bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells
Authors: Rio-Vilariño Anxo , Cenigaonandia-Campillo Aiora , García-Bautista Ana , Mateos-Gómez Pedro A. , Schlaepfer Marina I. , del Puerto-Nevado Laura , Aguilera Oscar , García-García Laura , Galeano Carlos , de Miguel Irene , Serrano-López Juana , Baños Natalia , Fernández-Aceñero María Jesús , Lacal Juan Carlos , Medico Enzo , García-Foncillas Jesús , Cebrián Arancha 
Published: March 2024

Abstract
Background
Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA’s role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer.

Methods
We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features.

Results
The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype.

Conclusions
AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.
mTORC1 accelerates osteosarcoma progression via m6A-dependent stabilization of USP7 mRNA
Authors: Yang Zhengming , Yu Wei , Xu Ankai , Liu Bing , Jin Libin , Tao Huimin , Wang Dimin 
Published: March 2024

AbstractOsteosarcoma (OS) is considered a sex steroid hormone-dependent bone tumor. The development and progression of OS are regulated by 17β-estradiol (E2). However, the detailed mechanisms of E2-modulated OS progression remained to be elucidated. Here, we found that E2-activated mammalian target of rapamycin (mTOR) signaling promoted N6-methyladenosine (m6A) modification through regulating WTAP. Inhibition of mTOR complex 1 (mTORC1) reversed E2-activated WTAP expression. Meanwhile, inhibition of mTORC1 suppressed OS cell proliferation and migration. Deficiency of TSC2 activated mTORC1 signaling and enhanced OS cell proliferation and migration, while abrogated by Rapamycin. Interestingly, mTOMC1 promoted mRNA stability of ubiquitin-specific protease 7 (USP7) through m6A modification. Loss of USP7 suppressed the proliferation, migration, and ASC specks, while promoted apoptosis of OS cells. USP7 interacted with NLRP3 and deubiquitinated NLRP3 through K48-ubiquitination. USP7 was upregulated and positive correlation with NLRP3 in OS patients with high level of E2. Loss of USP7 suppressed the progression of OS via inhibiting NLRP3 inflammasome signaling pathway. Our results demonstrated that E2-activtated mTORC1 promoted USP7 stability, which promoted OS cell proliferation and migration via upregulating NLRP3 expression and enhancing NLRP3 inflammasome signaling pathway. These results discover a novel mechanism of E2 regulating OS progression and provide a promising therapeutic target for OS progression.
Multiple cancer cell types release LIF and Gal3 to hijack neural signals
Authors: Xu Qun , Cao Ying , Kong Fanni , Liu Jiaqi , Chen Xin , Zhao Yifei , Lai Chin-Hui , Zhou Xin , Hu Hao , Fu Wei , Chen Jian , Yang Jing 
Published: March 2024

AbstractNeural signals can significantly influence cancer prognosis. However, how cancer cells may proactively modulate the nervous system to benefit their own survival is incompletely understood. In this study, we report an overlapping pattern of brain responses, including that in the paraventricular nucleus of the hypothalamus, in multiple mouse models of peripheral cancers. A multi-omic screening then identifies leukemia inhibitory factor (LIF) and galectin-3 (Gal3) as the key cytokines released by these cancer cell types to trigger brain activation. Importantly, increased plasma levels of these two cytokines are observed in patients with different cancers. We further demonstrate that pharmacologic or genetic blockage of cancer cell-derived LIF or Gal3 signaling abolishes the brain responses and strongly inhibits tumor growth. In addition, ablation of peripheral sympathetic actions can similarly restore antitumor immunity. These results have elucidated a novel, shared mechanism of multiple cancer cell types hijacking the nervous system to promote tumor progression.
Head to head comparison of diagnostic performance of three non-mydriatic cameras for diabetic retinopathy screening with artificial intelligence
Authors: Doğan Mehmet Erkan , Bilgin Ahmet Burak , Sari Ramazan , Bulut Mehmet , Akar Yusuf , Aydemir Mustafa 
Published: March 2024

Abstract
Background
Diabetic Retinopathy (DR) is a leading cause of blindness worldwide, affecting people with diabetes. The timely diagnosis and treatment of DR are essential in preventing vision loss. Non-mydriatic fundus cameras and artificial intelligence (AI) software have been shown to improve DR screening efficiency. However, few studies have compared the diagnostic performance of different non-mydriatic cameras and AI software.

