bluuebunny/crossref_metadata_2025_split huggingface dataset:
GBA1-associated parkinsonism: new insights and therapeutic opportunities
Authors: Ryan Emory , Seehra Gurpreet , Sharma Pankaj , Sidransky Ellen 
Published: June 2019

Purpose of review

GBA1 mutations, which result in the lysosomal disorder Gaucher disease, are the most common known genetic risk factor for Parkinson disease and Dementia with Lewy Bodies (DLB). The pathogenesis of this association is not fully understood, but further elucidation of this link could lead to new therapeutic options.

Recent findings
The characteristic clinical phenotype of GBA1-PD resembles sporadic Parkinson disease, but with an earlier onset and more severe course. Many different GBA1 mutations increase the risk of Parkinson disease, some primarily detected in specific populations. Glucocerebrosidase deficiency appears to be associated with increased α-synuclein aggregation and accumulation, mitochondrial dysfunction because of impaired autophagy, and increased endoplasmic reticulum stress.

Summary
As our understanding of GBA1-associated Parkinson disease increases, new treatment opportunities emerge. MicroRNA profiles are providing examples of both up-regulated and down-regulated proteins related to GBA1 and may provide new therapeutic targets. Chaperone therapy, directed at either misfolded glucocerebrosidase or α-synuclein aggregation, is currently under development and there are several early clinical trials ongoing. Substrate reduction therapy, aimed at lowering the accumulation of metabolic by-products, especially glucosylsphingosine, is also being explored. Basic science insights from the rare disorder Gaucher disease are serving to catapult drug discovery for parkinsonism.
Long-term experimental evolution reveals purifying selection on piRNA-mediated control of transposable element expression
Authors: Bergthorsson Ulfar , Sheeba Caroline J. , Konrad Anke , Belicard Tony , Beltran Toni , Katju Vaishali , Sarkies Peter 
Published: June 2019

AbstractTransposable elements (TEs) are an almost universal constituent of eukaryotic genomes. In animals, Piwi-interacting small RNAs (piRNAs) and repressive chromatin often play crucial roles in preventing TE transcription and thus restricting TE activity. Nevertheless, TE content varies widely across eukaryotes and the dynamics of TE activity and TE silencing across evolutionary time is poorly understood. Here we used experimentally evolved populations ofC. elegansto study the dynamics of TE expression over 400 generations. The experimental populations were evolved at three different population sizes to manipulate the efficiency of natural selection versus genetic drift. We demonstrate increased TE expression relative to the ancestral population, with the largest increases occurring in the smallest populations. We show that the transcriptional activation of TEs within active regions of the genome is associated with failure of piRNA-mediated silencing, whilst desilenced TEs in repressed chromatin domains retain small RNAs. Additionally, we find that the sequence context of the surrounding region influences the propensity of TEs to lose silencing through failure of small RNA-mediated silencing. Together, our results show that natural selection inC. elegansis responsible for maintaining low levels of TE expression, and provide new insights into the epigenomic features responsible.
The Frizzled-ligand Norrin acts as a tumour suppressor linking oncogenic RAS signalling to p53
Authors: Sulli Gabriele , D’Elia Errico , Moroni M. Cristina 
Published: June 2019

AbstractTumour suppressor genes are frequently affected by somatic alterations in cancer, and the impairment of their normal function provides a strong contribution to tumourigenesis. Short-hairpin (sh) RNA library screens have been employed as powerful genetic tools to uncover important new players in human cancer 1–5. To identify potential novel tumour suppressor genes acting in the p53 pathway, we performed an shRNA screen using a cell-based model in which only a single additional genetic event disrupting the p53 pathway is required to obtain in vitro transformation. By using this approach, we report here on the identification of the Frizzled-ligand Norrin (Norrie disease protein) as a candidate tumour suppressor. Inhibition of Norrin expression promotes anchorage-independent growth, confers a strong growth advantage to cells and causes a reduction in p53 protein levels. Conversely, recombinant human Norrin increases p53 levels in a β-catenin dependent fashion. Interestingly, Norrin expression is stimulated by oncogenic H-RAS and BRAF, suggesting that Norrin is part of an early fail-safe mechanism to suppress transformation, and that mutation or down regulation of Norrin could contribute to tumour progression. Indeed, we found that Norrin expression is significantly decreased in melanoma, breast, prostate and ovarian cancer. These findings support the existence of a novel autocrine/paracrine feedback loop that constrains tumourigenesis, in which the crosstalk between the RAS and β–catenin pathways play an unanticipated role.
NG2 glia are required for maintaining microglia homeostatic state
Authors: Liu Yingjun , Aguzzi Adriano 
Published: June 2019

