bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic Activity of Repurposed Peptide Drug Glatiramer Acetate with Tobramycin Against Cystic Fibrosis Pseudomonas aeruginosa
Authors: Murphy Ronan A. , Coates Matthew , Thrane Sophia , Sabnis Akshay , Harrison James , Schelenz Silke , Edwards Andrew M. , Vorup-Jensen Thomas , Davies Jane C. 
Published: February 2022

ABSTRACTPseudomonas aeruginosa is the most common pathogen infecting the lungs of people with cystic fibrosis (CF), causing both acute and chronic infections. Intrinsic and acquired antibiotic resistance, coupled with the physical barriers resulting from desiccated CF sputum, allow P. aeruginosa to colonise and persist in spite of antibiotic treatment. As well as the specific difficulties in eradicating P. aeruginosa from CF lungs, P. aeruginosa is also subject to the wider, global issue of antimicrobial resistance. Glatiramer acetate (GA) is a peptide drug, used in the treatment of multiple sclerosis (MS), which has been shown to have moderate anti-pseudomonal activity. Other antimicrobial peptides (AMPs) have been shown to be antibiotic resistance breakers; potentiating the activities of antibiotics when given in combination restoring and/or enhancing antibiotic efficacy. Growth, viability, minimum inhibitory concentration (MIC)-determination and synergy analysis showed that GA improved the efficacy of TOB against reference strains of P. aeruginosa, reducing TOB MICs and synergising with the aminoglycoside. This was also the case for clinical strains from people with CF. GA significantly reduced the concentration of TOB required to inhibit 50% (MIC50) of viable cells (from 1.69 [95%CI 0.26-8.97] to 0.62 [95%CI 0.15-3.94] mg/L, p=0.002) and inhibit 90% (MIC90) (from 7.00 [95%CI 1.18-26.50] to 2.20 [95%CI 0.99-15.03] mg/L, p=0.001) compared with TOB-only. Investigating mechanisms of GA activity showed that GA resulted in significant disruption of outer membranes, depolarisation of cytoplasmic membranes and permeabilisation of P. aeruginosa and was the only agent tested (including cationic AMPs) to significantly affect all three.
Graph theoretical analysis reveals the adaptive role of the left ventral occipito-temporal cortex in the brain networks during speech processing
Authors: Wang Shuai , Planton Samuel , Chanoine Valérie , Sein Julien , Anton Jean-Luc , Nazarian Bruno , Dubarry Anne-Sophie , Pallier Christophe , Pattamadilok Chotiga 
Published: February 2022

AbstractThe left ventral occipito-temporal cortex (left-vOT) plays a key role in reading. Several studies have also reported its activation during speech processing, suggesting that it may play a role beyond written word recognition. Here, we adopt a graph theoretical analysis to investigate the functional role of this area in the whole-brain network while participants processed spoken sentences in different tasks. We find that its role and interactions with other areas changes in an adaptive manner. In a low-level speech perception task, the left-vOT is part of the visual network and acts as a connector that supports the communication with other cognitive systems. When speech comprehension is required, the area becomes a connector within the sensorimotor-auditory network typically recruited during speech processing. However, when comprehension is compromised due to degradation of speech input, the area disengages from the sensorimotor-auditory network. It becomes part of the visual network again and turns from connector into a simple peripheral node. These varying connectivity patterns are coherent with the Interactive Account considering the left-vOT as a convergent zone with multiple functions and interaction patterns that depend on task demands and the nature of sensory input.
A mono- and intralink filter (mi-filter) to improve false-discovery rates in cross-linking mass spectrometry data
Authors: Chen Xingyu , Sailer Carolin , Kammer Kai Michael , Fürsch Julius , Eisele Markus R. , Sakata Eri , Stengel Florian 
Published: February 2022

