bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integratedin vivofunctional screens and multi-omics analyses identify α-2,3-sialylation as essential for melanoma maintenance
Authors: Agrawal Praveen , Chen Shuhui , de Pablos Ana , Jame-Chenarboo Faezeh , Miera Saenz de Vega Eleazar , Darvishian Farbod , Osman Iman , Lujambio Amaia , Mahal Lara K. , Hernando Eva 
Published: March 2024

AbstractGlycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma growth and progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma maintenance, we conducted anin vivogrowth screen with a pooled shRNA library of glycosyltransferases, lectin microarray profiling of benign nevi and melanoma patient samples, and mass spectrometry-based glycoproteomics. We found that α-2,3 sialyltransferases ST3GAL1 and ST3GAL2 and corresponding α-2,3-linked sialosides are upregulated in melanoma compared to nevi and are essential for melanoma growthin vivoandin vitro. Glycoproteomics revealed that glycoprotein targets of ST3GAL1 and ST3GAL2 are enriched in transmembrane proteins involved in growth signaling, including the amino acid transporter Solute Carrier Family 3 Member 2 (SLC3A2/CD98hc). CD98hc suppression mimicked the effect of ST3GAL1 and ST3GAL2 silencing, inhibiting melanoma cell proliferation. We found that both CD98hc protein stability and its pro-survival effect in melanoma are dependent upon α-2,3 sialylation mediated by ST3GAL1 and ST3GAL2. In summary, our studies reveal that α-2,3-sialosides functionally contribute to melanoma maintenance, supporting ST3GAL1 and ST3GAL2 as novel therapeutic targets in these tumors.
Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of Multiple Sulfatase Deficiency
Authors: Pham Vi , Tricoli Lucas , Hong Xinying , Wongkittichote Parith , Castruccio Castracani Carlo , Guerra Amaliris , Schlotawa Lars , Adang Laura A. , Kuhs Amanda , Cassidy Margaret M. , Kane Owen , Tsai Emily , Presa Maximiliano , Lutz Cathleen , Rivella Stefano B. , Ahrens-Nicklas Rebecca C. 
Published: March 2024

ABSTRACTMultiple sulfatase deficiency (MSD) is a severe, lysosomal storage disorder caused by pathogenic variants in the geneSUMF1,encoding the sulfatase modifying factor formylglycine-generating enzyme. Patients with MSD exhibit functional deficiencies in all cellular sulfatases. The inability of sulfatases to break down their substrates leads to progressive and multi-systemic complications in patients, similar to those seen in single-sulfatase disorders such as metachromatic leukodystrophy and mucopolysaccharidoses IIIA. Here, we aimed to determine if hematopoietic stem cell transplant withex vivo SUMF1lentiviral gene therapy could improve outcomes in a clinically relevant mouse model of MSD. We first tested our approach in MSD patient-derived cells and found that ourSUMF1lentiviral vector improved protein expression, sulfatase activities, and glycosaminoglycan accumulation.In vivo, we found that our gene therapy approach rescued biochemical deficits, including sulfatase activity and glycosaminoglycan accumulation, in affected organs of MSD mice treated post-symptom onset. In addition, treated mice demonstrated improved neuroinflammation and neurocognitive function. Together, these findings suggest thatSUMF1HSCT-GT can improve both biochemical and functional disease markers in the MSD mouse.
An Amygdalar Oscillator Coordinates Cellular and Behavioral Rhythms
Authors: Liu Qiang , Xiong Jiali , Kim Dong Won , Lee Sang Soo , Bell Benjamin J. , Alexandre Chloe , Blackshaw Seth , Latremoliere Alban , Wu Mark N. 
Published: March 2024

