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Keywords = spindle orientation

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14 pages, 4680 KB  
Article
Performance Evaluation of Five-Axis CNC Milling via Spindle Current and Vibration Monitoring
by Beatriz Cardoso, José Ferreira, Tiago E. F. Silva, Pedro Sá Couto, Ana Reis and Abílio M. P. de Jesus
Metals 2026, 16(1), 129; https://doi.org/10.3390/met16010129 - 22 Jan 2026
Viewed by 327
Abstract
The digitalization of machining processes is increasingly recognized as essential for achieving higher productivity, reliability, and traceability. However, access to reliable in-process sensor data remains limited, particularly in multi-axis CNC machining, where dimensional accuracy and surface integrity strongly depend on stable and optimized [...] Read more.
The digitalization of machining processes is increasingly recognized as essential for achieving higher productivity, reliability, and traceability. However, access to reliable in-process sensor data remains limited, particularly in multi-axis CNC machining, where dimensional accuracy and surface integrity strongly depend on stable and optimized process conditions. This study investigates sensor-based monitoring as a practical approach for evaluating process performance in five-axis CNC milling. Electric current and vibration signals were acquired during three machining operations, under distinct cutting parameters, using current clamps and a plug-and-play MEMS accelerometer. The signals were processed using the root mean square method to assess the correlation between sensor data and machining conditions. Dimensional inspection of each workpiece was carried out to verify geometric conformity. The results show that spindle current measurements exhibit a strong linear correlation with material removal rate and cutting power, supporting their use as indicators of cutting forces and energy consumption. Vibration signals revealed pronounced dynamic behaviour for specific tool orientations, particularly in transverse to tool axis direction. The proposed methodology provides a simple and low-cost framework for integrating sensor-based monitoring into five-axis CNC milling, particularly relevant for semi-roughing operations, and offers a basis for future studies on process optimization and real-time condition monitoring. Full article
(This article belongs to the Special Issue Numerical and Experimental Advances in Metal Processing, 2nd Edition)
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22 pages, 20100 KB  
Article
Real-Time Detection and Validation of a Target-Oriented Model for Spindle-Shaped Tree Trunks Leveraging Deep Learning
by Kang Zheng, Shuo Yang, Zhichong Wang, Hao Fu, Xiu Wang, Wei Zou, Changyuan Zhai and Liping Chen
Agronomy 2026, 16(2), 210; https://doi.org/10.3390/agronomy16020210 - 15 Jan 2026
Viewed by 369
Abstract
To enhance the automation and intelligence of trenching fertilization operations, this research proposes a real-time trunk detection model (Trunk-Seek) designed for spindle-shaped orchards. The model employs a customized data augmentation strategy and integrates the YOLO deep learning framework to effectively address visual challenges [...] Read more.
To enhance the automation and intelligence of trenching fertilization operations, this research proposes a real-time trunk detection model (Trunk-Seek) designed for spindle-shaped orchards. The model employs a customized data augmentation strategy and integrates the YOLO deep learning framework to effectively address visual challenges such as lighting variation, occlusion, and motion blur. Multiple object tracking algorithms were evaluated, and ByteTrack was selected for its superior performance in dynamic trunk tracking. In addition, a Positioning and Triggering Algorithm (PTA) was developed to enable precise localization and triggering for target-oriented fertilization. The system was deployed on an edge device, a test bench was established, and both laboratory and field experiments were conducted to validate its performance. Experimental results demonstrated that the detection model achieved an mAP50 of 98.9% and maintained a stable 32.53 FPS on the edge device, fulfilling real-time detection requirements. Test bench analysis revealed that variations in trunk diameter and operation speed affected triggering accuracy, with an average dynamic localization error of ±1.78 cm. An empirical model (T) was developed to describe the time-delay behavior associated with positioning errors. Field verification in orchards confirmed that Trunk-Seek achieved a triggering accuracy of 91.08%, representing a 24.08% improvement over conventional training methods. Combining high accuracy with robust real-time performance, Trunk-Seek and the proposed PTA provide essential technical support for the development of a visual target-oriented fertilization system in modern orchards. Full article
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29 pages, 416 KB  
Article
RETRACTED: Seismic Performance of Space-Saving Special-Shaped Concrete-Filled Steel Tube (CFST) Frames with Different Joint Types: Symmetry Effects and Design Implications for Civil Transportation Buildings
by Liying Zhang and Jingfeng Xia
Symmetry 2025, 17(9), 1545; https://doi.org/10.3390/sym17091545 - 15 Sep 2025
Viewed by 1164 | Retraction
Abstract
Special-shaped concrete-filled steel tube (CFST) frames can be embedded in partition walls to improve space utilization, but their frame-level seismic behavior across joint types remains under-documented. This study examines six two-story, single-bay frames with cruciform, T-, and L-shaped CFST columns and three joint [...] Read more.
