptors and direct their intracellular itinerary. In response to β blocker therapy with carvedilol, MARCH2 E3 ligase activity regulates cell surface β2AR expression and, consequently, its signaling.
Association between Methicillin-Resistant Staphylococcus aureus Colonization and Infection May Not Differ by Age Group
Authors: Ajao Adebola O. , Harris Anthony D. , Johnson J. Kristie , Roghmann Mary-Claire , Perencevich Eli N. , Schweizer Marin L. , Zhan Min , Chen Wilbur H. , Furuno Jon P.
Published: November 2012

We assessed whether age modified the association between methicillin-resistant Staphylococcus aureus (MRSA) anterior nares colonization and subsequent infection. Among 7,405 patients (9,511 admissions), MRSA colonization was significantly associated with infection (adjusted odds ratio, 13.7 [95% confidence interval, 7.325.7]) but did not differ significantly by age group.
Magnetostatic behaviour of antidot arrays under the local influence of nanopillars
Authors: Béron Fanny , Knobel Marcelo , Pirota Kleber R
Published: November 2012

We fabricated highly ordered patterned Permalloy nanometric structures by means of ion beam sputtering on top of an anodic aluminium oxide nanoporous template. First-order reversal curve (FORC) results and micromagnetic simulations indicate the presence of Permalloy inside one side of the pores, leading to a nanopillar array anisotropically arranged combined with an antidot array. The strong shape anisotropy of the pillar forces it to maintain the magnetization along its axis, even for a large in-plane applied field. This phenomenon induces out-of-plane hysteresis, as well as in-plane anisotropic behaviour. Depending on the in-plane applied field direction, the presence of nanopillars differently modifies the regular domain pattern, and therefore they could act as a new parameter for tailoring of magnetic anisotropy in antidot arrays.
Kreck-Stolz invariants for quaternionic line bundles
Authors: Crowley Diarmuid , Goette Sebastian
Published: November 2012

We generalise the Kreck-Stolz invariants

s
2

s_2

and

s
3

s_3

by defining a new invariant, the

t
t

-invariant, for quaternionic line bundles 

E
E

over closed spin-manifolds

M
M

of dimension

4
k
−
1

4k-1

with 

H
3

(
M
;

Q

)
=
0

H^3(M; \mathbb Q) = 0

such that 

c
2

(
E
)
∈

H
4

(
M
)

c_2(E)\in H^4(M)

is torsion. The

t
t

-invariant classifies closed smooth oriented

2
2

-connected rational homology

7
7

-spheres up to almost-diffeomorphism, that is, diffeomorphism up to a connected sum with an exotic sphere. It also detects exotic homeomorphisms between such manifolds.

The

t
t

-invariant also gives information about quaternionic line bundles over a fixed manifold, and we use it to give a new proof of a theorem of Feder and Gitler about the values of the second Chern classes of quaternionic line bundles over

H

P
k

\mathbb H P^k

. The

t
t

-invariant for

S

4
k
−
1

S^{4k-1}

is closely related to the Adams

e
e

-invariant on the

(
4
k
−
5
)

(4k-5)

-stem.
The rate constant for the reaction of CO2 with enzymebound ribulose 1,5-bisphosphate in vivo
Authors: Viil Juta , Pärnik Tut
Published: November 2012

The partial reactions during carboxylation of ribulose-1,5-bisphosphate (RuBP) were studied. A method is proposed for the in vivo estimation of the rate constant for the reaction of CO2 with the ene-diol of RuBP formed in the active site of RuBP carboxylase/ oxygenase (Rubisco). The method involves a pretreatment of the leaves, in the light, with different concentrations of CO2 in nitrogen, followed by 6 s exposure to CO2-free air. Then the leaves are exposed to 14CO2 and the kinetics of 14C uptake are determined after 0.2–0.4 s. It is assumed that the mechanism is a regular bimolecular reaction with the rate linearly dependent on the concentrations of substrates. A value for the rate constant of 0.06 μM−1 s−1 was obtained, independent of the CO2 concentration during pretreatment. However, high pretreatment-[CO2] decreased the concentration of the competent RuBP-binding sites.
Photosynthetic limitations: use in guiding effort in crop improvement
Authors: Jones Hamlyn G.
Published: November 2012

Methods for identifying the important processes limiting crop production and especially photosynthesis are discussed with special reference to the use of transgenic plants with altered expression of the small subunit of ribulose-1,5-bisphosphate carboxylase-oxygenase (Rubisco). Recent advances in the use of metabolic control analysis are reviewed and some restrictions in their application to crop improvement are discussed. Metabolic control and other sensitivity approaches are compared with the opportunities offered by ‘elimination’ analyses where the contribution of one component is estimated from the change in assimilation rate when any limitation by that component is removed. It is concluded that although control or sensitivity analyses provide effective tools for describing the importance of component processes, especially when using transgenic approaches to generation of isogenic material, our present limited knowledge of the complex interactions between various metabolic pathways restricts the value of these approaches in guiding breeding effort.
Photosynthesis, productivity and environment
Authors: Lawlor David W.
Published: November 2012

