bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MYCN/Aurora-A complex is a cyclin activating kinase for CDK12
Authors: Müller Mareike , Eing Lorenz , Uhl Leonie , Schmitz Maximilian , Kaneva Iliyana , Byrne Dominic P. , Fleischhauer Daniel , Burgess Selena G. , Fischer Sophia , Gebauer Nick , Nancy-Portebois Vanessa , Kaltheuner Ines H. , Ha Stefanie Ahn , Schülein-Völk Christina , Solvie Daniel , Richards Mark W. , Vidal Raphael , Brand Matthias , Papadopoulos Dimitrios , Bayliss Richard , Eyers Patrick A. , Eyers Claire E. , Geyer Matthias , Eilers Martin , Büchel Gabriele 
Published: January 2025

SummaryDeregulated MYCN is a driver of aggressive pediatric and adult neuroendocrine tumors, but critical oncogenic processes downstream of MYCN remain poorly defined. In neuroblastoma, MYCN interacts with and activates the Aurora-A kinase. Here we show that Aurora-A is a CDK-activating kinase for CDK12 by phosphorylating T893 in the T-loop, thereby enhancing its kinase activity. Aurora-A-dependent activation of CDK12 controls phosphorylation of T4 of RNA polymerase and recruits transcription termination complexes, thereby preventing transcription-replication conflicts. Enhanced crosslinking and immunoprecipitation sequencing reveals that Aurora-A associates with splice sites on nascent RNA. RNA-bound Aurora-A is catalytically inactive. MYCN competes with RNA for binding to Aurora-A and displaces Aurora-A from RNA in cells, promoting its CDK12 kinase activity. Combining Aurora-A and CDK12 inhibition potently suppresses the growth ofMYCN-amplified neuroblastoma cells and patient-derived xenografts. Our data demonstrate that an Aurora-A/CDK12-dependent transcription termination pathway is a critical and targetable dependency of MYCN-driven tumors.
In vitroActivity of Citrus IntegroPectin against Lung Cancer Cells
Authors: Di Sano Caterina , D’Anna Claudia , Petri Giovanna Li , Angellotti Giuseppe , Meneguzzo Francesco , Ciriminna Rosaria , Pagliaro Mario 
Published: January 2025

Citrus IntegroPectin bioconjugates obtained through acoustic cavitation in water of different citrus fruit (lemon, red orange, and sweet orange) processing waste show substantial anticancer activityin vitroagainst human non- small cell lung cancer cells. Dissolved in aqueous phase at different concentrations, all IntegroPectin phytocomplexes tested affected long-term proliferation and cell migration of adenocarcinoma cells of line A549. Compared to sweet orange, IntegroPectin from lemon and red orange were more effective in reducing colony formation activity. Pointing to significant reduction in cancer cell progression, these results support further investigation of these new low methoxyl pectins rich in citrus flavonoids and RG-I regions for the treatment of lung cancer.Abstract Figure
Protein-Formatted Biomarker Enrichment Tag for the Detection of Carcinoembryonic Antigen
Authors: Liu Chang , Barricella Sara , Cortez-Jugo Christina , Steer David L. , He Lizhong 
Published: January 2025

AbstractThe streptavidin-biotin interaction has long been a cornerstone of immunoassays, valued for its exceptionally high affinity and specificity, and has been widely used in routine diagnostic assays for decades. However, elevated biotin levels in plasma, often resulting from oral supplements, can interfere with streptavidin-biotin binding, compromising signal detection in these assays. To address this limitation, we present a biotin-insensitive antigen enrichment system based on the ultra-strong binding pair barnase (Bn) and barstar (Bs) for effective antigen capture. This high-affinity system enables efficient detection of nanobody-antigen complexes with picomolar sensitivity, as demonstrated by the detection of carcinoembryonic antigen (CEA, CEACAM5). When paired with a fluorescent secondary nanobody reporter, the system achieved a detection limit as low as 98.9 pM, with a limit of detection (LOD) of 17.8 ng/mL, representing a four-order-of-magnitude improvement in sensitivity compared to light interferometry-based binding analysis. Both Bn and Bs are small (<15 kDa), single-chain proteins that can be generically incorporated into immunoactive molecules. Compared to the traditional biotin-streptavidin system, the Bn-Bs system offers enhanced specificity, improved stability, and reduced cost and complexity.
A simple age-structured, temperature-dependent population growth model of brown rice hopper (Nilaparvata lugens(Stål))
Authors: Wei Xiaojing , Balanza Jane Girly , Ngoc Vu Thi Bich , Giles James , Swaans Cornelis 
Published: January 2025

