bluuebunny/crossref_metadata_2025 huggingface dataset:
Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ
Authors: Merrick David , Mistry Kavita , Wu Jingshing , Gresko Nikolay , Baggs Julie E , Hogenesch John B , Sun Zhaoxia , Caplan Michael J
Published: September 2018

Polycystin-1 (PC1), encoded by the PKD1 gene that is mutated in the autosomal dominant polycystic kidney disease, regulates a number of processes including bone development. Activity of the transcription factor RunX2, which controls osteoblast differentiation, is reduced in Pkd1 mutant mice but the mechanism governing PC1 activation of RunX2 is unclear. PC1 undergoes regulated cleavage that releases its C-terminal tail (CTT), which translocates to the nucleus to modulate transcriptional pathways involved in proliferation and apoptosis. We find that the cleaved CTT of PC1 (PC1-CTT) stimulates the transcriptional coactivator TAZ (Wwtr1), an essential coactivator of RunX2. PC1-CTT physically interacts with TAZ, stimulating RunX2 transcriptional activity in pre-osteoblast cells in a TAZ-dependent manner. The PC1-CTT increases the interaction between TAZ and RunX2 and enhances the recruitment of the p300 transcriptional co-regulatory protein to the TAZ/RunX2/PC1-CTT complex. Zebrafish injected with morpholinos directed against pkd1 manifest severe bone calcification defects and a curly tail phenotype. Injection of messenger RNA (mRNA) encoding the PC1-CTT into pkd1-morphant fish restores bone mineralization and reduces the severity of the curly tail phenotype. These effects are abolished by co-injection of morpholinos directed against TAZ. Injection of mRNA encoding a dominant-active TAZ construct is sufficient to rescue both the curly tail phenotype and the skeletal defects observed in pkd1-morpholino treated fish. Thus, TAZ constitutes a key mechanistic link through which PC1 mediates its physiological functions.
Hfq, a RNA Chaperone, Contributes to Virulence by Regulating Plant Cell Wall–Degrading Enzyme Production, Type VI Secretion System Expression, Bacterial Competition, and Suppressing Host Defense Response in Pectobacterium carotovorum
Authors: Wang Chunting , Pu Tianxin , Lou Wangying , Wang Yujie , Gao Zishu , Hu Baishi , Fan Jiaqin
Published: September 2018

Hfq is a RNA chaperone and participates in a wide range of cellular processes and pathways. In this study, mutation of hfq gene from Pectobacterium carotovorum subsp. carotovorum PccS1 led to significantly reduced virulence and plant cell wall–degrading enzyme (PCWDE) activities. In addition, the mutant exhibited decreased biofilm formation and motility and greatly attenuated carbapenem production as well as secretion of hemolysin coregulated protein (Hcp) as compared with wild-type strain PccS1. Moreover, a higher level of callose deposition was induced in Nicotiana benthamiana leaves when infiltrated with the mutant. A total of 26 small (s)RNA deletion mutants were obtained among a predicted 27 sRNAs, and three mutants exhibited reduced virulence in the host plant. These results suggest that hfq plays a key role in Pectobacterium virulence by positively impacting PCWDE production, secretion of the type VI secretion system, bacterial competition, and suppression of host plant responses.
Plant-Based Culture Media for Improved Growth and Sporulation of Cercospora janseana
Authors: Uppala Sai Sree , Zhou Xin-Gen , Liu Baohua , Wu Mingliang
Published: September 2018

Cercospora janseana is the causal agent of narrow brown leaf spot, one of the major diseases of rice in the United States. In vitro studies were conducted to evaluate various plant-based agar media in comparison with potato dextrose agar (PDA) for their effects on radial growth and sporulation of C. janseana. The agar media were evaluated individually with the following plant-extract ingredients: fresh rice leaves, dried rice leaves, dried rice stems, dried rice roots, dried rice hulls, dried rice straw, rice bran, dried sorghum leaves, and dried barnyard grass leaves. Plant-based extracts obtained from 25, 50, 100, or 200 g/liter (plant material/water) were tested either alone or in combination with 10 and 20% clarified V8 juice. PDA served as the control medium. Media with 10 and 20% V8 juice were also included for comparison. Media were inoculated with a disc of 1-week-old actively growing C. janseana at the center of Petri plates and incubated at 28°C with a 12/12-h (light/dark) cycle for 2 weeks. Radial growth was measured at 7 and 14 days after inoculation (DAI), whereas sporulation was measured at 14 DAI. Radial growth and sporulation differed among various media and their amendment concentrations. Media with extracts of fresh rice leaves, dried rice leaves, dried rice stems, dried barnyard grass leaves, and clarified V8 juice enhanced radial growth compared with the PDA control. Of all the agar media evaluated, fresh rice leaf extract amendment at 25 g/liter with no V8 supplementation consistently supported the greatest radial growth, and 10% V8-only medium resulted in greater sporulation of C. janseana than other media evaluated.
c302: a multiscale framework for modelling the nervous system of
Caenorhabditis elegans
Authors: Gleeson Padraig , Lung David , Grosu Radu , Hasani Ramin , Larson Stephen D.
Published: September 2018

The OpenWorm project has the ambitious goal of producing a highly detailed
in silico
model of the nematode
Caenorhabditis elegans
. A crucial part of this work will be a model of the nervous system encompassing all known cell types and connections. The appropriate level of biophysical detail required in the neuronal model to reproduce observed high-level behaviours in the worm has yet to be determined. For this reason, we have developed a framework, c302, that allows different instances of neuronal networks to be generated incorporating varying levels of anatomical and physiological detail, which can be investigated and refined independently or linked to other tools developed in the OpenWorm modelling toolchain.

