bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy
Authors: Yang Liuqing , Yang Ye , Zhang Jing , Li Minghui , Yang Long , Wang Xing , Chen Meifang , Zhang Hua , He Bing , Wang Xueqing , Dai Wenbing , Wang Yiguang , Zhang Qiang 
Published: October 2024

AbstractPROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (<10 nm) in response to an acidic tumor microenvironment, facilitating tumor penetration and cellular internalization. Eventually, the CDK4/6 degrading PROTACs were released intracellularly following the cleavage of cathepsin B. Importantly, PSRNs led to the enhanced degradation of target protein in vitro and in vivo. The degradation of CDK4/6 also augmented the efficacy of immune checkpoint blockades, through the upregulation of programmed cell death-ligand 1 (PD-L1) expression in cancer cells and the suppression of regulatory T cells cell proliferation in tumor microenvironment. By combination with α-PD-1, an enhanced anti-tumor outcome is well achieved in CT26 tumor model. Overall, our study verifies the significance of precise intracellular delivery of PROTACs and introduces a promising therapeutic strategy for the targeted combination treatment of CRC.
Latexin deficiency limits foam cell formation and ameliorates atherosclerosis by promoting macrophage phenotype differentiation
Authors: He Guozhang , Ni Yuanting , Hua Rong , Wan Huaibin , Tan Yanhui , Chen Qiwei , Xu Shaohua , Yang Yuzhong , Zhang Lijun , Shu Wei , Huang Ke-Bin , Mo Yi , Liang Hong , Chen Ming 
Published: October 2024

AbstractLatexin (LXN) is abundant in macrophages and plays critical roles in inflammation. Much is known about macrophages in atherosclerosis, the role of macrophage LXN in atherosclerosis has remained elusive. Here, the expression of LXN in human and mouse atherosclerotic lesions was examined by immunofluorescence and immunohistochemistry. LXN knockout and LXN/ApoE double-knockout mice were generated to evaluate the functions of LXN in atherosclerosis. Bone marrow transplantation (BMT) experimentation was carried out to determine whether macrophage LXN regulates atherosclerosis. We found that LXN is enriched in human and murine atherosclerotic lesions, mainly localized to macrophages. LXN deletion ameliorated atherosclerosis in ApoE-/- mice. BMT demonstrate that deletion of LXN in bone marrow protects ApoE-/- mice against atherosclerosis. Mechanistically, we found that LXN targets and inhibits JAK1 in macrophages. LXN deficiency stimulates the JAK1/STAT3/ABC transporter pathway, thereby enhancing the anti-inflammatory and anti-oxidant phenotype, cholesterol efflux, subsequently minimizing foam cell formation and atherosclerosis. Gene therapy by treatment of atherosclerotic mice with adeno-associated virus harbouring LXN-depleting shRNA attenuated the disease phenotype. In summary, our study provides new clues for the role of LXN in the pathological regulation of atherosclerosis, and determines that LXN is a target for preventing atherosclerosis, which may be a potential new anti-atherosclerosis therapeutic target.
Tumor-secreted LCN2 impairs gastric cancer progression via autocrine inhibition of the 24p3R/JNK/c-Jun/SPARC axis
Authors: Huang Zhixin , Li Ying , Qian Yan , Zhai Ertao , Zhao Zeyu , Zhang Tianhao , Liu Yinan , Ye Linying , Wei Ran , Zhao Risheng , Li Zikang , Liang Zhi , Cai Shirong , Chen Jianhui 
Published: October 2024

