bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction of amisulpride with GLUT1 at the blood-brain barrier. Relevance to Alzheimer’s disease
Authors: Boyanova Sevda T. , Lloyd-Morris Ethlyn , Corpe Christopher , Rahman K. Miraz , Farag Doaa B. , Page Lee K. , Wang Hao , Fleckney Alice L. , Gatt Ariana , Troakes Claire , Barrena Gema Vizcay- , Fleck Roland , Reeves Suzanne J. , Thomas Sarah A. 
Published: May 2023

AbstractBlood-brain barrier (BBB) dysfunction may be involved in the increased sensitivity of Alzheimer’s disease (AD) patients to antipsychotics, including amisulpride. Studies indicate that antipsychotics interact with facilitated glucose transporters (GLUT), including GLUT1, and that GLUT1 BBB expression decreases in AD. We tested the hypotheses that amisulpride (charge: +1) interacts with GLUT1, and that BBB transport of amisulpride is compromised in AD.GLUT1 substrates and inhibitors, and GLUT-interacting antipsychotics were identified by literature review and their physicochemical characteristics summarised. Interactions between amisulpride, and GLUT1 were studied usingin silicoapproaches and the human cerebral endothelial cell line, hCMEC/D3. Brain distribution of [3H]amisulpride was determined usingin situperfusion in wild type (WT) and 5xFamilial AD (5xFAD) mice. With transmission electron microscopy (TEM) we investigated brain capillary degeneration in WT and 5xFAD mice, and human samples. Western blots determined BBB transporter expression in mouse and human.Literature review revealed that, although D-glucose has no charge, charged molecules can interact with GLUT1. GLUT1 substrates are smaller (184.95±6.45g/mol) than inhibitors (325.50±14.40g/mol), and GLUT-interacting antipsychotics (369.38±16.04). Molecular docking showed beta-D-glucose (free energy binding: –15.39kcal/mol) and amisulpride (–29.04kcal/mol) interact with GLUT1. Amisulpride did not affect [14C]D-glucose accumulation in hCMEC/D3. 5xFAD mice showed increased brain [3H]amisulpride uptake, and no cerebrovascular space changes compared to WT. TEM revealed brain capillary degeneration in human AD. There was no significant effect of AD on mouse GLUT1 and P-gp BBB expression, and in human GLUT1 expression. In contrast, caudate P-glycoprotein expression was decreased in human AD capillaries versus controls.This study provides new details about the BBB transport of amisulpride, evidence that amisulpride interacts with GLUT1, and that BBB transporter expression is altered in AD. This suggests that antipsychotics exacerbate the cerebral hypometabolism in AD. Further research into the mechanism of amisulpride transport by GLUT1 is important for improving antipsychotics safety.
Transcription factor exchange enables prolonged transcriptional bursts
Authors: Pomp Wim , Meeussen Joseph V.W. , Lenstra Tineke L. 
Published: May 2023

AbstractSingle-molecule imaging inside living cells has revealed that transcription factors (TFs) bind to DNA transiently, but a long-standing question is how this transient binding is related to transcription activation. Here, we devised a microscopy method to simultaneously measure transient TF binding at a single locus and the effect of these binding events on transcription. We show that DNA binding of the yeast TF Gal4 activates transcription of a target gene within a few seconds, with at least∼20% efficiency and with a high initiation rate of∼1 RNA/s. Gal4 DNA dissociation decreases transcription rapidly. Moreover, at a gene with multiple binding sites, individual Gal4 molecules only rarely stay bound throughout the entire burst, but instead frequently exchange during a burst to increase the transcriptional burst duration. Our results suggest a mechanism for enhancer regulation in more complex eukaryotes, where TF cooperativity and exchange enable robust transcription activation.
On the Quina side: A Neanderthal bone industry at Chez-Pinaud site, France
Authors: Baumann Malvina , Plisson Hugues , Maury Serge , Renou Sylvain , Coqueugnio Hélène , Vanderesse Nicolas , Kolobova Ksenyia , Shnaider Svetlana , Rots Veerle , Guérin Guillaume , Rendu William 
Published: May 2023