AbstractBrown rice hopper (BRH), a key insect pest to rice, is known can change its longevity and fecundity due to rising temperature. Here we modeled the response of BRH population growth to temperature using an age-structured population growth model, based on reported responses of BRH development time, survival, and fecundity to temperature. We applied this model to predict historical level of BRH population growth in the Mekong River Delta (MRD) and compared the predictions with historically observed percentages of rice fields infested by BRH. The model was able to capture the seasonal variation in BRH infestation and the optimal temperature for BRH activities (app. 26.5°C). These results highlighted the importance of temperature in regulating BRH population growth. The model, with further improvements as discussed, could be used for projecting BRH activity under rising temperatures or predicting BRH outbreaks due to seasonal temperature anomalies.
Autoantibody hotspots reveal origin and impact of immunogenic XIST ribonucleoprotein complex
Authors: Yan Bingyu , Lee Jinwoo , Srinivasan Suhas , Shi Quanming , Dou Diana R. , Davuluri Srijana , Nandyala Swarna , Woods Adrianne , Leatherman Gwendolyn , Zhao Yanding , Reggiardo Roman E. , Sawant Manasi , Thiam Hawa R. , Shah Ami A. , Fiorentino David F. , Chung Lorinda S. , Chang Howard Y. 
Published: January 2025

AbstractFour out of five patients with autoimmune diseases are women. The XIST ribonucleoprotein (RNP) complex, comprising the female-specific long noncoding RNA XIST and over 100 associated proteins, may drive several autoimmune diseases that disproportionately affect women, who have elevated levels of autoantibodies against the XIST RNP. However, the structural distribution, potential origin, and clinical significance of XIST RNP autoantibodies remained unexplored. Here, we find that XIST RNP is associated with autoantigens associated with six female-biased autoimmune conditions. Mapping autoantibody targets to their occupancy sites on XIST shows that these autoantigens are concentrated at discrete “hotspots” along the XIST lncRNA, notably the A-repeat. Cell type-specific protein expression data nominated neutrophils as a predominant source of hotspot antigens, and we confirmed the presence of both XIST and hotspot antigens in neutrophil extracellular traps during NETosis, an immunogenic programmed cell death pathway triggered by neutrophil activation upon which neutrophils extrude their nuclear content. Furthermore, we found that levels of autoantibodies against a top hotspot antigen, SPEN, that binds the A-repeat, correlate with severe digital ischemia in systemic sclerosis in two independent cohorts. Together, these data show a plausible mechanism for the origin of AXA, guided by RNA structure and RNA-protein interactions, and show that antibodies to XIST RNP holds promise for disease endotyping and prognostication in female-biased autoimmune conditions.One Sentence SummaryNovel autoantibodies target hotspots on XIST ribonucleoprotein complex in female-biased autoimmune diseases.
Fluorogenic Interacting Protein Stabilization for Orthogonal RNA Imaging
Authors: Zhou Wen-Jing , Wu Mei-Yan , Shao Xin-Juan , Tang Li-Juan , Wang Fenglin , Jiang Jian-Hui 
Published: January 2025