The relation between photosynthetic rate per unit leaf area (Pn), total photosynthesis by canopies and dry matter production (DMP) of crops is reviewed. Although Pn is the driving force for all plant growth, total DMP is determined by processes integrated over the canopy, primarily light interception and thus by leaf area index (LAI) and canopy architecture and leaf area duration (LAD). The processes are not linearly related so that effects on DMP of changes in the efficiency of conversion of energy of radiation to dry matter are smaller than those associated with LAI. Photosynthesis is much less sensitive to changing environmental conditions than development of leaf area. This explains the apparent anomaly that Pn does not determine the variation in productivity of a crop under normal agronomic practice, despite the role of photosynthesis in providing all the assimilates for DMP. Breeding and selection of crops for higher yield has not resulted in improvements in dry matter production. Indeed, potential photosynthetic rate has decreased under selection breeding, compensated by increased leaf area: the causes are considered. Crops growing at or near their potential rate use most of the available solar energy and there is a strong correlation between radiation absorbed and DMP and canopy photosynthesis is not light saturated. To increase production it will be necessary to extend either the growing season or to improve light conversion efficiency; the latter is best achieved by increasing Pn. The limiting factors in photosynthetic metabolism which determine Pn under different environmental conditions, are reviewed. Increased Pn is not likely to come from altering light harvesting, electron transport or ATP and NADPH synthesis which are potentially very flexible and have large capacity: there is large genetic variation. Synthesis of ribulose bisphosphate (RuBP) depends on activity of Calvin cycle enzymes which may be limiting due to environmental factors. Increasing the atmospheric CO2 supply increases production of C3 plants under current conditions: this is due to a decrease in the oxygenase function of ribulose bisphosphate carboxylase-oxygenase (Rubisco). Improving the specificity factor of Rubisco is a long-term goal to decrease photorespiration. Even if Pn is increased, evidence from theoretical and crop canopy studies suggest that the increase in biomass production will only be a small proportion of the increase in Pn, and DMP also depends on the crop's sink capacity. Crop production is a function of many processes, at the level of the chloroplast, the leaf and the canopy. To increase Pn and production of crops will require knowledge of processes at all levels in the plant-environment system.
Leaf Spot on Lettuce (Lactuca sativa) Caused by Stemphylium solani, a New Disease in Malaysia
Authors: Nasehi A. , Kadir J. B. , Esfahani M. Nasr , Mahmodi F. , Ghadirian H. , Ashtiani F. Abed , Soleimani N.
Published: November 2012

In June 2011, lettuce (Lactuca sativa) plants cultivated in major lettuce growing areas in Malaysia, including the Pahang and Johor states, had extensive leaf spots. In severe cases, disease incidence was recorded more than 80%. Symptoms on 50 observed plants initially were as water soaked spots (1 to 2 mm in diameter) on leaves, and then became circular spots spreading over much of the leaves. In this research, main lettuce growing areas infected by the pathogen in the mentioned states were investigated and the pathogen was isolated onto potato dextrose agar (PDA). Colonies observed were greyish green to light brown. Single conidia were formed at the terminal end of conidiophores that were 28.8 to 40.8 μm long and 11.0 to 19.2 μm wide, and 2 to 7 transverse and 1 to 4 longitudinal septa. To produce conidia, the fungus was grown on potato carrot agar (PCA) and V8 juice agar media under 8-h/16-h light/dark photoperiod. Fourteen isolates were identified Stemphylium solani based on morphological criteria described by Kim et al. (1). To confirm morphological characterization, DNA of the fungus was extracted from mycelium and PCR was done using universal primers ITS5 (5′-GGAAGTAAAAGTCGTAACAAGG-3′) and ITS4 (5′-TCCTCCGCTTATTGATATGC-3′), which amplified the internal transcribed spacer (ITS) region of rDNA (2). The sequencing result was subjected to BLAST analysis which was 99% identical to the other published sequences in the GenBank database (GenBank Accession Nos. AF203451 and HQ840713). The nucleotide sequence was deposited in GenBank under Accession No. JQ736022. Pathogenicity testing of representative isolate was done using 20 μl of conidial suspension with a concentration of 1 × 105/ml in droplets (three drops on each leaf) on four detached 45-day-old lettuce leaves cv. BBS012 (3). Fully expended leaves were placed on moist filter paper in petri dishes and were incubated in humid chambers at 25°C. The leaves inoculated with sterile water served as control. After 7 days, disease symptoms were observed, which were similar to those symptoms collected in infected fields and the fungus was reisolated and confirmed as S. solani based on morphological criteria (1) and molecular characterization (2). Control leaves remained healthy. Pathogenicity testing was completed twice. To our knowledge, this is the first report of S. solani on lettuce in Malaysia and it may become a serious problem because of its broad host range, variability in pathogenic isolates, and prolonged active phase of the disease cycle. Previous research has shown that S. solani is a causal agent of gray leaf spot on lettuce in China (4).