This article is part of a discussion meeting issue ‘Connectome to behaviour: modelling
C. elegans
at cellular resolution’.
Life Inside a Dinosaur Bone: a Thriving Microbiome
Authors: Saitta Evan T. , Liang Renxing , Lau Chui Y. , Brown Caleb M. , Longrich Nicholas R. , Kaye Thomas G. , Novak Ben J. , Salzberg Steven , Donohoe Paul , Dickinson Marc , Vinther Jakob , Bull Ian D. , Brooker Richard A. , Martin Peter , Abbott Geoffrey D. , Knowles Timothy D. J. , Penkman Kirsty , Onstott Tullis C.
Published: September 2018

Fossils were long thought to lack original organic material, but the discovery of organic molecules in fossils and sub-fossils, thousands to millions of years old, has demonstrated the potential of fossil organics to provide radical new insights into the fossil record. How long different organics can persist remains unclear, however. Non-avian dinosaur bone has been hypothesised to preserve endogenous organics including collagen, osteocytes, and blood vessels, but proteins and labile lipids are unstable during diagenesis or over long periods of time. Furthermore, bone is porous and an open system, allowing microbial and organic flux. Some of these organics within fossil bone have therefore been identified as either contamination or microbial biofilm, rather than original organics. Here, we use biological and chemical analyses of Late Cretaceous dinosaur bones and sediment matrix to show that dinosaur bone hosts a diverse microbiome. Fossils and matrix were freshly-excavated, aseptically-acquired, and then analysed using microscopy, spectroscopy, chromatography, spectrometry, DNA extraction, and 16S rRNA amplicon sequencing. The fossil organics differ from modern bone collagen chemically and structurally. A key finding is that 16S rRNA amplicon sequencing reveals that the subterranean fossil bones host a unique, living microbiome distinct from that of the surrounding sediment. Even in the subsurface, dinosaur bone is biologically active and behaves as an open system, attracting microbes that might alter original organics or complicate the identification of original organics. These results suggest caution regarding claims of dinosaur bone ‘soft tissue’ preservation and illustrate a potential role for microbial communities in post-burial taphonomy.
Alzheimer’s disease Phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Authors: Magno Lorenza , Lessard Christian B , Martins Marta , Cruz Pedro , Katan Matilda , Bilsland Jamie , Chakrabaty Paramita , Golde Todd E , Whiting Paul J
Published: September 2018

Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset AD (LOAD). Amongst these, a polymorphism in Phospholipase C-gamma 2 (PLCG2) P522R, has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function.

We confirmed that PLCG2 expression is restricted primarily to microglia in both the healthy and AD brain. Functional analysis of the P522R variant in heterologous systems demonstrated a small hypermorphic effect of the mutation on enzyme function. PLCγ2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLCγ2 may be one potential therapeutic approach.

ThePLCG2P522R variant is protective against Alzheimer’s disease (AD). We show that PLCG2 is expressed in CNS-resident myeloid cells, and the P522R polymorphism weakly activates enzyme function. These data suggest that activation of PLCG2 and not inhibition could be therapeutically beneficial in AD.
Quantification of protein mobility and associated reshuffling of cytoplasm during chemical fixation
Authors: Huebinger Jan , Spindler Jessica , Holl Kristin J. , Koos Björn
Published: September 2018

To understand cellular functionalities, it is essential to unravel spatio-temporal patterns of molecular distributions and interactions within living cells. The technological progress in fluorescence microscopy now allows in principle to measure these patterns with sufficient spatial resolution. However, high resolution imaging comes along with long acquisition times and high phototoxicity. Physiological live cell imaging is therefore often unfeasible and chemical fixation is employed. However, fixation methods have not been rigorously reviewed to preserve patterns at the resolution at which they can be nowadays imaged. A key parameter for this is the time span until fixation is completed. During this time, cells are under unphysiological conditions and patterns decay. We demonstrate here that formaldehyde fixation takes more than one hour for cytosolic proteins in cultured cells. Associated with this, we found a distinct displacement of proteins and lipids, including their loss from the cells. Other small aldehydes like glyoxal or acrolein showed inferior results. Fixations using glutaraldehyde were faster than four minutes and retained most cytoplasmic proteins. Surprisingly, autofluorescence produced by glutaraldehyde was almost completely antagonized by supplementary addition of formaldehyde without compromising fixation speed. These findings indicate, which cellular processes can actually be reliably imaged after a certain chemical fixation.
Comparative Performance of the Finite Element Method and the Boundary Element Fast Multipole Method for Problems Mimicking Transcranial Magnetic Stimulation (TMS)
Authors: Htet Aung Thu , Saturnino Guilherme B. , Burnham Edward H. , Noetscher Gregory M. , Nummenmaa Aapo , Makarov Sergey N.
Published: September 2018

