bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nascent transcription and the associatedcis-regulatory landscape in rice
Authors: Choi Jae Young , Platts Adrian E. , Johary Aurore , Purugganan Michael D. , Joly-Lopez Zoé 
Published: July 2022

AbstractBackgroundPlant genomes encode transcripts that require spatio-temporal regulation for proper cellular function, and a large fraction of the regulators can be found in intergenic regions. In animals, distal intergenic regions described as enhancer regions are actively transcribed as enhancer RNAs (eRNAs); the existence of eRNAs in plants has only been fairly recently documented. In this study, we evaluated with high sensitivity the synthesis of eRNAs that arise at genomic elements both distal and proximal to genes by combining PRO-seq with chromatin accessibility, histone modification, and methylation profiles in rice.ResultsWe found that regions defined as transcribed intergenic regions are widespread in the rice genome, and many likely harbor transcribed regulatory elements. In addition to displaying evidence of selective constraint, the presence of these transcribed regulatory elements are correlated with an increase in nearby gene expression. We further identified molecular interactions between genic regions and intergenic transcribed regulatory elements using 3D chromosomal contact data, and found that these interactions were both associated with eQTLs as well as promoting transcription. We also compared the profile of accessible chromatin regions to our identified transcribed regulatory elements, and found less overlap than expected. Finally, we also observed that transcribed intergenic regions that overlapped partially or entirely with repetitive elements had a propensity to be enriched for cytosine methylation, and were likely involved in TE silencing rather than promoting gene transcription.ConclusionThe characterization of eRNAs in the rice genome reveals that many share features of enhancers and are associated with transcription regulation, which could make them compelling candidate enhancer elements.
Muscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes
Authors: Hildebrandt Ryan P. , Moss Kathryn R. , Janusz-Kaminska Aleksandra , Knudson Luke A. , Denes Lance T. , Saxena Tanvi , Boggupalli Devi Prasad , Li Zhuangyue , Lin Kun , Bassell Gary J. , Wang Eric T. 
Published: July 2022

SummaryRNA transport and local translation provide spatial control of gene expression, and RNA binding proteins (RBPs) act as critical adapters in this multi-step process. Muscleblind-like (MBNL) RNA binding proteins, implicated in myotonic dystrophy and cancer, localize RNAs to myoblast membranes and distal neurites through unknown mechanisms. We found that MBNL forms motile and anchored granules in neurons and myoblasts, and selectively associates with kinesins Kif1bα and Kif1c through its zinc finger (ZnF) domains. Other RBPs with similar ZnFs also associate with these kinesins, implicating a motor-RBP specificity code. Live cell imaging and fractionation revealed that membrane anchoring is mediated through the unstructured carboxy-terminal tail of MBNL1. Both kinesin- and membrane-recruitment functions were reconstituted using MBNL-MS2 coat protein fusions. This approach, termed RBP Module Recruitment and Imaging (RBP-MRI), decouples RNA binding, kinesin recruitment, and membrane anchoring functions, while also establishing general strategies for studying multi-functional, modular domains of RBPs.
Mosquito metabolism shapes life-history strategies ofPlasmodiumparasites
Authors: Carrillo-Bustamante Paola , Costa Giulia , Lampe Lena , Levashina Elena A. 
Published: July 2022