ABSTRACTCross-Linking Mass Spectrometry (XL-MS) has become an indispensable tool for the emerging field of systems structural biology over the recent years. However, the confidence in individual protein-protein interactions (PPIs) depends on the correct assessment of individual inter protein cross-links. This can be challenging, in particularly in samples where relatively few PPIs are detected, as is often the case in complex samples containing low abundant proteins or in in-vivo settings. In this manuscript we are describing a novel mono- and intralink filter (mi-filter) that is applicable to any kind of crosslinking data and workflow. It stipulates that only proteins for which at least one monolink or intra-protein crosslink has been identified within a given dataset are considered for an inter-protein cross-link and therefore participate in a PPI. We show that this simple and intuitive filter has a dramatic effect on different types of crosslinking-data ranging from single protein complexes, over medium-complexity affinity enrichments to proteome-wide cell lysates and significantly lowers the number of false-positive identifications resulting in improved false-discovery rates for inter-protein links in all these types of XL-MS data.
Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer
Authors: Anstee Joanne E. , Opzoomer James W. , Dean Isaac , Muller Henrike P. , Bahri Meriem , Liakath-Ali Kifayathullah , Liu Ziyan , Choy Desmond , Caron Jonathan , Sosnowska Dominika , Beatson Richard , Muliaditan Tamara , An Zhengwen , Gillett Cheryl E. , Lan Guocheng , Zou Xiangang , Watt Fiona M. , Ng Tony , Burchell Joy M. , Kordasti Shahram , Withers David R. , Lawrence Toby , Arnold James N. 
Published: February 2022

AbstractA subset of tumor associated macrophages (TAMs) identified by their expression of the lymphatic vessel endothelial hyaluronan receptor-1 (Lyve-1) reside proximal to blood vasculature and contribute to disease progression. Using a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT), we show that Lyve-1+ TAMs, which co-express heme oxygenase-1, form coordinated multi-cellular ‘nest’ structures in the perivascular niche. We show that TAM nest formation is dependent on IL-6 and a communication axis involving CCR5 and its cognate ligands CCL3/4. We demonstrate that Lyve-1+ TAM nests are associated with CD8+ T-cell exclusion from the tumor and the resistance to immune-stimulating chemotherapeutics. This study highlights an unappreciated collaboration between TAMs and uncovers a spatially driven therapeutic resistance mechanism of these cells in cancer which can be therapeutically targeted.
Identification of a suitable endogenous control miRNA in bone aging and senescence
Authors: Kaur Japneet , Saul Dominik , Doolittle Madison L. , Rowsey Jennifer L. , Vos Stephanie J. , Farr Joshua N. , Khosla Sundeep , Monroe David G. 
Published: February 2022

ABSTRACTObjectiveMicroRNAs (miRNAs) are promising tools as biomarkers and therapeutic agents in various chronic diseases such as osteoporosis, cancers, type I and II diabetes, and cardiovascular diseases. Considering the rising interest in the regulatory role of miRNAs in bone metabolism, aging, and cellular senescence, accurate normalization of qPCR-based miRNA expression data using an optimal endogenous control becomes crucial.MethodsWe used a systematic approach to select candidate endogenous control miRNAs that exhibit high stability with aging from our miRNA sequence data and literature search. Validation of miRNA expression was performed using qPCR and their comprehensive stability was assessed using the RefFinder tool which is based on four statistical algorithms: GeNorm, NormFinder, BestKeeper, and comparative delta CT. The selected endogenous control was then validated for its stability in mice and human bone tissues, and in bone marrow stromal cells (BMSCs) following induction of senescence and senolytic treatment. Finally, the utility of selected endogenous control versus U6 was tested by using each as a normalizer to measure the expression of miR-34a, a miRNA known to increase with age and senescence.ResultsOur results show that Let-7f did not change across the groups with aging, senescence or senolytic treatment, and was the most stable miRNA, whereas U6 was the least stable. Moreover, using Let-7f as a normalizer resulted in significantly increased expression of miR-34a with aging and senescence and decreased expression following senolytic treatment. However, the expression pattern for miR-34a reversed for each of these conditions when U6 was used as a normalizer.ConclusionsWe show that optimal endogenous control miRNAs, such as Let-7f, are essential for accurate normalization of miRNA expression data to increase the reliability of results and prevent misinterpretation. Moreover, we present a systematic strategy that is transferrable and can easily be used to identify endogenous control miRNAs in other biological systems and conditions.
ABA signaling prevents phosphodegradation of the Arabidopsis SR45 splicing factor to negatively autoregulate inhibition of early seedling development
Authors: Albuquerque-Martins Rui , Szakonyi Dóra , Rowe James , Jones Alexander M. , Duque Paula 
Published: February 2022