AbstractGastric cancer (GC) is one of the most lethal malignancies worldwide. Despite extensive efforts to develop novel therapeutic targets, effective drugs for GC remain limited. Recent studies have indicated that Lipocalin (LCN)2 abnormalities significantly impact GC progression; however, its regulatory network remains unclear. Our study investigates the functional role and regulatory mechanism of action of LCN2 in GC progression. We observed a positive correlation between LCN2 expression, lower GC grade, and better prognosis in patients with GC. LCN2 overexpression suppressed GC proliferation and metastasis both in vitro and in vivo. Transcriptome sequencing identified secreted protein acidic and rich in cysteine (SPARC) as a pivotal downstream target of LCN2. Mechanistically, c-Jun acted as a transcription factor inducing SPARC expression, and LCN2 downregulated SPARC by inhibiting the JNK/c-Jun pathway. Moreover, LCN2 bound to its receptor, 24p3R, via autocrine signaling, which directly inhibited JNK phosphorylation and then inhibited the JNK/c-Jun pathway. Finally, analysis of clinical data demonstrated that SPARC expression correlated negatively with lower GC grade and better prognosis, and that LCN2 expression correlated negatively with p-JNK, c-Jun, and SPARC expression in GC. These findings suggest that the LCN2/24p3R/JNK/c-Jun/SPARC axis is crucial in the malignant progression of GC, offering novel prognostic markers and therapeutic targets.
Novel platinum nanoclusters (Pt NCs) induce mitochondrial apoptosis and damaging autophagy for the treatment of osteosarcoma—from the perspective of P53 mutation status in different cell lines
Authors: Wang Jialin , Yue Haodi , Huang Xin , Liu Hongjian , Zhang Mengjun 
Published: October 2024

Abstract
This study aimed to investigate the anticancer efficacy and underlying mechanism of novel platinum nanoclusters (Pt NCs) in osteosarcoma cell lines exhibiting distinct P53 expression profiles, namely MG-63 (P53−) and U2-OS (P53+). The findings revealed that Pt NCs exerted an inhibitory effect on proliferation, migration, and colony formation while promoting apoptosis in both MG-63 (P53−) and U2-OS (P53+) cells. The inhibitory effect on the malignant characteristics of MG-63 (P53−) cells was more obvious, indicating that the potential anticancer effect of Pt NCs was not dependent on P53. Animal experiments have substantiated the in vivo anticancer properties of Pt NCs, while also revealing their lower toxicity on cells and tissues. Pt NCs possess the ability to impede cell proliferation by inducing DNA damage and arresting the cell cycle in the G1 phase and possess the ability to promote BAX/Bcl-2/Caspase-3/mitochondrial apoptosis. Pt NCs may promote mitochondrial apoptosis by promoting damaging autophagy, thereby promoting cellular demise. This study has confirmed the P53-independent anticancer impact of Pt NCs on osteosarcoma in vitro and in vivo. Pt NCs may play a therapeutic role in more sensitive MG-63 (P53−) cells by promoting DNA damage to arrest the cell cycle, stimulating BAX/Bcl-2/Caspase-3/mitochondrial apoptosis, and initiating damaging autophagy.
Ligand-induced conformational changes in the β1-adrenergic receptor revealed by hydrogen-deuterium exchange mass spectrometry
Authors: Toporowska Joanna , Kapoor Parth , Musgaard Maria , Gherbi Karolina , Sengmany Kathy , Qu Feng , Soave Mark , Yen Hsin-Yung , Hansen Kjetil , Jazayeri Ali , Hopper Jonathan T. S. , Politis Argyris 
Published: October 2024

AbstractG Protein Coupled Receptors (GPCRs) constitute the largest family of signalling proteins responsible for translating extracellular stimuli into intracellular functions. They play crucial roles in numerous physiological processes and are major targets for drug discovery. Dysregulation of GPCRs is implicated in various diseases, making understanding their structural dynamics critical for therapeutic development. Here, we use Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS) to explore the structural dynamics of the turkey β1-adrenergic receptor (tβ1AR) bound with nine different ligands, including agonists, partial agonists, and antagonists. We find that these ligands induce distinct dynamic patterns across the receptor, which can be grouped by compound modality. Notably, full agonist binding destabilises the intracellular loop 1 (ICL1), while antagonist binding stabilises it, highlighting ICL1’s role in G protein recruitment. Our findings indicate that the conserved L72 residue in ICL1 is crucial for maintaining receptor structural integrity and stabilising the GDP-bound state. Overall, our results provide a platform for determining drug modality and highlight how HDX-MS can be used to dissect receptor ligand interaction properties and GPCR mechanism.
Effect of sub-micron deformations at opposing strain rates on the micromagnetic behaviour of non-oriented electrical steel
Authors: Winter Kieran , Liao Zhirong , Abbá Erik , Robles Linares Jose A. , Axinte Dragos 
Published: October 2024

