bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional regulation profiling reveals disrupted lipid metabolism in failing hearts with a pathogenic phospholamban mutation
Authors: Pei Jiayi , Maas Renee G.C. , Nagyova Ema , Gho Johannes M.I.H. , Blok Christian Snijders , van Adrichem Iris , Calis Jorg J.A. , van Es René , Sepehrkhouy Shahrzad , Feyen Dries , van den Dungen Noortje , Lansu Nico , de Jonge Nicolaas , den Ruijter Hester M. , Huibers Manon M.H. , de Weger Roel A. , van Laake Linda W. , Verhaar Marianne C. , van Tintelen Peter , van Steenbeek Frank G. , van Mil Alain , Buikema Jan W. , Burgering Boudewijn , Kararikes Ioannis , Mercola Mark , Doevendans Pieter A. , Sluijter Joost , Vink Aryan , Cheng Caroline , Mokry Michal , Asselbergs Folkert W. , Harakalova Magdalena 
Published: December 2020

ABSTRACTBackgroundThe R14del mutation in the phospholamban (PLN) gene is associated with various types of cardiomyopathies and increases the risk of developing life-threatening ventricular arrhythmias. In this study, we focused on a homogeneous Dutch founder cohort of genetic cardiomyopathy due to PLN R14del mutation and aimed to study the influence of epigenetic changes from a multi-dimensional perspective.ResultsUsing cardiac tissue of PLN R14del patients and donors, we identified differentially acetylated promoters and enhancers (H3K27ac ChIPseq), annotated enriched transcription factor (TF) binding motifs located in those regions, and identified differentially expressed genes (RNA-seq). In line with the fibrofatty replacement in PLN R14del hearts at the histological level, our integrative analysis detected the downregulation of key TF regulators in fatty acid oxidation (FAO) metabolisms and their downstream target in PLN R14del hearts as compared to controls. We further examined heart tissue using immunofluorescence staining (IF) and to confirm the mitochondrial lipid abnormalities in the PLN R14del hearts. Furthermore, we observed the accumulation and deformation of lipid droplets and a disrupted morphology of mitochondria, the key organelle where FAO takes place, in PLN R14del heart using transmission electron microscopy (TEM).ConclusionUsing multi-omics approaches, we successfully obtained a unique list of chromatin regions and genes, including TF-coding genes, which played important roles in the metabolism-related signalling in PLN R14del hearts.
Large uncertainty in individual PRS estimation impacts PRS-based risk stratification
Authors: Ding Yi , Hou Kangcheng , Burch Kathryn S. , Lapinska Sandra , Privé Florian , Vilhjálmsson Bjarni , Sankararaman Sriram , Pasaniuc Bogdan 
Published: December 2020

AbstractLarge-scale genome-wide association studies have enabled polygenic risk scores (PRS), which estimate the genetic value of an individual for a given trait. Since PRS accuracy is typically assessed using cohort-level metrics (e.g., R2), uncertainty in PRS estimates at individual level remains underexplored. Here we show that Bayesian PRS methods can estimate the variance of an individual’s PRS and can yield well-calibrated credible intervals for the genetic value of a single individual. For real traits in the UK Biobank (N=291,273 unrelated “white British”) we observe large variance in individual PRS estimates which impacts interpretation of PRS-based stratification; for example, averaging across 13 traits, only 0.8% (s.d. 1.6%) of individuals with PRS point estimates in the top decile have their entire 95% credible intervals fully contained in the top decile. We provide an analytical estimator for individual PRS variance—a function of SNP-heritability, number of causal SNPs, and sample size—and observe high concordance with individual variances estimated via posterior sampling. Finally as an example of the utility of individual PRS uncertainties, we explore a probabilistic approach to PRS-based stratification that estimates the probability of an individual’s genetic value to be above a prespecified threshold. Our results showcase the importance of incorporating uncertainty in individual PRS estimates into subsequent analyses.
Optimized chemogenomic library design strategies for precision oncology
Authors: Athanasiadis Paschalis , Ravikumar Balaguru , Carragher Neil O. , Clemons Paul A. , Johanssen Timothy , Ebner Daniel , Aittokallio Tero 
Published: December 2020

