bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitabilityviaoveractivation of neuronal GluN2C NMDA receptors
Authors: Pineau Louison , Buhler Emmanuelle , Tarhini Sarah , Bauer Sylvian , Crepel Valérie , Watrin Françoise , Cardoso Carlos , Represa Alfonso , Szepetowski Pierre , Burnashev Nail 
Published: December 2023

AbstractObjectiveGenetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood. Previously, the role of upregulated GluN2C-containing glutamate- gated NMDA receptors (NMDARs) has been demonstrated for germline defects in theTSCgenes. Here, we questioned whether this mechanism would expand to other mTORopathies in the different context of a somatic genetic variation of the MTOR protein recurrently found in FCD type II.MethodsWe used a rat model of FCD created byin uteroelectroporation of neural progenitors of dorsal telencephalon with expression vectors encoding either the wild-type or the pathogenic MTOR variant (p.S2215F). In this mosaic configuration, patch-clamp whole-cell recordings of the electroporated, spiny stellate neurons and extracellular recordings of the electroporated areas were performed in neocortical slices. Selective inhibitors were used to target mTOR activity and GluN2C- mediated currents.ResultsNeurons expressing the mutant protein displayed an excessive activation of GluN2C NMDAR-mediated spontaneous excitatory post-synaptic currents. GluN2C-dependent increase in spontaneous spiking activity was detected in the area of electroporated neurons in the mutant condition and was restricted to a critical time-window between postnatal days P9 and P20.SignificanceSomatic MTOR pathogenic variant recurrently found in FCD type II resulted in overactivation of GluN2C-mediated NMDARs in neocortices of rat pups. The related and time- restricted hyperexcitability was sensitive to subunit GluN2C-specific blockade. Our study suggests that GluN2C-related pathomechanisms might be shared in common by mTOR pathway-related cortical dysplasia.Key pointsExcessive activation of GluN2C NMDAR-mediated currents in spiny stellate neurons expressing FCD-causing MTOR somatic variationGluN2C-dependent increase in spontaneous spiking activity in rat somatosensory cortex containing mutant MTOR-expressing neuronsGluN2C-dependent excessive network activity is time-restricted to a critical period between P9 and P20
Differential development of antibiotic resistance and virulence betweenAcinetobacterspecies
Authors: Darby Elizabeth M. , Moran Robert A. , Holden Emma , Morris Theresa , Harrison Freya , Clough Barbara , McInnes Ross S. , Schneider Ludwig , Frickel Eva M. , Webber Mark A. , Blair Jessica M. A. 
Published: December 2023

AbstractThe two species that account for most cases ofAcinetobacter-associated bacteraemia in the UK areAcinetobacter lwoffii, often a commensal but also an emerging pathogen, andA. baumannii, a well-known antibiotic-resistant species. While these species both cause similar types of human infection and occupy the same niche,A. lwoffii(unlikeA. baumannii) has thus far remained susceptible to antibiotics. Comparatively little is known about the biology ofA. lwoffiiand this is the largest study on it conducted to date, providing valuable insights into its behaviour and potential threat to human health.This study aimed to explain the antibiotic susceptibility, virulence, and fundamental biological differences between these two species. The relative susceptibility ofA. lwoffii, was explained as it encoded fewer antibiotic resistance and efflux pump genes thanA. baumannii(9 and 30 respectively). While both species had markers of horizontal gene transfer,A. lwoffiiencoded more DNA defence systems and harboured a far more restricted range of plasmids. Furthermore,A. lwoffiidisplayed a reduced ability to select for antibiotic resistance mutations, form biofilm and infect bothin vivoandin vitromodels of infection.This study suggests that the emerging pathogenA. lwoffiihas remained susceptible to antibiotics because mechanisms exist to make it highly selective about the DNA it acquires, and we hypothesise that the fact that it only harbours a single RND system restricts the ability to select for resistance mutations. This provides valuable insights into how development of resistance can be constrained in Gram negative bacteria.ImportanceAcinetobacter lwoffiiis often a harmless commensal but is also an emerging pathogen and is the most common cause ofAcinetobacter-derived blood stream infections in England and Wales. In contrast to the well-studied, and often highly drug resistantA. baumannii,A. lwoffiihas remained susceptible to antibiotics. This study explains why this organism has not evolved resistance to antibiotics. These new insights are important to understand why and how some species develop antibiotic resistance, while others do not and could inform future novel treatment strategies.
Germline transformation of the West Nile Virus and avian malaria vectorCulex quinquefasciatusSay using the piggyBac transposon system
Authors: Nevard Katherine , Kaur Rajdeep , Harvey-Samuel Tim 
Published: December 2023