AbstractWe are entering an era of re-electrification, seeking high-power density electrical machines with minimal resource use. Significant performance gains in electrical machines have been achieved through precise manufacturing processes, including the shaping/cutting of soft magnetic materials. However, most studies have evaluated magnetic performance at a macro level, focusing on components, while the fundamental mechanisms, e.g., how the micromagnetic behaviour is affected by mechanical interference, remain unclear. In this study, we examine the impact of sub-micron deformations at opposing strain rates (10−2 to 101 s−1) on the micromagnetic behaviour of soft magnetic non-oriented electrical steel. Using a diamond probe to indent within a single grain of polycrystalline material at different velocities, we induce quasi-static and dynamic mechanical loading. Our analysis, employing magnetic force microscopy, transmission Kikuchi diffraction, and scanning transmission electron microscopy with a pixelated detector, reveals that magnetic texture disturbances rely on the time-dependent dislocation dynamics of the Fe-BCC material. Additionally, we compress micro-pillars to further investigate these effects under bulk-isolated deformation. These findings highlight the importance of considering even ultra-small loads, such as nano-indentations and micro-pillar compressions, in the manufacturing of next-generation electric machines, as they can affect magnetic texture and performance.
A solution for constraining past marine Polar Amplification
Authors: Morley A. , de la Vega E. , Raitzsch M. , Bijma J. , Ninnemann U. , Foster G. L. , Chalk T. B. , Meilland J. , Cave R. R. , Büscher J. V. , Kucera M. 
Published: October 2024

AbstractMost climate proxies of sea surface temperatures suffer from severe limitations when applied to cold temperatures that characterize Arctic environments. These limitations prevent us from constraining uncertainties for some of the most sensitive climate tipping points that can trigger rapid and dramatic global climate change such as Arctic/Polar Amplification, the disruption of the Atlantic Meridional Overturning Circulation, sea ice loss, and permafrost melting. Here, we present an approach to reconstructing sea surface temperatures globally using paired Mg/Ca - δ18Oc recorded in tests of the polar to subpolar planktonic foraminifera Neogloboquadrina pachyderma. We show that the fidelity of Mg/Ca-based paleoclimate reconstructions is compromised by variations in seawater carbonate chemistry which can be successfully quantified and isolated from paleotemperature reconstructions using a multiproxy approach. By applying the calibration to the last glacial maximum, we show that marine polar amplification has been underestimated by up to 3.0 ± 1.0 °C in model-based estimates.
Observation of super-Alfvénic slippage of reconnecting magnetic field lines on the Sun
Authors: Lörinčík Juraj , Dudík Jaroslav , Sainz Dalda Alberto , Aulanier Guillaume , Polito Vanessa , De Pontieu Bart 
Published: October 2024

Abstract
Slipping motions of magnetic field lines are a distinct signature of three-dimensional magnetic reconnection, a fundamental process driving solar and stellar flares. While being a key prediction of numerical experiments, the rapid super-Alfvénic field line slippage driven by the ‘slip-running’ reconnection has remained elusive in previous observations. New frontiers into exploring transient flare phenomena were introduced by recently designed high cadence observing programs of the Interface Region Imaging Spectrograph (IRIS). By exploiting high temporal resolution imagery (~2 s) of IRIS, here we reveal slipping motions of flare kernels at speeds reaching thousands of kilometres per second. The fast kernel motions are direct evidence of slip-running reconnection in quasi-separatrix layers, regions where magnetic field strongly changes its connectivity. Our results provide observational proof of theoretical predictions unaddressed for nearly two decades and extend the range of magnetic field configurations where reconnection-related phenomena can occur.
Deep learning based approach for actinidia flower detection and gender assessment
Authors: Pinheiro Isabel , Moreira Germano , Magalhães Sandro , Valente António , Cunha Mário , dos Santos Filipe Neves 
Published: October 2024