AbstractMicroglia play vital roles in the health and diseases of the central nervous system. Loss of microglia homeostatic state is a key feature of brain aging and neurodegeneration. However, the mechanisms underlying the maintenance of distinct microglia states are largely unclear. Here we show that NG2 glia, also known as oligodendrocyte precursor cells, are essential for maintaining the homeostatic microglia state. We developed a highly efficient and selective NG2 glia depletion method using small-molecule inhibitors of platelet-derived growth factor signaling in cultured brain slices. We found that loss of NG2 glia abolished the homeostatic microglia signature without affecting the disease-associated microglia profiles. Similar findings were also observedin vivoby genetically ablating NG2 glia in the adult mouse brain. These data suggest that NG2 glia exert a crucial influence onto microglia cellular states that are relevant to brain aging and neurodegenerative diseases. In addition, our results provide a powerful, convenient and selective tool for the investigation of NG2 glia function.Main pointsPostnatal NG2 glia maintenance obligatorily depends on continuous PDGF signaling.A highly efficient, selective and versatile NG2 glia depletion method is established.Loss of NG2 glia abolishes the homeostatic microglia signature bothin vitroandin vivo.
Cyclic oligoadenylate signalling mediatesMycobacterium tuberculosisCRISPR defence
Authors: Grüschow Sabine , Athukoralage Januka S. , Graham Shirley , Hoogeboom Tess , White Malcolm F. 
Published: June 2019

ABSTRACTThe CRISPR system provides adaptive immunity against mobile genetic elements (MGE) in prokaryotes. In type III CRISPR systems, an effector complex programmed by CRISPR RNA detects invading RNA, triggering a multi-layered defence that includes target RNA cleavage, licencing of an HD DNA nuclease domain and synthesis of cyclic oligoadenylate (cOA) molecules. cOA activates the Csx1/Csm6 family of effectors, which degrade RNA non-specifically to enhance immunity. Type III systems are found in diverse archaea and bacteria, including the human pathogenMycobacterium tuberculosis. Here, we report a comprehensive analysis of thein vitroandin vivoactivities of the type III-AM. tuberculosisCRISPR system. We demonstrate that immunity against MGE is achieved predominantly via a cyclic hexa-adenylate (cA6) signalling pathway and the ribonuclease Csm6, rather than through DNA cleavage by the HD domain. Furthermore, we show that the mechanism can be reprogrammed to operate as a cyclic tetra-adenylate (cA4) system by replacing the effector protein. These observations demonstrate thatM. tuberculosishas a fully-functioning CRISPR interference system that generates a range of cyclic and linear oligonucleotides of known and unknown functions, potentiating fundamental and applied studies.
Macromolecule Translocation in a Nanopore: Center of Mass Drift–Diffusion over an Entropic Barrier
Authors: Dell Z. E. , Muthukumar M. 
Published: June 2019

