bluuebunny/crossref_metadata_2025_split huggingface dataset:
Divergent patterns of healthy aging across human brain regions at single-cell resolution reveal links to neurodegenerative disease
Authors: Duffy Megan F. , Ding Jinhui , Langston Rebekah G. , Shah Syed I. , Nalls Mike A. , Scholz Sonja W. , Whitaker D. Thad , Auluck Pavan K. , Marenco Stefano , Gibbs J. Raphael , Cookson Mark R. 
Published: August 2023

AbstractAge is a major common risk factor underlying neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether expression associations with age are due to changes in cell numbers and/or gene expression per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) to examine changes in cell proportions and transcriptomes in four different brain regions, each from 12 donors aged 20-30 years (young) or 60-85 years (old). We sampled 155,192 nuclei from two cortical regions (entorhinal cortex and middle temporal gyrus) and two subcortical regions (putamen and subventricular zone) relevant to neurodegenerative diseases or the proliferative niche. We found no changes in cellular composition of different brain regions with healthy aging. Surprisingly, we did find that each brain region has a distinct aging signature, with only minor overlap in differentially associated genes across regions. Moreover, each cell type shows distinct age-associated expression changes, including loss of protein synthesis genes in cortical inhibitory neurons, axonogenesis genes in excitatory neurons and oligodendrocyte precursor cells, enhanced gliosis markers in astrocytes and disease-associated markers in microglia, and genes critical for neuron-glia communication. Importantly, we find cell type-specific enrichments of age associations with genes nominated by Alzheimer’s disease and Parkinson’s disease genome-wide association studies (GWAS), such as apolipoprotein E (APOE), and leucine-rich repeat kinase 2 (LRRK2) in microglia that are independent of overall expression levels across cell types. We present this data as a new resource which highlights, first, region- and cell type-specific transcriptomic changes in healthy aging that may contribute to selective vulnerability and, second, provide context for testing GWAS-nominated disease risk genes in relevant subtypes and developing more targeted therapeutic strategies. The data is readily accessible without requirement for extensive computational support in a public website,https://brainexp-hykyffa56a-uc.a.run.app/Graphical Abstract*Created usingBiorender.comHighlightsEstablishment of a single nuclei atlas of human aging in four brain regionsEach region and cell type exhibits a unique aging-associated transcriptome signatureGene expression changes occur in absence of overt cell loss and are categorically unique across cell typesNeurological disease-associated genes have age-associated expression patterns in specific cell types in the context of healthy aging
Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion
Authors: Flores Andrew J. , Bartlett Mitchell J. , Samtani Grace , Seaton Blake T. , Sexauer Morgan R. , Weintraub Nathan C. , Siegenthaler James R. , Lu Dong , Heien Michael L. , Porreca Frank , Sherman Scott J. , Falk Torsten 
Published: August 2023

AbstractLevels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinson’s disease (PD) and following the development of L-DOPA-induced dyskinesia (LID). It remains unclear whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) via measuring of tonic levels of striatal DA. While nor-BNI (3 mg/kg;s.c.) did not lead to functional restoration in the DA-depleted state, it affected the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of L-DOPA in a rat PD model with a moderate striatal 6-hydroxdopamine (6-OHDA) lesion. We tested five escalating doses of L-DOPA (6, 12, 24, 48, 72 mg/kg;i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg L-DOPA doses. However, after reaching the 72 mg/kg L-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of L-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we observed an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.HighlightsMild L-DOPA-induced dyskinesia develops in moderately lesioned parkinsonian ratsIn the moderately-lesioned dorsolateral striatum tonic dopamine is increasedAntagonizing dynorphin does not affect parkinsonian motor symptoms in rodentsAntagonizing dynorphin increases rate of development of L-DOPA-induced dyskinesiaTonic dopamine in dorsolateral striatum is unchanged after antagonizing dynorphin
Interdependence of plasma membrane nanoscale dynamics of a kinase and its cognate substrate underliesArabidopsisresponse to viral infection
Authors: Jolivet Marie-Dominique , Deroubaix Anne-Flore , Boudsocq Marie , Abel Nikolaj B. , Rocher Marion , Robbe Terezinha , Wattelet-Boyer Valérie , Huard Jennifer , Lefebvre Dorian , Lu Yi-Ju , Day Brad , Saias Grégoire , Ahmed Jahed , Cotelle Valérie , Giovinazzo Nathalie , Gallois Jean-Luc , Yamaji Yasuyuki , German-Retana Sylvie , Gronnier Julien , Ott Thomas , Mongrand Sébastien , Germain Véronique 
Published: August 2023