References: (1) B. S. Kim et al. Plant Pathol. J. 20:85, 2004. (2) Y. R. Mehta et al. Current Microbiol. 44:323, 2002. (3) B. M. Pryor and T. J. Michailides. Phytopathology 92:406, 2002. (4) F. L. Tai. Sylloge Fungorum Sinicorum, Sci. Press, Acad. Sin., Peking, 1979.
First Report of Ageratum yellow vein China virus Infecting Zinnia elegans in Vietnam
Authors: Li Z.-B. , Qin B.-X. , Cai J.-H.
Published: November 2012

Whitefly-transmitted geminiviruses belong to the Geminiviridae family, which includes a group of plant DNA viruses that occurs in tropical and subtropical regions worldwide and caused severe leaf curl diseases on many crops. In July 2011, symptoms of mild yellowing and curling of leaves were observed on Zinnia elegans in Hue City, Vietnam. To identify possible begomoviruses, two samples with typical symptoms (Z1 and Z2) were collected and total DNA was extracted using PlantGen DNA Kit (CoWin Biotech Co., China). Using begomovirus-specific degenerate primer pair AV494 and AC1048 to amply geminivirus capsid protein gene (3), a 586-bp DNA fragment was amplified from both collected samples. The PCR products from Z1 and Z2 were cloned and sequenced. The partial sequences from two isolates had 96.8% similarity to each other and most closely related to Ageratum yellow vein China virus (AYVCNV) (98% identity to GenBank Accession Nos. AM940137.1 and AJ849916.1). Using two degenerate primer pairs bego1 (5′-ACMGGCCYATGWAYMGGAAG-3′)/bego6 (5′-ACNGGDAARACRATGTGGGC-3′) and bego2 (5′-CTTDATRTTBTCRTCCATCC-3′)/bego3 (5′-CCWGGATTGCANARSAMGAT-3′) to amplify full-length viral genome from Z1 (1). The complete DNA-A sequence from Z1 were determined to be 2,741 nucleotides (JX911332), showed high levels of sequence identity (89% [JN809812] to 98% [AJ849916.1 and AJ558120]) with AYVCNV and shared 98% nucleotide sequence identity with AYVCNV-G68 (AJ849916.1) and AYVCNV-G13 (AJ558120). No DNA-B component nor DNA-β could be detected using primers described previously (4). Zinnia leaf curl virus, Ageratum enation virus, Tobacco leaf curl virus, and Alternanthera yellow vein virus have been reported to be associated with Zinnia leaf curl disease (2). To our knowledge, this is the first report of AYVCNV infecting Z. elegans. AYVCNV was first reported in A. conyzoides on Hainan Island, China, and could infect L. esculentum (Solanaceae), A. conyzoides (Asteraceae), or tobacco (Solanaceae). Our results further corroborate that AYVCNV can infect Asteraceae plants. Therefore, this virus may pose a serious threat to many plants.

References: (1) L. Lin et al. Plant Prot. 37:44, 2011. (2) P. Naveen et al. J. Biotechnol. Bioinform. 2:6, 2012. (3) S. D. Wyatt et al. Phytopathology 86:1288, 1996. (4) X. P. Zhou et al. J. Gen. Virol. 84:237, 2003.
Importance of the matriline for genomic imprinting, brain development and behaviour
Authors: Keverne E. B.
Published: November 2012

Mammalian brain development commences during foeto-placental development and is strongly influenced by the epigenetic regulation of imprinted genes. The foetal placenta exerts considerable influence over the functioning of the adult maternal hypothalamus, and this occurs at the same time as the foetus itself is developing a hypothalamus. Thus, the action and interaction of two genomes in one individual, the mother, has provided a template for co-adaptive functions across generations that are important for maternal care and resource transfer, while co-adaptively shaping the mothering capabilities of each subsequent generation. The neocortex is complex, enabling behavioural diversity and cultural learning such that human individuals are behaviourally unique. Retrotransposons may, in part, be epigenetic mediators of such brain diversity. Interestingly some imprinted genes are themselves retrotransposon-derived, and retrotransposon silencing by DNA methylation is thought to have contributed to the evolutionary origins of imprint control regions. The neocortex has evolved to be adaptable and sustain both short-term and long-term synaptic connections that underpin learning and memory. The adapted changes are not themselves inherited, but the predisposing mechanisms for such epigenetic changes are heritable. This provides each generation with the same ability to make new adaptations while constrained by a transgenerational knowledge-based predisposition to preserve others.
Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers
Authors: Seisenberger Stefanie , Peat Julian R. , Hore Timothy A. , Santos Fátima , Dean Wendy , Reik Wolf
Published: November 2012