ABSTRACTAlternative splicing is a key posttranscriptional mechanism to expand the coding capacity of eukaryotic genomes. Although the functional relevance of this process remains poorly understood in plant systems, major modulators of alternative splicing called serine/arginine-rich (SR) proteins have been implicated in plant stress responses mediated by the abscisic acid (ABA) hormone. Loss of function of the Arabidopsis thaliana SR-like protein SR45, a bona fide splicing factor, has been shown to cause plant hypersensitivity to environmental cues and activation of the ABA pathway. Also, consistent with both animal and plant SR proteins being extensively and reversibly phosphorylated at their C-termini, ABA-induced changes in the phosphorylation status of SR45 have been reported.Here, we show that SR45 overexpression reduces Arabidopsis sensitivity to ABA during early seedling development. Moreover, exposure to ABA dephosphorylates SR45 at multiple amino acid residues and leads to accumulation of the protein via reduction of SR45 ubiquitination and proteasomal degradation. Using phosphomutant and phosphomimetic transgenic Arabidopsis lines, we demonstrate the functional relevance of ABA-mediated dephosphorylation of a single SR45 residue, T264, in antagonizing SR45 ubiquitination and degradation to promote its function as a repressor of seedling ABA sensitivity. Taken together, our results reveal a mechanism in which ABA signaling negatively autoregulates during early plant development via posttranslational control of the SR45 splicing factor.
Therapeutic vulnerability to ATR inhibition in concurrent NF1 and ATRX-deficient high-grade solid tumors
Authors: Yuan Ming , Eberhart Charles G. , Pratilas Christine A. , Blakeley Jaishri O. , Davis Christine , Stojanova Marija , Reilly Karlyne , Meeker Alan K. , Heaphy Christopher M. , Rodriguez Fausto J. 
Published: February 2022

AbstractSubsets of Neurofibromatosis Type 1 (NF1)-associated solid tumors have been shown to display high frequencies of ATRX mutations and presence of alternative lengthening of telomeres (ALT). In addition, a potential biologic vulnerability of ALT-positive cancer cells is ATR inhibition, a regulator of homologous recombination. We studied the phenotype of combined NF1 and ATRX deficiency in malignant solid tumors. For these experiments, cell lines derived from NF1-deficient sporadic glioblastomas (U251, SF188), a NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1), a NF1-derived sarcoma cell line (JHH-CRC65), and two NF1-deficient MPNST cell lines (ST88-14, NF90.8) were utilized. Cancer cells were treated with ATR inhibitors (AZD6738 and VE-822), in vitro, with or without a MEK inhibitor (AZD6244, selumetinib) or temozolomide. In contrast to the glioma cell line SF188, combined ATRX knockout (KO) and TERC KO led to ALT-like properties and sensitized U251 glioma cells to ATR inhibition (AZD6738 and VE-822) in vitro and in vivo. In addition, ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition (AZD6244), irrespective of ATRX level manipulation; whereas, the JHH-NF1-GBM1 cell line (ATRX loss/ALT-positive) demonstrated sensitivity to ATR inhibition (AZD6738), but not temozolomide. Similar effects were noted using the MPNST cell line NF90.8 after combined ATRX knockdown and TERC KO; however, not in the MPNST cell line ST88-14. Taken together, our study supports the feasibility of targeting the ATR pathway in subsets of NF1-deficient and associated tumors. Tumors with pre-existing ALT, or that subsequently develop ALT after ATRX downregulation, are particularly vulnerable to this therapeutic approach.
Perilipin 5 interacts with Fatp4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport
Authors: Miner Gregory E. , So Christina M. , Edwards Whitney , Herring Laura E. , Coleman Rosalind A. , Klett Eric L. , Cohen Sarah 
Published: February 2022