SUMMARYCircadian rhythms are generated by the master pacemaker suprachiasmatic nucleus (SCN), in concert with local clocks throughout the body. While many brain regions exhibit cycling clock gene expression, the identity of a discrete extra-SCN brain oscillator that produces rhythmic behavior has remained elusive. Here, we show that an extra-SCN oscillator in the lateral amygdala (LA) is defined by expression of the clock-output molecule mWAKE/ANKFN1. mWAKE is enriched in the anterior/dorsal LA (adLA), and strikingly, selective disruption of clock function or excitatory signaling in adLAmWAKEneurons abolishes Period2 (Per2) rhythms throughout the LA. mWAKE levels rise at night and promote rhythmic excitability of adLAmWAKEneurons by upregulating Ca2+-activated K+channel activity specifically at night. adLAmWAKEneurons coordinate rhythmic sensory perception and anxiety in a clock-dependent and WAKE-dependent manner. Together, these data reveal the cellular identity of an extra-SCN brain oscillator and suggest a multi-level hierarchical system organizing molecular and behavioral rhythms.
NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms
Authors: Koerber Ruth-Miriam , Krollmann Calvin , Cieslak Kevin , Tregel Elisabeth , Brümmendorf Tim H. , Koschmieder Steffen , Griesshammer Martin , Gütgemann Ines , Brossart Peter , Skoda Radek C. , Kolbe Carl Christian , Latz Eicke , Wolf Dominik , Teichmann Lino L. 
Published: March 2024

AbstractThe development of Philadelphia chromosome-negative classical myeloproliferative neoplasms (MPN) involves an inflammatory process that facilitates outgrowth of the malignant clone and correlates with clinical outcome measures. This raises the question to which extent inflammatory circuits in MPN depend on activation of innate immune sensors. Here, we investigated whether NLRP3, which precipitates inflammasome assembly upon detection of cellular stress, drives murine JAK2V617F mutant MPN. Deletion ofNlrp3within the hematopoietic compartment completely prevented increased IL-1β and IL-18 release in MPN. NLRP3 in JAK2V617F hematopoietic cells, but not in JAK2 wild type radioresistant cells, promoted excessive platelet production via stimulation of the direct thrombopoiesis differentiation pathway, as well as granulocytosis. It also promoted expansion of the hematopoietic stem and progenitor cell compartment despite inducing pyroptosis at the same time. Importantly, NLRP3 inflammasome activation enhanced bone marrow fibrosis and splenomegaly. Pharmacological blockade of NLRP3 in fully established disease led to regression of thrombocytosis and splenomegaly. These findings suggest that NLRP3 is critical for MPN development and its inhibition represents a new therapeutic intervention for MPN patients.Key pointsThe increased IL-1β and IL-18 release in JAK2V617F mutant MPN depends on NLRP3 inflammasome activationNLRP3 in MPN promotes excess platelet production, granulocytosis, HSPC compartment expansion, splenomegaly and bone marrow fibrosis
Transcriptome analysis reveals a novel DNA element that may interact with chromatin-associated proteins inPlasmodium bergheiduring erythrocytic development
Authors: Okafor Adaobi , Adam Yagoub , Brors Benedikt , Adebiyi Ezekiel 
Published: March 2024

AbstractBackgroundThe life cycle ofPlasmodiumparasites is intricate and multistage, alternating between dynamic environments. Temporal regulation of transcription by stage-specific transcription factor binding at particular regulatory regions within gene promoters facilitates its progression. As a result, each new developmental stage is endowed with its unique gene sets, whose just-in-time expression enables the parasite to completely adapt to the necessary circumstances. Our understanding of these transcriptome-level regulatory processes is limited, and more so, a thorough examination of the entire life cycle in the experimentally tractable rodent model organismP. bergheiis lacking.ResultsWe performed a genome-wide analysis of RNA-Seq data from different developmental stages ofP. berghei. Integrated data from the human malaria parasitesP. falciparumandP. vivaxdemonstrated thatPlasmodiumparasites have a unique transcriptional signature. We identified the sets of genes differentially expressed at each stage, clustered them based on similarities of their expression profiles, and predicted the regulatory motifs governing their expression. We interpreted the motifs using known binding sites for established eukaryotic transcription factors, including those of the ApiAP2s, and identified eight potentially novel motifs. Additionally, we expanded the annotation of another motif—AGGTAA—found in genes exclusive to erythrocytic development and identified members of thePfMORC and GCN5 complexes among its possible interacting proteins.ConclusionThis study provides new insights into gene usage and its regulation duringP. bergheidevelopment.
A Mem-dELISA platform for dual color and ultrasensitive digital detection of colocalized proteins on extracellular vesicles
Authors: Sharma Himani , Yadav Vivek , Burchett Alice , Shi Tiger , Senapati Satyajyoti , Datta Meenal , Chang Hsueh-Chia 
Published: March 2024