A study pertinent to the numerical modeling of cortical neurostimulation is conducted in an effort to compare the performance of the finite element method (FEM) and an original formulation of the boundary element fast multipole method (BEM-FMM) at matched computational performance metrics. We consider two problems: (i) a canonic multi-sphere geometry and an external magnetic-dipole excitation where the analytical solution is available and; (ii) a problem with realistic head models excited by a realistic coil geometry. In the first case, the FEM algorithm tested is a fast open-source getDP solver running within the SimNIBS 2.1.1 environment. In the second case, a high-end commercial FEM software package ANSYS Maxwell 3D is used. The BEM-FMM method runs in the MATLAB®2018a environment.

In the first case, we observe that the BEM-FMM algorithm gives a smaller solution error for all mesh resolutions and runs significantly faster for high-resolution meshes when the number of triangular facets exceeds approximately 0.25 M. We present other relevant simulation results such as volumetric mesh generation times for the FEM, time necessary to compute the potential integrals for the BEM-FMM, and solution performance metrics for different hardware/operating system combinations. In the second case, we observe an excellent agreement for electric field distribution across different cranium compartments and, at the same time, a speed improvement of three orders of magnitude when the BEM-FMM algorithm used.

This study may provide a justification for anticipated use of the BEM-FMM algorithm for high-resolution realistic transcranial magnetic stimulation scenarios.
Pituitary carcinoma: The University of Texas MD Anderson Cancer Center experience
Authors: Santos-Pinheiro Fernando , Penas-Prado Marta , Kamiya-Matsuoka Carlos , Waguespack Steven G , Mahajan Anita , Brown Paul D , Shah Komal B , Fuller Gregory N , McCutcheon Ian E
Published: September 2018

Background: Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and frequently recur. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits accurate assessment. Methods: We describe a single-center experience in managing PC over a 22-year period and review previously published PC series. Results: 17 patients were identified. Median age at PC diagnosis was 44 years (range 16-82), and the median PA-to-PC conversion time was 5 years (range 1-29). Median follow-up was 28 months (range 8-158) with 7 deaths. Most PC were hormone-positive based on immunohistochemistry (n=12): ACTH (n=5), PRL (n=4), LH/FSH (n=2), GH (n=1). All patients underwent at least one resection and one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had metastases only to the CNS, and 6 (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest period of disease control in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression in 8 (47%) cases. The 2, 3 and 5-year survival rate of the entire cohort was 71%, 59% and 35%, respectively. All patients surviving >5 years were treated with TMZ-based therapy. Conclusions: PC treatment requires a multidisciplinary approach and multimodality therapy including surgery, radiation and chemotherapy. TMZ-based therapy was associated with higher survival rates and longer disease control.

Precis

We describe 17 PC patients who were diagnosed and treated at MDACC over a 22-year period. We have found that TMZ-based therapy correlated with longer disease control and higher survival rate.
Evolution of Replication Origins in Vertebrate Genomes: Rapid Turnover Despite Selective Constraints
Authors: Massipa Florian , Laurent Marc , Brossas Caroline , Fernández-Justel José Miguel , Gómez María , Prioleau Marie-Noelle , Duret Laurent , Picardb Franck
Published: September 2018

Background

The replication programme of vertebrate genomes is driven by the chro-mosomal distribution and timing of activation of tens of thousands of replication origins. Genome-wide studies have shown the frequent association of origins with promoters and CpG islands, and their enrichment in G-quadruplex sequence motifs (G4). However, the genetic determinants driving their activity remain poorly understood. To gain insight on the functional constraints operating on replication origins and their spatial distribution, we conducted the first evolutionary comparison of genome-wide origins maps across vertebrates.

Results

We generated a high resolution genome-wide map of chicken replication origins (the first of a bird genome), and performed an extensive comparison with human and mouse maps. The analysis of intra-species polymorphism revealed a strong depletion of genetic diversity on an ~ 40 bp region centred on the replication initiation loci. Surprisingly, this depletion in genetic diversity wasnotlinked to the presence of G4 motifs, nor to the association with promoters or CpG islands. In contrast, we also showed that origins experienced a rapid turnover during vertebrates evolution, since pairwise comparisons of origin maps revealed that only 4 to 24% of them were conserved between any two species.