Methods
This clinical study was conducted at the endocrinology clinic of Akdeniz University with 900 volunteer patients that were previously diagnosed with diabetes but not with diabetic retinopathy. Fundus images of each patient were taken using three non-mydriatic fundus cameras and EyeCheckup AI software was used to diagnose more than mild diabetic retinopathy, vision-threatening diabetic retinopathy, and clinically significant diabetic macular oedema using images from all three cameras. Then patients underwent dilation and 4 wide-field fundus photography. Three retina specialists graded the 4 wide-field fundus images according to the diabetic retinopathy treatment preferred practice patterns of the American Academy of Ophthalmology. The study was pre-registered on clinicaltrials.gov with the ClinicalTrials.gov Identifier: NCT04805541.

Results
The Canon CR2 AF AF camera had a sensitivity and specificity of 95.65% / 95.92% for diagnosing more than mild DR, the Topcon TRC-NW400 had 95.19% / 96.46%, and the Optomed Aurora had 90.48% / 97.21%. For vision threatening diabetic retinopathy, the Canon CR2 AF had a sensitivity and specificity of 96.00% / 96.34%, the Topcon TRC-NW400 had 98.52% / 95.93%, and the Optomed Aurora had 95.12% / 98.82%. For clinically significant diabetic macular oedema, the Canon CR2 AF had a sensitivity and specificity of 95.83% / 96.83%, the Topcon TRC-NW400 had 98.50% / 96.52%, and the Optomed Aurora had 94.93% / 98.95%.

Conclusion
The study demonstrates the potential of using non-mydriatic fundus cameras combined with artificial intelligence software in detecting diabetic retinopathy. Several cameras were tested and, notably, each camera exhibited varying but adequate levels of sensitivity and specificity. The Canon CR2 AF emerged with the highest accuracy in identifying both more than mild diabetic retinopathy and vision-threatening cases, while the Topcon TRC-NW400 excelled in detecting clinically significant diabetic macular oedema. The findings from this study emphasize the importance of considering a non mydriatic camera and artificial intelligence software for diabetic retinopathy screening. However, further research is imperative to explore additional factors influencing the efficiency of diabetic retinopathy screening using AI and non mydriatic cameras such as costs involved and effects of screening using and on an ethnically diverse population.
Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson’s disease
Authors: Summa K. C. , Jiang P. , González-Rodríguez P. , Huang X. , Lin X. , Vitaterna M. H. , Dan Y. , Surmeier D. J. , Turek F. W. 
Published: March 2024

AbstractDisrupted sleep has a profound adverse impact on lives of Parkinson’s disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD – the MCI-Park mouse – was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities resemble those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.
Late Pleistocene emergence of an anthropogenic fire regime in Australia’s tropical savannahs
Authors: Bird Michael I. , Brand Michael , Comley Rainy , Fu Xiao , Hadeen Xennephone , Jacobs Zenobia , Rowe Cassandra , Wurster Christopher M. , Zwart Costijn , Bradshaw Corey J. A. 
Published: March 2024

AbstractAt the time of European arrival on the Australian continent, sophisticated Indigenous societies practiced land management across Australia’s extensive tropical savannahs. Fire was one of the main tools people used to manipulate fuel loads and connectivity to reduce uncontrolled wildfire, maintain vegetation structure and enhance biodiversity. When this alteration of a ‘natural’ fire regime to a human-dominated fire regime occurred is not known. Here we assessed fire incidence and intensity over the past 150,000 years through a continuous lacustrine record by comparing the accumulation rates of micro-charcoal and stable polycyclic aromatic hydrocarbon that form during the combustion of vegetation. We also compared grass (mainly C4) pollen as a percentage of total dryland pollen with the carbon isotope composition of the stable polycyclic aromatic hydrocarbon. We established with high statistical certainty that a change in fire regime occurred at least 11,000 years ago from less-frequent, more-intense fires to more-frequent, less-intense fires. This change marked the overprinting of a largely natural fire regime by one at least modulated by Indigenous management. Our findings demonstrate that human fire use has modified fire regimes throughout the Holocene and also show how people have managed the potential for the type of high-intensity fires that are likely to increase in the future.
Enhancer–promoter interactions become more instructive in the transition from cell-fate specification to tissue differentiation
Authors: Pollex Tim , Rabinowitz Adam , Gambetta Maria Cristina , Marco-Ferreres Raquel , Viales Rebecca R. , Jankowski Aleksander , Schaub Christoph , Furlong Eileen E. M. 
Published: March 2024