AbstractDesigning a focused compound screening library of bioactive small molecules is a challenging task since many compounds modulate their effects through multiple protein targets with various degrees of potency and selectivity. We describe here several analytic procedures with adjustable cut-off parameters that enable one to design anticancer target-focused compound libraries optimized for library size, cellular activity, biological and chemical diversity and target selectivity. Even though our focus was on designing compound libraries to enable a comprehensive investigation of the target biology of glioblastoma (GBM), the compound collections cover a wide range of protein targets and biological pathways implicated in various types of cancers, making the libraries widely applicable in precision oncology studies. We published the final screening set library, called theComprehensive anti-Cancer small-CompoundLibrary, orC3L.We hope these general library design principles and the current, widely annotated small molecule libraries will prove useful for the community in various phenotypic screening experiments in GBM and other cancers.
On the permeability of cell membranes subjected to lipid oxidation
Authors: Wiczew Daniel , Szulc Natalia , Tarek Mounir 
Published: December 2020

AbstractThe formation of transient hydrophilic pores in their membranes is a well-recognized mechanism of permeabilization of cells exposed to high-intensity electric pulses. However, the formation of such pores alone is not able to explain all aspects of the so-called electroporation phenomenon. In particular, the reasons for the sustained permeability of cell membranes, which persist long after the pulses’ application, remain elusive. The complete resealing of the cell membranes takes indeed orders of magnitude longer than the time of electropore closure as reported from molecular modelling investigations. A possible alternative mechanism to explain the observed long-lived permeability of cell membranes, lipid peroxidation, has been previously suggested but the theoretical investigations of membrane lesions, containing excess amounts of hydroperoxides, have shown that the conductivities of such lesions were not high enough to reasonably explain the entire range of experimental measurements. Here, we expand on these studies and investigate the permeability of cell membrane lesions that underwent secondary oxidation. Molecular dynamics simulations and free energy calculations on lipid bilayers in different states show that such lesions provide a better model for post-pulsed permeable and conductive electropermeabilized cells. These results are further discussed in context of sonoporation and ferroptosis, respectively a procedure and a phenomena, among others, in which alike electroporation substantial lipid oxidation might be triggered.HighlightsThe contribution of secondary lipids’ oxidation to the permeabilization of model membranes is quantitatively assessedSmall patches of secondary lipids’ oxidation cause formation long-lived pores in lipid bilayers.The cholesterol content of membranes enhances the life-time of the formed pores.A single pore accounts for the measured post-pulse electropermeabilization of cells.The diffusion of the secondary oxidation lipids, even after pores closure leads to permeability of lipid membrane.
Interactive Web-based Annotation of Plant MicroRNAs with iwa-miRNA
Authors: Zhang Ting , Zhai Jingjing , Zhang Xiaorong , Ling Lei , Li Menghan , Xie Shang , Song Minggui , Ma Chuang 
Published: December 2020

AbstractMicroRNAs (miRNAs) are important regulators of gene expression. The large-scale detection and profiling of miRNAs has accelerated with the development of high-throughput small RNA sequencing (sRNA-Seq) techniques and bioinformatics tools. However, generating high-quality comprehensive miRNA annotations remains challenging, due to the intrinsic complexity of sRNA-Seq data and inherent limitations of existing miRNA predictions. Here, we present iwa-miRNA, a Galaxy-based framework that can facilitate miRNA annotation in plant species by combining computational analysis and manual curation. iwa-miRNA is specifically designed to generate a comprehensive list of miRNA candidates, bridging the gap between already annotated miRNAs provided by public miRNA databases and new predictions from sRNA-Seq datasets. It can also assist users to select promising miRNA candidates in an interactive mode through the automated and manual steps, contributing to the accessibility and reproducibility of genome-wide miRNA annotation. iwa-miRNA is user-friendly and can be easily deployed as a web application for researchers without programming experience. With flexible, interactive, and easy-to-use features, iwa-miRNA is a valuable tool for annotation of miRNAs in plant species with reference genomes. We illustrated the application of iwa-miRNA for miRNA annotation of plant species with varying complexity. The sources codes and web server of iwa-miRNA is freely accessible at:http://iwa-miRNA.omicstudio.cloud/.
Hierarchical development of dominance through the winner-loser effect and socio-spatial structure
Authors: van Haeringen E.S. , Hemelrijk C.K. 
Published: December 2020