ABSTRACTMany fundamental biological processes involve moving macromolecules across membranes, through nanopores, in a process called translocation. Such motion is necessary for gene expression and regulation, tissue formation, and viral infection. Furthermore, in recent years nanopore technologies have been developed for single molecule detection of biological and synthetic macromolecules, which have been most notably employed in next generation DNA sequencing devices. Many successful theories have been established, which calculate the entropic barrier required to elongate a chain during translocation. However, these theories are at the level of the translocation coordinate (number of forward steps) and thus lack a clear connection to experiments and simulations. Furthermore, the proper diffusion coefficient for such a coordinate is unclear. In order to address these issues, we propose a center of mass (CM) theory for translocation. We start with the entropic barrier approach and show that the translocation coordinate is equivalent to the center of mass of the chain, providing a direct interpretation of previous theoretical studies. We thus recognize that the appropriate dynamics is given by CM diffusion, and calculate the appropriate diffusion constant (Rouse or Zimm) as the chain translocates. We illustrate our theoretical approach with a planar nanopore geometry and calculate some characteristic dynamical predictions. Our main result is the connection between the translocation coordinate and the chain CM, however, we also find that the translocation time is sped up by 1–2 orders of magnitude if hydrodynamic interactions are present. Our approach can be extended to include the details included in previous translocation theories. Most importantly this work provides a direct connection between theoretical approaches and experiments or simulations.SIGNIFICANCEMacromolecule motion through nanopores is critical for many biological processes, and has been recently employed for nucleic acid sequencing. Despite this, direct theoretical understandings of translocation are difficult to evaluate due to the introduction of the translocation coordinate. In this manuscript, we propose a theory for translocation written at the center of mass level of the polymer chain. This theoretical approach is more easily compared to experimental and simulation results, and additionally allows one to accurately account for hydrodynamic interactions on the macromolecule dynamics.
Activation or inhibition of PPARα-mediated fatty acid β-oxidation does not active cardiomyocyte proliferation in normal or infarcted adult mice
Authors: Roy Rajika , Leigh Tani , Gao Erhe , Zhang Xiaoying , Tian Ying 
Published: June 2019

ABSTRACTObjectivesPPAR genes are known as the important regulators of fatty acid oxidation and energy homeostasis. PPARα is highly expressed in the embryonic and adult heart. Previous studies from infant mouse hearts have suggested that activation of PPARα using GW7647 treatment or cardiac-restricted activation of PPARα using αMHC-PPARα transgenic mice enhanced fatty acid β-oxidation and promoted cardiomyocyte proliferation rate in the postnatal day 4 mouse heart. Here, we further investigate the impact of PPARα-mediated fatty acid β-oxidation on cardiomyocyte proliferation in the adult mouse heart.Methods and ResultsAdult wild-type (C57BL/6J) mice were subjected to five injections of GW7647, a highly specific PPARα agonist, or vehicle (saline). Cardiomyocyte proliferation was analyzed by quantification of DNA synthesis via ethynyldeoxyuridine (EdU) incorporation and quantification of cells undergoing mitosis using phosphorylated histone H3 (PH3). GW7647 treatment resulted in activation of PPARα target genes associated with fatty acid metabolism and β-oxidation, validating its biological activity. However, GW7647 treatment did not active cardiomyocyte proliferation in the normal heart. In parallel, mice were subjected to myocardial infarction (MI) using permanent coronary artery occlusion. Both GW7647-treatd wild-type mice and αMHC-PPARα transgenic mice showed no significant differences in cardiomyocyte DNA synthesis and mitosis compared with vehicle-treated wild-type mice after MI. Furthermore, inhibition of PPARα-mediated fatty acid β-oxidation using etomoxir (ETO) treatment had no impact on cardiomyocyte proliferation in both normal and infarcted hearts of wild-type mice compared with vehicle treatment.SummaryThese findings suggest that activation or inhibition of PPARα-mediated fatty acid β-oxidation did not active cardiomyocyte proliferation in normal or infarcted hearts of adult mice. Any effects on cardiac function observed following PPARα activation treatment is independent of enhanced cardiomyocyte renewal in the adult heart.
A CLEAR pipeline for direct comparison of circular and linear RNA expression
Authors: Ma Xu-Kai , Wang Meng-Ran , Liu Chu-Xiao , Dong Rui , Carmichael Gordon G. , Chen Ling-Ling , Yang Li 
Published: June 2019