AbstractAccurate, multiplex, and ultrasensitive measurement of different colocalized protein markers on individual tumor-derived extracellular vesicles (EVs) and dimerized proteins with multiple epitopes could provide insights into cancer heterogeneity, therapy management and early diagnostics that cannot be extracted from bulk methods. However, current digital protein assays lack certain features to enable robust colocalization, including multi-color detection capability, large dynamic range, and selectivity against background proteins. Here, we report a lithography-free, inexpensive (< $0.1) and ultrasensitive dual-color Membrane Digital ELISA (Mem-dELISA) platform by using track-etched polycarbonate (PCTE) membranes to overcome these shortcomings. Their through-pores remove air bubbles through wicking before they are sealed on one side by adhesion to form microwells. Immunomagnetic bead-analyte complexes and substrate solution are then loaded into the microwells from the opposite side, with >80% loading efficiency, before sealing with oil. This enables duplex digital protein colorimetric assay with beta galactosidase and alkaline phosphatase enzymes. The platform achieves 5 logs of dynamic range with a limit of detection of 10 aM for both Biotinylated β-galactosidase (B-βG) and Biotin Alkaline Phosphatase Conjugated (B-ALP) proteins. We demonstrate its potential by showing that a higher dosage of paclitaxel suppresses EpCAM-positive EVs but not GPC-1 positive EVs from breast cancer cells, a decline in chemo-resistance that cannot be detected with Western blot analysis of cell lysate. The Mem-dELISA is poised to empower researchers to conduct ultrasensitive, high throughput protein colocalization studies for disease diagnostics, treatment monitoring and biomarker discovery.
OmeSim: a genetics-based nonlinear simulator for in-between-ome and phenotype
Authors: Long Zhou , Zhang Qingrun 
Published: March 2024

AbstractMotivationDeciphering genetic basis of complex traits via genotype-phenotype association studies is a long-standing theme in genetics. The availability of molecular omics data (such as transcriptome) has enabled researchers to utilize “in-between-omes” in association studies, for instance transcriptome-wide association study. Although many statistical tests and machine learning models integrating omics in genetic mapping are emerging, there is no standard way to simulate phenotype by genotype with the role of in-between-omes incorporated. Moreover, the involvement of in-between-omes usually bring substantial nonlinear architecture (e.g., co-expression network), that may be non-trivial to simulate. As such, rigorous power estimations, a critical step to test novel models, may not be conducted fairly.ResultsTo address the gap between emerging methods development and the unavailability of adequate simulators, we developed OmeSim, a phenotype simulator incorporating genetics, an in-between-ome (e.g., transcriptome), and their complex relationships including nonlinear architectures. OmeSim outputs detailed causality graphs together with original data, correlations, and associations structures between phenotypic traits and omes terms as comprehensive gold-standard datasets for the verifications of novel tools integrating an in-between-ome in genotype-phenotype association studies. We expect OmeSim to enable rigorous benchmarking for the future multi-omics integrations.Availabilityhttps://github.com/zhoulongcoding/OmeSimContactqingrun.zhang@ucalgary.ca
Blinatumomab Trimer Formation: Insights From A Mechanistic PKPD Model Into The Implications For Switching From Infusion To Subcutaneous Dosing Regimen
Authors: Kapitanov Georgi I. , Head Sarah A. , Flowers David , Apgar Joshua F. , Grant Joshuaine 
Published: March 2024