AbstractDid Neanderthal produce a bone industry? The recent discovery of a large bone tool assemblage at the Neanderthal site of Chagyrskaya (Altai, Siberia, Russia) and the increasing discoveries of isolated finds of bone tools in various Mousterian sites across Eurasia stimulate the debate. Assuming that the isolate finds may be the tip of the iceberg and that the Siberian occurrence did not result from a local adaptation of easternmost Neanderthals, we looked for evidence of a similar industry in the Western side of their spread area. We assessed the bone tool potential of the Quina bone-bed level currently under excavation at chez Pinaud site (Jonzac, Charente-Maritime, France) and found as many bone tools as flint ones: not only the well-known retouchers but also beveled tools, retouched artifacts and a smooth-ended rib. Their diversity opens a window on a range of activities not expected in a butchering site and not documented by the flint tools, all involved in the carcass processing. The re-use of 20% of the bone blanks, which are mainly from large ungulates among faunal remains largely dominated by reindeer, raises the question of blank procurement and management. From the Altai to the Atlantic shore, through a multitude of sites where only a few objects have been reported so far, evidence of a Neanderthal bone industry is emerging which provides new insights on Middle Paleolithic subsistence strategies.
KIS counteracts PTBP2 and regulates alternative exon usage in neurons
Authors: Moreno-Aguilera Marcos , Mendoza Mònica B. , Neher Alba M. , Dodel Martin , Mardakheh Faraz K. , Ortiz Raúl , Gallego Carme 
Published: May 2023

AbstractAlternative RNA splicing is an essential and dynamic process to control neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here we show that KIS, a brain-enriched kinase with a domain shared by splicing factors, controls exon usage in differentiated neurons at a genome-wide level. KIS phosphorylates the splicing regulator PTBP2 complex and markedly counteracts its role in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from key co-regulators and hinders its RNA-binding capacity. Taken together, our data provide new insights into the post-translational control of splicing regulators and uncover an essential role of KIS in setting alternative exon usage in neurons.
Host-aware RNA-based control of synthetic microbial consortia
Authors: Boo Alice , Mehta Harman , Amaro Rodrigo Ledesma , Stan Guy-Bart 
Published: May 2023

AbstractMicrobial consortia have been utilised for centuries to produce fermented foods and have great potential in applications such as therapeutics, biomaterials, fertilisers, and biobased production. Working together, microbes become specialized and perform complex tasks more efficiently, strengthening both cooperation and stability of the microbial community. However, imbalanced proportions of microbial community members can lead to unoptimized and diminished yields in biotechnology. To address this, we developed a burden-aware RNA-based multicellular feedback control system that stabilises and tunes coculture compositions. The system consists of three modules: a quorum sensing-based communication module to provide information about the densities of cocultured strains, an RNA-based comparator module to compare the ratio of densities of both strains to a pre-set desired ratio, and a customisable growth module that relies either on heterologous gene expression or on CRISPRi knockdowns to tune growth rates. We demonstrated that heterologous expression burden could be used to stabilise composition in a two-memberE. colicoculture. This is the first coculture composition controller that does not rely on toxins or syntrophy for growth regulation and uses RNA sequestration to stabilise and control coculture composition. This work provides a fundamental basis to explore burden-aware multicellular feedback control strategies for robust stabilisation of synthetic community compositions.
Antagonism and selective modulation of the human glucocorticoid receptor both reduce recruitment of p300/CBP and the Mediator complex
Authors: Van Moortel Laura , Verhee Annick , Houtman René , Melchers Diana , Delhaye Louis , Thommis Jonathan , Gevaert Kris , Eyckerman Sven , De Bosscher Karolien 
Published: May 2023