ABSTRACTSequences of circular RNAs (circRNAs) produced from back-splicing of exon(s) completely overlap with sequences from cognate linear RNAs transcribed from the same gene loci with the exception of their back-splicing junction (BSJ) sites. Examination of global circRNA expression from RNA-seq datasets generally relies on the detection of RNA-seq fragments spanning BSJ sites, but a direct comparison of circular and linear RNA expression from the same gene loci in a genome-wide manner has remained challenging. This is because quantification of BSJ fragments differs from that of linear RNA expression that uses normalized RNA-seq fragments mapped to the whole gene bodies. Here, we have developed a computational pipeline for circular and linear RNA expression analysis from ribosomal-RNA depleted RNA-seq (CLEAR, https://github.com/YangLab/CLEAR). A new quantitation parameter, FPB (fragments per billion mapped bases), is applied to evaluate circular and linear RNA expression individually by fragments mapped to circRNA-specific BSJ sites or to linear RNA-specific splicing junction (SJ) sites. Then, circular and linear RNA expression are directly compared by dividing FPBcirc by FPBlinear to generate a CIRCscore, which indicates the relative circRNA expression using linear RNA expression as the background. Highly-expressed circRNAs with low cognate linear RNA expression background can be identified for further investigation.
Highly Genotype- and Tissue-specific Single-Parent Expression Drives Dynamic Gene Expression Complementation in Maize Hybrids
Authors: Li Zhi , Zhou Peng , Coletta Rafael Della , Zhang Tifu , Brohammer Alex B. , Vaillancourt Brieanne , Lipzen Anna , Daum Chris , Barry Kerrie , de Leon Natalia , Hirsch Cory D. , Buell C. Robin , Kaeppler Shawn M. , Springer Nathan M. , Hirsch Candice N. 
Published: June 2019

AbstractMaize exhibits tremendous gene expression variation between different lines. Complementation of diverse gene expression patterns in hybrids could play an important role in the manifestation of heterosis. In this study, we used transcriptome data of five different tissues from 33 maize inbreds and 89 hybrids (430 samples in total) to survey the global gene expression landscape of F1-hybrids relative to their inbred parents. Analysis of this data set revealed that single parent expression (SPE), which is defined as gene expression in only one of the two parents, while commonly observed, is highly genotype- and tissue-specific. Genes that have SPE in at least one pair of inbreds also tend to be tissue-specific. Genes with SPE caused by genomic presence/absence variation (PAV SPE) are much more frequently expressed in hybrids than genes that are present in the genome of both inbreds, but expressed in only a single-parent (non-PAV SPE) (74.7% vs. 59.7%). For non-PAV SPE genes, allele specific expression was used to investigate whether parental alleles not expressed in the inbred line (“silent allele”) can be actively transcribed in the hybrid. We found that expression of the silent allele in the hybrid is relatively rare (∼6.3% of non-PAV SPE genes), but is observed in almost all hybrids and tissues. Non-PAV SPE genes with expression of the silent allele in the hybrid are more likely to exhibit above high-parent expression level in the hybrid than those that do not express the silent allele. Finally, both PAV SPE and non-PAV SPE genes are highly enriched for being classified as non-syntenic, but depleted for curated genes with experimentally determined functions. This study provides a more comprehensive understanding of the potential role of non-PAV SPE and PAV SPE genes in heterosis.
A grassroots research approach for branding urban districts
Authors: Pasalar Celen , Hallowell George Dewey 
Published: June 2019

Purpose
To produce effective urban district branding strategies, the factors impacting its unique characteristics and identity must be examined first. The purpose of this paper is to present a bottom-up participatory process for uncovering the identity of an urban district to ensure that its community goals and future branding are consistent and genuine.

Design/methodology/approach
This paper examines a recently completed grassroots effort that was used to uncover key physical, economic and cultural resources of the Southwest Raleigh district. Interdisciplinary methods, including surveys, interviews, mapping and economic analysis, were used to reveal how residents and businesses perceived the district’s identity.