AbstractIn many groups of animals the dominance hierarchy is linear. What mechanisms underlie this linearity of the dominance hierarchy is under debate. Linearity is often attributed to cognitively sophisticated processes, such as transitive inference and eavesdropping. An alternative explanation is that it develops via the winner-loser effect. This effect implies that after a fight has been decided the winner is more likely to win again, and the loser is more likely to lose again. Although it has been shown that dominance hierarchies may develop via the winner-loser effect, the degree of linearity of such hierarchies is unknown.The aim of the present study is to investigate whether a similar degree of linearity, like in real animals, may emerge as a consequence of the winner-loser effect and the socio-spatial structure of group members. For this purpose, we use the model DomWorld, in which agents group and compete and the outcome of conflicts are self-reinforcing. Here dominance hierarchies are shown to emerge. In the model, we apply analytical methods previously used in a study on dominance in real hens including an analysis of behaviourial dynamics and network triad motifs.We show that when in the complete model one parameter, representing the intensity of aggression, was set high, the model reproduced the high linearity and many patterns of hierarchical development typical of groups of hens. Yet, when omitting from the model the winner-loser effect or spatial location of individuals, this resemblance decreased markedly.Our results demonstrate that the spatial structure and the winner-loser effect provide a plausible alternative for hierarchical linearity to processes that are cognitively more sophisticated. Further research should determine whether the winner-loser effect and spatial structure of group members also explains the characteristics of hierarchical development in other species.
Modeling of Internal and External Factors affecting a Complex Dengue Network
Authors: Malik Hafiz Abid Mahmood , Abid Faiza , Wahiddin Mohamed Ridza , Waqas Ahmad 
Published: December 2020

AbstractThere are different factors that are the cause of abrupt spread of arbovirus. We modelled the factors (internal & external) that can increase the diffusion of dengue virus and observed their effects. These factors have influenced on theAedes aegypti(a dengue virus carrier); factors which increase the dengue transmission. Interestingly, there are some factors that can suppress theAedes aegypti. The species ofAedes aegyptiformalizes its own network by which dengue virus is spread. Internal & external exposures of the dengue epidemic complex network have been modelled and analyzed. Influence of internal and external diffusion with two scenarios has been discussed. ‘Genetically modified mosquito’ technique has been applied and its associated simulated results are discussed. From the outcomes, the best time duration to contain the spread of dengue virus has been proposed, and our simulation model showed the possibility of suppressing theAedes aegyptinetwork.
Viral Packaging ATPases Utilize a Glutamate Switch to Couple ATPase Activity and DNA Translocation
Authors: Pajak Joshua , Atz Rockney , Hilbert Brendan J. , Morais Marc C. , Kelch Brian A. , Jardine Paul , Arya Gaurav 
Published: December 2020