Special-shaped concrete-filled steel tube (CFST) frames can be embedded in partition walls to improve space utilization, but their frame-level seismic behavior across joint types remains under-documented. This study examines six two-story, single-bay frames with cruciform, T-, and L-shaped CFST columns and three joint configurations: external hoops with vertical ribs, fully bolted joints, and fully bolted joints with replaceable flange plates. Low-cycle reversed loading tests were combined with validated ABAQUS and OpenSees models to interpret mechanisms and conduct parametric analyses. All frames exhibited stable spindle-shaped hysteresis with minor pinching; equivalent viscous damping reached 0.13–0.25, ductility coefficients 3.03–3.69, and drift angles 0.088–0.126 rad. Hooped-and-ribbed joints showed the highest capacity and energy dissipation, while replaceable joints localized damage for rapid repair. Parametric results revealed that increasing the steel grade and steel ratio (≈5–20%) improved seismic indices more effectively than raising the concrete strength. Recommended design windows include axial load ratio < 0.4–0.5, slenderness ≤ 30, stiffness ratio ≈ 0.36, and flexural-capacity ratio ≈ 1.0. These findings provide symmetry-based, repair-oriented guidance for transportation buildings requiring rapid post-earthquake recovery. Full article
19 pages, 5474 KB  
Article
Structure and Fractal Characteristics of Organic Matter Pores in Wufeng–Lower Longmaxi Formations in Southern Sichuan Basin, China
by Quanzhong Guan, Dazhong Dong, Bin Deng, Cheng Chen, Chongda Li, Kun Jiao, Yuehao Ye, Haoran Liang and Huiwen Yue
Fractal Fract. 2025, 9(7), 410; https://doi.org/10.3390/fractalfract9070410 - 25 Jun 2025
Cited by 4 | Viewed by 1363
Abstract
Organic matter pores constitute a significant storage space in shale gas reservoirs, contributing to approximately 50% of the total porosity. This study employed a comprehensive approach, utilizing scanning electron microscopy, low-pressure N2 adsorption, thermal analysis, image statistics, and fractal theory, to quantitatively [...] Read more.
Organic matter pores constitute a significant storage space in shale gas reservoirs, contributing to approximately 50% of the total porosity. This study employed a comprehensive approach, utilizing scanning electron microscopy, low-pressure N2 adsorption, thermal analysis, image statistics, and fractal theory, to quantitatively characterize the structure and complexity of organic matter pores in the Wufeng–lower Longmaxi Formations (WLLFs). The WLLFs exhibit a high organic matter content, averaging 3.20%. Organic matter pores are typically well-developed, predominantly observed within organic matter clusters, organic matter–clay mineral complexes, and the internal organic matter of pyrite framboid. The morphology of these pores is generally elliptical and spindle-shaped, with the primary pore diameter displaying a bimodal distribution at 10~40 nm and 100~160 nm, potentially influenced by the observational limit of scanning electron microscopy. Shales from greater burial depths within the same gas well contain more organic matter pores; however, the development of organic matter pores in deep gas wells is roughly equivalent to that in medium and shallow gas wells. Fractal dimension values can be utilized to characterize the complexity of organic matter pores, with organic matter macropores (D>50) being more complex than organic matter mesopores (D2–50), which in turn are more complex than organic matter micropores (D<2). The development of macropores and mesopores is a key factor in the heterogeneity of organic matter pores. The complexity of organic matter pores in the same well increases gradually with the burial depth of the shale, and the complexity of organic matter pores in deep gas wells is roughly equivalent to that in medium and shallow gas wells. The structure and fractal characteristics of organic matter pores in shale are primarily controlled by components, diagenesis, tectonism, etc. The lower Longmaxi shale exhibit a high biogenic quartz content and robust hydrocarbon generation from organic matter. This composition effectively shields organic matter pores from multi-directional extrusion, leading to the formation of macropores and mesopores without specific orientation. High-quality shale sections (one and two sublayers) have relatively high fractal dimension D2–50 and D>50 values of organic matter pores and gas content. Consequently, the quality parameters of shale and fractal dimension characteristics can be comprehensively evaluated to identify high-quality shale sections. Full article
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16 pages, 3791 KB  
Article
Spindle Orientation Regulation Is Governed by Redundant Cortical Mechanosensing and Shape-Sensing Mechanisms
by Rania Hadjisavva and Paris A. Skourides
Int. J. Mol. Sci. 2025, 26(12), 5730; https://doi.org/10.3390/ijms26125730 - 15 Jun 2025
Viewed by 1041
Abstract
Spindle orientation (SO) plays a critical role in tissue morphogenesis, homeostasis, and tumorigenesis by ensuring accurate division plane positioning in response to intrinsic and extrinsic cues. While SO has been extensively linked to cell shape sensing and cortical forces, the interplay between shape- [...] Read more.