AbstractCulex quinquefasciatusSay is a mosquito which acts as a vector for numerous diseases including West Nile Virus, lymphatic filariasis and avian malaria, over a broad geographical range. As the effectiveness of insecticidal mosquito control methods declines, the need has grown to develop genetic control methods to curb the spread of disease. The piggyBac transposon system - the most widely used genetic transformation tool in insects, including mosquitoes - generates quasi-random insertions of donor DNA into the host genome. However, despite the broad reported species range of piggyBac, previous attempts to use this tool to transformCulex quinquefasciatusmosquitoes have failed. Here we report the first successful transformation ofCulex quinquefasciatuswith the piggyBac transposon system. Using commercially synthesised piggyBac mRNA as a transposase source, we were able to generate three independent insertions of aZsGreenfluorescent marker gene, with transformation efficiencies of up to 5%. Through this work, we have expanded the genetic toolkit available for the genetic manipulation ofCulexmosquitoes and thus removed a barrier to developing novel genetic control methods in this important disease vector.
Inferring Disease Progressive Stages in Single-Cell Transcriptomics Using Weakly-Supervised Deep Learning Approach
Authors: Wehbe Fabien , Adams Levi , Yuen Samantha , Kim Yoon-Seong , Tanaka Yoshiaki 
Published: December 2023

AbstractBackgroundApplication of single-cell/nucleus genomic sequencing to patient-derived tissues offers potential solutions to delineate disease mechanisms in human. However, individual cells in patient-derived tissues are in different pathological stages, and hence such cellular variability impedes subsequent differential gene expression analyses.ResultTo overcome such heterogeneity issue, we present a novel deep learning approach, scIDST, that infers disease progressive levels of individual cells with weak supervision framework. The inferred disease progressive cells displayed significant differential expression of disease-relevant genes, which could not be detected by comparative analysis between patients and healthy donors. In addition, we demonstrated that pre-trained models by scIDST are applicable to multiple independent data resources, and advantageous to infer cells related to certain disease risks and comorbidities.ConclusionTaken together, scIDST offers a new strategy of single-cell sequencing analysis to identify bona fide disease-associated molecular features.
Spatial Relationships Matter: Kinesin-1 Molecular Motors Transport Liposome Cargo Through 3D Microtubule IntersectionsIn Vitro
Authors: Bensel Brandon M , Previs Samantha , Bookwalter Carol , Trybus Kathleen M , Walcott Sam , Warshaw David M 
Published: December 2023

AbstractKinesin-1 ensembles maneuver vesicular cargoes through intersections in the 3-dimensional (3D) intracellular microtubule (MT) network. To characterize directional outcomes (straight, turn, terminate) at MT intersections, we challenge 350 nm fluid-like liposomes transported by ∼10 constitutively active, truncated kinesin-1 KIF5B (K543) with perpendicular 2-dimensional (2D) and 3D intersectionsin vitro. Liposomes frequently pause at 2D and 3D intersections (∼2s), suggesting that motor teams can simultaneously engage each MT and undergo a tug-of-war. Once resolved, the directional outcomes at 2D MT intersections have a straight to turn ratio of 1.1; whereas at 3D MT intersections, liposomes more frequently go straight (straight to turn ratio of 1.8), highlighting that spatial relationships at intersections bias directional outcomes. Using 3D super-resolution microscopy (STORM), we define the gap between intersecting MTs and the liposome azimuthal approach angle heading into the intersection. We develop anin silicomodel in which kinesin-1 motors diffuse on the liposome surface, simultaneously engage the intersecting MTs, generate forces and detach from MTs governed by the motors’ mechanochemical cycle, and undergo a tug-of-war with the winning team determining the directional outcome in 3D. The model predicts that 1-3 motors typically engage the MT, consistent with optical trapping measurements. Modeled liposomes also predominantly go straight through 3D intersections over a range of intersection gaps and liposome approach angles, even when obstructed by the crossing MT. Our observations and modeling offer mechanistic insights into how cells might tune the MT cytoskeleton, cargo, and motors to modulate cargo transport.Significance StatementKinesin-1 molecular motors transport vesicles containing essential cellular resources along the dense 3D microtubule (MT) cytoskeleton, with dysfunctions linked to neurodegenerative diseases such as Alzheimer’s. Despite its importance, the mechanism by which kinesin-1s maneuver intracellular cargoes through MT-MT intersections towards their destination remains unclear. Therefore, we developed a 3Din vitromodel transport system, which challenges kinesin-1 motor teams to maneuver vesicle-like liposomes through MT-MT intersections. Surprisingly, liposomes are biased to pass straight through 3D MT intersections rather than turn, even when the MT intersection presents as a physical barrier. A mechanistic model informs this observation, suggesting that spatial relationships between the cargo and MT intersection influence how molecular motors maneuver intracellular cargoes towards their destination to satisfy cellular demands.
Hemodynamics regulate spatiotemporal artery muscularization in the developing circle of Willis
Authors: Cheng Siyuan , Xia Ivan Fan , Wanner Renate , Abello Javier , Stratman Amber N. , Nicoli Stefania 
Published: December 2023

AbstractVascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries, playing a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular diseases and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating differentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on the zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that the arterial expression of CoW endothelial cells (ECs) occurs after their migration from the cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors upon recruitment to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity wall shear stress. Furthermore, pulsatile blood flow is required for differentiation of human brain pdgfrb+ mural cells into VSMCs as well as VSMC differentiation on zebrafish CoW arteries. Consistently, the flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, andklf2aknockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight the role of blood flow activation of endothelial klf2a as a mechanism regulating the initial VSMC differentiation on vertebrate brain arteries.
Getting there in one piece: The Rac pathway prevents cell fragmentation in a nonprotrusively migrating leader cell during organogenesis
Authors: Singh Noor , Li Karen Jian , Gordon Kacy Lynn 
Published: December 2023

SUMMARYTheC. eleganshermaphrodite distal tip cell (DTC) leads gonadogenesis. Loss-of-function mutations in aC. elegansortholog of the Rac1 GTPase (ced-10) and its GEF complex (ced-5/DOCK180,ced-2/CrkII,ced-12/ELMO) cause gonad migration defects related to directional sensing; we discovered an additional defect class of gonad bifurcation in these mutants. Using genetic approaches, tissue-specific and whole-body RNAi, andin vivoimaging of endogenously tagged proteins and marked cells, we find that loss of Rac1 or its regulators causes the DTC to fragment as it migrates. Both products of fragmentation—the now-smaller DTC and the membranous patch of cellular material—localize important stem cell niche signaling (LAG-2/DSL ligand) and migration (INA-1/integrin subunit alpha) factors to their membranes, but only one retains the DTC nucleus and therefore the ability to maintain gene expression over time. The enucleate patch can lead a bifurcating branch off the gonad arm that grows through germ cell proliferation. Germ cells in this branch differentiate as the patch loses LAG-2 expression. While the nucleus is surprisingly dispensable for aspects of leader cell function, it is required for stem cell niche activity long-term. Prior work found thatRac1−/−;Rac2−/−mouse erythrocytes fragment; in this context, our new findings support the conclusion that maintaining a cohesive but deformable cell is a conserved function of this important cytoskeletal regulator.
Co-production revisited: from knowledge plurality to action for disaster risk reduction
Authors: Tran Minh , Kim Dayoon 
Published: December 2023

PurposeThe authors revisit the notion of co-production, highlight more critical and re-politicized forms of co-production and introduce three principles for its operationalization. The paper’s viewpoint aims to find entry points for enabling more equitable disaster research and actions via co-production.Design/methodology/approachThe authors draw insights from the authors’ reflections as climate and disaster researchers and literature on knowledge politics in the context of disaster and climate change, especially within critical disaster studies and feminist political ecology.FindingsDisaster studies can better contribute to disaster risk reduction via political co-production and situating local and Indigenous knowledge at the center through three principles, i.e. ensuring knowledge plurality, surfacing norms and assumptions in knowledge production and driving actions that tackle existing knowledge (and broader sociopolitical) structures.Originality/valueThe authors draw out three principles to enable the political function of co-production based on firsthand experiences of working with local and Indigenous peoples and insights from a diverse set of co-production, feminist political ecology and critical disaster studies literature. Future research can observe how it can utilize these principles in its respective contexts.
Sustainable value creation through customization for smart PSS models: a multi-industry case study
Authors: Chang Yuan , Ming Xinguo , Liao Xiaoqiang , Bao Yuguang , Chen Zhihua , Song Wenyan 
Published: December 2023