AbstractPollination is critical for crop development, especially those essential for subsistence. This study addresses the pollination challenges faced by Actinidia, a dioecious plant characterized by female and male flowers on separate plants. Despite the high protein content of pollen, the absence of nectar in kiwifruit flowers poses difficulties in attracting pollinators. Consequently, there is a growing interest in using artificial intelligence and robotic solutions to enable pollination even in unfavourable conditions. These robotic solutions must be able to accurately detect flowers and discern their genders for precise pollination operations. Specifically, upon identifying female Actinidia flowers, the robotic system should approach the stigma to release pollen, while male Actinidia flowers should target the anthers to collect pollen. We identified two primary research gaps: (1) the lack of gender-based flower detection methods and (2) the underutilisation of contemporary deep learning models in this domain. To address these gaps, we evaluated the performance of four pretrained models (YOLOv8, YOLOv5, RT-DETR and DETR) in detecting and determining the gender of Actinidia flowers. We outlined a comprehensive methodology and developed a dataset of manually annotated flowers categorized into two classes based on gender. Our evaluation utilised k-fold cross-validation to rigorously test model performance across diverse subsets of the dataset, addressing the limitations of conventional data splitting methods. DETR provided the most balanced overall performance, achieving precision, recall, F1 score and mAP of 89%, 97%, 93% and 94%, respectively, highlighting its robustness in managing complex detection tasks under varying conditions. These findings underscore the potential of deep learning models for effective gender-specific detection of Actinidia flowers, paving the way for advanced robotic pollination systems.
Enhanced optical and structural traits of irradiated lead borate glasses via Ce3+ and Dy3+ ions with studying Radiation shielding performance
Authors: Sallam O. I. , Rammah Y. S. , Nabil Islam M. , El-Seidy Ahmed M. A. 
Published: October 2024

AbstractLead borate glass is the best radiation shielding glass when lead is in high concentration. However, it has low transparency after radiation exposure. Radiation decreases transparency due to chemical and physical changes in the glass matrix, such as creating or healing defects in the glass network. The addition of rare earth elements like cerium and dysprosium oxides to lead borate glasses can improve their transparency and durability as radiation shielding barriers. The newly manufactured glasses’ optical absorption, structural, and radiation shielding properties were measured. The optical characteristics of the generated samples were examined to determine the effect of the cerium/dysprosium ratio on the structural alterations, specifically in the presence of bridging oxygen (BO) and non-bridging oxygen (NBO). Incorporating Ce3+ results in peaks at 195 nm for borate units, 225 nm for Ce3+, and a broadened peak at 393 nm due to overlapping peaks for Ce3+ and Ce4+ in the UV region. By adding Dy, multiple peaks are observed at 825, 902, 1095, 1275, and 1684 nm, corresponding to the transition from 6H15/2 ground state to 6F5/2, 6F7/2, 6F9/2, 6F11/2, and 6H11/2. The samples were also tested before and after exposure to gamma irradiation from a 60Co source at a dose of 75 kGy to assess their stability against radiation. The energy gap value during irradiation shows decreased non-bridging oxygen. The energy gap difference before and after irradiation for the M4 sample shows higher NBO to BO conversion, reducing radiation damage and improving structural stability. Furthermore, X-ray photoelectron spectroscopy was utilized to get insight into the coordination chemistry of the created glass samples. The half-value layer (HVL), radiation protection efficiency (RPE), neutron removal cross-section (FRNCS), mean free path (MFP), mass attenuation coefficients (MAC), and effective atomic numbers (Zef) of the glassy structure were calculated theoretically to assess its radiation shielding qualities. The linear attenuation coefficient order for the prepared samples was M1 > M2 > M3 > M4. The FRNCS values were 0.090, 0.083, 0.081, and 0.079 cm−1 for samples M1, M2, M3, and M4, respectively.
A multi-function glass shield for neutrons and gamma rays of boron- and bismuth-reinforced silicate glass
Authors: Din Hadeer M. Nasr El , Saeed Aly , Salem Eman , Shazly R. M. El , Wahab Magda Abdel 
Published: October 2024

