bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of PEI-coated MNPs on the Regulation of Cellular Focal Adhesions and Actin Stress Fibres
Authors: Narayanasamy Kaarjel K. , Price Joshua C. , Merkhan Marwan , Elttayef Ajile , Dobson Jon , Telling Neil D. 
Published: April 2019

ABSTRACTThe biocompatibility of surface coated/functionalised magnetic nanoparticles (MNPs) is key to their successful incorporation and application in biological systems. Polyethylene imine (PEI) -coated MNPs provide improvedin vitrotransfection efficiency compared to conventional chemical methods such as Lipofectamine and cationic polymers, and are also safer than viral transduction. Commercial cell toxicity assays are useful for end-point and high-throughput screening, providing fast results and an overview of cell health. However these assays only take into account cells that have undergone an extreme toxic response leading to cell death. Cell toxicity is a complex process which can be expressed in many forms, through morphological, metabolic, and epigenetic changes. A common indicator of cell stress and toxic response is increased cell adhesion and stress fibre formation. It is important to identify these changes in cells as it may affect downstream results and applications in biomedicine. This study explores the effect of the nanomagnetic transfection agent PEI-coated MNPs (MNP-PEIs) and an external magnetic field on cell behaviour, by studying particle internalization, changes in cellular morphology, and cell adhesion. We found that MNP-PEIs induced cell stress through a dose-dependent increase in cell adhesion via the overexpression of vinculin and formation of actin stress fibres. While the presence of PEI was the main contributor to increased cell stress, free PEI polyplexes induced higher toxicity compared to PEI bound to MNPs. MNPs without PEI coating however did not adversely affect cells suggesting a chemical effect instead of a mechanical one. In addition, genes identified as being associated with actin fibre regulation and cell adhesion, showed significant increases in expression due to the internalization of the MNP-PEI complex. From these results, we identify anomalous cell behaviour, morphology, and gene expression after interaction with MNP-PEIs, as well as a safe dosage to reduce acute cell toxicity.
White matter microstructure and its relation to longitudinal measures of depressive symptoms in mid-late life
Authors: Shen Xueyi , Adams Mark J , Ritakari Tuula E , Cox Simon R , McIntosh Andrew M , Whalley Heather C 
Published: April 2019

AbstractBackgroundStudies of white matter microstructure in depression typically show alterations in depressed individuals, but they are frequently limited by small sample sizes and the absence of longitudinal measures of depressive symptoms. Depressive symptoms are however dynamic, and understanding the neurobiology of different trajectories could have important clinical implications.MethodsWe examined associations between current and longitudinal measures of depressive symptoms and white matter microstructure (Fractional Anisotropy, FA; Mean Diffusivity; MD) in the UK Biobank Imaging study. Depressive symptoms were assessed on 2-4 occasions over 5.9 to 10.7 years (on N=18,959 individuals on at least two occasions, N=4,444 on four occasions) from which we derived four measures of depressive symptomatology; (i) cross-sectional measure at the time of scan (imaging was conducted at a single time point), and three longitudinal measures, (ii) trajectory (iii) mean and (iv) intra-subject variance over time.ResultsDecreased white matter microstructure in the anterior thalamic radiation demonstrated significant associations across all four measures of depressive symptoms (for MD: β=0.020 to 0.029, pcorr<0.030). The greatest effect sizes were however seen between decreasing white matter integrity and increasing longitudinal progression of symptoms (for MD: β=0.030 to 0.040, pcorr<0.049). Cross-sectional symptom severity was particularly associated with decreased white matter integrity in association fibres and thalamic radiations (MD: β=0.015 to 0.039, pcorr<0.041). While greater mean and within subject variance of depressive symptoms were mainly associated with decreased white matter microstructure within projection fibres (MD: β=0.019 to 0.029, pcorr<0.044).ConclusionsThese findings indicate shared and differential neurobiological associations with severity, course and intra-subject variability of depressive symptoms. This enriches our understanding of the neurobiology underlying dynamic features of the disorder.
Trophic plasticity of the highly invasive topmouth gudgeon (Pseudorasbora parva) inferred from stable isotope analysis
Authors: Rolla Matteo , Consuegra Sofia , de Leaniz Carlos Garcia 
Published: April 2019