In mammalian development, epigenetic modifications, including DNA methylation patterns, play a crucial role in defining cell fate but also represent epigenetic barriers that restrict developmental potential. At two points in the life cycle, DNA methylation marks are reprogrammed on a global scale, concomitant with restoration of developmental potency. DNA methylation patterns are subsequently re-established with the commitment towards a distinct cell fate. This reprogramming of DNA methylation takes place firstly on fertilization in the zygote, and secondly in primordial germ cells (PGCs), which are the direct progenitors of sperm or oocyte. In each reprogramming window, a unique set of mechanisms regulates DNA methylation erasure and re-establishment. Recent advances have uncovered roles for the TET3 hydroxylase and passive demethylation, together with base excision repair (BER) and the elongator complex, in methylation erasure from the zygote. Deamination by AID, BER and passive demethylation have been implicated in reprogramming in PGCs, but the process in its entirety is still poorly understood. In this review, we discuss the dynamics of DNA methylation reprogramming in PGCs and the zygote, the mechanisms involved and the biological significance of these events. Advances in our understanding of such natural epigenetic reprogramming are beginning to aid enhancement of experimental reprogramming in which the role of potential mechanisms can be investigatedin vitro. Conversely, insights intoin vitroreprogramming techniques may aid our understanding of epigenetic reprogramming in the germline and supply important clues in reprogramming for therapies in regenerative medicine.
Nonlinear Demodulation and Channel Coding in EBPSK Scheme
Authors: Chen Xianqing , Wu Lenan
Published: November 2012

The extended binary phase shift keying (EBPSK) is an efficient modulation technique, and a special impacting filter (SIF) is used in its demodulator to improve the bit error rate (BER) performance. However, the conventional threshold decision cannot achieve the optimum performance, and the SIF brings more difficulty in obtaining the posterior probability for LDPC decoding. In this paper, we concentrate not only on reducing the BER of demodulation, but also on providing accurate posterior probability estimates (PPEs). A new approach for the nonlinear demodulation based on the support vector machine (SVM) classifier is introduced. The SVM method which selects only a few sampling points from the filter output was used for getting PPEs. The simulation results show that the accurate posterior probability can be obtained with this method and the BER performance can be improved significantly by applying LDPC codes. Moreover, we analyzed the effect of getting the posterior probability with different methods and different sampling rates. We show that there are more advantages of the SVM method under bad condition and it is less sensitive to the sampling rate than other methods. Thus, SVM is an effective method for EBPSK demodulation and getting posterior probability for LDPC decoding.
Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4
Authors: Herz Hans-Martin , Mohan Man , Garruss Alexander S. , Liang Kaiwei , Takahashi Yoh-hei , Mickey Kristen , Voets Olaf , Verrijzer C. Peter , Shilatifard Ali
Published: November 2012

Monomethylation of histone H3 on Lys 4 (H3K4me1) and acetylation of histone H3 on Lys 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and on enhancers. Although in yeast all H3K4 methylation patterns, including H3K4me1, are implemented by Set1/COMPASS (complex of proteins associated with Set1), there are three classes of COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers: dSet1, Trithorax, and Trithorax-related (Trr). Here, we report that Trr, the Drosophila homolog of the mammalian Mll3/4 COMPASS-like complexes, can function as a major H3K4 monomethyltransferase on enhancers in vivo. Loss of Trr results in a global decrease of H3K4me1 and H3K27ac levels in various tissues. Assays with the cut wing margin enhancer implied a functional role for Trr in enhancer-mediated processes. A genome-wide analysis demonstrated that Trr is required to maintain the H3K4me1 and H3K27ac chromatin signature that resembles the histone modification patterns described for enhancers. Furthermore, studies in the mammalian system suggested a role for the Trr homolog Mll3 in similar processes. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing a unique subunit, the H3K27 demethylase UTX, we propose a model in which the H3K4 monomethyltransferases Trr/Mll3/Mll4 and the H3K27 demethylase UTX cooperate to regulate the transition from inactive/poised to active enhancers.
Generating extracellular amyloid aggregates using E. coli cells
Authors: Sivanathan Viknesh , Hochschild Ann
Published: November 2012

