bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimizing PSC culture for generating neural organoids
Authors: Sutcliffe Magdalena A. , Jensen Pia , Tan Joycelyn , Morris Charles A.J. , Fazakerley Daniel , Larsen Martin R. , Lancaster Madeline A. 
Published: November 2024

AbstractCerebral organoids generated according to unguided protocols produce neural tissue with exceptional cell diversity and fidelity to in vivo. However, with only minimal extrinsic intervention, the importance of high quality starting material becomes paramount. Better understanding of what constitutes a high quality stem cell line and how to maintain those properties throughout prolonged culture is therefore a crucial foundation for successful organoid differentiation. In this study, we investigate the proteome and phospho-proteome of human pluripotent stem cells to uncover the mechanisms that drive neural organoid competence. We identify aberrant cell-extracellular matrix interaction and increased oxidative metabolism as hallmarks of poor neural differentiators. Drawing on the proteomic data and published literature, we optimise culturing conditions by using improved coating matrix, sustained supply of the key growth factor FGF2 and reducing oxidative stress. These adjustments improve brain organoid generation across all tested cell lines, though with varying degrees of efficiency. This work highlights the importance of optimal culture conditions to best support stem cells, ultimately enhancing the quality of brain organoids produced.
Inhibition of Cardiac p38 Highlights the Role of the Phosphoproteome in Heart Failure Progression
Authors: Sedighi Sogol , Liu Ting , O’Meally Robert , Cole Robert N. , O’Rourke Brian , Foster D. Brian 
Published: November 2024

AbstractHeart failure (HF) is a complex condition characterized by the inability of the heart to pump sufficient oxygen to the organs to meet their metabolic needs. Among the altered signal transduction pathways associated with HF pathogenesis, the p38 mitogen-activated protein kinase (p38 MAPK) pathway—activated in response to stress— has attracted considerable attention for its potential role in HF progression and cardiac hypertrophy. However, the exact mechanisms by which p38 MAPK influences HF remain unclear. Addressing knowledge gaps may provide insight on why p38 inhibition has yielded inconsistent outcomes in clinical trials. Here we investigate the effects of p38 MAPK inhibition via SB203580 on cardiac remodeling in a guinea pig model of HF and sudden cardiac death. Using a well-established HF model with ascending aortic constriction and daily isoproterenol (ACi) administration, we assessed proteomic changes across three groups: sham-operated controls, untreated ACi, and ACi treated with SB203580 (ACiSB). Cardiac function was evaluated by M-mode echocardiography, while proteome and phosphoproteome profiles were analyzed using multiplexed tandem mass tag labeling and LC-MS/MS. Our findings demonstrate that chronic SB203580 treatment offers protection against progressive decline in cardiac function in HF. The proteomic data indicate that SB203580-treatment exerts broad protection of the cardiac phosphoproteome, beyond inhibiting maladaptive p38-dependent phosphorylation, extending to PKA and AMPK networks among others, ultimately protecting the phosphorylation status of critical myofibrillar and Ca2+-handling proteins. Though SB203580 had a more restricted impact on widespread protein changes in HF, its biosignature was consistent with preserved mitochondrial energetics as well as reduced oxidative and inflammatory stress.
What’s in Cow Dung Manure? Insights into Its Potential for Supporting Plant Defense System
Authors: Wilson Karun , Arunachalam Sathiavelu 
Published: November 2024