Conclusions

This study unravels the existence of a novel genetic determinant of replication origins, the precise functional role of which remains to be determined. Despite the importance of replication initiation activity for the fitness of organisms, the distribution of replication origins along vertebrate chromosomes is highly flexible.
Dynamic Control of Ca2+Binding in the C2 Domains of Synaptotagmin 1
Authors: Rock Patrick J. , Meyer Austin G. , Evans Chantell S. , Chapman Edwin R. , Sutton R. Bryan
Published: September 2018

Synaptotagmin senses fluctuations in the Ca2+environment of neurons near active zones and transduces a signal to the SNARE complex to initiate exocytosis at the presynaptic terminus. The 3D structures of the two tandem C2 domains of synaptotagmin have been determined to high resolution; however, it is currently unclear how each domain dynamically interacts with Ca2+at the atomic level. To study the mechanistic consequences of the lethal mutations at the AD3 locus, we introduced tyrosine to asparagine point mutations in both the C2A and C2B domains of synaptotagmin 1, and we have constructed a model that describes the relationship between Ca2+-binding and the structural changes within each C2 domain. We show that the mobility of loop 3 in the Ca2+binding pocket increases markedly in C2A, while the mobility of loop 1 changes in C2B with the AD3 mutation. This increase in loop mobility results in an increase in the average volume and variance of the Ca2+-binding pockets of C2A and C2B. The volume of the unbound Ca2+-binding pocket in C2A is usually restrained by intra-domain interactions between the tyrosine residue at the AD3 locus and residues on loop 3; however, the AD3 mutation decouples the restraint and results in a larger, more variable Ca2+-binding pocket in C2A. C2B maintains a more compact Ca2+-binding pocket; however, its volume also fluctuates significantly with the AD3 mutation. Changes in binding pocket volume that involve more variable Ca2+binding loops would likely affect Ca2+affinity in the neurons of the affected organism. Using molecular-dynamics simulations, we show that mutations at the AD3 locus alter the mobility of the Ca2+-binding loops by removing a key stabilization mechanism that is normally present in C2 domains. The lack of loop stabilization results in a net increase in the volume of the Ca2+-binding pocket and provides an explanation for the observed lethal phenotype.
The adequacy of tissue microarrays in the assessment of inter- and intra-tumoural heterogeneity of infiltrating lymphocyte burden in leiomyosarcoma
Authors: Lee ATJ , Chew W , Smith MJ , Strauss DC , Fisher C , Hayes AJ , Judson I , Thway K , Jones RL , Huang PH
Published: September 2018

The characterisation and clinical relevance of tumour-infiltrating lymphocytes (TILs) in leiomyosarcoma (LMS), a subtype of soft tissue sarcoma that exhibits histological heterogeneity, is not established. The use of tissue microarrays (TMA) in studies that profile TIL burden is attractive but given the potential for intra-tumoural heterogeneity to introduce sampling errors, the adequacy of this approach is undetermined. In this study, we assessed the histological inter-and intra-tumoural heterogeneity in TIL burden within a retrospective cohort of primary LMS specimens. Using a virtual TMA approach, we also analysed the optimal number of TMA cores required to provide an accurate representation of TIL burden in a full tissue section. We establish that LMS have generally low and spatially homogenous TIL burdens, although a small proportion exhibit higher levels and more heterogeneous distribution of TILs. We show that a conventional and practical number (1-3) of TMA cores is adequate for correct ordinal categorisation of tumours with high or low TIL burden, but that many more cores (≥ 11) is required to accurately estimate absolute TIL numbers. Our findings provide a benchmark for the design of future studies aiming to define the clinical relevance of the immune microenvironments of LMS and other sarcoma subtypes.
Large-scale analysis of redox-sensitive conditionally disordered protein regions reveal their widespread nature and key roles in high-level eukaryotic processes
Authors: Erdős Gábor , Mészáros Bálint , Reichmann Dana , Dosztányi Zsuzsanna
Published: September 2018

Recently developed quantitative redox proteomic studies enable the direct identification of redox-sensing cysteine residues that regulate the functional behavior of target proteins in response to changing levels of reactive oxygen species (ROS). At the molecular level, redox regulation can directly modify the active sites of enzymes, although a growing number of examples indicate the importance of an additional underlying mechanism that involves conditionally disordered proteins. These proteins alter their functional behavior by undergoing a disorder-to-order transition in response to changing redox conditions. However, the extent to which this mechanism is used in various proteomes is currently unknown. Here, we use a recently developed sequence-based prediction tool incorporated into the IUPred2A web server to estimate redox-sensitive conditionally disordered regions on a large scale. We show that redox-sensitive conditional disorder is fairly widespread in various proteomes and that its presence strongly correlates with the expansion of specific domains in multicellular organisms that largely rely on extra stability provided by disulfide bonds or zinc ion binding. The analyses of yeast redox proteomes and human disease data further underlie the significance of this phenomenon in the regulation of a wide range of biological processes, as well as its biomedical importance.
A tensile ring drives tissue flows to shape the gastrulating amniote embryo
Authors: Saadaoui Mehdi , Corson Francis , Rocancourt Didier , Roussel Julian , Gros Jerome
Published: September 2018