AbstractExogenous glucocorticoids are frequently used to treat inflammatory disorders and as adjuncts for treatment of solid cancers. However, their use is associated with severe side effects and therapy resistance. Novel glucocorticoid receptor (GR) ligands with a patient-validated reduced side effect profile have not yet reached the clinic. GR is a member of the nuclear receptor family of transcription factors and heavily relies on interactions with coregulator proteins for its transcriptional activity. To elucidate the role of the GR interactome in the differential transcriptional activity of GR following treatment with agonists, antagonists, or lead selective GR agonists and modulators (SEGRAMs), we generated comprehensive interactome maps by high-confidence proximity proteomics in lung epithelial carcinoma cells. We found that the GR antagonist RU486 and the SEGRAM Dagrocorat both reduced GR interaction with CREB-binding protein (CBP)/p300 and the Mediator complex when compared to the full GR agonist Dexamethasone. Our data offer new insights into the role of differential coregulator recruitment in shaping ligand-specific GR-mediated transcriptional responses.In BriefGlucocorticoids are commonly prescribed for the treatment of inflammatory disorders but are associated with severe side effects. Novel glucocorticoid receptor (GR) ligands with strong anti-inflammatory effects but reduced side effects are still sought after. Despite decades-long GR research, there is still an incomplete understanding of the molecular mechanisms driving context-specific GR activity. Using proximity labeling proteomics, we identified CREB-binding protein (CBP), p300 and the Mediator complex as potential crucial GR coregulators driving ligand-induced changes in GR’s transcriptional activity.HighlightsGlucocorticoids (GCs), potent anti-inflammatory agents, can elicit side effectsMore selective GCs, causing less side effects, are currently still unavailableLack of fundamental insights on context-specific actions of the GC receptor (GR)We mapped ligand-specific GR interactomes using proximity labeling proteomicsp300/CBP and Mediator undergo ligand-dependent changes in interaction with GR
Inferring multi-locus selection in admixed populations
Authors: Ayala Nicolas M. , Corbett-Detig Russell 
Published: May 2023

AbstractAdmixture, the exchange of genetic information between distinct source populations, is thought to be a major source of adaptive novelty. Unlike mutation events, which periodically generate single alleles, admixture can introduce many selected alleles simultaneously. As such, the effects of linkage between selected alleles may be especially pronounced in admixed populations. However, existing tools for identifying selected mutations within admixed populations only account for selection at a single site, overlooking phenomena such as interference among proximal selected alleles. Here, we develop and extensively validate a method for identifying and quantifying the individual effects of multiple linked selected sites on a chromosome in admixed populations. Our approach numerically calculates the expected local ancestry landscape in an admixed population for a given multi-locus selection model, and then maximizes the likelihood of the model. After applying this method to admixed populations ofDrosophila melanogaster,we found that the impacts between linked sites may be an important contributor to natural selection in admixed populations. Furthermore, for the situations we considered, the selection coefficients and number of selected sites are overestimated in analyses that do not consider the effects of linkage among selected sites. Our results imply that linkage among selected sites may be an important evolutionary force in admixed populations. This tool provides a powerful generalized method to investigate these crucial phenomena in diverse populations.
Robust differential expression testing for single-cell CRISPR screens at low multiplicity of infection
Authors: Barry Timothy , Mason Kaishu , Roeder Kathryn , Katsevich Eugene 
Published: May 2023

AbstractSingle-cell CRISPR screens (perturb-seq) link genetic perturbations to phenotypic changes in individual cells. The most fundamental task in perturb-seq analysis is to test for association between a perturbation and a count outcome, such as gene expression. We conduct the first-ever comprehensive benchmarking study of association testing methods for low multiplicity-of-infection (MOI) perturb-seq data, finding that existing methods produce excess false positives. We conduct an extensive empirical investigation of the data, identifying three core analysis challenges: sparsity, confounding, and model misspecification. Finally, we develop an association testing method — SCEPTRE low-MOI — that resolves these analysis challenges and demonstrates improved calibration and power.
Hierarchical syntax models of music predict theta power during music listening
Authors: Herff Steffen A. , Bonetti Leonardo , Cecchetti Gabriele , Vuust Peter , Kringelbach Morten L. , Rohrmeier Martin A. 
Published: May 2023