AbstractSolanum lycopersicum, a prominent vegetable crop, suffers major yield losses from early blight disease driven byAlternaria solani.Sustainable alternatives to conventional chemical fungicides are urgently needed to mitigate these losses while minimizing environmental impact. This study investigates the application of the microbial consortium derived from Gir cow dung for enhancing tomato resistance against early blight. Metagenomic analysis of Gir cow dung revealed a rich diversity of beneficial microbes, withBacillusspecies being one of the prominent. Three key strainsBacillus subtilis,Bacillus tequilensis, andBacillus licheniformiswere isolated, characterized, and tested for their antagonistic activity againstA. solani. The microbial consortium exhibited significant antifungal properties, and the application of the consortium on tomato plants led to a marked reduction in disease progression. Histochemical analyses of treated plants revealed a pronounced increase of hydrogen peroxide, phenolic compounds, and superoxide dismutase, suggesting enhanced activation of plant defense pathways. Comparative gene expression profiling showed the upregulation of key defense-related genes, including PR2b, Chi3, and Pto kinase, in Bo-treated plants, indicating a systemic activation of host defense mechanisms.Untargeted metabolomic analysis using LC-MS/MS further demonstrated significant metabolic reprogramming in microbial consortium-treated plants. Pathway enrichment analysis revealed enhanced accumulation of secondary metabolites, including phenolics and terpenoids, which are known to play vital roles in pathogen defense. Additionally, hierarchical clustering of metabolite profiles highlighted distinct metabolic signatures between Bo-treated and control plants, underscoring the broad biochemical impact of the microbial treatment. Collectively, our findings demonstrate that the microbial consortium derived from Gir cow dung significantly enhances tomato plant resistance toA. solanithrough multifaceted biochemical, molecular, and metabolic mechanisms. This study provides a sustainable biocontrol strategy that could effectively replace chemical fungicides, contributing to resilient tomato production and advancing the field of agroecological plant disease management.
Multi-year drought strengthens positive and negative functional diversity effects on tree growth response
Authors: Serrano-León Hernán , Blondeel Haben , Glenz Paula , Steurer Johannes , Schnabel Florian , Baeten Lander , Guillemot Joannès , Martin-StPaul Nicolas , Skiadaresis Georgios , Scherer-Lorenzen Michael , Bonal Damien , Boone Matthieu , Decarsin Renaud , Druel Arsène , Godbold Douglas L. , Gong Jialiang , Hajek Peter , Jactel Hervé , Koricheva Julia , Mereu Simone , Ponette Quentin , Rewald Boris , Sandén Hans , Van den Bulcke Jan , Verheyen Kris , Werner Ramona , Bauhus Jürgen 
Published: November 2024

AbstractMixed-species forests are proposed as strategy to increase the resistance and resilience of forests to drought stress. However, evidence suggest that increasing tree species richness does not consistently enhance tree growth responses to drought. Moreover, tree diversity effects under unprecedented multiyear droughts remain uncertain, calling for a better understanding of the underlying processes.Here, we used a network of planted tree diversity experiments to investigate how drought-induced growth responses of individual trees are influenced by neighborhood tree diversity and the functional traits of the focal tree species. We analyzed tree cores (948 trees across 16 species) from nine experiments across Europe featuring gradients of tree species richness (1–6 species), which experienced severe droughts in recent years. Radial growth response to drought was quantified as tree-ring biomass increment using X-ray computed tomography. We applied hydraulic trait-based growth models to analyze single-year drought responses across all sites and site-specific responses during consecutive drought years for six sites as a function of neighborhood tree diversity.The large variability in tree growth responses to a single-year drought was partially explained by the focal species’ hydraulic safety margin (representing species’ drought tolerance) and drought intensity, but independent of neighborhood species richness or functional trait diversity. However, tree diversity effects on growth responses strengthened during consecutive drought years and were site-specific, with contrasting direction (both positive and negative). This indicated opposing pathways of diversity effects under consecutive drought events, possibly resulting from competitive release or greater water consumption in diverse mixtures.We conclude that tree diversity effects on growth responses to single-year droughts may differ considerably from responses to consecutive drought years. Our study highlights the need to consider trait-based approaches (specifically, hydraulic traits) and tree neighborhood scale processes to understand the multifaceted growth responses of tree mixtures under prolonged drought stress.
Lactate potentiates NMDA receptor currents via an intracellular redox mechanism targeting cysteines in the C-terminal domain of GluN2B subunits: implications for synaptic plasticity
Authors: Fiumelli Hubert , Herrera-López Gabriel , Lemtiri-Chlieh Fouad , Mottier Lorène , Girgis John , Ben-Adiba Carine , Jourdain Pascal , Carrano Nicolò , Mahmood Hanan , Ooi Amanda , Arold Stefan T. , Luca Monica Di , Gardoni Fabrizio , Magistretti Pierre J. 
Published: November 2024