Findings
The study revealed strong connections between a growing economy and factors related to liveability and identity, such as walkability, proximity, connectivity and availability of amenities. It provided a framework for communities to understand the forces of change that may influence the urban identity and potential branding strategies that would align with growing creative district goals.

Practical implications
Analyzing and evaluating the factors involved in the district’s identity, including diversified economies, demographics and urban qualities, is essential to the creation of an authentic brand that aligns with community perceptions.

Social implications
A research strategy is necessary to uncover the identity of a growing city. This requires a thorough assessment of its unique, localized characteristics, including the perceptions of its residents and businesses.

Originality/value
This paper and its outcomes can inform future in-depth investigations using similar comprehensive and bottom-up approaches for uncovering perceptions and urban identity in support of growing creative economies.
Differences between organic and conventional leafy green vegetables perceived by university students
Authors: Da Cunha Diogo Thimoteo , Antunes Adriane Elisabete Costa , Da Rocha Julia Gabriela , Dutra Talita Gaspar , Manfrinato Catarina Vezetiv , Oliveira Julicristie Machado , Rostagno Mauricio Ariel 
Published: June 2019

PurposeThe purpose of this paper is to evaluate perceived sensory differences of organic and conventional leafy green vegetables through three sensory tests – blind, informed and inverted and the willingness to buy (WTB) them, and associated factors of organic food consumption by these students.Design/methodology/approachThe research had a cross-sectional design with university students. First, a questionnaire with 16 statements was presented to 233 consumers with a five-point Likert scale response. The assertions were categorized into five domains: trust in organic production; trust in conventional production; positive attitude to organic; affordable price; and perceived quality. Afterwards, a hedonic scaling was conducted with 150 consumers, 50 in each type of test with conventional and organic leafy green vegetables: lettuce (Lactuca sativa L.); kale (Brassica oleracea L.); common chicory (Cichorium intybus); and endive (Cichorium endivia). Visual aspect, taste, texture, bitterness and overall liking for all samples were evaluated on a nine-point hedonic scale.FindingsIn general, the participants did not perceive sensory differences during the blind test, but when the information about the vegetables was provided, higher scores were obtained by those products labelled as organic in the informed test and in the inverted test (conventional labelled as organic). This effect was higher for students with stronger attitudes towards organic food. These results indicated that the perceived differences between organic and conventional leafy green by university students tended to be attitudinal and, therefore, can be greatly influenced by the information provided with the product.Originality/valueThis research showed that university students were influenced by the organic label, revealing their sensory perception about vegetables. This study had multiple methodological approaches, including hedonic scaling and consumers’ WTB. This combination allowed identifying the students’ attitudinal tendency in relation to their sensory perceptions of organic green leafy green vegetables.
Jurisprudence and demand for halal meat in OIC
Authors: Majeed Imran , Al-Zyoud Hussein , Ahmad Naved 
Published: June 2019

Purpose
The purpose of this paper is to estimate the import demand function for halal meat in member countries of the Organization of Islamic Cooperation (OIC) and to suggest some policy recommendations for OIC members that can enhance intra-OIC halal meat trade.

Design/methodology/approach
By using an augmented gravity model, this study empirically estimates the major determinants of halal meat import demand in OIC member countries. Moreover, a major determinant is the difference in Islamic jurisprudence (fiqh).

Findings
The results of this study show that the variation in Islamic jurisprudence is one of the primary determinants of intra-regional trade of halal meat import demand in OIC member countries.

Research limitations/implications
Although trade flows are set up in several years and lag variables are well capable to examine trade flows, this study only includes the static nature of halal meat trade flows toward selected top 20 OIC member countries.

Practical implications
This study suggests that developing a common halal meat market and one halal certification body under the OIC can enhance intra-OIC halal meat trade, this may be a challenge given the five diverse interpretations of halal meat within Islamic jurisprudence among OIC member countries.

Originality/value
This paper identifies the role of Islamic jurisprudence (fiqh) in determining the import demand of halal meat in OIC countries, which has not been addressed in empirical literature. It also provides some policy implications to ameliorate the declining trend of intra-OIC trade flows of halal meat.