Spindle orientation (SO) plays a critical role in tissue morphogenesis, homeostasis, and tumorigenesis by ensuring accurate division plane positioning in response to intrinsic and extrinsic cues. While SO has been extensively linked to cell shape sensing and cortical forces, the interplay between shape- and force-sensing mechanisms remains poorly understood. Here, we reveal that SO is governed by two parallel mechanisms that ensure redundancy and adaptability in diverse cellular environments. Using live-cell imaging of cultured cells, we demonstrate that the long prometaphase axis (LPA) is a superior predictor of SO compared to the long interphase axis, reflecting adhesive geometry and force distribution efficiently at prometaphase. Importantly, we uncover a pivotal role for focal adhesion kinase (FAK) in mediating cortical mechanosensing to regulate SO in cells undergoing complete metaphase rounding. We show that in cells with complete metaphase rounding, FAK-dependent force sensing aligns the spindle with the major force vector, ensuring accurate division. Conversely, in cells retaining shape anisotropy during mitosis, a FAK-independent shape-sensing mechanism drives SO. These findings highlight a dual regulatory system for SO, where shape sensing and force sensing operate in parallel to maintain division plane fidelity, shedding light on the mechanisms that enable cells to adapt to diverse physical and mechanical environments. Full article
(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)
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24 pages, 2938 KB  
Review
Ciliary and Non-Ciliary Roles of IFT88 in Development and Diseases
by Xuexue Wang, Guoyu Yin, Yaru Yang and Xiaoyu Tian
Int. J. Mol. Sci. 2025, 26(5), 2110; https://doi.org/10.3390/ijms26052110 - 27 Feb 2025
Cited by 4 | Viewed by 3656
Abstract
Cilia are highly specialized cellular projections emanating from the cell surface, whose defects contribute to a spectrum of diseases collectively known as ciliopathies. Intraflagellar transport protein 88 (IFT88) is a crucial component of the intraflagellar transport-B (IFT-B) subcomplex, a protein complex integral to [...] Read more.
Cilia are highly specialized cellular projections emanating from the cell surface, whose defects contribute to a spectrum of diseases collectively known as ciliopathies. Intraflagellar transport protein 88 (IFT88) is a crucial component of the intraflagellar transport-B (IFT-B) subcomplex, a protein complex integral to ciliary transport. The absence of IFT88 disrupts the formation of ciliary structures; thus, animal models with IFT88 mutations, including the oak ridge polycystic kidney (ORPK) mouse model and IFT88 conditional allelic mouse model, are frequently employed in molecular and clinical studies of ciliary functions and ciliopathies. IFT88 plays a pivotal role in a variety of cilium-related processes, including organ fibrosis and cyst formation, metabolic regulation, chondrocyte development, and neurological functions. Moreover, IFT88 also exhibits cilium-independent functions, such as spindle orientation, planar cell polarity establishment, and actin organization. A deeper understanding of the biological events and molecular mechanisms mediated by IFT88 is anticipated to advance the development of diagnostic and therapeutic strategies for related diseases. Full article
(This article belongs to the Section Biochemistry)
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17 pages, 94163 KB  
Article
Investigation of Machining Characteristics and Parameter Optimization for Laser-Assisted Milling of CF/PEEK Composites
by Qijia Wang, Li Fu, Minghai Wang, Kang Xiao and Xuezhi Wang
Micromachines 2025, 16(2), 151; https://doi.org/10.3390/mi16020151 - 28 Jan 2025
Cited by 4 | Viewed by 1736
Abstract
Carbon fiber/polyether ether ketone (CF/PEEK) is widely used in aerospace, transportation, and other high-end industries for its light weight, high strength, and recyclability. However, its inherently brittle–ductile two-phase structure presents challenges in processing CF/PEEK. This paper introduces a laser-assisted milling method, wherein four [...] Read more.