AbstractA wide trophic niche and high trophic plasticity are often invoked to explain the successful establishment of many aquatic invaders, but there is little information regarding the diet of most invasive fish in European waters. We combined stomach content and stable isotope analysis (SIA) of13C and15N to examine the trophic niche of the highly invasive topmouth gudgeon (Pseudorasbora parva) in four contrasting ponds and reservoirs in South Wales. Marked differences in diet and trophic position were found among neighbouring systems only a few kilometres apart. The most diverse diet was found in ponds with the fewest number of inter-specific competitors, and resulted in topmouth gudgeon having the highest condition factor, the widest variation in δ13C and δ15N values, and the highest carbon content, typical of generalist feeders. In contrast, topmouth gudgeon that coexisted with other cyprinids, were much more likely to have empty stomachs and relied almost exclusively on plant seeds, resulting in fish having a poor condition factor and low trophic position. Comparisons with other trophic studies indicate that variation in isotope values among neighbouring sites can exceed variation across continents, making it difficult to predict the diet or trophic impacts of the invasive topmouth gudgeon. Given the importance of obtaining reliable data on trophic position for risk assessment, our study shows that the use of SIA could be used to prioritize control and eradication measures that take into account trophic plasticity.
STXBP5/tomosyn regulates the small RhoA GTPase to control the dendritic stability of neurons and the surface expression of AMPA receptors
Authors: Shen Wenjuan , Kilander Michaela B.C. , Bridi Morgan S. , Frei Jeannine A. , Niescier Robert F. , Huang Shiyong , Lin Yu-Chih 
Published: April 2019

AbstractTomosyn, a protein encoded by syntaxin-1-binding protein 5 (STXBP5) gene, has a well-established presynaptic role in the inhibition of neurotransmitter release and the reduction of synaptic transmission by its conical interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) machinery. The postsynaptic role of tomosyn in dendritic arborization, spine stability, and trafficking of ionotropic glutamate receptors remains to be elucidated. We used short hairpin RNA (shRNA) to knock down tomosyn in mouse primary neurons to evaluate the postsynaptic cellular function and molecular signaling regulated by tomosyn. Knockdown of tomosyn led to an increase of RhoA GTPase activity accompanied by compromised dendritic arborization, loss of dendritic spines, decreased surface expression of AMPA receptors, and reduced miniature excitatory postsynaptic current (mEPSC) frequency. Inhibiting RhoA signaling was sufficient to rescue the abnormal dendritic morphology and the surface expression of AMPA receptors. The function of tomosyn regulating RhoA is mediated through the N-terminal WD40 motif, where two variants each carrying a single nucleotide mutation in this region, were found in individuals with autism spectrum disorder (ASD). We demonstrated that these variants displayed loss-of-function phenotypes. Unlike the wild-type tomosyn, these two variants failed to restore the reduced dendritic complexity, spine density, as well as decreased surface expression of AMPA receptors in tomosyn knockdown neurons. This study uncovers a critical role of tomosyn, independent of its interaction with the SNARE machinery, in maintaining neuronal function by inhibiting RhoA activity. Further analysis of tomosyn variants also provides a potential mechanism for explaining cellular pathology in ASD.Significance StatementThis study unveils a vital role of tomosyn in the maintenance of neuronal morphology, basal synaptic transmission, and AMPA receptor surface expression that is distinct from its presynaptic role. Tomosyn affects dendritic stability and glutamate receptor trafficking via the regulation of the Rho signaling pathway and this interaction is likely independent of the interaction with the dendritic SNARE complex, such as syntaxin-4. The WD40 domain of tomosyn is necessary to conduct the Rho regulation and two autism-associated variants localized at the WD40 domain perturb this function. The current study reveals a novel molecular link between dendritic stability and synaptic function, which could advance a greater understanding of the cellular pathologies involved in neurodevelopmental disorders, such as ASD.
Deep learning enables therapeutic antibody optimization in mammalian cells by deciphering high-dimensional protein sequence space
Authors: Mason Derek M , Friedensohn Simon , Weber Cédric R , Jordi Christian , Wagner Bastian , Meng Simon , Gainza Pablo , Correia Bruno E , Reddy Sai T 
Published: April 2019