AbstractA successful attempt to produce a multi-function glass shield for attenuating neutrons and gamma rays by reinforcing a silicate glass network with boron and bismuth has been accomplished. A composition of 20SiO2-80Na2O (BSiBi0) was proposed to be used as a host glass network and prepared using the melt/annealing techniques. The low concentration of SiO2 in BSiBi0 was not sufficient to form a stable glass network. Then, the proposed BSiBi0 was modified with 10, 20, 30, and 40 mol% of each of B2O3 and Bi2O3 (BSiBi1, BSiBi2, BSiBi3, and BSiBi4) simultaneously. The structural effects of adding B3+ and Bi3+ were studied through X-ray diffraction, density, and FTIR, which all showed enhancement of glass forming ability, a former role of Bi3+ ions, and crowded the glass network by BO4 units. The derived structural parameters $$-$$
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molar volume, mean silicon – silicon separation, mean boron – boron separation, oxygen packing density, packing density, and number of bridging/non-bridging oxygen $$-$$
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were extensively discussed to explore the impact of B3+ and Bi3+ on the formed network. The richness of the proposed host glass network by B3+ and Bi3+ enhanced its thermal stability. The obtained elastic properties by ultrasonic measurements reflect the increase of the glass rigidity with increasing concentrations of B3+ and Bi3+ ions. The obtained glasses have high visible light transparency and almost complete UV absorption. The measured shielding parameters against two types of neutron energies (total slow and slow) and a wide range of gamma rays’ energies showed a significant improvement in the shielding efficiency of the considered glasses. The total slow neutrons, slow neutrons, and gamma rays’ attenuation abilities were improved by 22.9, 135.5, and 73.8 $$-$$
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199.5%. High thermal stability, elasticity, visible light transparency, and neutrons and gamma rays’ attenuation performance features give the produced glasses, especially BSiBi4 glass, preference as shielding materials in nuclear fields.
Visual imagination can influence visual perception – towards an experimental paradigm to measure imagination
Authors: Mozhdehfarahbakhsh Azadeh , Hecker Lukas , Joos Ellen , Kornmeier Jürgen 
Published: October 2024

AbstractDuring visual imagination, a perceptual representation is activated in the absence of sensory input. This is sometimes described as seeing with the mind’s eye. A number of physiological studies indicate that the brain uses more or less the same neural resources for visual perception of sensory information and visual imagination. The intensity of visual imagination is typically assessed with questionnaires, while more objective measures are missing. Aim of the present study was, to test a new experimental paradigm that may allow to objectively quantify imagination. For this, we used priming and adaptation effects during observation of ambiguous figures. Our perception of an ambiguous stimulus is unstable and alternates spontaneously between two possible interpretations. If we first observe an unambiguous stimulus variant (the conditioning stimulus), the subsequently presented ambiguous stimulus can either be perceived in the same way as the test stimulus (priming effect) or in the opposite way (adaptation effect) as a function of the conditioning time. We tested for these conditioning effects (priming and adaptation) using an ambiguous Necker Cube and an ambiguous Letter /Number stimulus as test stimuli and unambiguous variants thereof as conditioning stimuli. In a second experimental condition, we tested whether the previous imagination of an unambiguous conditioning stimulus variant – instead of its observation – can have similar conditioning effects on the subsequent test stimulus. We found no systematic conditioning effect on the group level, neither for the two stimulus types (Necker Cube stimuli and Letter /Number stimuli) nor for the two conditions (Real and Imaginary). However, significant correlations between effects of Real and Imaginary Condition were observed for both stimulus types. The absence of conditioning effects at the group level may be explained by using only one conditioning time, which may fit with individual priming and adaptation constants of some of our participants but not of others. Our strong correlation results indicate that observers with clear conditioning effects have about the same type (priming or adaptation) and intensity of imaginary conditioning effects. As a consequence, not only past perceptual experiences but also past imaginations can influence our current percepts. This is further confirmation that the mechanisms underlying perception and imagination are similar. Our post-hoc qualitative observations from three self-defined aphantasic observers indicate that our paradigm may be a promising objective measure to identify aphantasia.