Carbon fiber/polyether ether ketone (CF/PEEK) is widely used in aerospace, transportation, and other high-end industries for its light weight, high strength, and recyclability. However, its inherently brittle–ductile two-phase structure presents challenges in processing CF/PEEK. This paper introduces a laser-assisted milling method, wherein four types of CF/PEEK unidirectional plates (0°, 45°, 90°, and 135°) are milled under varying laser powers and spindle speeds. The results are compared with conventional milling (CM) techniques, based on cutting forces, temperatures, surface roughness, and damage defects. The cutting force, temperature, and surface quality were optimal at a fiber direction of 0° and were least favorable at 90° under identical machining conditions. When the fiber direction was 90°, the milling temperatures at 400 W and 500 W laser power decreased by 19.8% and 7.9%, respectively, while the average values of Fx and Fy decreased by 20.5% and 9.55%, compared to conventional milling. Furthermore, the laser-assisted milling method significantly reduces surface defects and improves surface roughness. In CF/PEEK composites, brittle fracture is the primary material removal mechanism, with damage characteristics such as fiber fracture, fiber pullout, and fiber/matrix debonding. The optimal parameter combination is a 0° fiber orientation, 400 W laser power, and a spindle speed of 4000 rpm. This study provides theoretical and technical support for the high-quality processing of CF/PEEK composites. Full article
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23 pages, 3680 KB  
Article
Geometric Modeling and Error Propagation Analysis of an Over-Constrained Spindle Head with Kinematic Interactions
by Yifeng Shen, Tengfei Tang and Hanliang Fang
Machines 2024, 12(9), 651; https://doi.org/10.3390/machines12090651 - 18 Sep 2024
Viewed by 1309
Abstract
This study presents a comprehensive geometric modeling and error propagation analysis for a 3-degrees-of-freedom spindle head, focusing on an over-constrained parallel mechanism. Four geometric error models are established for the over-constrained spindle head, each considering different combinations of constraint wrenches. A set of [...] Read more.
This study presents a comprehensive geometric modeling and error propagation analysis for a 3-degrees-of-freedom spindle head, focusing on an over-constrained parallel mechanism. Four geometric error models are established for the over-constrained spindle head, each considering different combinations of constraint wrenches. A set of sensitivity indices is formulated to evaluate the effectiveness of these models. Comparative sensitivity analysis suggests that a model incorporating all constraint wrenches is suitable for error propagation analysis. Two error propagation indices are introduced to quantify the impact of the geometric source errors on the position and orientation of an individual limb structure. The coupled error propagation indices account for the kinematic interactions among limb structures, allowing for a detailed analysis of the spindle head’s terminal accuracy. The relative deviations of error propagation indices are utilized to assess the quantitative impact of kinematic interactions on the geometric errors of an individual limb structure. Furthermore, this study analyzes the cumulative effects of kinematic errors from three limb structures to reflect the influence of kinematic interactions on the terminal accuracy of the spindle head. The findings indicate that geometric errors of the limbs in such an over-constrained spindle head are mutually compensatory, reducing linear and angular errors and enhancing the spindle head’s terminal accuracy. Full article
(This article belongs to the Section Machine Design and Theory)
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22 pages, 10471 KB  
Article
Improving Robotic Milling Performance through Active Damping of Low-Frequency Structural Modes
by Govind Narayan Sahu, Andreas Otto and Steffen Ihlenfeldt
J. Manuf. Mater. Process. 2024, 8(4), 160; https://doi.org/10.3390/jmmp8040160 - 27 Jul 2024
Cited by 4 | Viewed by 3306
Abstract
Industrial robots are increasingly prevalent due to their large workspace and cost-effectiveness. However, their limited static and dynamic stiffness can lead to issues like mode coupling chatter and regenerative chatter in robotic milling processes, even at shallow cutting depths. These problems significantly impact [...] Read more.