AbstractLive imaging of RNAs is crucial to interrogate their cellular functions, and approaches allowing fluorogenic RNA imaging with high orthogonality and contrast remains underexplored. We propose a fluorogenic interacting protein stabilization (FLIPS) strategy that enables orthogonal RNA imaging in live cells with fluorescence-labeled RNA interacting proteins (RIPs) stabilized by cognate RNA motifs. We show that the RNA motif stabilizes the otherwise degraded cognate RIP fused to a poly(arginine)- extended C-terminal degron, and the stabilizing effect is enhanced with circular permutation of the RIP. This design affords a generally applicable strategy for different RNA motifs and RIPs, enabling orthogonal and multi-color fluorescence-activated RNA imaging. Our strategy is broadly demonstrated for multiplexed, high-contrast RNA detection and imaging, single molecule RNA imaging and RNA dynamic translocation tracking in live cells. The versatility of our system highlights its potential for interrogating RNA biology and developing RNA-based imaging tools.
HoloMoA: Fast holography and deep-learning-based tool for the novelty detection of mechanism of action of antimicrobial candidates
Authors: Sedaghat Zohreh , Courbon Benoît , Botrel Héloise , Dugua Hélène , Tulinski Pawel , Alibaud Laethitia , Pagani Lucia , Mercer Derry , Guyard Cyril , Védrine Christophe , Dixneuf Sophie 
Published: January 2025

ABSTRACTWe propose an innovative technology to classify the Mechanism of Action (MoA) of antimicrobials and predict their novelty, called HoloMoA. HoloMoA is a rapid, robust, inexpensive, and versatile tool based on the combination of time-lapse Digital Inline Holographic Microscopy (DIHM) and Deep Learning (DL). In combination with proper image reconstruction, DIHM enables a label-free, time-resolved visualization of bacterial cell morphology and phase map (i.e. refractive index × thickness) to reveal phenotypic responses to antimicrobials, while DL techniques are powerful tools to extract discriminative features from image sequences and classify them. We assessed the performance of HoloMoA technology on Escherichia coli (E. coli) ATCC 25922 treated for up to 2 hours with 22 antibiotic molecules representing 5 functional classes (i.e. Cell Wall synthesis inhibitors, Cell Membrane inhibitors, Protein synthesis inhibitors, DNA and RNA synthesis inhibitors). First, using reconstructed phase images as input to a 3D Convolutional Neural Network classifier, we detected the MoA of known antibiotics with 89% accuracy. Secondly, we showed how our CNN models combined with a Siamese neural network architecture can be used for the novelty assessment of the MoA of a candidate antibiotic. The HoloMoA novelty detection tool succeeded in detecting trimethoprim-sulfamethoxazole (Folic Acid synthesis inhibitors) as belonging to a novel functional class (i.e. different from the 5 aforementioned classes). We demonstrated that combining DHIM and DL gives a promising tool for determining the MoA of new antimicrobial candidates provided that a large image database for known antimicrobials is available.
Engineered spermidine-secretingSaccharomyces boulardiiameliorate colitis and colon cancer in mice
Authors: Mohaqiq Mahdi , Palou Roger , Li Ruizhen , Zhang Guijun , Vaishnav Het , Parweez Florance , Moyana Terence , Carragher Damian , Cameron D.W. , Ramsay Timothy , van der Sloot Almer , Murthy Sanjay , Coombes Brian , Tyers Mike , Liu X. Johné 
Published: January 2025

AbstractExperimental studies suggest that the probiotic yeastSaccharomyces boulardiican mitigate the symptoms of inflammatory bowel disease. However, these results are equivocal andS boulardiiprobiotic therapy has not gained widespread acceptance in clinical practice. To assess whether the therapeutic properties ofS boulardiimight be improved upon, we engineeredS boulardiito overproduce and secrete spermidine, a pro-regenerative natural metabolite. We employed CRISPR gene deletion and transposon-mediated gene integration to manipulate expression of key enzymes in the polyamine synthetic and transport pathways. We tested the engineered yeast by oral gavage of mice treated with azoxymethane and dextran sulfate sodium to induce chronic colitis and colon cancer. We demonstrate that oral delivery of spermidine-secretingS boulardiiin mice populates the gastrointestinal tract with viable spermidine-secretingS boulardiicells and raises free spermidine levels in the gastrointestinal tract. Strikingly, spermidine-secretingS boulardiistrains were significantly more effective than wild-typeS boulardiiin reducing dextran sulfate sodium-induced colitis as well as colitis-associated colon cancer in mice. These results suggest that in situ spermidine secretion by engineered synthetic biotic yeast strains may be an effective and low-cost therapy to mitigate inflammatory bowel disease and colon cancer.
Expression of the p53 Network Aging-associated Genes “shaken, not stirred” in a 3-Week Microgravity Simulation Human Study
Authors: Kuznetsov Nik V. 
Published: January 2025