ABSTRACTThe life-history of multicellular organisms is a collection of traits determining fitness described by growth, survival, and reproduction. Within-host survival and between-host transmission are key life-history traits of single-celled malaria parasites. Therefore, understanding the evolutionary forces that shape these components is crucial to predict malaria epidemiology, drug resistance, and virulence. The evolutionary strategies ofPlasmodiumparasites have been largely investigated in the vertebrate host. In contrast, very little is known about their adaptation strategies in the mosquito vector, possibly due to the experimental challenges encountered while studying vector-parasite interactions. Mathematical models offer a unique tool to study such complex biological systems, and have been extensively employed in malaria epidemiology. However, all models developed so far do not consider mosquito physiology. Here, we examine the life-history evolution ofPlasmodiumparasites with a novel individual-based model of malaria transmission that includes mosquito metabolism. Specifically, we model the metabolic cascade of resource allocation induced by blood-feeding, as well as the influence of multiple blood meals on parasite development. Our model shows that successful vector-to-human transmission events are rare, and are caused by long-lived mosquitoes. Interestingly, we observe that the life-history strategies of malaria parasites depend on the mosquito metabolic status. In our model, additional resources provided by multiple blood meals benefit selection for parasites with slow or intermediate developmental time. These results challenge the current concept that evolution selects for fast developing parasites to maximize their chances to complete their within-mosquito life cycle. We propose that the long sporogonic cycle observed forPlasmodiumis not a constraint but rather an adaptation to increase transmission potential.
In vitro and in vivo immunogenicity assessment of protein aggregate characteristics
Authors: Thorlaksen Camilla , Schultz Heidi S. , Gammelgaard Simon K. , Jiskoot Wim , Hatzakis Nikos S. , Nielsen Flemming S. , Solberg Helene , Foderà Vito , Bartholdy Christina , Groenning Minna 
Published: July 2022

AbstractThe immunogenicity risk of therapeutic protein aggregates has been extensively investigated over the past decades. While it is established that not all aggregates are equally immunogenic, the specific aggregate characteristics which are most likely to induce an immune response, remain ambiguous. The aim of this study was to perform comprehensive in vitro and in vivo immunogenicity assessment of human insulin aggregates varying in size, structure and chemical modifications, while keeping other morphological characteristics constant. We found that flexible aggregates with highly altered secondary structure were most immunogenic in all setups, while compact aggregates with native-like structure were found to be immunogenic primarily in vivo. Moreover, sub-visible (1-100 µm) aggregates were found to be more immunogenic than sub-micron (0.1-1 µm) aggregates, while chemical modifications (deamidation, ethylation and covalent dimers) were not found to have any measurable impact on immunogenicity. The findings highlight the importance of utilizing aggregates varying in few characteristics for assessment of immunogenicity risk of specific morphological features and provides a universal workflow for reliable particle analysis in biotherapeutics.
Rubisco is evolving for improved catalytic efficiency and CO2assimilation in plants
Authors: Bouvier Jacques W. , Emms David M. , Kelly Steven 
Published: July 2022

AbstractRubisco is the primary entry point for carbon into the biosphere. However, rubisco is widely regarded as inefficient leading many to question whether the enzyme can adapt to become a better catalyst. Through a phylogenetic investigation of the molecular and kinetic evolution of Form I rubisco we demonstrate that rubisco is not stagnant. Instead, we demonstraterbcLis among the 1% of slowest evolving genes and enzymes on Earth, accumulating one nucleotide substitution every 0.9 million years and one amino acid mutation every 7.2 million years. Despite this, we demonstrate that rubisco catalysis is continuing to evolve toward improved CO2/O2specificity, carboxylase turnover, and carboxylation efficiency. Consistent with this kinetic adaptation, we reveal that increased rubisco evolution leads to a concomitant improvement in leaf-level CO2assimilation. Thus, rubisco is continually evolving toward improved catalytic efficiency and CO2assimilation in plants.
A yeast-based tool for mammalian DGATs inhibitors screening
Authors: Gajdoš Peter , Ledesma-Amaro Rodrigo , Nicaud Jean-Marc , Rossignol Tristan 
Published: July 2022

AbstractDysregulation of lipid metabolism is associated with obesity, metabolic diseases but there is also increasing evidences of a relationship between lipid bodies (LBs) excess and some cancer. LBs synthesis requires diacylglycerol acyltransferases (DGATs) which catalyses the last step of triacylglycerol (TAG) synthesis, the main storage lipid form in lipid bodies. DGATs and in particular DGAT2, are therefore considered as potential therapeutic targets for the control of these pathologies. Here, the murine and the human DGAT2 were overexpressed in the oleaginous yeast Yarrowia lipolytica deleted for all DGATs activities, for evaluating the functionality of the enzymes in this heterologous host and to evaluate DGAT activity inhibitors. This work provide evidence that mammalian DGATs expressed in Y. lipolytica is a useful tool for screening chemical libraries to identify potential inhibitors or activators of these enzymes of therapeutic interest.
Selection of rAAV Vectors that Cross the Human Blood-Brain Barrier and Target the Central Nervous System Using a Transwell Model
Authors: Song Ren , Pekrun Katja , Khan Themasap A. , Zhang Feijie , Pasca Sergiu P. , Kay Mark A. 
Published: July 2022