AbstractBlinatumomab is a bispecific T-cell engager (BiTE) that binds to CD3 on T cells and CD19 on B cells. It has been approved for use in B-cell acute lymphoblastic leukemia (B-ALL) with a regimen that requires continuous infusion (cIV) for four weeks per treatment cycle. It is currently in clinical trials for Non-Hodgkin lymphoma (NHL) with cIV administration. Recently, there have been studies investigating dose-response after subcutaneous (SC) dosing in B-ALL and in NHL to determine whether this more convenient method of delivery would have a similar efficacy/safety profile as continuous infusion. We constructed mechanistic PKPD models of blinatumomab activity in B-ALL and NHL patients, investigating the amount of CD3:blinatumomab:CD19 trimers the drug forms at different dosing administrations and regimens.The modeling and analysis demonstrate that the explored SC doses in B-ALL and NHL achieve similar trimer numbers as the cIV doses in those indications. We further simulated various subcutaneous dosing regimens, and identified conditions where trimer formation dynamics are similar between constant infusion and subcutaneous dosing. Based on the model results, subcutaneous dosing is a viable and convenient strategy for blinatumomab and is projected to result in similar trimer numbers as constant infusion.
Heterogeneity of layer 4 in visual areas of rhesus macaque cortex
Authors: Günther Dorothee M. , Batiuk Mykhailo Y. , Petukhov Viktor , Oliveira Romain De , Wunderle Thomas , Buchholz Christian J. , Fries Pascal , Khodosevich Konstantin 
Published: March 2024

AbstractRecently, single-cell RNA-sequencing (scRNA-seq) has enabled unprecedented insights to the cellular landscape of the brains of many different species, among them the rhesus macaque as a key animal model. Building on previous, broader surveys of the macaque brain, we closely examined five immediately neighboring areas within the visual cortex of the rhesus macaque: V1, V2, V4, MT and TEO.To facilitate this, we first devised a novel pipeline for brain spatial archive – the BrainSPACE – which enabled robust archiving and sampling from the whole unfixed brain. SnRNA-sequencing of ∼100,000 nuclei from visual areas V1 and V4 revealed conservation within the GABAergic neuron subtypes, while seven and one distinct principle neuron subtypes were detected in V1 and V4, respectively, all most likely located in layer 4. Moreover, using small molecule fluorescence in situ hybridization, we identified cell type density gradients across V1, V2, V4, MT, and TEO appearing to reflect the visual hierarchy. These findings demonstrate an association between the clear areal specializations among neighboring areas with the hierarchical levels within the visual cortex of the rhesus macaque.
Persistence of wicked problems in opaque global value chains
Authors: Dindial Miguel , Voss Hinrich 
Published: March 2024

Purpose
This paper engages with the important work of Raškovic (2024). The authors agree with Raškovic’s (2024) argument that international business (IB) policy is well positioned to inform and address many of society’s wicked problems, including modern slavery. Beyond supporting this position, the purpose of this paper is to highlight IB’s internal and ongoing debate regarding multinational ownership and control, and how this unresolved theoretical issue can hinder the contribution of IB policy in addressing wicked problems.

Design/methodology/approach
By leveraging prior literature, this paper synthesises opposing views on the extent of control that multinational enterprises (MNEs) exert across global value chains (GVCs). The authors then demonstrate why these conflicting perspectives should be resolved to fully realise the task that Raškovic (2024) has laid out for IB policy.

Findings
This study argues that IB is steeped in a tradition where ownership has been a proxy for meaningful control. Rising GVCs have complicated this relationship, and while IB recognises this, the field remains short of explicating a set of robust conditions that can detect control in the absence of ownership. Given that responsibility is often based on an assumption of who has control, this ongoing and unresolved debate limits IB’s utility in advancing appropriate policy interventions to tame wicked problems.