AbstractBackgroundThe hostile space environment affects human health and aging. NASA has named five main hazards astronauts will face in space, including space radiation and changes in gravity. However, the contribution of each of these factors, along with others, to the overall impact on biomolecular and cellular processes is not always clear.ObjectiveTo explore the effects of microgravity on the transcriptomes of healthy volunteers, with a focus on aging-related gene expression in p53 cell signaling pathways.MethodsTen healthy young men were exposed to simulated microgravity (SMG) for three weeks and blood samples were collected at five time point before, during and after the course of SMG. T cells were purified from the peripheral blood samples and total RNA was isolated and sequenced followed by bioinformatics analysis of volunteers’ global transcriptomes.ResultsA differential expression of p53 network genes was observed. The expression of nearly 30 genes involved in p53 gene network was affected during a 3-week course of simulated microgravity environment in dry immersion including classic p53 downstream target genes involved in cellular senescence: GADD45, p21, PUMA, IGF1 and other targets and potential target genes.ConclusionFor the first time, the p53-associated cell signaling pathways and gene network in human T cells were reported to be affectedin vivoby dry immersion SMG. It is evident that the relatively mild effects of simulated weightlessness on the human body are sufficient to activate these pathways and influence aging-related genes in the p53 gene network. These findings should not be dismissed, as they could open the door to the discovery of a novel category of drugs - MG-senolytics.
Allosteric factors in the calcium/calmodulin-responsive kinase II hub domain determine selectivity of GHB ligands for CaMKIIα
Authors: Gauger Stine Juul , Palmelund Line B. , Tian Yongsong , Marek Aleš , Namini Mathias R , Griem-Krey Nane , Kickinger Stefanie , Mortensen Jonas S. , Frølund Bente , Wellendorph Petrine 
Published: January 2025

AbstractThe Ca2+/CaM-dependent protein kinase II alpha (CaMKIIα) is a highly important synaptic protein, which comprises a unique holoenzyme structure organized via the central hub domain. Recently, a distinct binding pocket in the CaMKIIα hub domain was identified for the endogenous neuromodulator γ-hydroxybutyric acid (GHB) and related synthetic analogues. Key interacting residues in CaMKIIα were revealed, but the pronounced selectivity towards thealphavariant of CaMKII has remained unresolved. Aimed at elucidating the molecular determinants for this selectivity, we here conducted binding studies to CaMKII-HEK whole-cell homogenates using two different in-house-developed GHB-related radioligands, [3H]HOCPCA and [3H]O-5-HDC, in combination with site-directed mutagenesis. Binding to CaMKIIα with the smaller-type radioligand [3H]HOCPCA validated key involvement of the four known residues (His395, Arg433, Arg453 and Arg469), but also revealed a role for the upper hub flexible loop containing the CaMKIIα-specific residue Trp403 (Leu in all other CaMKII isozymes). Insertion of the corresponding residues (L467W/C533R) into CaMKIIβ failed to introduce [3H]HOCPCA binding. However, with the larger-type radioligand, [3H]O-5-HDC, specific binding in CaMKIIβ (L467W/C533R) was achieved. Thus, of the four native CaMKII isozymes, only CaMKIIα accommodates GHB ligands. The study identifies the CaMKIIα flexible pocket loop as a distantly located “allosteric” factor in determining selectivity of GHB analogues for CaMKIIα. It sheds light on a remarkable interplay of the entire hub cavity for accommodation of ligands, and corroborates GHB analogues as CaMKIIα-selective.
Investigating the factors influencing teachers’ adoption of gamification strategies in higher education: insights from Korthagen’s onion model
Authors: Desgourdes Clément , Carmagnac Liliane , O'Neill Caroline Rosaleen 
Published: January 2025