AbstractLinguistic research showed that the depth of syntactic embedding is reflected in brain theta power. Here, we test whether this also extends to non-linguistic stimuli, specifically music. We used a hierarchical model of musical syntax to continuously quantify two types of expert-annotated harmonic dependencies throughout a piece of Western classical music: prolongation and preparation. Prolongations can roughly be understood as a musical analogue to linguistic coordination between constituents that share the same function (e.g., ‘pizza’ and ‘pasta’ in ‘I ate pizza and pasta’). Preparation refers to the dependency between two harmonies whereby the first implies a resolution towards the second (e.g., dominant towards tonic; similar to how the adjective implies the presence of a noun in ‘I like spicy…’). Source reconstructed MEG data of sixty-eight participants listening to the musical piece was then analysed. We used Bayesian Mixed Effects models to predict theta envelope in the brain, using the number of open prolongation and preparation dependencies as predictors whilst controlling for audio envelope. We observed that prolongation and preparation both carry independent and distinguishable predictive value for theta band fluctuation in key linguistic areas such as the Angular, Supramarginal, Superior Temporal and Heschl’s Gyri, or their right-lateralised homologues, with preparation showing additional predictive value for areas associated with the reward system and prediction. Musical expertise further mediated these effects in language-related brain areas. Results show that predictions of precisely formalised music-theoretical models are reflected in the brain activity of listeners.
Are intermediate school meals a real contribution to improve a healthy and sustainable diet?
Authors: Melo Rita , Lima João , Baltazar Ana Lúcia , Pinto Ezequiel , Fialho Sónia 
Published: May 2023

PurposeThe purpose is to analyse the nutritional adequacy and carbon footprint of intermediated meals provided to preschool children and primary-level students in a Portuguese municipality.Design/methodology/approachAn observational cross-sectional study was conducted with a convenience sampling consisting of school snacks from a Portuguese municipality. The nutritional assessment used food labels and a Portuguese food composition table. The literature review for carbon footprint assessment was conducted by searching for the products under analysis or similar ones.FindingsThe results showed that 80% of snacks have a higher energy value than recommended. The majority of options are below recommendations for protein and fat and above recommendations for carbohydrates. The intermediated meals with more dairy products in composition have the highest carbon footprint. The carbon footprint included the packaging of the products, and it wasn't possible to determine the influence of non-food products.Research limitations/implicationsThis study has limitations in the fact that we do not know the carbon footprint of Portuguese products and we had to compare them with others, from different countries, with possibly different types of production.Practical implicationsIntermediate meals are inadequate, and the carbon footprint is higher when the intermediated meals include products of animal origin – the reason why the composition of intermediated meals should be redesigned considering the achievement of these targets.Social implicationsThe promotion of intermediated meals that promote the Mediterranean eating pattern contributes to health and well-being and is a vehicle for nutrition education and healthy food consumption in schools.Originality/valueMany studies have been conducted to analyse the carbon footprint and environmental impact of school meals, but commonly lunch is the meal evaluated and the assessment of intermediated meals' impact is an open field.
Predict the priority of end-users’ maintenance requests and the required technical staff through LSTM and Bi-LSTM recurrent neural networks
Authors: D’Orazio Marco , Bernardini Gabriele , Di Giuseppe Elisa 
Published: May 2023

Purpose
This paper aims to develop predictive methods, based on recurrent neural networks, useful to support facility managers in building maintenance tasks, by collecting information coming from a computerized maintenance management system (CMMS).

Design/methodology/approach
This study applies data-driven and text-mining approaches to a CMMS data set comprising more than 14,500 end-users’ requests for corrective maintenance actions, collected over 14 months. Unidirectional long short-term memory (LSTM) and bidirectional LSTM (Bi-LSTM) recurrent neural networks are trained to predict the priority of each maintenance request and the related technical staff assignment. The data set is also used to depict an overview of corrective maintenance needs and related performances and to verify the most relevant elements in the building and how the current facility management (FM) relates to the requests.