SummaryThrough the Astrocyte Neuron Lactate Shuttle, astrocyte-derived lactate fuels the high-energy demands of neurons and acts as a signaling molecule, promoting synaptic plasticity and memory consolidation. Lactate regulates neuronal excitability and modulates the expression of genes related to synaptic plasticity and neuroprotection, but the molecular mode for these signaling actions is uncertain. Using patch-clamp recordings in cultured cortical neurons, we found that lactate enhances both the amplitude and the inactivation time constant of NMDA receptor currents (INMDAR) evoked by brief applications of glutamate and glycine. Not reproduced by HCAR1 agonists, this modulation depends on monocarboxylate transporters and lactate dehydrogenase, indicating the requirement for lactate entry and metabolic conversion into pyruvate and NADH formation within neurons. Disruption of intracellular calcium dynamics or inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a NMDAR-associated kinase linking Ca2+signal to long-term potentiation (LTP), significantly diminishes the effects of lactate on INMDAR. We identified two redox-sensitive cysteine- containing sequences in the intrinsically disordered intracellular C-terminal domain of the GluN2B subunit that play a role in the potentiation of NMDAR by lactate. In a compelling set of experiments using HEK cells, we observed that the presence of functional CaMKII and GluN2B-containing NMDARs is necessary for the lactate-enhancing effects. Mutations in GluN2B that prevent CaMKII binding or redox regulation via cysteines abrogate the modulatory action of lactate. Immunoprecipitation experiments in neurons attest that lactate increases the association between CaMKII and GluN2B. This interaction is crucial for the potentiation of INMDARamplitude by lactate. Proximity ligation assays between GluN2B and the postsynaptic density marker PSD-95 revealed that lactate induced an accumulation of GluN2B in dendritic spines, an effect that was prevented by a CaMKII peptide inhibitor. These results highlight a mechanistic pathway whereby lactate boosts NMDAR function through intracellular metabolic conversion and redox-sensitive interactions requiring CaMKII, establishing a link between astrocyte metabolism and synaptic modulation in neurons.
Loss of PI3Kδ activity drives autoimmune colitis by impairing extrathymic Treg differentiation
Authors: Lim Ee Lyn , Qian Yamin , Sugihara Fuminori , Tanaka Atsushi , Sakaguchi Shimon 
Published: November 2024

AbstractPeripherally-derived regulatory T cells (pTregs) have a prominent role in maintaining intestinal immune homeostasis. In cases of phosphoinositide-3-kinase δ (PI3Kδ) inactivation, such as in patients receiving PI3Kδ inhibitor idelalisib as a cancer treatment, breakdown of intestinal immune tolerance occurs frequently in the form of diarrhoea and colon inflammation. In a mouse model of systemic PI3Kδ inactivation, both enhancement of anti-tumor immunity and colitis have been described, as a result of Treg impairment. However, in view of the critical role for Tregs in the prevention of systemic autoimmunity, the basis for such tissue-restricted breach of immune tolerance upon loss of PI3Kδ function is not yet understood. We report here that mice lacking PI3Kδ activity do not suffer a general defect in Treg immunosuppression, but specifically fail to develop Helios-pTregs in the colon. We demonstrate reduced extrathymic Treg induction, in vitro and in vivo, from naïve CD4+T cells with inactive PI3Kδ, along with dysregulation of a tissue-resident phenotype. These results suggest a non-redundant role for PI3Kδ-dependent pTreg differentiation in maintaining tolerance to commensal microbial antigens in the gut.
Genotype-by-environment interactions shape ubiquitin-proteasome system activity
Authors: Avery Randi R. , Collins Mahlon A. , Albert Frank W. 
Published: November 2024