ABSTRACTTherapeutic antibody optimization is time and resource intensive, largely because it requires low-throughput screening (103 variants) of full-length IgG in mammalian cells, typically resulting in only a few optimized leads. Here, we use deep learning to interrogate and predict antigen-specificity from a massively diverse sequence space to identify globally optimized antibody variants. Using a mammalian display platform and the therapeutic antibody trastuzumab, rationally designed site-directed mutagenesis libraries are introduced by CRISPR/Cas9-mediated homology-directed repair (HDR). Screening and deep sequencing of relatively small libraries (104) produced high quality data capable of training deep neural networks that accurately predict antigen-binding based on antibody sequence. Deep learning is then used to predict millions of antigen binders from an in silico library of ~108 variants, where experimental testing of 30 randomly selected variants showed all 30 retained antigen specificity. The full set of in silico predicted binders is then subjected to multiple developability filters, resulting in thousands of highly-optimized lead candidates. With its scalability and capacity to interrogate high-dimensional protein sequence space, deep learning offers great potential for antibody engineering and optimization.
Evaluating chromatin accessibility differences across multiple primate species using a joint modelling approach
Authors: Edsall Lee E. , Berrio Alejandro , Majoros William H. , Swain-Lenz Devjanee , Morrow Shauna , Shibata Yoichiro , Safi Alexias , Wray Gregory A. , Crawford Gregory E. , Allen Andrew S. 
Published: April 2019

AbstractChanges in transcriptional regulation are thought to be a major contributor to the evolution of phenotypic traits, but the contribution of changes in chromatin accessibility to the evolution of gene expression remains almost entirely unknown. To address this important gap in knowledge, we developed a new method to identify DNase I Hypersensitive (DHS) sites with differential chromatin accessibility between species using a joint modeling approach. Our method overcomes several limitations inherent to conventional threshold-based pairwise comparisons that become increasingly apparent as the number of species analyzed rises. Our approach employs a single quantitative test which is more sensitive than existing pairwise methods. To illustrate, we applied our joint approach to DHS sites in fibroblast cells from five primates (human, chimpanzee, gorilla, orangutan, and rhesus macaque). We identified 89,744 DHS sites, of which 41% are identified as differential between species using the joint model compared with 33% using the conventional pairwise approach. The joint model provides a principled approach to distinguishing single from multiple chromatin accessibility changes among species. We found that non differential DHS sites are enriched for nucleotide conservation. Differential DHS sites with decreased chromatin accessibility relative to rhesus macaque occur more commonly near transcription start sites (TSS), while those with increased chromatin accessibility occur more commonly distal to TSS. Further, differential DHS sites near TSS are less cell type-specific than more distal regulatory elements. Taken together, these results point to distinct classes of DHS sites, each with distinct characteristics of selection, genomic location, and cell type specificity.
The temporal dynamics of background selection in non-equilibrium populations
Authors: Torres Raul , Stetter Markus G , Hernandez Ryan D , Ross-Ibarra Jeffrey 
Published: April 2019