ABSTRACTPlant viruses represent a risk to agricultural production and as only a few treatments exist, it is urgent to identify resistance mechanisms and factors. In plant immunity, plasma membrane (PM)-localized proteins play an essential role in sensing the extracellular threat presented by bacteria, fungi or herbivores. Viruses are intracellular pathogens and as such the role of the plant PM in detection and resistance against viruses is often overlooked. We investigated the role of the partially PM-bound Calcium-dependent protein kinase 3 (CPK3) in viral infection and we discovered that it displayed a specific ability to hamper viral propagation over CPK isoforms that are involved in immune response to extracellular pathogens. More and more evidence support that the lateral organization of PM proteins and lipids underlies signal transduction in plants. We showed here that CPK3 diffusion in the PM is reduced upon activation as well as upon viral infection and that such immobilization depended on its substrate, Remorin (REM1.2), a scaffold protein. Furthermore, we discovered that the viral infection induced a CPK3-dependent increase of REM1.2 PM diffusion. Such interdependence was also observable regarding viral propagation. This study unveils a complex relationship between a kinase and its substrate that contrasts with the commonly described co-stabilisation upon activation while it proposes a PM-based mechanism involved in decreased sensitivity to viral infection in plants.
De novo production of an antitumor precursor actinocin and other medicinal molecules from kynurenine pathway inEscherichia coli
Authors: Sharma Komal , Ghiffary Mohammad Rifqi , Lee GaRyoung , Kim Hyun Uk 
Published: August 2023

AbstractKynurenine pathway has a potential to convert L-tryptophan into multiple medicinal molecules. This study aims to explore the biosynthetic potential of kynurenine pathway for the efficient production of actinocin, an antitumor precursor selected as a proof-of-concept target molecule. Kynurenine pathway is first constructed inEscherichia coliby testing various combinations of biosynthetic genes from four different organisms. Metabolic engineering strategies are next performed to improve the production by inhibiting a competing pathway, and enhancing intracellular supply of a cofactorS-adenosyl-L-methionine, and ultimately to produce actinocin from glucose. Metabolome analysis further suggests additional gene overexpression targets, which finally leads to the actinocin titer of 719 mg/L.E. colistrain engineered to produce actinocin is further successfully utilized to produce 350 mg/L of kynurenic acid, a neuroprotectant, and 1401 mg/L of 3-hydroxyanthranilic acid, an antioxidant, also from glucose. These competitive production titers demonstrate the biosynthetic potential of kynurenine pathway as a source of multiple medicinal molecules. The approach undertaken in this study can be useful for producing other molecules associated with kynurenine pathway.
Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypicalSetbp1S858RSchinzel Giedion Syndrome mice
Authors: Whitlock Jordan H. , Soelter Tabea M. , Howton Timothy C. , Wilk Elizabeth J. , Oza Vishal H. , Lasseigne Brittany N. 
Published: August 2023

AbstractSchinzel Giedion Syndrome (SGS) is an ultra-rare autosomal dominant Mendelian disease presenting with abnormalities spanning multiple organ systems. The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures. SGS is caused by spontaneous variants inSETBP1, which encodes for the epigenetic hub SETBP1 transcription factor (TF).SETBP1variants causing classical SGS cluster at the degron, disrupting SETBP1 protein degradation resulting in toxic accumulation, while those located outside cause milder atypical SGS. Due to the multi-system phenotype, we evaluated gene expression and regulatory programs altered in atypical SGS by snRNA-seq of cerebral cortex and kidney ofSetbp1S858Rheterozygous mice (corresponds to the human likely pathogenicSETBP1S867Rvariant) compared to matched wild-type mice by constructing cell-type-specific regulatory networks.Setbp1was differentially expressed in excitatory neurons, but known SETBP1 targets were differentially expressed and regulated in many cell types. Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and are present in the kidney. Our results indicate SETBP1’s role as an epigenetic hub leads to cell-type-specific differences in TF activity, gene targeting, and regulatory rewiring. This research provides a framework for investigating cell-type-specific variant impact on gene expression and regulation.
Nitrogen starvation leads to TOR kinase-mediated downregulation of fatty acid synthesis in the algaeChlorella sorokinianaandChlamydomonas reinhardtii
Authors: Vijayan Jithesh , Alvarez Sophie , Naldrett Michael J , Maliva Amanda , Wase Nishikant , Riekhof Wayne R. 
Published: August 2023