PurposeThis study is a reference for manufacturers who are promoting their product-service system (PSS) development. Currently, improvements in both digital customization and sustainability for various smart PSS categories have been considered rarely. This paper addresses this research gap by developing relevant models.Design/methodology/approachThe development trends of customization-oriented PSS are described in a literature review. An in-depth multiple-case study methodology is adopted, and seven manufacturing companies are sampled. The goal is to identify digital customization measures that can be employed on representative smart PSS models and to explore how these models can create sustainable value.FindingsThis study provides valuable insights by uncovering a synthesis framework for achieving customization of the product/use/result-oriented smart PSSs, and the relevant representative smart functions are summarized. This identifies how digital customization capabilities can improve sustainability, including direct economic value for customers as well as additional social benefits and environmental improvements during customization.Originality/valueCurrently, the influence of digitalization on customized offerings and the relevant impact on sustainability development have not been fully addressed to date. This study provides comprehensive information with a reference value for digital customization transformation among the three main types of smart PSS.
Aging of stallion spermatozoa stored in vitro is delayed at 22°C using a 67 mm glucose–10 mm pyruvate‐based media
Authors: Becerro‐Rey Laura , Martín‐Cano Francisco Eduardo , Ferrusola Cristina Ortega , Rodríguez‐Martínez Heriberto , Gaitskell‐Phillips Gemma , da Silva‐Álvarez Eva , Silva‐Rodríguez Antonio , Gil María Cruz , Peña Fernando J. 
Published: December 2023

AbstractBackgroundMost commerce of equine seminal doses is carried out using commercial extenders under refrigeration at 5°C.ObjectivesTo determine if 10 mm pyruvate in a 67 mm glucose extender and storage at 22°C could be the basis of an alternative storage method to cooling to 5°C.Material and methodsStallion ejaculates were extendedin: INRA96 (67 mm glucose, non‐pyruvate control), modified Tyrode's (67 mm glucose–10 mm pyruvate), supplemented with 0, 10, 50, and 100 μM itaconate. As itaconate was vehiculated in DMSO, a control vehicle was also included. Sperm motility, viability, mitochondrial membrane potential, and production of reactive oxygen species were measured after collection and again after 48 and 96 h of storage at 22°C. To disclose molecular metabolic changes, spermatozoa were incubated up to 3 h in modified Tyrode's 67 mm glucose–10 mm pyruvate and modified Tyrode's 67 mm glucose, and metabolic analysis conducted.ResultsAfter 96 h of storage aliquots stored in the control, INRA96 had a very poor total motility of 5.6% ± 2.3%, while in the 67 mm glucose–10 mm pyruvate/10 μm itaconate extender, total motility was 34.7% ± 3.8% (p = 0.0066). After 96 h, viability was better in most pyruvate‐based media, and the mitochondrial membrane potential in spermatozoa extended in INRA96 was relatively lower (p < 0.0001). Metabolomics revealed that in the spermatozoa incubated in the high pyruvate media, there was an increase in the relative amounts of NAD+, pyruvate, lactate, and ATP.Discussion and conclusionsAliquots stored in a 67 mm glucose–10 mm pyruvate‐based medium supplemented with 10 μM itaconate, maintained a 35% total motility after 96 h of storage at 22°C, which is considered the minimum acceptable motility for commercialization. Improvements may be related to the conversion of pyruvate to lactate and regeneration of NAD+.
A comparative analysis of colour–emotion associations in 16–88‐year‐old adults from 31 countries
Authors: Jonauskaite Domicele , Epicoco Déborah , Al‐rasheed Abdulrahman S. , Aruta John Jamir Benzon R. , Bogushevskaya Victoria , Brederoo Sanne G. , Corona Violeta , Fomins Sergejs , Gizdic Alena , Griber Yulia A. , Havelka Jelena , Hirnstein Marco , John George , Jopp Daniela S. , Karlsson Bodil , Konstantinou Nikos , Laurent Éric , Marquardt Lynn , Mefoh Philip C. , Oberfeld Daniel , Papadatou‐Pastou Marietta , Perchtold‐Stefan Corinna M. , Spagnulo Giulia F. M. , Sultanova Aygun , Tanaka Takumi , Tengco‐Pacquing Ma. Criselda , Uusküla Mari , Wąsowicz Grażyna , Mohr Christine 
Published: December 2023

AbstractAs people age, they tend to spend more time indoors, and the colours in their surroundings may significantly impact their mood and overall well‐being. However, there is a lack of empirical evidence to provide informed guidance on colour choices, irrespective of age group. To work towards informed choices, we investigated whether the associations between colours and emotions observed in younger individuals also apply to older adults. We recruited 7393 participants, aged between 16 and 88 years and coming from 31 countries. Each participant associated 12 colour terms with 20 emotion concepts and rated the intensity of each associated emotion. Different age groups exhibited highly similar patterns of colour–emotion associations (average similarity coefficient of .97), with subtle yet meaningful age‐related differences. Adolescents associated the greatest number but the least positively biased emotions with colours. Older participants associated a smaller number but more intense and more positive emotions with all colour terms, displaying a positivity effect. Age also predicted arousal and power biases, varying by colour. Findings suggest parallels in colour–emotion associations between younger and older adults, with subtle but significant age‐related variations. Future studies should next assess whether colour–emotion associations reflect what people actually feel when exposed to colour.