Findings
The study shows that LSTM and Bi-LSTM recurrent neural networks can properly recognize the words contained in the requests, thus correctly and automatically assigning the priority and predicting the technical staff to assign for each end-user’s maintenance request. The obtained global accuracy is very high, reaching 93.3% for priority identification and 96.7% for technical staff assignment. Results also show the main critical building elements for maintenance requests and the related intervention timings.

Research limitations/implications
This work shows that LSTM and Bi-LSTM recurrent neural networks can automate the assignment process of end-users’ maintenance requests if trained with historical CMMS data. Results are promising; however, the trained LSTM and Bi-LSTM RNN can be applied only to different hospitals adopting similar categorization.

Practical implications
The data-driven and text-mining approaches can be integrated into the CMMS to support corrective maintenance management by facilities management contractors, i.e. to properly and timely identify the actions to be carried out and the technical staff to assign.

Social implications
The improvement of the maintenance of the health-care system is a key component of improving health service delivery. This work shows how to reduce health-care service interruptions due to maintenance needs through machine learning methods.

Originality/value
This study develops original methods and tools easily integrable into IT workflow systems (i.e. CMMS) in the FM field.
How small organisations develop sustainability-oriented strategies: evidence from northwest Himalayas
Authors: Gonibeed Aparna , Kah Sally , Wanjiru Roseline 
Published: May 2023

PurposeUsing Gibson and Tarrant's (2010) resilience triangle model, this study explores how small northwest Himalayan organisations respond to contextual challenges and opportunities and embed sustainability strategies in the organisations' operational values.Design/methodology/approachA qualitative exploratory design through individual and group interviews with owner-managers and employees was held in five small northwest Himalayan organisations.FindingsThe findings reveal multiple contextual challenges facing small organisations in northwest Himalayas, including ecological conditions, remoteness, underdeveloped infrastructure and human competencies. The investigated organisations respond to these challenges through reactive and innovation-based services like eco-tourism, conservation and educational initiatives. The organisations engage communities through participatory and educational activities. Owner-managers adjust the respective vision and mission statements, train employees on sustainability values and lobby the government on policy changes to embed sustainability strategies. Some organisations invest in resources and capabilities and others in process capabilities.Practical implicationsSmall organisations can improve how the organisations predict contextual issues by developing the organisations' process capabilities, specifically by creating practical tools with parameters relevant to ecological conditions. These organisations can set the tools through participatory actions with the broader communities to ensure the (un)intended consequences of environmental issues are considered. Furthermore, improvements in process and human capabilities will provide new approaches to raising business opportunities, especially in post-pandemic business environments.Originality/valueThis study develops a framework that enhances the understanding of how process capabilities, leadership, people and knowledge capabilities are critical to developing and embedding sustainability strategies in small organisations.
Conducting educational escape rooms during a global pandemic
Authors: Ross Robert , Hall Richard , Ross Sarah 
Published: May 2023

PurposeEscape room-based learning is a new educational game-based learning trend which embeds student learning within an exciting escape room scenario. Ordinarily these educational escape rooms are in a table-top format which involves learners decoding clues together around a table. In the age of a global pandemic [coronavirus disease 2019 (COVID-19)] with stringent social distancing and lock-downs, this normal game modality was not possible and so an alternate online approach was required. Thus, this paper aims to study escape room activities during global pandemics.Design/methodology/approachIn this paper, the authors outline how these escape room activities have been taken online, in an synchronous virtual environment and evaluate the student perception of these escape rooms, in contrast to previous cohorts of students who completed escape rooms together in person.FindingsThe authors' results indicate that although students enjoy the escape room game-based learning environment, the remote nature of the activity means the students take longer to solve the puzzles. The students are also more likely to struggle in the activity and find them less engaging than the in-person escape room challenges.Originality/valueAlthough educational escape rooms have been devised for a variety of subjects and can be run through several different modalities (table-top, full rooms and online), this study compares different modalities (online vs table-top) for identical puzzles taken over different cohorts of students.