SummaryMany viruses utilize ringed packaging ATPases to translocate double-stranded DNA into procapsids during replication. A critical step in the mechanochemical cycle of such ATPases is ATP binding, which causes a subunit within the motor to grip DNA tightly. Here, we probe the underlying molecular mechanism by which ATP binding is coupled to DNA gripping and show that a glutamate switch residue found in AAA+ enzymes is central to this coupling in viral packaging ATPases. Using free energy landscapes computed through molecular dynamics simulations, we determined the stable conformational state of the ATPase active site in apo, ATP-bound, and ADP-bound states. Our results show that the catalytic glutamate residue transitions from an inactive to an active pose upon ATP binding, and that a residue assigned as the glutamate switch is necessary for regulating the transition. Further, we identifiedviamutual information analyses the intramolecular signaling pathway mediated by the glutamate switch that is responsible for coupling ATP binding to conformational transitions of DNA-gripping motifs. We corroborated these predictions with both structural and functional experimental data. Specifically, we showed that the crystal structure of the ADP-bound P74-26 packaging ATPase is consistent with the predicted structural coupling from simulations, and we further showed that disrupting the predicted signaling pathway indeed decouples ATPase activity from DNA translocation activity in the φ29 DNA packaging motor. Our work thus establishes a signaling pathway in viral DNA packaging motors that ensures coordination between chemical and mechanical events involved in viral DNA packaging.
Designed proteins assemble antibodies into modular nanocages
Authors: Divine Robby , Dang Ha V. , Ueda George , Fallas Jorge A. , Vulovic Ivan , Sheffler William , Saini Shally , Zhao Yan Ting , Raj Infencia Xavier , Morawski Peter A. , Jennewein Madeleine F. , Homad Leah J. , Wan Yu-Hsin , Tooley Marti R. , Seeger Franzika , Etemadi Ali , Fahning Mitchell L. , Lazarovits James , Roederer Alex , Walls Alexandra C. , Stewart Lance , Mazloomi Mohammadali , King Neil P. , Campbell Daniel J. , McGuire Andrew T. , Stamatatos Leonidas , Ruohola-Baker Hannele , Mathieu Julie , Veesler David , Baker David 
Published: December 2020

AbstractAntibodies are widely used in biology and medicine, and there has been considerable interest in multivalent antibody formats to increase binding avidity and enhance signaling pathway agonism. However, there are currently no general approaches for forming precisely oriented antibody assemblies with controlled valency. We describe the computational design of two-component nanocages that overcome this limitation by uniting form and function. One structural component is any antibody or Fc fusion and the second is a designed Fc-binding homo-oligomer that drives nanocage assembly. Structures of 8 antibody nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage match the corresponding computational models. Antibody nanocages targeting cell-surface receptors enhance signaling compared to free antibodies or Fc-fusions in DR5-mediated apoptosis, Tie2-mediated angiogenesis, CD40 activation, and T cell proliferation; nanocage assembly also increases SARS-CoV-2 pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-ACE2 fusion proteins. We anticipate that the ability to assemble arbitrary antibodies without need for covalent modification into highly ordered assemblies with different geometries and valencies will have broad impact in biology and medicine.
Considerations and principles for conducting a participatory capacity and vulnerability analysis (PCVA) for disaster risk reduction and climate change adaptation
Authors: Ahmed Iftekhar 
Published: December 2020

Purpose
While there are many such toolkits on community-based participatory methods, the key considerations and principles of conducting a participatory capacity and vulnerability analysis (PCVA) are less covered, yet they are central to the effective conduct of a PCVA, the reason why this paper focuses on such issues.

Design/methodology/approach
This paper is derived from a toolkit that was produced for Oxfam Australia. Disasters and climate change are major drivers of poverty and significantly affect the communities that development programs of Oxfam Australia aim to assist. Recognising the importance of building its organisational capacity to address these risks, Oxfam Australia initiated and commissioned the production of a PCVA toolkit to support disaster risk reduction and climate change adaptation programs; the production of the toolkit was led by the author. The methodology of producing the toolkit consisted of discussions with experts and a review of similar toolkits.

Findings
Details of the PCVA process and how to conduct one in a community setting are provided including PCVA concepts, briefing, logistics and management and principles of working with communities. Importantly, the different stages of conducting a PCVA are explained, and some selected tools are presented as illustrative examples. In conclusion, the importance of the PCVA considerations and principles are reaffirmed vis-à-vis the sensitivity and soft skills required in a low-income developing country setting.