AbstractIn genotype-by-environment interactions (GxE), the effect of a genetic variant on a trait depends on the environment. GxE influences numerous organismal traits across eukaryotic life. However, we have a limited understanding of how GxE shapes the molecular processes that give rise to organismal traits. Here, we characterized how GxE shapes protein degradation, an essential molecular process that influences numerous aspects of cellular and organismal physiology. Using the yeastSaccharomyces cerevisiae, we characterized GxE in the activity of the ubiquitin-proteasome system (UPS), the primary protein degradation system in eukaryotes. By mapping genetic influences on the degradation of six substrates that engage multiple distinct UPS pathways across eight diverse environments, we discovered extensive GxE in the genetics of UPS activity. Hundreds of locus effects on UPS activity varied depending on the substrate, the environment, or both. Most of these cases corresponded to loci that were present in one environment but not another (“presence / absence” GxE), while a smaller number of loci had opposing effects in different environments (“sign change” GxE). The number of loci exhibiting GxE, their genomic location, and the type of GxE (presence / absence or sign change) varied across UPS substrates. Loci exhibiting GxE were clustered at genomic regions that contain core UPS genes and especially at regions containing variation that affects the expression of thousands of genes, suggesting indirect contributions to UPS activity. Our results reveal highly complex interactions at the level of substrates and environments in the genetics of protein degradation.
Characterization and engineering of a blue-sensitive, Gi/o-biased, and bistable ciliary opsin from a fan worm
Authors: Fukuzawa Sachiko , Kawaguchi Tomoki , Shimomura Takushi , Kubo Yoshihiro , Tsukamoto Hisao 
Published: November 2024

AbstractCiliary opsins have been identified not only in vertebrates but also in invertebrates. An invertebrate ciliary opsin was recently identified in the fan wormAcromegalomma interruptum(formerly namedMegalomma interrupta); however, its spectral and signaling characteristics are unknown. In the present study, we characterized the spectral properties and light-induced cellular signaling properties of the opsin (AcrInvC-opsin).AcrInvC-opsin showed an absorption maximum at 464 nm and upon blue-light absorption, the spectrum was red-shifted by approximately 50 nm. The two states are inter-convertible by illumination with blue and orange light. Blue light illumination ofAcrInvC-opsin caused specific coupling with Gi, sustained Gi dissociation, decreased intracellular cAMP levels, and activation of GIRK channels. The cellular responses by the activated opsin were partially terminated by orange light illumination. These light-dependent responses indicate that the InvC-opsin is a typical bistable pigment wherein the resting and activated states can be inter-converted by visible light illumination. We also attempted to modulate the spectral and functional properties ofAcrInvC-opsin using site-directed mutagenesis. Substitution of Ser-94 with Ala caused little spectral shift in the resting state but a further red-shift of ∼10 nm in the activated state, indicating that the absorption spectra of the two states were tuned differently. In contrast, the S94A substitution did not significantly affect the light-dependent signaling properties ofAcrInvC-opsin. BecauseAcrInvC-opsin is a blue-sensitive, Gi/o-biased, and bistable pigment, it has the potential to serve as an optical control tool to specifically and reversibly regulate Gi/o-dependent signaling pathways by visible light.
Research on the spillover effects of promotion preannouncements on other selling products within and across brands
Authors: Gu Chenyan , Jia Shuyue , Chang Xinsiyu 
Published: November 2024