AbstractThe accumulation of triacylglycerol (TAG) as a storage compound in eukaryotic algae has been the subject of extensive studies over the last 50 years. The model industrial algaChlorella sorokinianaaccumulates TAG and other storage compounds under nitrogen (N)-limited growth. Previously we used transcriptomics to explore the regulation of TAG synthesis inC. sorokiniana. Surprisingly, our analysis showed that the expression of several key genes encoding enzymes involved in plastidic fatty acid synthesis are significantly repressed. Metabolic labeling with radiolabeled acetate showed thatde novofatty acid synthesis is indeed downregulated under N-limitation. Likewise, inhibition of the Target of Rapamycin kinase (TOR), a key regulator of metabolism and growth, decreased fatty acid synthesis. We compared the changes in proteins and phosphoprotein abundance using a proteomics and phosphoproteomics approach inC. sorokinianacells under N-limitation or TOR inhibition and found extensive overlap between the N-limited and TOR-inhibited conditions. We also identified changes in the phosphorylation levels of TOR complex proteins, TOR-kinase and RAPTOR, under N-limitation, indicating that TOR signaling is altered. Our results indicate that under N-limitation there is significant metabolic remodeling, including fatty acid synthesis, mediated by TOR signaling. We find that TOR-mediated metabolic remodeling of fatty acid synthesis under N-limitation is conserved in the chlorophyte algaeChlorella sorokinianaandChlamydomonas reinhardtii.
A diversified, widespread microbial gene cluster encodes homologs of methyltransferases involved in methanogenesis
Authors: Kountz Duncan J. , Balskus Emily P. 
Published: August 2023

AbstractAnalyses of microbial genomes have revealed unexpectedly wide distributions of enzymes from specialized metabolism, including methanogenesis, providing exciting opportunities for discovery. Here, we identify a family of gene clusters (the type 1mlpgene clusters (MGCs)) that encodes homologs of the soluble coenzyme M methyltransferases (SCMTs) involved in methylotrophic methanogenesis and is widespread in bacteria and archaea. Type 1 MGCs are expressed and regulated in medically, environmentally, and industrially important organisms, making them likely to be physiologically relevant. Enzyme annotation, analysis of genomic context, and biochemical experiments suggests these gene clusters play a role in methyl-sulfur and/or methyl-selenide metabolism in numerous anoxic environments, including the human gut microbiome, potentially impacting sulfur and selenium cycling in diverse, anoxic environments.
Rethinking engagement in urban design: reimagining the value of co-design and participation at every stage of planning for autonomous vehicles
Authors: Belkouri Daria , Khairy Lina , Laing Richard , Lanng Ditte Bendix 
Published: August 2023

PurposeThe practical demonstrations and research which led to the preparation of this paper involved a combination of stakeholder engagement, policy debate and the practical demonstration and testing of autonomous vehicles. By adhering to a design approach which in centred on participation and human-centred engagement, the advent of autonomous vehicles might avoid many of the problems encountered in relation to conventional transport.Design/methodology/approachThe research explored how a new and potentially disruptive technology might be incorporated in urban settings, through the lens of participation and problem-based design. The research critically reviews key strands in the literature (autonomous vehicles, social research and participatory design), with allusion to current case study experiments.FindingsAlthough there are numerous examples of autonomous vehicles (AV) research concentrating on technical aspects alone, this paper finds that such an approach appears to be an unusual starting point for the design of innovative technology. That is, AVs would appear to hold the potential to be genuinely disruptive in terms of innovation, yet the way that disruption takes place should surely be guided by design principles and by issues and problems encountered by potential users.Practical implicationsThe research carries significant implications for practice in that it advocates locating those socio-contextual issues at the heart of the problem definition and design process and ahead of technical solutions.Originality/valueWhat sets this research apart from other studies concerning AVs was that the starting point for investigation was the framing of AVs within contexts and scenarios leading to the emergence of wicked problems. This begins with a research position where the potential uses for AVs are considered in a social context, within which the problems and issues to be solved become the starting point for design at a fundamental level.
The impact of social media communication on consumer-based brand equity and purchasing intent in a pandemic
Authors: Wei Lee Heng , Huat Ong Chuan , Thurasamy Ramayah 
Published: August 2023

PurposeThis study aims to investigate the impact of the source of the content in social media communication and the content distribution intensity on consumer-based brand equity (CBBE) dimensions and how the study will eventually impact purchase intention.Design/methodology/approachA total of 521 samples were collected using an online survey questionnaire. The respondents' validity was verified using purposive sampling techniques, and the responses were analysed using SmartPLS 3.0.FindingsThe authors outlined the fundamental mechanisms of what makes social media communication effective and discovered that emotional-based brand equity dimensions (brand association and brand loyalty) remained significant in influencing purchase intention. However, attribution-based brand equity dimensions (perceived quality, brand trust and brand awareness) are found to have no impact.Originality/valueThis study decomposed social media communication into three different dimensions, and the authors' result showed that the dimensions do not impact CBBE to the same extent. The authors concluded that some CBBE dimensions, which appear to be a rigour determinant of purchase intention over time, have a feeble effect during the pandemic. The existing relationship between the CBBE dimensions with purchase intention might not hold in the pandemic context. The authors suggested that anxiety or pandemic fear could alter the normal consumer buying process and make some well-established relationships not hold. As research indicates that pandemics are reoccurring events, the authors' study contributes to the global effort to dampen some of the pandemic-related effects on business and marketing.
Trade credit supply and financial distress outcomes: evidence from Australian voluntary administrations
Authors: Routledge James 
Published: August 2023