AbstractTo regulate expression, enhancers must come in proximity to their target gene. However, the relationship between the timing of enhancer–promoter (E–P) proximity and activity remains unclear, with examples of uncoupled, anticorrelated and correlated interactions. To assess this, we selected 600 characterized enhancers or promoters with tissue-specific activity in Drosophila embryos and performed Capture-C in FACS-purified myogenic or neurogenic cells during specification and tissue differentiation. This enabled direct comparison between E–P proximity and activity transitioning from OFF-to-ON and ON-to-OFF states across developmental conditions. This showed remarkably similar E–P topologies between specified muscle and neuronal cells, which are uncoupled from activity. During tissue differentiation, many new distal interactions emerge where changes in E–P proximity reflect changes in activity. The mode of E–P regulation therefore appears to change as embryogenesis proceeds, from largely permissive topologies during cell-fate specification to more instructive regulation during terminal tissue differentiation, when E–P proximity is coupled to activation.
A solid beta-sheet structure is formed at the surface of FUS droplets during aging
Authors: Emmanouilidis Leonidas , Bartalucci Ettore , Kan Yelena , Ijavi Mahdiye , Pérez Maria Escura , Afanasyev Pavel , Boehringer Daniel , Zehnder Johannes , Parekh Sapun H. , Bonn Mischa , Michaels Thomas C. T. , Wiegand Thomas , Allain Frédéric H.-T. 
Published: March 2024

AbstractPhase transitions are important to understand cell dynamics, and the maturation of liquid droplets is relevant to neurodegenerative disorders. We combined NMR and Raman spectroscopies with microscopy to follow, over a period of days to months, droplet maturation of the protein fused in sarcoma (FUS). Our study reveals that the surface of the droplets plays a critical role in this process, while RNA binding prevents it. The maturation kinetics are faster in an agarose-stabilized biphasic sample compared with a monophasic condensed sample, owing to the larger surface-to-volume ratio. In addition, Raman spectroscopy reports structural differences upon maturation between the inside and the surface of droplets, which is comprised of β-sheet content, as revealed by solid-state NMR. In agreement with these observations, a solid crust-like shell is observed at the surface using microaspiration. Ultimately, matured droplets were converted into fibrils involving the prion-like domain as well as the first RGG motif.
Structure of the human 20S U5 snRNP
Authors: Schneider Sarah , Brandina Irina , Peter Daniel , Lagad Sonal , Fraudeau Angelique , Portell-Montserrat Júlia , Tholen Jonas , Zhao Jiangfeng , Galej Wojciech P. 
Published: March 2024

AbstractThe 20S U5 small nuclear ribonucleoprotein particle (snRNP) is a 17-subunit RNA–protein complex and a precursor of the U4/U6.U5 tri-snRNP, the major building block of the precatalytic spliceosome. CD2BP2 is a hallmark protein of the 20S U5 snRNP, absent from the mature tri-snRNP. Here we report a high-resolution cryogenic electron microscopy structure of the 20S U5 snRNP, shedding light on the mutually exclusive interfaces utilized during tri-snRNP assembly and the role of the CD2BP2 in facilitating this process.
Digital pathology with artificial intelligence analysis provides insight to the efficacy of anti-fibrotic compounds in human 3D MASH model
Authors: Kostadinova Radina , Ströbel Simon , Chen Li , Fiaschetti‑Egli Katia , Gadient Jana , Pawlowska Agnieszka , Petitjean Louis , Bieri Manuela , Thoma Eva , Petitjean Mathieu 
Published: March 2024

AbstractMetabolic dysfunction-associated steatohepatitis (MASH) is a severe liver disease characterized by lipid accumulation, inflammation and fibrosis. The development of MASH therapies has been hindered by the lack of human translational models and limitations of analysis techniques for fibrosis. The MASH three-dimensional (3D) InSight™ human liver microtissue (hLiMT) model recapitulates pathophysiological features of the disease. We established an algorithm for automated phenotypic quantification of fibrosis of Sirius Red stained histology sections of MASH hLiMTs model using a digital pathology quantitative single-fiber artificial intelligence (AI) FibroNest™ image analysis platform. The FibroNest™ algorithm for MASH hLiMTs was validated using anti-fibrotic reference compounds with different therapeutic modalities-ALK5i and anti-TGF-β antibody. The phenotypic quantification of fibrosis demonstrated that both reference compounds decreased the deposition of fibrillated collagens in alignment with effects on the secretion of pro-collagen type I/III, tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-3 and pro-fibrotic gene expression. In contrast, clinical compounds, Firsocostat and Selonsertib, alone and in combination showed strong anti-fibrotic effects on the deposition of collagen fibers, however less pronounced on the secretion of pro-fibrotic biomarkers. In summary, the phenotypic quantification of fibrosis of MASH hLiMTs combined with secretion of pro-fibrotic biomarkers and transcriptomics represents a promising drug discovery tool for assessing anti-fibrotic compounds.
Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening
Authors: Pahl Ina , Pahl Axel , Hauk Armin , Budde Dana , Sievers Sonja , Fruth Lothar , Menzel Roberto 
Published: March 2024