Originality/value
The participatory development approach, which the toolkit follows, has been widely advocated for the past few decades and most non-governmental organisations involved in community development espouse this approach. Consequently, a wide range of participatory development toolkits have been developed, many of which relate to disasters and climate change. The PCVA toolkit discussed in this paper draws on the repertoire of toolkits already available and used over a long time. Nonetheless, effort was given to assembling a range of tools that were most suitable for the purpose of this particular PCVA toolkit. Instead of focussing on the tools, which are available from the freely downloadable toolkit and available in the public domain, in this paper, the PCVA process and its main principles are explained, and the key considerations to carry out an effective PCVA is discussed. Perhaps even more than the actual tools, these considerations and an understanding of the PCVA principles are significant because they underpin the utilisation of the toolkit.
PAPR reduction using OQAM for spectrum sensing
Authors: N. Renuka , M. Satya Sairam 
Published: December 2020

Purpose
The tremendous growth of wireless applications and the demand for high data rate, the spectrum utilization improvement has been the most crucial challenges for wireless communication. Adapting cognitive radio with orthogonal frequency division multiplexing or offset quadrature amplitude modulation (OFDM/OQAM) improves the spectrum and energy efficiencies.

Design/methodology/approach
Thus, it overcomes the spectral leakage problem at the transmitter side and leads to less interference from secondary user (SUs) to primary user (PUs) and between the SUs in cognitive radio technology. The benefit of exploiting pulse shape filtering in the OFDM/OQAM is to not only eliminate the requirement of the guard bands but also reduce the out of band energy transmission, which also improves the spectral isolation from the neighboring systems. But the high peak to average power ratio (PAPR) phenomenon is a common issue in the majority of the multicarrier modulation systems and thus OFDM/OQAM is no exception in this case.

Findings
Therefore, this paper aims to examine the effect of integrating the Walsh–Hadamard Transform (WHT) on the power spectral density and investigates the problem of PAPR in the WHT/OQAM system.

Originality/value
Thus, it overcomes the spectral leakage problem at the transmitter side and leads to less interference from SUs to PUs and between the SUs in cognitive radio technology. The benefit of exploiting pulse shape filtering in the OFDM/OQAM is to not only eliminate the requirement of the guard bands but also reduce the out of band energy transmission, which also improves the spectral isolation from the neighboring systems. But the high PAPR phenomenon is a common issue in the majority of the multicarrier modulation systems thus OFDM/OQAM is no exception in this case.
Self-care, A1C and stigmatization as predictors of a negative perception of insulin among adults with type 2 diabetes: a hospital-based study in Turkey
Authors: Arda Sürücü Hamdiye , Okur Arslan Hatice , Çetik Sıdıka 
Published: December 2020

PurposeThe purpose of this study was to investigate diabetes self-care behaviors, stigmatization and A1C as predictors of a negative perception of insulin treatment in insulin-treated type 2 diabetic patients.Design/methodology/approachA descriptive cross-sectional and relational design was used. The study was carried out in the Diabetes Training Centre and Endocrine and Metabolism Clinic of a university hospital in the southeast of Turkey between May and October 2017. The research sample consisted of 100 type 2 diabetic patients determined by using a convenience sampling method. An introductory information form for type 2 diabetic patients, the Insulin Treatment Appraisal Scale (ITAS), Diabetes Self-Care Activities Survey (DSCAS) and Barriers to Insulin Treatment Scale (BIT) were used to collect the research data. The data were analyzed using descriptive statistics, correlations and step wise multi-linear regression.FindingsThe number of daily insulin injections, training received about insulin and stigmatization was significant predictors of a negative perception of insulin treatment.Originality/valueStrategies to decrease diabetic individuals' fear of stigmatization should be utilized to minimize their negative insulin treatment perception (giving diabetic individuals training about diabetes, planning public training to inform society and using mass media tools). Diabetes educators should know that diabetic individuals' perception of the severity of the illness could influence the daily number of injections applied and decrease the negative perception regarding insulin.