SummaryCells adjust their metabolism by remodeling membrane contact sites that channel metabolites to different fates. Lipid droplet (LD)-mitochondria contacts change in response to fasting, cold exposure, and exercise. However, their function and mechanism of formation have remained controversial. We focused on perilipin 5 (Plin5), an LD protein that tethers mitochondria, to probe the function and regulation of LD-mitochondria contacts. We demonstrate that efficient LD-to-mitochondria fatty acid (FA) trafficking and ß-oxidation during starvation of myoblasts requires both phosphorylation of Plin5 and an intact Plin5 mitochondrial tethering domain. We further identified the acyl-CoA synthetase, Fatp4 (ACSVL4) as a novel mitochondrial interactor of Plin5. The C-terminal domains of Plin5 and Fatp4 constitute a minimal protein interaction capable of inducing organelle contacts. Our work suggests that starvation leads to phosphorylation of Plin5, lipolysis, and subsequent channeling of FAs from LDs to Fatp4 on mitochondria for conversion to fatty-acyl-CoAs and subsequent oxidation.
SKN-1 is a metabolic surveillance factor that monitors amino acid catabolism to control stress resistance
Authors: Frankino Phillip A. , Siddiqi Talha F. , Bolas Theodore , Bar-Ziv Raz , Gildea Holly K. , Zhang Hanlin , Higuchi-Sanabria Ryo , Dillin Andrew 
Published: February 2022

SUMMARYThe deleterious potential to generate oxidative stress and damage is a fundamental challenge to metabolism. The oxidative stress response transcription factor, SKN-1/NRF2, can sense and respond to changes in metabolic state, although the mechanism and physiological consequences of this remain unknown. To explore this connection, we performed a genetic screen in C. elegans targeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that genetic perturbation of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated detoxification genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires the GATA transcription factor ELT-3, nuclear hormone receptor NHR-49, and mediator complex subunit MDT-15. This activation of SKN-1 is dependent on upstream histidine catabolism genes HALY-1 and Y51H4A.7/UROC-1 and may occur through accumulation of a catabolite, 4-imidazolone-5-propanoate (IP). Triggering SKN-1 activation results in a physiological trade off of increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 is a key surveillance factor which senses and responds to metabolic perturbations to influence physiology and stress resistance.
Two broadly conserved families of polyprenyl-phosphate transporters
Authors: Roney Ian J. , Rudner David Z. 
Published: February 2022

AbstractPeptidoglycan and virtually all surface glycopolymers in bacteria are built in the cytoplasm on the lipid carrier undecaprenyl-phosphate (UndP). These UndP-linked precursors are transported across the membrane and polymerized or directly transferred to surface polymers, lipids, or proteins. UndP is then flipped to regenerate the pool of cytoplasmic-facing UndP. The identity of the flippase that catalyzes transport has eluded identification for decades. Here, using the antibiotic amphomycin that targets UndP, we discovered two broadly conserved families that catalyze UndP recycling. One (UptA) is a member of the DedA superfamily; the other (PopT) contains the domain DUF368. We show that family members from gram-positive and gram-negative bacteria catalyze UndP transport in Bacillus subtilis. Inhibitors of these flippases could potentiate the current arsenal of cell envelope-targeting antibiotics.One Sentence SummaryWe define two transporter families that recycle the universal lipid carrier in surface glycopolymer biogenesis.
Modulation of stress-related behaviour by hypothalamic engagement of preproglucagon neurons in the nucleus of the solitary tract
Authors: Holt Marie K. , Valderrama Natalia , Polanco Maria J , Rinaman Linda 
Published: February 2022

AbstractStress-induced behaviours are driven by complex neural circuits and some neuronal populations concurrently modulate diverse behavioural and physiological responses to stress. Glucagon-like peptide-1 (GLP1)-producing preproglucagon (PPG) neurons within the lower brainstem caudal nucleus of the solitary tract (cNTS) are particularly sensitive to stressful stimuli and are implicated in multiple physiological and behavioural responses to interoceptive and psychogenic threats. However, the afferent inputs driving stress-induced activation of PPG neurons are largely unknown, and the role of PPG neurons in anxiety-like behaviour is controversial. Through chemogenetic manipulations we reveal that cNTS PPG neurons have the ability to moderately increase anxiety-like behaviours in mice in a sex-dependent manner. Using an intersectional approach, we show that a corticotropin-releasing hormone (CRH)-rich input from the paraventricular nucleus of the hypothalamus (PVN) drives activation of both the cNTS as a whole and PPG neurons in particular in response to acute stress. Finally, we demonstrate that NTS-projecting PVN neurons are necessary for the ability of acute stress to suppress food intake. Our findings reveal sex differences in behavioural responses to PPG neural activation and highlight a hypothalamic-brainstem pathway in stress-induced hypophagia.
Understanding accountability in blockchain systems
Authors: Tyma Bridget , Dhillon Rina , Sivabalan Prabhu , Wieder Bernhard 
Published: February 2022