AbstractA limitation for rAAV-mediated gene transfer into the central nervous system (CNS) is the low penetration of vectors across the human blood-brain barrier (BBB). High doses of intravenously-delivered vector are required to reach the CNS, which has resulted in varying adverse effects. Moreover, selective transduction of various cell types might be important depending on the disorder being treated. To enhance BBB penetration and improve CNS cell selectivity, we screened an AAV capsid-shuffled library using an in vitro transwell BBB system with separate layers of human endothelial cells, primary astrocytes and/or hiPSC-derived cortical neurons. After multiple passages through the transwell, we identified chimeric AAV capsids with enhanced penetration and improved transduction of astrocytes and/or neurons compared to wild-type capsids. We identified the amino acid (aa) from region 451-470 of AAV2 associated with the capsids selected for neurons, and a combination of aa from regions 413-496 of AAV-rh10 and 538-598 of AAV3B/LK03 associated with capsids selected for astrocytes. An siRNA screen identified several genes that affect transcytosis of AAV across the BBB. Our work supports the use of a human transwell system for selecting enhanced AAV capsids targeting the CNS and may allow for unraveling the underlying molecular mechanisms of BBB penetration.
Neurodevelopmental disorder associated mutations in TAOK1 reveal its function as a plasma membrane remodeling kinase
Authors: Beeman Neal , Sapre Tanmay , Ong Shao-En , Yadav Smita 
Published: July 2022

ABSTRACTMutations in TAOK1, a serine-threonine kinase encoding gene are strongly associated with both autism spectrum disorder (ASD) and neurodevelopmental delay (NDD). However, molecular function of this evolutionarily conserved kinase and the mechanisms through which TAOK1 mutations lead to neuropathology are unknown. Here, we showed that TAOK1 is highly expressed in neurons within the brain, and has a functional role in remodeling the plasma membrane through direct association with phosphoinositides. We characterized four NDD-associated TAOK1 mutations, and demonstrated that these mutations render TAOK1 catalytically dead. Kinase dead TAOK1 mutants were aberrantly trapped in membrane-bound state, which induced exuberant membrane protrusions. Expression of TAOK1 disease mutants in hippocampal neurons led to abnormal growth of the dendritic arbor. The coiled-coil region C-terminal to the kinase domain are predicted to fold into a triple helix. We showed that this triple helix directly bound phospholipids, and was required for both TAOK1 membrane association and induction of aberrant protrusions. Further, TAOK1 mutants were rescued from their membrane-trapped state by exogenous expression of the isolated kinase domain. Utilizing mass-spectrometry, we identified critical residues in the triple helix phosphorylated by TAOK1 that autoregulated its plasma membrane association. These findings define a previously unknown function of TAOK1 as a unique plasma membrane remodeling kinase, and reveal the underlying mechanisms through which TAOK1 dysfunction leads to neurodevelopmental disorders.
Soluble TREM2 and Alzheimer-related biomarker trajectories in the blood of diabetic patients based on their cognitive status
Authors: Satoh-Asahara Noriko , Yamakage Hajime , Tanaka Masashi , Kawasaki Teruaki , Matsuura Sayo , Tatebe Harutsugu , Akiguchi Ichiro , Tokuda Takahiko 
Published: July 2022