ABSTRACTNeutral genetic diversity across the genome is determined by the complex interplay of mutation, demographic history, and natural selection. While the direct action of natural selection is limited to functional loci across the genome, its impact can have effects on nearby neutral loci due to genetic linkage. These effects of selection at linked sites, referred to as genetic hitchhiking and background selection (BGS), are pervasive across natural populations. However, only recently has there been a focus on the joint consequences of demography and selection at linked sites, and empirical studies have sometimes come to apparently contradictory conclusions as to their combined effects. In order to understand the relationship between demography and selection at linked sites, we conducted an extensive forward simulation study of BGS under a range of demographic models. We found that the relative levels of diversity in BGS and neutral regions vary over time and that the initial dynamics after a population size change are often in the opposite direction of the long-term expected trajectory. Our detailed observations of the temporal dynamics of neutral diversity in the context of selection at linked sites in non-equilibrium populations provides new intuition about why patterns of diversity under BGS vary through time in natural populations and help reconcile previously contradictory observations. Most notably, our results highlight that classical models of BGS are poorly suited for predicting diversity in non-equilibrium populations.
Transcriptomics of monarch butterflies (Danaus plexippus) reveals strong differential gene expression in response to host plant toxicity, but weak response to parasite infection
Authors: Tan Wen-Hao , Acevedo Tarik , Harris Erica V. , Alcaide Tiffanie Y. , Walters James R. , Hunter Mark D. , Gerardo Nicole M. , de Roode Jacobus C. 
Published: April 2019

ABSTRACTHerbivorous insects have evolved many mechanisms to overcome plant chemical defenses, including detoxification and sequestration. Herbivores may also use toxic plants to reduce parasite infection. Plant toxins could directly interfere with parasites or could enhance endogenous immunity. Alternatively, plant toxins could favor down-regulation of endogenous immunity by providing an alternative (exogenous) defense against parasitism. However, studies on genome-wide transcriptomic responses to plant defenses and the interplay between host plant toxicity and parasite infection remain rare. Monarch butterflies (Danaus plexippus) are specialist herbivores that feed on milkweeds (Asclepiasspp.), which contain toxic cardenolides. Monarchs have adapted to cardenolides through multiple resistance mechanisms and can sequester cardenolides to defend against bird predators. In addition, high-cardenolide milkweeds confer medicinal effects to monarchs against a specialist protozoan parasite (Ophryocystis elektroscirrha). We used this system to study the interplay between the effects of plant toxicity and parasite infection on global gene expression. Our results demonstrate that monarch larvae differentially express several hundred genes when feeding onA. curassavicaandA. incarnata, two species that are similar in nutritional content but differ substantially in cardenolide concentrations. These differentially expressed genes include genes within multiple families of canonical insect detoxification genes, suggesting that they play a role in monarch toxin resistance and sequestration. Interestingly, we found little transcriptional response to infection. However, parasite growth was reduced in monarchs reared onA. curassavica, and in these monarchs, a small number of immune genes were down-regulated, consistent with the hypothesis that medicinal plants can reduce reliance on endogenous immunity.
Application of grey entropy weight cluster in clinical department sorting
Authors: Zheng Jiachun , Chen Xiao-Jun , Qiu Suihong , Liu Sifeng , Chen Shaoxing 
Published: April 2019

Purpose
The purpose of this paper is to explore the method of clinical department classification in comprehensive hospital to provide a scientific management reference in performance evaluation.

Design/methodology/approach
In order to perform the classification of clinical departments, a grey cluster model was constructed. In this model, the benefit index of each clinical department was analyzed using grey associative analysis, and a superior index was chosen to incorporate in this model. Through the relevancy degree of superior index, the authors confirmed the weight of index, and the quintile threshold was calculated by a quintile method and whitening weight functions were constructed.

Findings
This model, based on grey entropy weight cluster, can reasonably distinguish the merits of clinical departments. From the case we study, neurology?/Cardiovasology?/Integrated disease and Emergency were the optimum assessing department.