PurposeInterest in gamification as a relevant and innovative pedagogical tool has increased in recent years among academics and educators. While considerable literature has focused on the effectiveness of gamified learning, little is known about the motivations behind its adoption. By examining teachers’ perspectives, which are often overlooked, we investigated the factors influencing teachers’ adoption of gamification strategies.Design/methodology/approachWe adopted Korthagen’s onion model as the main theoretical lens to identify the influencing factors. A qualitative study involving interviews with 15 French higher education teachers was conducted to achieve our purpose.FindingsThe results were organized within the six layers of the onion model, through which we demonstrated the factors influencing teachers’ adoption of gamification. The institutional environment and teachers’ internal characteristics (beliefs, values, identity and mission) were identified as the determinants of gamification use.Originality/valueUnlike most gamification studies, this research contributes to the literature by considering teachers’ perspectives and integrating the Korthagen model into the educational setting. We also propose an integrative theoretical approach that uncovers synergies between the Korthagen model and the educational leadership literature.
How big data impacting CSR application in listed companies in emerging countries: evidence from Vietnam
Authors: Phan Hai Hong , Tran Hung Ngoc 
Published: January 2025

Purpose
This study aims to use the SmartPLS method for empirical analysis and explore the impact of various factors on the enhancement of corporate social responsibility (CSR) application among listed companies in Vietnam. With the increasing scrutiny over CSR disclosures and the pivotal role of internal and external factors, the research seeks to uncover how factors such as management’s perception, big data application, firm characteristics, organisational culture and stakeholder pressure significantly influence CSR application.

Design/methodology/approach
The research assesses the relationships among these factors by drawing on a sample of 255 listed Vietnamese companies across various sectors. Partial least squares structural equation modeling (SmartPLS) is applied to analyse the data and uncover the impact of the identified factors on CSR application.

Findings
The findings demonstrate that big data applications, organisational cultures and firm characteristics significantly impact CSR applications. Additionally, management’s perception, directly and indirectly, influences CSR applications through its effect on big data applications.

Research limitations/implications
The study is limited to listed companies in Vietnam, which may affect the generalizability of the findings to other contexts. Further research is needed to validate these findings in different markets and settings.

Practical implications
These results provide valuable insights for corporate governance practitioners in Vietnam and similar emerging markets. By highlighting the critical role of big data applications in CSR practices, the study suggests pathways for enhancing corporate governance frameworks to improve CSR applications.

Social implications
Improved CSR practices driven by the factors identified in this study can lead to more sustainable and socially responsible business operations.

Originality/value
This study contributes to the existing literature by using the SmartPLS method to analyse the impact of various factors on CSR applications in an emerging market. It emphasises the importance of big data applications in shaping effective CSR practices and offers valuable recommendations for corporate governance enhancements.
Digital transformation, international competition and productivity progress: evidence from Health Silk Road
Authors: Wan Lu , Fang Yanqi , Ban Nannan , Cheng Guo , Huang Guohua 
Published: January 2025

PurposeThis paper aims to explore the relationship between digital transformation, international competition and productivity progress by examining the dual margins of export, thereby identifying the digital development pathway for key industrial chains within the context of regional medical and health cooperation.Design/methodology/approachBy constructing models incorporating both the extensive margin and intensive margin, this paper delves into the reasons underlying changes in product trade value and variety within international market competition. Utilizing export data for medical products from China to Belt and Road Initiative partner countries spanning from 2007 to 2020, an industry–destination–time panel benchmark model is established to assess the impact of digital transformation on product expansion and international competition.FindingsThe findings reveal the following insights. First, digital transformation positively impacts the intensive margin of medical products, whereas it does not exert a positive influence on the extensive margin. Second, the impact mechanism test indicates that digital transformation fosters the intensive export margin by enhancing the technical efficiency of exports but exhibits an inverted U-shaped effect on technological progress. Third, digital transformation demonstrates a notable non-linear characteristic, with a substantial increase in the lifting effect once a certain threshold is surpassed.Originality/valueWhile previous research has extensively explored the effects of digital transformation on export trade, this study uniquely integrates the concepts of the intensive and extensive margins of export, thereby enriching the research insights derived from existing literature. It focuses on the nonlinear effects and threshold dynamics of digital transformation, particularly in relation to total factor productivity. Additionally, the paper makes a contribution to the understanding of the Health Silk Road by incorporating the health index.