Tissue morphogenesis is driven by local cellular deformations, themselves powered by contractile actomyosin networks. While it is well demonstrated that cell-generated forces at the microscopic scale underlie a variety of local morphogenetic processes (e.g. lengthening/ narrowing1–4, bending5–8, or folding9,10), how such local forces are transmitted across tissues to shape them at a mesoscopic scale remains largely unknown. Here, by performing a quantitative analysis of gastrulation in entire avian embryos, we show that the formation of the primitive streak and the associated large-scale rotational tissue flows (i.e. ‘polonaise’ movements11,12) are integral parts of a global process that is captured by the laws of fluid mechanics. We identify a large-scale supracellular actomyosin ring (2 mm in diameter and 250 μm thick) that shapes the embryo by exerting a graded tension along the margin between the embryonic and extra-embryonic territories. Tissue-wide flows arise from the transmission of these localized forces across the embryonic disk and are quantitatively recapitulated by a fluid-mechanical model based on the Stokes equations for viscous flow. We further show that cell division, the main driver of cell rearrangements at this stage13, is required for fluid-like behavior and for the progress of gastrulation movements. Our results demonstrate the power of a hydrodynamic approach to tissue-wide morphogenetic processes14–16 and provide a simple, unified mechanical picture of amniote gastrulation. A tensile embryo margin, in addition to directing tissue motion, could act as an interface between mechanical and molecular cues, and play a central role in embryonic self-organization.
Identifying functional targets from transcription factor binding data using SNP perturbation
Authors: Xiang Jing , Kim Seyoung
Published: September 2018

Transcription factors (TFs) play a key role in transcriptional regulation by binding to DNA to initiate the transcription of target genes. Techniques such as ChIP-seq and DNase-seq provide a genome-wide map of TF binding sites but do not offer direct evidence that those bindings affect gene expression. Thus, these assays are often followed by TF perturbation experiments to determine functional binding that leads to changes in target gene expression. However, such perturbation experiments are costly and time-consuming, and have a well-known limitation that they cannot distinguish between direct and indirect targets. In this study, we propose to use the naturally occurring perturbation of gene expression by genetic variation captured in population SNP and expression data to determine functional targets from TF binding data. We introduce a computational methodology based on probabilistic graphical models for isolating the perturbation effect of each individual SNP, given a large number of SNPs across genomes perturbing the expression of all genes simultaneously. Our computational approach constructs a gene regulatory network over TFs, their functional targets, and further downstream genes, while at the same time identifying the SNPs perturbing this network. Compared to experimental perturbation, our approach has advantages of identifying direct and indirect targets, and leveraging existing data collected for expression quantitative trait locus mapping, a popular approach for studying the genetic architecture of expression. We apply our approach to determine functional targets from the TF binding data for a lymphoblastoid cell line from the ENCODE Project, using SNP and expression data from the HapMap 3 and 1000 Genomes Project samples. Our results show that from TF binding data, functional target genes can be determined by SNP perturbation of various aspects that impact transcriptional regulation, such as TF concentration and TF-DNA binding affinity.
Invadopodia degrade ECM in the G1 phase of the cell cycle
Authors: Bayarmagnai Battuya , Perrin Louisiane , Esmaeili Pourfarhangi Kamyar , Gligorijevic Bojana
Published: September 2018

Invadopodia are cancer cell protrusions rich in structural proteins (e.g. Tks5, cortactin) and proteases (e.g. MT1-MMP) and are responsible for degradation of the extracellular matrix (ECM). Tumor cell invasion and metastasis require cancer cells to be both proliferative and invasive, i.e. migrate through the tissue and assemble invadopodia. While several studies addressed how cell motility parameters change throughout the cell cycle, the relationship between invadopodia and cell cycle progression has not been elucidated. In this study, using invadopodia- and cell cycle- fluorescent markers, we show in 2D and 3D cell cultures, as well as in vivo, that breast carcinoma cells assemble invadopodia and invade into the surrounding ECM preferentially during the G1 phase of the cell cycle. Cells synchronized in the G0/G1 phase of the cell cycle degrade at significantly higher levels during the first 20 hours post-synchronization release. Consistent with this, mRNA and protein levels of the invadopodia key components, cortactin and MT1-MMP, peak at 14 hours post-release. Cell cycle progression is faster in cells in which invadopodia are abolished (by Tks5 knockdown), evidenced by earlier induction of cyclins A and B. A close look at the regulators of G1 revealed that the overexpression of p27kip1, but not p21cip1, causes faster turnover of invadopodia and increased ECM degradation. Furthermore, both endogenous and over-expressed p27kip1 localizes to the sites of invadopodia assembly. Taken together, these findings suggest that invadopodia function is tightly linked to cell cycle progression and is controlled by specific cell cycle regulators. Our results caution that this coordination between invasion and cell cycle must be considered when designing effective chemotherapies.
Onecut factors and Pou2f2 regulate the distribution of V2 interneurons in the mouse developing spinal cord
Authors: Harris Audrey , Masgutova Gauhar , Collin Amandine , Toch Mathilde , Hidalgo-Figueroa Maria , Jacob Benvenuto , Corcoran Lynn M. , Francius Cédric , Clotman Frédéric
Published: September 2018