Diverse proteins are known to be capable of forming amyloid aggregates, self-seeding fibrillar assemblies that may be biologically functional or pathological. Well-known examples include neurodegenerative disease-associated proteins that misfold as amyloid, fungal prion proteins that can transition to a self-propagating amyloid form and certain bacterial proteins that fold as amyloid at the cell surface and promote biofilm formation. To further explore the diversity of amyloidogenic proteins, generally applicable methods for identifying them are critical. Here we describe a cell-based method for generating amyloid aggregates that relies on the natural ability of Escherichia coli cells to elaborate amyloid fibrils at the cell surface. We use several different yeast prion proteins and the human huntingtin protein to show that protein secretion via this specialized export pathway promotes acquisition of the amyloid fold specifically for proteins that have an inherent amyloid-forming propensity. Furthermore, our findings establish the potential of this E. coli-based system to facilitate the implementation of high-throughput screens for identifying amyloidogenic proteins and modulators of amyloid aggregation.
Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta‐analysis of the LEAD program
Authors: Armstrong M. J. , Houlihan D. D. , Rowe I. A. , Clausen W. H. O. , Elbrønd B. , Gough S. C. L. , Tomlinson J. W. , Newsome P. N.
Published: November 2012

Background

Non‐alcoholic fatty liver disease has reached epidemic proportions in type 2 diabetes (T2D). Glucagon‐like peptide‐1 analogues are licensed in T2D, yet little data exist on efficacy and safety in liver injury.

Aim

To assess the safety and efficacy of 26‐week liraglutide on liver parameters in comparison with active‐placebo.

Methods

Individual patient data meta‐analysis was performed using patient‐level data combined from six 26‐week, phase‐III, randomised controlled T2D trials, which comprise the ‘Liraglutide Effect and Action in Diabetes’ (LEAD) program. The LEAD‐2 sub‐study was analysed to assess the effect on CT‐measured hepatic steatosis.

Results

Of 4442 patients analysed, 2241 (50.8%) patients had an abnormal ALT at baseline [mean ALT 33.8(14.9) IU/L in females; 47.3(18.3) IU/L in males]. Liraglutide 1.8 mg reduced ALT in these patients vs. placebo (−8.20 vs. −5.01 IU/L; P = 0.003), and was dose‐dependent (no significant differences vs. placebo with liraglutide 0.6 or 1.2 mg). This effect was lost after adjusting for liraglutide's reduction in weight (mean ALT difference vs. placebo −1.41 IU/L, P = 0.21) and HbA1c (+0.57 IU/L, P = 0.63). Adverse effects with 1.8 mg liraglutide were similar between patients with and without baseline abnormal ALT. In LEAD‐2 sub‐study, liraglutide 1.8 mg showed a trend towards improving hepatic steatosis vs. placebo (liver‐to‐spleen attenuation ratio +0.10 vs. 0.00; P = 0.07). This difference was reduced when correcting for changes in weight (+0.06, P = 0.25) and HbA1c (0.00, P = 0.93).

Conclusions

Twenty‐six weeks' liraglutide 1.8 mg is safe, well tolerated and improves liver enzymes in patients with type 2 diabetes. This effect appears to be mediated by its action on weight loss and glycaemic control.
Genetic relationship of body measurement traits at early age with carcass traits in Japanese black cattle
Authors: Munim Tahmina , Oikawa Takuro , Ibi Takayuki , Kunieda Tetsuo
Published: November 2012

Estimates of genetic parameters were obtained for body measurement traits of 648 animals at 4 months of age, of 545 at 8 months and carcass traits of 14 972 animals with the use of an animal model by the restricted maximum likelihood procedure. The estimated heritabilities for carcass traits were high (0.41 to 0.54). At 4 months the estimated direct heritabilities for body measurement traits were moderate to high (0.28 to 0.64), except for chest width (0.19); at 8 months they were also moderate to high (0.23 to 0.49), except for chest depth and chest width (0.18 and 0.06, respectively). Maternal heritabilities for all body measurement traits were low at both ages. The results indicate that because of their moderate direct genetic correlations with body measurement traits, carcass weight, rib thickness and subcutaneous fat thickness can be improved; however, rib eye area and beef marbling standard show little such possibility considering their correlation with body measurement traits.
Salt application as an effective measure to control ruderal invaders threatening endangered halophytic plant species
Authors: Khan Zeeba , Albrecht Matthias , Traveset Anna
Published: November 2012

Questions

How does salinity affect germination, seedling performance and survival of the critically endangered Limonium barceloi, compared to ruderal species invading its salt marsh habitat? Is salt application an effective management tool for controlling invaders and favouring endangered halophytes?

Location

Ses Fontanelles, Mallorca, Balearic Islands, Spain.