PurposeAs e-commerce platforms and merchants increasingly adopt promotion preannouncements, understanding their spillover effects on other products within and across brands is crucial. This study aims to comprehensively investigate these spillover effects to optimize the use of promotion preannouncements.Design/methodology/approachThe study uses quantitative analysis of real-world e-commerce data and four between-subjects experiments to examine the spillover effects of promotion preannouncements.FindingsPromotion preannouncements negatively impact products within the same brand and category, while positively influencing products in different categories. Additionally, preannouncements create negative spillover effects on products within the same brand echelon. Moreover, powerful brands are more likely to harm different-echelon products compared to weak brands.Research limitations/implicationsThe experiment has its own limitations because there will be differences between the simulated scenario and the real shopping scenario. Considering the practical factors, randomized field experiments cannot be conducted at the e-commerce platform level.Practical implicationsThe findings provide managerial insights on brands and merchants to arrange the preannounced products and products being sold.Originality/valueThis study contributes to the field of preannouncements by developing new knowledge through a combination of quantitative analysis using e-commerce data and experiments, capturing the novel phenomenon of promotion preannouncement and its spillover effects. We study the preannouncement phase of promotions, thus enriching the multistage research on promotions. In addition, this paper innovatively divides the spillover effects of promotion preannouncement into four components and uses brand echelon as a categorization factor.
Organizational justice and proactive customer service performance mediate the role of work engagement in the hospitality industry
Authors: Sharma Praveen Kumar , Kumra Rajeev 
Published: November 2024

PurposeThis study aims to evaluate the mediating role of work engagement (WE) in the relationship between four independent variables, such as procedural justice (PJ), distributive justice (DJ), interactional justice (INTJ) and informational justice (INFJ), along with an outcome variable, i.e. proactive customer service performance (PCSP) within the hospitality industry.Design/methodology/approachWe used 432 frontline supervisor–subordinate dyads. Using partial least squares structural equation modeling, we obtained data for 47 supervisors and 432 subordinates from the hotel industry. Notably, we used two distinct questionnaires to capture data from each pair in order to avoid common method bias.FindingsBroadly, the findings show that there is a significant and positive relationship between DJ, PJ, INTJ and INFJ vis-à-vis WE. Besides, WE is also significantly and positively associated with PCSP. Additionally, the results indicate that WE acts as a mediator between the four independent variables (DJ, PJ, INTJ and INFJ) and one outcome variable, PCSP.Practical implicationsBased on our findings, whereby different forms of justice (DJ, PJ, INTJ and INFJ) have a positive impact on WE, and PCSP has practical ramifications, organizations would need to set priorities and implement OJ strategies within the work environment. In turn, this would enable the employees to be more engaged in their work, resulting in improved performance and greater job satisfaction.Originality/valueThis study offers unique theoretical and practical learnings for the hospitality industry with the usage of supervisor–subordinate dyads.
Effectiveness of value co-creation in healthcare system from patients' perspectives
Authors: Sandhu Maqsood Ahmad , AlMeraikhi Mariam Hamad , Saleem Asima , Farooq Mariam 
Published: November 2024

PurposeThis study explores the determinants of value co-creation in the semi-government hospitals managed by Abu Dhabi Health Services Company (SEHA) and Mubadala in the United Arab Emirates (UAE).Design/methodology/approachThe data were collected through a structured survey questionnaire from 1,000 patients attending different healthcare facilities in the UAE. To minimize errors, a pilot study was performed on 50 respondents. The study took the structural equation modelling (SEM) approach, adopting confirmatory factor analysis (CFA), reliability analysis and regression analysis to test the hypothesis.FindingsThis study confirms the substantial influence of communication, relationships, technological enhancement and customized service delivery on the co-creation of value. The findings also confirm in all respects the mediating role of trust in building value co-creation. This sheds light on the ways that healthcare facilities can enhance value co-creation and elevate healthcare services. Notably, the direct and indirect influence of knowing on trust is deemed insignificant in the context of value creation.Research limitations/implicationsThe main limitation of this research derives from its coverage of a subject that few empirical studies have targeted before; there were few models to draw on to demonstrate validity.Practical implicationsThe research aids healthcare administrators in uncovering the dynamics of interactions between practitioners and patients, facilitating advances in the commitment to co-create value. The comprehensive insights into value co-creation contribute to the development of a versatile knowledge foundation, empowering proactive initiatives in the design of healthcare delivery models.Originality/valueThe uniqueness of this study lies in its expansion of previous research, making clear the effectiveness of various engagements that contribute to value co-creation in healthcare settings. It specifically focuses on semi-government hospitals managed by SEHA and Mubadala in the UAE.