Acquisition of proper neuronal identity and position is critical for the formation of neural circuits. In the embryonic spinal cord, cardinal populations of interneurons diversify into specialized subsets and migrate to defined locations within the spinal parenchyma. However, the factors that control interneuron diversification and migration remain poorly characterized. Here, we show that the Onecut transcription factors are necessary for proper diversification and distribution of the V2 interneurons in the developing spinal cord. Furthermore, we uncover that these proteins restrict and moderate the expression of spinal isoforms ofPou2f2, a transcription factor known to regulate B-cell differentiation. By gain- or loss-of-function experiments, we show that Pou2f2 contribute to regulate the position of V2 populations in the developing spinal cord. Thus, we uncovered a genetic pathway that regulates the diversification and the distribution of V2 interneurons during embryonic development.

Significance statement

In this study, we identify the Onecut and Pou2f2 transcription factors as regulators of spinal interneuron diversification and migration, two events that are critical for proper CNS development.
Quantitative comparison of camera technologies for cost-effective Super-resolution Optical Fluctuation Imaging (SOFI)
Authors: Van den Eynde Robin , Sandmeyer Alice , Vandenberg Wim , Duwé Sam , Hübner Wolfgang , Huser Thomas , Dedecker Peter , Müller Marcel
Published: September 2018

Super-Resolution (SR) fluorescence microscopy is typically carried out on high-end research microscopes. Super-resolution Optical Fluctuation Imaging (SOFI) is a fast SR technique capable of live-cell imaging, that is compatible with many wide-field microscope systems. However, especially when employing fluorescent proteins, a key part of the imaging system is a very sensitive and well calibrated camera sensor. The substantial costs of such systems preclude many research groups from employing super-resolution imaging techniques.

Here, we examine to what extent SOFI can be performed using a range of imaging hardware comprising different technologies and costs. In particular, we quantitatively compare the performance of an industry-grade CMOS camera to both state-of-the-art emCCD and sCMOS detectors, with SOFI-specific metrics. We show that SOFI data can be obtained using a cost-efficient industry-grade sensor, both on commercial and home-built microscope systems, though our analysis also readily exposes the merits of the per-pixel corrections performed in scientific cameras.
Brain age prediction of healthy subjects on anatomic MRI with deep learning: going beyond with an "explainable AI" mindset
Authors: Herent Paul , Jegou Simon , Wainrib Gilles , Clozel Thomas
Published: September 2018

Objectives: Define a clinically usable preprocessing pipeline for MRI data. Predict brain age using various machine learning and deep learning algorithms. Define Caveat against common machine learning traps.
Data and Methods: We used 1597 open-access T1 weighted MRI from 24 hospitals. Preprocessing consisted in applying: N4 bias field correction, registration to MNI152 space, white and grey stripe intensity normalization, skull stripping and brain tissue segmentation. Prediction of brain age was done with growing complexity of data input (histograms, grey matter from segmented MRI, raw data) and models for training (linear models, non linear model such as gradient boosting over decision trees, and 2D and 3D convolutional neural networks). Work on interpretability consisted in (i) proceeding on basic data visualization like correlations maps between age and voxels value, and generating (ii) weights maps of simpler models, (iii) heatmap from CNNs model with occlusion method.
Results: Processing time seemed feasible in a radiological workflow: 5 min for one 3D T1 MRI. We found a significant correlation between age and gray matter volume with a correlation r = -0.74. Our best model obtained a mean absolute error of 3.60 years, with fine tuned convolution neural network (CNN) pretrained on ImageNet. We carefully analyzed and interpreted the center effect. Our work on interpretability on simpler models permitted to observe heterogeneity of prediction depending on brain regions known for being involved in ageing (grey matter, ventricles). Occlusion method of CNN showed the importance of Insula and deep grey matter (thalami, caudate nuclei) in predictions.
Conclusions: Predicting the brain age using deep learning could be a standardized metric usable in daily neuroradiological reports. An explainable algorithm gives more confidence and acceptability for its use in practice. More clinical studies using this new quantitative biomarker in neurological diseases will show how to use it at its best.
The Integration of Pharmacophore-based 3D QSAR Modeling and Virtual Screening in Safety Profiling: a Case Study to Identify Antagonistic Activities against Adenosine Receptor, A2aR, using 1,897 Known Drugs
Authors: Fan Fan , Warshaviak Dora Toledo , Hamadeh Hisham K. , Dunn Robert T.
Published: September 2018