Originality/value
This paper makes a contribution by bringing together diverse perspectives on the ongoing debate regarding MNE control in GVC. It demonstrates how this seemingly abstract debate can have significant implications for IB’s role in addressing society’s grand challenges. The authors further suggest that embracing interdisciplinarity and novel analytical tools can assist in demystifying the opaqueness of GVCs and resolving the control “fuzziness” that confuses responsibility boundaries across the GVC.
The effect of augmented reality applied to learning process with different learning styles in structural engineering education
Authors: Liu Pengkun , Yang Zhewen , Huang Jing , Wang Ting-Kwei 
Published: March 2024

PurposeThe purpose of this study is to scrutinize the influence of individual learning styles on the effectiveness of augmented reality (AR)-based learning in structural engineering. There has been a lack of research examining the correlation between learning efficiency and learning style, particularly in the context of quantitatively assessing the efficacy of AR in structural engineering education.Design/methodology/approachUsing Kolb’s experiential learning theory (ELT), a model that emphasizes learning through experience, students from the construction management department are assigned four learning styles (converging, assimilating, diverging and accommodating). Performance data were gathered, appraised, and compared through the three dimensions from the Knowledge, Attitude and Practices (KAP) survey model across four categories of Kolb’s learning styles in both text-graph (TG)-based and AR-based learning settings.FindingsThe findings indicate that AR-based materials positively impact structural engineering education by enhancing overall learning performance more than TG-based materials. It is also found that the learning style has a profound influence on learning effectiveness, with AR technology markedly improving the information retrieval processes, particularly for converging and assimilating learners, then diverging learners, with a less significant impact on accommodating learners.Originality/valueThese results corroborate prior research analyzing learners' outcomes with hypermedia and informational learning systems. It was found that learners with an “abstract” approach (convergers and assimilators) outperform those with a “concrete” approach (divergers and accommodators). This research emphasizes the importance of considering learning styles before integrating technologies into civil engineering education, thereby assisting software developers and educational institutions in creating more effective teaching materials tailored to specific learning styles.
Online corporate communication of diversity and inclusion: washing as aspirational talk
Authors: Gillberg Nanna 
Published: March 2024

PurposeThe article aims to investigate how washing practices focused on appeasing sceptics of diversity work in for-profit organizations play out in corporate online communication of diversity and inclusion efforts, and how these enable communication to a wide audience that includes social equity advocates.Design/methodology/approachOnline corporate communication data of diversity and inclusion themes were compiled from the websites of eight Swedish-based multinational corporations. The data included content from the companies’ official websites and annual reports and sustainability reports as well as diversity and inclusion-themed blog posts. A thematic analysis was conducted on the website content.FindingsThe study showcases how tensions between conflicting external demands are navigated by keeping the communication open to several interpretations and thereby achieving multivocality. In the studied corporate texts on diversity and inclusion, this is achieved by alternating between elements catering to a business case audience and those that appeal to a social justice audience, with some procedures managing to appease both audiences at the same time.Originality/valueThe article complements previously described forms of washing by introducing an additional type of washing – business case washing – an articulation of the business case rhetoric that characterizes the diversity management discourse. While much has been written about washing to satisfy advocates of social change and equity, washing to appease shareholders and boardroom members, who are focused on profit and economic growth, has received less attention. The article suggests that online corporate communication on diversity and inclusion, by appeasing diverse audiences, can be seen as aspirational talk.
The role of destination personality in the relationship between destination image and behavioral intention among ski tourists
Authors: Zhang Qiang , Yim Brian , Kim Kyungsik , Tian Zhibo 
Published: March 2024

PurposeThe aim of this study was (1) to investigate the relationship between destination image (DI), destination personality (DP) and behavioral intention (BI) in the context of ski tourism and (2) especially the role of DP in the relationship between DI and BI among ski tourists.Design/methodology/approachWe collected data using WJX.CN (N = 400) to test the hypothesized model. Confirmatory factor analysis (CFA) was used to examine the psychometric properties of the measurement model and partial least squares structural equation modeling (PLS-SEM) was used to test the hypotheses.FindingsThe results show that DI directly affects DP and partially affects BI, while DP directly affects ski tourists' BI. In addition, the indirect effect of DP between affective image and BI was significant, showing full mediation, and the indirect effect of DP between cognitive image and BI was significant, showing a partial mediation effect.Originality/valueThe findings enrich the ski tourism literature, contribute to the development of ski tourism in destination cities and the strategic marketing of ski resorts and provide recommendations for ski tourism researchers and marketers.