Methods

The germination of seeds of L. barceloi and nine ruderal species was tested in five salinity levels (0–37 g·L−1), and also in freshwater after a pre‐treatment with seawater. The ruderal study species were: Asphodelus fistulosus, Avena barbata, Geranium molle, Hypochoeris achyrophorus, Oryzopsis miliacea, Plantago coronopus, Reichardia picroides, Sonchus asper and Sonchus tenerrimus. Two salt concentration levels (18 and 37 g·L−1) were applied twice monthly, weekly or twice weekly to examine the effect of salt irrigation schemes on the performance and seedling survival of L. barceloi compared to two of the principal species invading these salt marshes, S. tenerrimus and A. fistulosus.

Results

Germination of L. barceloi and most ruderal species was highest at low salinity (0–8 g·L−1). Seeds of L. barceloi, A. fistulosus and S. tenerrimus were also able to germinate at the highest salinity level, in contrast to the other species. Germination in freshwater after seawater pre‐treatment was highest in L. barceloi (72 ± 6%). Seedling performance and survival of A. fistulosus and S. tenerrimus decreased with frequency and concentration of the salt treatment. An application of 37 g·L−1 salt twice a week reduced seedling survival of A. fistulosus and S. tenerrimus by 83.3 and 91.6%, respectively. In contrast, 100% of the L. barceloi seedlings survived and showed similar performance among treatments.

Conclusions

Limonium barceloi had higher seedling growth and survival than ruderal invaders when salinity levels were high (37 g·L−1). Nevertheless, at lower salinity, ruderal species may germinate and grow better and thus salinity level changes may represent a threat to the survival of this critically endangered species. Although further field testing is required, our experiments suggest that salt application could be an effective measure to protect L. barceloi and other endangered halophytic plant species from less salt‐tolerant invaders.
Prognostic and therapeutic relevance of c‐FLIP in acute myeloid leukaemia
Authors: McLornan Donal , Hay Jodie , McLaughlin Kirsty , Holohan Caitriona , Burnett Alan K. , Hills Robert K. , Johnston Patrick G. , Mills Ken I. , McMullin Mary Frances , Longley Daniel B.
Published: November 2012

Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti‐apoptotic proteins c‐FLIPL and c‐FLIPS (CFLARL and CFLARS, respectively) that play important roles in drug resistance. In univariate analyses of CFLAR mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form CFLAR(L) (but not the short splice form) had significantly lower 3 year overall survival (P = 0·04) compared to those with low expression. In cell line studies, simultaneous down‐regulation of c‐FLIPL and c‐FLIPS proteins using siRNA induced apoptosis in U937 and NB‐4 AML cells, but not K562 or OCI‐AML3 cells. However, dual c‐FLIPL/S downregulation sensitized all four cell lines to apoptosis induced by recombinant tumour necrosis factor‐related apoptosis‐inducing ligand (rTRAIL). Moreover, specific downregulation of c‐FLIPL was found to recapitulate the phenotypic effects of dual c‐FLIPL/S downregulation. The histone deacetylase (HDAC)1/2/3/6 inhibitor Vorinostat was found to potently down‐regulate c‐FLIPL expression by transcriptional and post‐transcriptional mechanisms and to sensitize AML cells to rTRAIL. Further analyses using more selective HDAC inhibitors revealed that HDAC6 inhibition was not required for c‐FLIPL down‐regulation. These results suggest that c‐FLIPL may have clinical relevance both as a prognostic biomarker and potential therapeutic target for HDAC inhibitors in AML although this requires further study.
High expression of KIBRA in low atypical protein kinase C‐expressing gastric cancer correlates with lymphatic invasion and poor prognosis
Authors: Yoshihama Yohei , Izumisawa Yusuke , Akimoto Kazunori , Satoh Yoshinori , Mizushima Taichi , Satoh Kei , Chida Kazuhiro , Takagawa Ryo , Akiyama Hirotoshi , Ichikawa Yasushi , Kunisaki Chikara , Inayama Yoshiaki , Endo Itaru , Nagashima Yoji , Ohno Shigeo
Published: November 2012