Safety pharmacology screening against a wide range of unintended vital targets usingin vitroassays is crucial to understand off-target interactions with drug candidates. With the increasing demand forin vitroassays, ligand-and structure-based virtual screening approaches have been evaluated for potential utilization in safety profiling. Although ligand based approaches have been actively applied in retrospective analysis or prospectively within well-defined chemical space during the early discovery stage (i.e., HTS screening and lead optimization), virtual screening is rarely implemented in later stage of drug discovery (i.e., safety). Here we present a case study to evaluate ligand-based 3D QSAR models built based onin vitroantagonistic activity data against adenosine receptor 2A (A2aR). The resulting models, obtained from 268 chemically diverse compounds, were used to test a set of 1,897 chemically distinct drugs, simulating the real-world challenge of safety screening when presented with novel chemistry and a limited training set. Due to the unique requirements of safety screening versus discovery screening, the limitations of 3D QSAR methods (i.e., chemotypes, dependence on large training set, and prone to false positives) are less critical than early discovery screen. We demonstrated that 3D QSAR modelling can be effectively applied in safety assessment prior toin vitroassays, even with chemotypes that are drastically different from training compounds. It is also worth noting that our model is able to adequately make the mechanistic distinction between agonists and antagonists, which is important to inform subsequent in vivo studies. Overall, we present an in-depth analysis of the appropriate utilization and interpretation of pharmacophore-based 3D QSAR models for safety screening.
COMPASS Family Histone Methyltransferase ASH2L Mediates Corticogenesis via Transcriptional Regulation of Wnt Signalling
Authors: Li Liang , Ruan Xiangbin , Wen Chang , Chen Pan , Liu Wei , Zhu Liyuan , Xiang Pan , Zhang Xiaoling , Wei Qunfang , Hou Lin , Yin Bin , Yuan Jiangang , Qiang Boqin , Shu Pengcheng , Peng Xiaozhong
Published: September 2018

Cell fate specification in neural progenitor cells (NPCs) is orchestrated via extrinsic and intrinsic molecular programs, and histone methylation in these decisions has been ascribed to a crucial function regulating gene expression. Here, we show that the COMPASS family histone methyltransferase co-factor ASH2L is required in NPCs proliferation and upper layer cortical projection neurons production and position. Deletion of Ash2l impairs trimethylation of H3K4 and transcriptional machinery specifically for subsets of Wnt-β-catenin signalling, disrupting their transcription and consequently inhibiting the proliferation ability of NPCs in late stages of neurogenesis. Consistently, Ash2l conditional mutants exhibit thinning neocortex with reduced upper layer neurons and altered neuronal position. Moreover, overexpressing β-catenin after Ash2l elimination or knockdown can rescue the proliferation deficiency of NPCs both in vivo and in vitro. These results demonstrate an essential and highly specific role for Ash2l in controlling NPCs proliferation and late-born neurons lamination in corticogenesis via transcriptionally regulating Wnt-β-catenin signalling, and provide clues to how the COMPASS family epigenetic factors coordinate cell fate determination during cortex development.
The model of relationships between pay for individual performance and work engagement
Authors: Kulikowski Konrad
Published: September 2018

Purpose

Research on the relationship between pay for individual performance (PFIP) and work engagement (WE) is limited. The purpose of this paper is to present a model outlining a threefold association between PFIP and WE: a direct association, an indirect association via pay satisfaction and a joint indirect association via pay level and pay satisfaction.

Design/methodology/approach

Structural equation modeling and bootstrapping procedures were used to test hypotheses with regard to these associations based on data obtained from two independent studies: the author’s own research project, and the European Work Conditions Survey 2015.

Findings

In both studies, the author found the hypothesized direct association between PFIP and WE; indirect association between PFIP and WE via pay satisfaction; and a joint indirect association between PFIP and WE via pay level and pay satisfaction.

Research limitations/implications

Given its limited cross-sectional design, future longitudinal research in this area is needed to test the model of relations presented in this paper.

Practical implications

The association between PFIP and WE is weak, and partially mediated by pay satisfaction; thus, it seems that to promote WE, it is not solely sufficient to introduce PFIP into remuneration systems, but that, in addition, PFIP should be aligned with employee pay expectations.

Originality/value

This study contributes to the career development literature by proposing and initially testing a model describing the three ways PFIP may be related to WE, one of the most crucial factors in achieving career success.
A controllable-accuracy stochastic time-domain technique for randomly varying microwave applications
Authors: Papadimopoulos Athanasios N. , Kantartzis Nikolaos V.
Published: September 2018

Purpose

This paper aims to introduce an efficient time-domain formulation of adjustable accuracy for a consistent and trustworthy computation of electromagnetic field characteristics in randomly varying configurations. The developed methodology is carefully certified via comprehensive comparisons with the corresponding outcomes obtained by the Monte Carlo approach.

Design/methodology/approach

The presented methodology uses higher-order approximations of Taylor series expansions of stochastic multivariable functions for the rapid estimation of the electromagnetic field component mean value and confidence intervals of their variance. Toward this objective, new time-update equations for the mean value and the variance of the involved electromagnetic field are elaborately derived.

Findings

The featured technique presents an efficient alternative to the excessively resource-consuming Monte Carlo finite-difference time-domain (MC–FDTD) implementation, which requires an unduly number of realizations to achieve a satisfying convergence. The higher-order stochastic algorithm retrieves accurately the statistical properties of all electromagnetic field in a single simulation, presenting promising accuracy, stability and convergence.