ABSTRACTAimType 2 diabetes mellitus (DM) increases the risk of dementia. We aimed to elucidate the dynamics of blood biomarkers according to the severity of cognitive impairment in patients with DM and to identify useful biomarkers for diabetes-related dementia.MethodsThis was a cross-sectional, nested case-control study of 121 Japanese diabetic and nondiabetic patients with different levels of cognitive functioning. We evaluated participants’ cognitive functions, blood biomarkers related to Alzheimer’s disease, and soluble triggering receptors expressed on myeloid cells 2 (sTREM2). We then compared these biomarkers between the DM and non-DM groups and across the different cognitive strata.ResultsSignificantly lower levels of serum sTREM2 were observed in the DM than in the non-DM patients. This was true across all the cognitive strata of the two groups, including those with normal cognition. We also found that plasma levels of phosphorylated tau 181 (p-tau181) increased with increasing levels of cognitive decline in both the DM and non-DM groups. However, this was accompanied by a decrease in plasma amyloid-β (Aβ)42/Aβ40 ratios in non-DM patients only.ConclusionThis study revealed novel characteristic trajectories of dementia-related blood biomarkers in diabetes-related dementia, suggesting the pathological involvement of molecular cascades initiated by impaired microglial activation. This results in decreased serum sTREM2, followed by tauopathy without substantial amyloid plaques, reflected by plasma p-tau elevation with no decrease in the Aβ42/Aβ40 ratio. Our results warrant further research into this molecular cascade to elucidate pathogenetic mechanisms of diabetes-related dementia and establish useful biomarkers.
Three-dimensional visualization of moss rhizoid system by refraction-contrast X-ray micro-computed tomography
Authors: Yamaura Ryohei , Tamaoki Daisuke , Kamachi Hiroyuki , Yamauchi Daisuke , Mineyuki Yoshinobu , Uesugi Kentaro , Hoshino Masato , Suzuki Tomomi , Shimazu Toru , Kasahara Haruo , Kamada Motoshi , Hanba Yuko T. , Kume Atsushi , Fujita Tomomichi , Karahara Ichirou 
Published: July 2022

AbstractLand plants have two types of shoot-supporting systems, root system and rhizoid system, in vascular plants and bryophytes. However, since the evolutionary origin of the systems are different, how much they exploit common systems or distinct systems to architect their structures are largely unknown. To understand the regulatory mechanism how bryophytes architect rhizoid system responding to an environmental factor, such as gravity, and compare it with the root system of vascular plants, we have developed the methodology to visualize and quantitatively analyze the rhizoid system of the moss, Physcomitrium patens in 3D. The rhizoids having the diameter of 21.3 μm on the average were visualized by refraction-contrast X-ray micro-CT using coherent X-ray optics available at synchrotron radiation facility SPring-8. Three types of shape (ring-shape, line, black circle) observed in tomographic slices of specimens embedded in paraffin were confirmed to be the rhizoids by optical and electron microscopy. Comprehensive automatic segmentation of the rhizoids which appeared in different three form types in tomograms was tested by a method using Canny edge detector or machine learning. Accuracy of output images was evaluated by comparing with the manually-segmented ground truth images using measures such as F1 score and IoU, revealing that the automatic segmentation using the machine learning was more effective than that using Canny edge detector. Thus, machine learning-based skeletonized 3D model revealed quite dense distribution of rhizoids, which was similar to root system architecture in vascular plants. We successfully visualized the moss rhizoid system in 3D for the first time.
Managing brand equity in the brewing sector
Authors: Francioni Barbara , Curina Ilaria , Hegner Sabrina M. , Cioppi Marco , Pencarelli Tonino 
Published: July 2022

PurposeThe paper analyzes the effect of country of origin (COO) image, word-of-mouth (WOM) and brand distinctiveness toward overall brand equity (OBE) and its dimensions (brand awareness/associations; perceived quality; brand loyalty) in the brewing sector.Design/methodology/approachA quantitative research has been conducted by adopting the survey technique and structural equation modeling based on a sample of 401 Italian beer consumers.FindingsResults corroborate a positive effect of (1) COO image and brand distinctiveness on brand awareness/associations, perceived quality and brand loyalty; (2) WOM on perceived quality and brand loyalty; (3) brand awareness/associations and brand loyalty on OBE. Findings also verify the mediating effects of the OBE dimensions on the relationships between the analyzed antecedents (COO image, WOM and brand distinctiveness) and OBE.Research limitations/implicationsAlthough the selection of a sample composed of Italian students guarantees good research internal validity, findings are not generalizable.Practical implicationsThe study offers valuable strategies for brewing firms to reach high levels of brand equity. In particular, it identifies the key role of COO image, WOM, brand distinctiveness and OBE dimensions in realizing careful brand management processes.Originality/valueThe paper focuses on analyzing the influence of COO image on brand equity in the brewing industry, thus enriching an area of investigation that requires further insights within an under-investigated sector.
Constructing interval models using neural networks with non-additive combinations of grey prediction models in tourism demand
Authors: Jiang Peng , Hu Yi-Chung 
Published: July 2022