Originality/value
The results demonstrated that the index selection, weight determination, whitening weight functions and model construction in this study could provide technique’s reference and application for hospital administrators. It avoids the subjective discrimination and reduces the influence of sample noise, and it is easy to perform while conducting performance evaluation in a comprehensive hospital.
Barriers to the use of property taxation in municipal finance
Authors: Grover Richard , Walacik Marek , Buzu Olga , Gunes Tugba , Raskovic Marija , Yildiz Umit 
Published: April 2019

Purpose
This study aims to present the findings from a series of case studies that examine the problems faced by countries seeking to introduce value-based recurrent property taxes to replace the ones levied on the basis of area or inventory value. It identifies that two of the most significant barriers are the absence of comprehensive list of taxable properties and inadequate data on transaction prices. Both of these can be overcome with sufficient resources, but this raises the question as to why governments are reluctant to do so, in spite of the advantages of such a change.

Design/methodology/approach
The paper makes particular use of case studies of Moldova, Poland, Serbia and Turkey, which have explored the potential of introducing value-based recurrent property taxes and the issues they have faced. The case studies have been produced by participant observers who have had the opportunity to examine developments over long periods of time. The case studies are set against a wider statistical analysis of the role of recurrent property taxes in tax systems.

Findings
Putting in place comprehensive systems for registering properties and recording their characteristics and systematically collecting data on transaction prices require significant investment over a long period of time. This requires commitment on behalf of governments. Governments may be reluctant to support this because of the opposition such reforms can face unless confronted with compelling fiscal or external pressures to act.

Research limitations/implications
The issues identified are the ones that many countries seeking to introduce value-based recurrent property taxes will face and puts forward how they can be tackled. The case study countries are middle-income ones with relatively well-developed infrastructure, which low-income countries may lack.

Practical implications
The solutions to overcoming the barriers to value-based recurrent property taxes encountered in the case study countries are the ones that are applicable to many other countries, who can learn from their experience.

Originality/value
The paper provides a perspective on overcoming the issues encountered in introducing value-based property taxes from the viewpoint of those who have been involved in working out ways of overcoming them and so provides insight that is a useful addition to the literature.
Rethinking the internal mechanism of the EGMONT group in financial crime control
Authors: Adetunji Johnson Adeoye 
Published: April 2019

PurposeThis paper aims to evaluate the use of Intelligence gathering, especially the exercise of customer due diligence (CDD), enhanced due diligence (EDD), know your customer (KYC) and recordkeeping as effective anti-money laundering (AML) and counter-terrorism financing (CTF) measures. It re-appraises the risk of breach of privacy associated with recordkeeping of clients’ information in countries where there are no data protection laws and the role of the EGMONT group against the backdrop of the recent suspension of Nigeria from the group; it argues that, in view of other existing liberal punitive measures, suspending a developing nation like Nigeria by the EGMONT group (arising from a rigid demand for an autonomous financial intelligence unit (FIU)) is draconian and counterproductive. Finally, it argues that the fundamental needs and challenges of developing member states of the EGMONT group, particularly members that are battling with weak and non-transparent investigation process and terrorism require, inter alia, technical and manpower assistance to disrupt financial crime and financing of terrorism.Design/methodology/approachA doctrinal approach is utilised to analyse AML and CTF from the social and historical perspectives. A comparative analysis of international control of money laundering and terrorist financing, appraising the challenges of developing member states in complying with the Financial Action Task Force regulations and the principles of the Egmont group.FindingsThere are liberal punitive measures than suspension which the EGMONT group could apply when dealing with developing members of the group, especially on the issue of rigid demand for an autonomy of a national FIU. The fundamental needs and challenges of developing member states of the Egmont group, particularly members that are battling with weak and non-transparent investigation process and terrorism require, inter alia, technical and manpower assistance to disrupt financial crime and financing of terrorism.Originality/valueThe paper queries the appropriateness of the decision to suspend Nigeria by the Egmont group for failure to comply with its policy autonomy of its FIU when there are other liberal disciplinary measures that could have been applied. And, it suggests the need to lay more emphasis on technical assistance for member states to achieve the objectives of the group.