Originality/value

The adjustable-accuracy higher-order scheme introduces a new framework for the derivation of the stochastic explicit time-update equations and precisely computes the required confidence intervals for the electromagnetic field variance instead of the variance itself, which can be deemed a key advantage over existing schemes. This fully controllable formulation results in significantly more accurate calculations of the electromagnetic field variance, especially for larger fluctuations of the involved electromagnetic media parameters.
Organisational ambidexterity in UK high-tech SMEs
Authors: Senaratne Chaminda , Wang Catherine L.
Published: September 2018

Purpose

The purpose of this paper is to explore the nature of organisational ambidexterity, and identify drivers of and barriers to ambidexterity in the high-tech small- and medium-sized enterprises (SMEs) in the UK, using fine-grained qualitative evidence. This is much needed to generate insights on how organisational ambidexterity actually takes place in SMEs.

Design/methodology/approach

This study is exploratory in nature, based on qualitative in-depth interview data collected from 20 UK high-tech SMEs in five industries.

Findings

The results reveal that SMEs leverage resources through intra-firm and inter-firm collaborations to pursue ambidexterity sequentially or simultaneously, using a range of drivers and overcoming a range of barriers.

Research limitations/implications

The data were gathered from a single informant from each firm. Therefore, more in-depth, longitudinal, qualitative research using multiple sources of data may be required to develop deeper insights into ambidexterity.

Practical implications

Managers of high-tech SMEs need to focus on specific barriers to ambidexterity and devise effective mechanisms to promote the drivers of ambidexterity. The mechanisms to achieve ambidexterity as identified in this study will benefit high-tech SMEs in particular, and firms in general.

Originality/value

The study contributes to the understanding of organisational ambidexterity in high-tech SMEs by exploring the mechanisms through which SMEs implement organisational ambidexterity despite their resource constraints. This counteracts the conventional view that it is difficult for SMEs to pursue ambidexterity.
Multiple family therapy for Chinese families of children with attention deficit hyperactivity disorder (ADHD): treatment efficacy from the children’s perspective and their subjective experiences
Authors: Ma Joyce L. C. , Lai Kelly Y. C. , Wan E. S. F. , Xia Lily L. L.
Published: September 2018

This paper reports the results of our study that assessed the treatment efficacy of multiple family therapy (MFT) from the perspective of participating Chinese children with attention deficit hyperactivity disorder (ADHD) and identified their subjective experiences. Forty‐three children with ADHD in the experimental group (EG) completed a forty‐two‐hour MFT, whilst forty‐five children with ADHD in the control group (CG) had attended two writing classes scheduled three months apart that were similar to those of the MFT. Data from the outcome study were gathered using standardized questionnaires and data from the qualitative study were drawn from thirteen children with ADHD who had completed the MFT and attended the focus group interviews (n = 5) or individual interviews (n = 8) conducted in the post‐treatment phase. The results of the Paired sample t‐test and MANOVA indicated no significant changes on the scores for the four measures adopted (perception of competence, hopefulness, parent‐child relationship and perceived social support) in the pre‐ and post‐treatment for the EG and the CG. Five themes emerged from the narratives of children with ADHD, which revealed the children’s subjective experiences with the MFT: (a) full of fun; (b) building friendships through common experiences; (c) a happy family time; (d) safe space; and (e) positive parental responses and communications.
Etalement urbain, comportement de mobilité et fonctionnement de l'offre de transport à Yaoundé
Authors: Mfoulou Olugu Jean Patrick
Published: September 2018

Ce papier évalue le lien entre l'étalement urbain, les comportements de mobilité et le fonctionnement de l'offre de transport à Yaoundé. Il s'agit spécifiquement d'évaluer l'influence des indicateurs urbains, de mobilité, et socio‐économiques d'une zone d'origine sur les choix de mobilités d'une part et les coûts d'autre part. Utilisant les données collectées par la communauté urbaine de Yaoundé (2010), et les modèles logit multinomial et régressions continues, ce papier montre que les indicateurs urbains telles que les densités, l'accessibilité, et les distances origine‐centre centre‐destination influencent les choix de mobilité et ont un impact sur le coût. L'étalement urbain, dû à la forte croissance urbaine non contrôlée par les collectivités territoriales, joue un rôle négatif dans le fonctionnement de l'offre de transport urbain parce qu'il favorise l'offre artisanal de petite capacité et réduit l'efficacité et la compétitivité du transport collectif de masse moins coûteux. Les résultats recommandent de réguler l'étalement urbain, de faciliter l'accessibilité aux transports de masse et de développer un transport collectif efficace et compétitif.
The role of foreign and domestic venture capital in innovation: evidence from China
Authors: Que Jiangjing , Zhang Xueyong
Published: September 2018

This paper analyses the different effects of foreign venture capital (FVC) and domestic venture capital (DVC) on innovation for IPOs. Using patent counts to measure innovation, the results indicate that FVC‐backed firms are less innovative than DVC‐backed firms. Our findings are robust after controlling for the sample selection bias using a propensity score matching approach. One possible underlying mechanism through which FVCs nurture less innovation is their inferior geographic proximity to investment targets.