PurposeThe purpose of this study is to examine how accountability is constructed for blockchain systems. With the aim of increasing knowledge on accountability across three different types of blockchains (public, private and consortium), the researchers ask: how do blockchain systems construct accountability?Design/methodology/approachThis study draws on theorising in the accountability literature to study how blockchains relate to our construction and understanding of accountability. A qualitative field study of the Australian blockchain technology landscape is conducted, with insights garnered from 18 blockchain experts.FindingsFindings reveal that different types of blockchains employ different forms and mechanisms of accountability and in novel ways previously less acknowledged in the literature. Importantly, this study finds that accountability does not require a principal–agent relation and can still manifest in less pure applications of blockchain technology across a wide range of stakeholders, contrary to that espoused in earlier exhortations of blockchain use in interdisciplinary literature. This study also finds that similar subtypes of accountability operate very differently across public, private and consortium blockchains and there exists an inverse relation between trust and consensus building through transparency as blockchains progress from public to private types. Overall, this study offers novel explanations for the relevance of greater accountability in blockchains, especially when the assumptions of public blockchains are softened and applied as private and consortium blockchains.Originality/valueThis study contributes to the accountability literature by addressing how different blockchain systems reshape the understanding of traditional accounting and accountability practices. This study questions the very need for a principal–agent relation to facilitate accountability and offers an additional perspective to how trust and transparency operate as key mechanisms of accountability.
Almost Kenmotsu 3-h-metric as a cotton soliton
Authors: Dey Dibakar , Majhi Pradip 
Published: February 2022

PurposeCotton soliton is a newly introduced notion in the field of Riemannian manifolds. The object of this article is to study the properties of this soliton on certain contact metric manifolds.Design/methodology/approachThe authors consider the notion of Cotton soliton on almost Kenmotsu 3-manifolds. The authors use a local basis of the manifold that helps to study this notion in terms of partial differential equations.FindingsFirst the authors consider that the potential vector field is pointwise collinear with the Reeb vector field and prove a non-existence of such Cotton soliton. Next the authors assume that the potential vector field is orthogonal to the Reeb vector field. It is proved that such a Cotton soliton on a non-Kenmotsu almost Kenmotsu 3-h-manifold such that the Reeb vector field is an eigen vector of the Ricci operator is steady and the manifold is locally isometric to.Originality/valueThe results of this paper are new and interesting. Also, the Proposition 3.2 will be helpful in further study of this space.
Food consumption and food waste behaviour in households in the context of the COVID-19 pandemic
Authors: Vásquez Neyra Jessika Milagros , Cequea Mirza Marvel , Gomes Haensel Schmitt Valentina , Ferasso Marcos 
Published: February 2022

PurposeThis research aims to understand the behaviour of food consumption and waste in Peruvian households at the beginning of the COVID-19 pandemic.Design/methodology/approachExploratory research was carried out with Peruvian households, using a descriptive method design. Data were analysed using descriptive and multivariate statistics. A self-administered questionnaire of 60 questions was used, applied by social networks in May 2020, obtaining 418 valid questionnaires.FindingsThe main findings allow the identification of a behaviour aiming the avoidance of waste and purchasing with a cost–benefit orientation, which is followed by purchase planning, knowledge and use of information on labels, food storage and cooking skills.Practical implicationsFor companies in the food sector, relevant information is provided on consumer behaviour. For policymakers, elements are provided for the promotion of responsible consumption and zero waste. For the academy, an explanation is provided of how and in what way crises influence the behaviour of food consumption and waste.Social implicationsEnvironmental-friendly and responsible consumption behaviour need to be supported, as well as to make consumers aware of the costs of food waste. These measures could be fostered by collective action that includes different actors – from civil society, the private and public sectors – and contribute to a sustainable solution, focused on improving consumption patterns and food waste.Originality/valueThe novelty of this research is based on exploring the understanding of the existing relation among food consumer behaviour, in a context of crisis, towards food waste prevention and avoidance, cost–benefit orientation and the knowledge about labelling, storage and handling.