AbstractPlastic components are essential in the pharmaceutical industry, encompassing container closure systems, laboratory handling equipment, and single-use systems. As part of their material qualification process, studies on interactions between plastic contact materials and process solutions or drug products are conducted. The assessment of single-use systems includes their potential impact on patient safety, product quality, and process performance. This is particularly crucial in cell and gene therapy applications since interactions with the plastic contact material may result in an adverse effect on the isolated therapeutic human cells. We utilized the cell painting assay (CPA), a non-targeted method, for profiling the morphological characteristics of U2OS human osteosarcoma cells in contact with chemicals related to plastic contact materials. Specifically, we conducted a comprehensive analysis of 45 common plastic extractables, and two extracts from single-use systems. Results of the CPA are compared with a standard cytotoxicity assay, an osteogenesis differentiation assay, and in silico toxicity predictions. The findings of this feasibility study demonstrate that the device extracts and most of the tested compounds do not evoke any measurable biological changes on the cells (induction  ≤ 5%) among the 579 cell features measured at concentrations  ≤ 50 µM. CPA can serve as an important assay to reveal unique information not accessible through quantitative structure–activity relationship analysis and vice versa. The results highlight the need for a combination of in vitro and in silico methods in a comprehensive assessment of single-use equipment utilized in advanced therapy medicinal products manufacturing.
Stress affects navigation strategies in immersive virtual reality
Authors: Varshney Apurv , Munns Mitchell E. , Kasowski Justin , Zhou Mantong , He Chuanxiuyue , Grafton Scott T. , Giesbrecht Barry , Hegarty Mary , Beyeler Michael 
Published: March 2024

AbstractThere are known individual differences in both the ability to learn the layout of novel environments and the flexibility of strategies for navigating known environments. However, it is unclear how navigational abilities are impacted by high-stress scenarios. Here we used immersive virtual reality (VR) to develop a novel behavioral paradigm to examine navigation under dynamically changing situations. We recruited 48 participants (24 female; ages 17–32) to navigate a virtual maze (7.5 m × 7.5 m). Participants learned the maze by moving along a fixed path past the maze’s landmarks (paintings). Subsequently, participants experienced either a non-stress condition, or a high-stress condition tasking them with navigating the maze. In the high-stress condition, their initial path was blocked, the environment was darkened, threatening music was played, fog obstructed more distal views of the environment, and participants were given a time limit of 20 s with a countdown timer displayed at the top of their screen. On trials where the path was blocked, we found self-reported stress levels and distance traveled increased while trial completion rate decreased (as compared to non-stressed control trials). On unblocked stress trials, participants were less likely to take a shortcut and consequently navigated less efficiently compared to control trials. Participants with more trait spatial anxiety reported more stress and navigated less efficiently. Overall, our results suggest that navigational abilities change considerably under high-stress conditions.
Engineered biosorbents of pomelo (Citrus maxima (Burm.f.) Merr) peels modified with zinc oxide and titanium dioxide for methylene blue dye sorption
Authors: Praipipat Pornsawai , Ngamsurach Pimploy , Srirat Pratchayaporn , Chaiphumee Punjaporn 
Published: March 2024

AbstractThe pomelo-doped zinc oxide beads (PZB), pomelo-doped titanium dioxide beads (PTB), and pomelo-doped zinc oxide and titanium dioxide beads (PZTB) were synthesized for sorbing methylene blue (MB) dye. Their characterizations were explored by X-Ray Diffractometer (XRD), Field Emission Scanning Electron Microscopy and Focus Ion Beam (FESEM-FIB), Energy Dispersive X-Ray Spectrometer (EDX), and Fourier Transform Infrared Spectroscopy (FT-IR). In addition, their sorbent efficiencies for sorbing MB dye were investigated through batch experiments, sorbent reusability studies, sorption isotherms, kinetics, and thermodynamic studies. They were crystalline phases presenting the specific peaks of zinc oxide (ZnO) or titanium dioxide (TiO2). Their surfaces had lamella structures with coarse surfaces, and they also found specific structures of ZnO or TiO2 on the surfaces. Zn–O or Ti–O–Ti was also detected in PZB or PTB or, PZTB depending upon metal oxide types added into pomelo beaded sorbents. For batch experiments, they could adsorb MB dye of more than 86%, and PZTB showed the highest MB dye removal efficiency. In addition, they could be reused for more than three cycles with high MB dye sorptions of more than 72%. They corresponded to Freundlich and pseudo-second-order kinetic models. Moreover, the increasing temperature affected their decreasing MB dye sorptions which were exothermic processes.