PurposeIn contrast to point forecasts, interval forecasts provide information on future variability. This research thus aimed to develop interval prediction models by addressing two significant issues: (1) a simple average with an additive property is commonly used to derive combined forecasts, but this unreasonably ignores the interaction among sequences used as sources of information, and (2) the time series often does not conform to any statistical assumptions.Design/methodology/approachTo develop an interval prediction model, the fuzzy integral was applied to nonlinearly combine forecasts generated by a set of grey prediction models, and a sequence including the combined forecasts was then used to construct a neural network. All required parameters relevant to the construction of an interval model were optimally determined by the genetic algorithm.FindingsThe empirical results for tourism demand showed that the proposed non-additive interval model outperformed the other interval prediction models considered.Practical implicationsThe private and public sectors in economies with high tourism dependency can benefit from the proposed model by using the forecasts to help them formulate tourism strategies.Originality/valueIn light of the usefulness of combined point forecasts and interval model forecasting, this research contributed to the development of non-additive interval prediction models on the basis of combined forecasts generated by grey prediction models.
The determinants of festival participants' event loyalty: a focus on millennial participants
Authors: Ho Jie Min , Tiew Fidella , Adamu Adamu Abbas 
Published: July 2022

PurposeThis study aims to determine how different event quality dimensions (i.e. information availability, program content, food, staff service, merchandises, ticketing, facility and convenience) individually affect the satisfaction of millennial festival participants, and how their satisfaction subsequently influence their behavioral intention.Design/methodology/approachThe research hypotheses were tested with a sample of 272 millennial participants attending the Borneo Jazz Festival held in Miri, Sarawak.FindingsThe results indicated that program content and facility are crucial predictors of millennial participants' level of satisfaction with the event. Furthermore, the level of satisfaction would, in turn, affect their intention to revisit the event and spread positive word-of-mouth.Research limitations/implicationsThe results are expected to assist festival planners in managing and designing festivals that can appeal to millennials who make up a significant percentage of tourism market.Originality/valueThe study adds to the knowledge of how music festival environment can yield loyalty amongst millennial festival participants in Sarawak, an Eastern state of Malaysia on the island of Borneo.
An empirical investigation of governance mechanism choices in service outsourcing
Authors: Ye Yuan , Peng Xiaosong (david) , Fan Raymond Lei , Narayanan Arunachalam 
Published: July 2022

PurposeDrawing on transaction cost economics (TCE) theory and organizational information processing theory (OIPT), this study investigates how the alignments between the characteristics of service (i.e. task complexity and measurement ambiguity) and governance mechanisms (i.e. contract specificity and monitoring) can affect service performance.Design/methodology/approachThe paper uses a rigorously designed survey to collect data from professionals who manage service outsourcing contracts in various industries. The respondent pool consists of randomly selected members of the Institute of Supply Management (ISM). The authors’ research question is analyzed using 261 completed and useable responses. Structural equation modeling is adopted to examine the data and test the proposed hypotheses.FindingsThe authors find that both contract specificity and monitoring have a positive impact on supplier performance. Further, for high task complexity services, contract specificity is more effective than monitoring, and for high measurement ambiguity services, the opposite is true. Moreover, the effect of contract specificity is mediated by monitoring.Practical implicationsService outsourcers should use both contract specificity and monitoring in governing outsourced services and know that the former depends on the latter during execution. Facing resource constraints, they can prioritize crafting detailed contract provisions over implementing monitoring for highly complex services but consider monitoring as the primary governance tool in services whose outcomes are difficult to measure.Originality/valueThis study is the first to couple TCE with OPIT and consider the nature of outsourced services in the choice of governance mechanisms and empirically test the simultaneous effects of contract specificity and monitoring in the context of service outsourcing.