PurposeThe objective of this study is to investigate the relationship between trade credit supply and financial distress outcomes, considering the role that trade credit plays as a substantial source of liquidity for distressed companies. Specifically, it examines whether there is an association between trade credit supply and the outcomes experienced by companies that undergo the voluntary administration (VA) insolvency procedure under Australian corporate law.Design/methodology/approachThe study examines a sample of companies that were listed on the Australian Securities Exchange and entered VA between 2002 and 2019. Ordered logistic regression is used to determine the relation between trade credit and VA outcomes. The VA outcomes considered are as follows: (1) company liquidation, (2) orderly dissolution through an agreement with creditors, or (3) an agreement with creditors for reorganization of all or part of the company's business.FindingsThe findings show that trade creditors' willingness to supply credit is influenced by their rational expectations about the future prospects of financially distressed customers. Higher levels of trade credit and an increase in trade credit supply prior to VA are associated with a greater probability of achieving a reorganization versus a liquidation or dissolution outcome.Originality/valueThere is no apparent prior study investigating the connection between trade credit supply and outcomes for distressed companies entering insolvency administration. Therefore, this study provides novel evidence on the role of trade credit in the context of financial distress. Understanding the relationship between trade credit supply and outcomes is particularly significant considering that many jurisdictions offer distressed companies the opportunity to pursue reorganization under their insolvency laws. Examining financial distress and trade credit in the Australian creditor-friendly context expands on existing research. Prior research has predominantly relied on data from the United States, which has debtor-friendly bankruptcy law. Consequently, these studies may lack generalizability to jurisdictions with creditor-friendly law such as Australia.
The challenges and approaches of measuring research impact and influence on public policy making
Authors: Siar Sheila 
Published: August 2023

PurposeMeasuring research’s policy influence is challenging, given the complexity of the policy process, the gradual nature of policy influence, and the time lag between research investment and impact. This paper assesses measurement approaches and discusses their merits and applications to overcome various hurdles.Design/methodology/approachRelevant articles and studies were selected and analyzed. First, the research-policy interface was revisited to understand their link and how research influences policy making. Second, the most common approaches for measuring policy influence were reviewed based on their features, strengths, and limitations.FindingsThe three approaches reviewed — pyramid, influencing, and results chain — have their respective strengths. Thus, research organizations planning to design a program for monitoring and evaluation (M&E) of policy influence have to adopt the best possible features of each approach and develop a customized method depending on their objectives and overall M&E framework.Originality/valueThis paper fosters a deeper understanding of leveraging the three approaches.
Competing realities, uncertain diagnoses of infectious disease: Mass self‐testing for COVID‐19 and liminal bio‐citizenship
Authors: Petersen Alan , Pienaar Kiran 
Published: August 2023

AbstractDiagnoses of infectious diseases are being transformed as mass self‐testing using rapid antigen tests (RATs) is increasingly integrated into public health. Widely used during the COVID‐19 pandemic, RATs are claimed to have many advantages over ‘gold‐standard’ polymerase chain reaction tests, especially their ease of use and production of quick results. Yet, while laboratory studies indicate the value of RATs in detecting the SARS‐CoV‐2 virus antigen, uncertainty surrounds their deployment and ultimate effectiveness in stemming infections. This article applies the analytic lens of biological citizenship (or bio‐citizenship) to explore Australia’s experience of implementing a RAT‐based mass self‐testing strategy to manage COVID‐19. Drawing on Annemarie Mol’s (1999, The Sociological Review, 47(1), 74–89) concept of ontological politics and analysing government statements, scientific articles and news media reporting published during a critical juncture of the strategy’s implementation, we explore the kind of bio‐citizenship implied by this strategy. Our analysis suggests the emergence of what we call liminal bio‐citizenship, whereby citizens are made responsible for self‐managing infection risk without the diagnostic certitude this demands. We discuss how the different realities of mass self‐testing interact to reinforce this liminal citizenship and consider the implications for the sociology of diagnosis.