Overexpression of atypical protein kinase Cλ/ι (aPKCλ/ι), a regulator of cell polarity, is frequently associated with the poor prognoses of several cancers, including gastric cancer. Recent studies revealed a molecular link between aPKC and KIBRA, an upstream regulator of tumor suppressor Hippo pathway that regulates cell proliferation and apoptosis. Further, KIBRA directly inhibits the kinase activity of aPKC to regulate epithelial cell polarity. These observations suggest that the KIBRA‐aPKC connection plays a role in cancer progression; however, clinical significance of the correlation between these factors remains unclear. Here we examined the correlation between KIBRA/aPKCλ/ι expression, as detected by immunohistochemistry, and clinicopathological outcomes in 164 gastric cancer patients using Fisher's exact test and Kaplan–Meier log‐rank test. We found an intimate correlation between the expression level of KIBRA and aPKCλ/ι (P = 0.012). Furthermore, high expression of KIBRA is correlated with lymphatic (P = 0.046) and venous invasion (P = 0.039). The expression level of KIBRA by itself did not correlate with the prognosis; however, high expression of KIBRA in low aPKCλ/ι‐expressing gastric cancer correlated with disease‐specific (P = 0.037) and relapse‐free survival (P = 0.041) by Kaplan–Meier with log‐rank test and higher lymphatic invasion cases by Fisher's exact test (P = 0.042). Furthermore, overexpression of the aPKC‐binding region of KIBRA disrupted tight junctions in epithelial cells. These results suggest that high expression of KIBRA in low aPKC‐expressing cells causes massive loss of aPKC activity, leading to loss of polarity and invasiveness of gastric cancer cells.
Ataxia telangiectasia mutated‐dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor
Authors: Tamaichi Hiroyuki , Sato Masaki , Porter Andrew C. G. , Shimizu Toshiaki , Mizutani Shuki , Takagi Masatoshi
Published: November 2012

Topoisomerase II alpha (TOP2A) has a crucial role in proper chromosome condensation and segregation. Here we report the interaction of TOP2A with ataxia telangiectasia mutated (ATM) and its phosphorylation in an ATM‐dependent manner after DNA damage. In vitro kinase assay and site‐directed mutagenesis studies revealed that serine 1512 is the target of phosphorylation through ATM. Serine 1512 to Alanine mutation of TOP2A showed increased stability of the protein, retaining TOP2A activity at least with regard to cell survival activity. Ataxia telangiectasia‐derived cell lines showed high levels of TOP2A that were associated with hypersensitivity to the TOP2 inhibitor etoposide. These findings suggest that ATM‐dependent TOP2A modification is required for proper regulation of TOP2 stability and subsequently of the sensitivity to TOP2 inhibitor. In a lymphoblastoid cell line derived from a patient who developed MLL rearrangement, positive infant leukemia, defective ATM expression, and increased TOP2A expression were shown. It was intriguing that hypersensitivity to TOP2 inhibitor and susceptibility to MLL gene rearrangement were shown by low‐dose etoposide exposure in this cell line. Thus, our findings have clinically important implications for the pathogenesis of infantile acute leukemia as well as treatment‐associated secondary leukemia following exposure to TOP2 inhibitors.
Making a connection: school engagement of young people in care
Authors: Tilbury Clare , Creed Peter , Buys Nicholas , Osmond Jennifer , Crawford Meegan
Published: November 2012

Intervention to improve educational attainment for children in out‐of‐home care is increasingly being recognized as important for their well‐being and future opportunities. This paper reports on a mixed method study of the school engagement or connectedness of young people in care. The study comprised a survey of 202 young people in care in Queensland, Australia, and a matched comparison group of young people not in care, plus interviews with a subset of 65 young people in care who were surveyed. Both the school environment and the perceived levels of support influenced school engagement, with those who were assisted by carers and caseworkers more likely to be positively connected with school. These young people perceived education as a pathway to achieving work and life goals. The findings suggest that active and focused attention on young people's school engagement should be part of case planning and monitoring as it offers an additional strategy for improving their educational experience.
Transient Lack of Glucose but not O2 is Involved in Ischemic Postconditioning‐Induced Neuroprotection
Authors: Fan Yan‐Ying , Zhang Xiang‐Nan , He Ping , Shen Zhe , Shen Yao , Wang Xiao‐Fen , Hu Wei‐Wei , Chen Zhong
Published: November 2012

Aim

Cerebral ischemic postconditioning has emerged recently as a kind of endogenous strategy for neuroprotection. We set out to test whether hypoxia or glucose deprivation (GD) would substitute for ischemia in postconditioning.

Methods

Adult male C57BL/6J mice were treated with postconditioning evoked by ischemia (bilateral common carotid arteries occlusion) or hypoxia (8% O2) after 45‐min middle cerebral arterial occlusion. Corticostriatal slices from mice were subjected to 1‐min oxygen‐glucose deprivation (OGD), GD, or oxygen deprivation (OD) postconditioning at 5 min after 15‐min OGD.

Results

Hypoxic postconditioning did not decrease infarct volume or improve neurologic function at 24 h after reperfusion, while ischemic postconditioning did. Similarly, OGD and GD but not OD postconditioning attenuated the OGD/reperfusion‐induced injury in corticostriatal slices. The effective duration of low‐glucose (1 mmol/L) postconditioning was longer than that of OGD postconditioning. Moreover, OGD and GD but not OD postconditioning reversed the changes of glutamate, GABA, glutamate transporter‐1 protein expression, and glutamine synthetase activity induced by OGD/reperfusion.

Conclusions

These results suggest that the transient lack of glucose but not oxygen plays a key role in ischemic postconditioning‐induced neuroprotection, at least partly by regulating glutamate metabolism. Low‐glucose postconditioning might be a clinically safe and feasible therapeutic approach against cerebral ischemia/reperfusion injury.
Interactive Team Cognition
Authors: Cooke Nancy J. , Gorman Jamie C. , Myers Christopher W. , Duran Jasmine L.
Published: November 2012

Cognition in work teams has been predominantly understood and explained in terms of shared cognition with a focus on the similarity of static knowledge structures across individual team members. Inspired by the current zeitgeist in cognitive science, as well as by empirical data and pragmatic concerns, we offer an alternative theory of team cognition. Interactive Team Cognition (ITC) theory posits that (1) team cognition is an activity, not a property or a product; (2) team cognition should be measured and studied at the team level; and (3) team cognition is inextricably tied to context. There are implications of ITC for theory building, modeling, measurement, and applications that make teams more effective performers.
Improving quality of care among COPD outpatients in Denmark 2008–2011
Authors: Tøttenborg Sandra Søgaard , Thomsen Reimar Wernich , Nielsen Henrik , Johnsen Søren Paaske , Frausing Hansen Ejvind , Lange Peter
Published: November 2012

Objective

To examine whether the quality of care among Danish patients with chronic obstructive pulmonary disease (COPD) has improved since the initiation of a national multidisciplinary quality improvement program.

Methods

We conducted a nationwide, population‐based prospective cohort study using data from the Danish Clinical Register of COPD. Since 2008, the register has systematically monitored and audited the use of recommended processes of COPD care.

Results

Substantial improvements were observed for all processes of care and registration fulfillment increased to well above 85% for all indicators. Compared with 2008, a higher proportion of COPD outpatients in 2011 received annual measurements of the forced expiratory volume in 1 s in percent of predicted [relative risk (RR) 2.14, 95% confidence interval (CI), 2.09; 2.19], assessment of body mass index (RR 2.24, 95% CI, 2.19; 2.29), assessment of dyspnea using the Medical Research Council scale (RR 2.25, 95% CI, 2.20; 2.31), registration of smoking status (RR 2.41, 95% CI, 2.35; 2.47), smoking cessation recommendation (RR 3.40, 95% CI, 3.18; 3.64) and offering of pulmonary rehabilitation (RR 2.78, 95% CI, 2.65; 2.90). Moderate variation in quality of care fulfillment between regions and hospital clinics still existed in 2011. The proportion of patients with mild to moderate COPD increased during the study period (P < 0.0001).

Conclusion

Based on increased registration practice of important processes of care, the present study indicates a substantial improvement in the quality of care of COPD in Danish hospitals following the initiation of a national multidisciplinary quality improvement program in 2008. In the forthcoming years, it will be interesting to observe if this will translate into a better prognosis for Danish patients with COPD.
Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose‐finding study
Authors: Wilding J. P. H. , Ferrannini E. , Fonseca V. A. , Wilpshaar W. , Dhanjal P. , Houzer A.
Published: November 2012

Aims

Ipragliflozin is a novel, selective inhibitor of sodium glucose co‐transporter 2 (SGLT2 inhibitor) in clinical development for type 2 diabetes mellitus (T2DM) treatment. This study assessed the efficacy and safety of different doses of ipragliflozin.

Methods

In a 12‐week, multicentre, double‐blind, randomized, placebo‐controlled, dose‐finding study patients with inadequate glycaemic control on metformin monotherapy (≥1500 mg/day) were randomized to one of four ipragliflozin treatment groups (12.5, 50, 150 or 300 mg once daily) or placebo. Primary efficacy outcome was mean change from baseline in haemoglobin A1c (HbA1c) compared to placebo at week 12. Adverse events (AEs), vital signs and laboratory safety measurements were assessed.

Results

Ipragliflozin dose dependently decreased HbA1c from baseline to week 12 compared to placebo (−0.22, −0.34, −0.40 and −0.48% for ipragliflozin 12.5, 50, 150 and 300 mg, respectively). Decreases in body weight and blood pressure were observed for all ipragliflozin groups. AEs occurred in 39.7–51.4% of the ipragliflozin groups and 39.4% of placebo patients. Urinary tract infections (1.4–6.9 vs. 6.1%), genital infections (0–4.3 vs. 1.5%) and hypoglycaemia (0–5.9 vs. 3.0%) were similar in the ipragliflozin and placebo groups, respectively, without dose dependency. There were no clinically relevant effects on other safety measurements.

Conclusions

Ipragliflozin treatment improved glycaemic control when added to metformin therapy and may be associated with weight loss and reductions in blood pressure compared to placebo. No safety or tolerability concerns were identified at any of the tested doses supporting the further development of ipragliflozin at ≥50 mg doses in T2DM patients.