Industrial robots are increasingly prevalent due to their large workspace and cost-effectiveness. However, their limited static and dynamic stiffness can lead to issues like mode coupling chatter and regenerative chatter in robotic milling processes, even at shallow cutting depths. These problems significantly impact performance, product quality, tool longevity, and can damage robot components. An active inertial actuator was deployed at the milling spindle to enhance dynamic stiffness and suppress low-frequency vibrations effectively. It was identified that the characteristics of the actuator change with its mounting orientation, a common scenario in robotic machining processes. This variation has not been reported in the literature. Our study includes the identification of model parameters for the actuator in both horizontal and vertical mountings. Additionally, the novelty of the present work lies in the specific design and implementation of compensation filters tailored for the active inertial actuator in both horizontal and vertical configurations. These filters address the unique challenges posed by low-frequency vibrations in robotic milling, offering significant improvements in dynamic stiffness and vibration suppression. Traditional model-based compensators were effective for vertical mounting, while pole-zero placement techniques with minimum phase systems were optimal for horizontal mounting. These compensators significantly enhanced dynamic stiffness, reducing maximum low-frequency robot structural modes by approximately 100% in horizontal mounting and approximately 214% in the vertical configuration of the actuator. This advancement promises to enhance industrial robot capabilities across diverse machining applications. Full article
(This article belongs to the Special Issue Dynamics and Machining Stability for Flexible Systems)
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19 pages, 7711 KB  
Article
High-Temperature and High-Pressure Tribological Properties of Siliconized Graphite for Water-Lubricated Thrust Bearing Application in Main Coolant Pump
by Sihang Liu, Baojun Zhang, Long Cai, Weiguang Wang, Taihe Liang and Mingkai Lei
Lubricants 2024, 12(5), 159; https://doi.org/10.3390/lubricants12050159 - 3 May 2024
Cited by 8 | Viewed by 2453
Abstract
The effect of the microstructure of siliconized graphite on tribological properties is investigated by using a high-temperature and high-pressure water-lubricated tribometer on a self-mated ring-on-ring configuration under an applied load of 500–1500 N with a spindle speed of 100–5000 rpm in both 90 [...] Read more.
The effect of the microstructure of siliconized graphite on tribological properties is investigated by using a high-temperature and high-pressure water-lubricated tribometer on a self-mated ring-on-ring configuration under an applied load of 500–1500 N with a spindle speed of 100–5000 rpm in both 90 °C (5 MPa) and 25 °C (1 MPa) water environments, respectively. The Stribeck curves measurement and continuous wear tests are performed and analyzed in both water environments. The wear behaviors of the graphite, SiC, and free-silicon phases in siliconized graphite are demonstrated to explore the wear mechanism. The larger wear depths of a low-worn surface roughness on the three phases contribute to the boundary lubrication. The shallower wear depths are observed on the SiC and Si phases under the mixed lubrication, corresponding to partial contact wear of surface asperities. The wavy surface of the SiC phase and uniform flow-oriented striae of the Si phase are attributed to hydrodynamic lubrication, caused by full water film scouring the worn surface. Finally, an integrated evaluation method of G duty parameters is successfully used to identify the lubrication regimes of siliconized graphite from the boundary, mixed, to hydrodynamic lubrications for a water-lubricated thrust bearing application in the main coolant pump of a nuclear power plant. Full article
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9 pages, 3841 KB  
Case Report
The Importance of In Vivo Reflectance Confocal Microscopy in a Case of Desmoplastic Melanoma
by Miruna Ioana Cristescu, Liliana Gabriela Popa, Elena Codruta Cozma, Ana Maria Celarel, Valentin Tudor Popa, Mihai Lupu and Vlad Mihai Voiculescu
Life 2024, 14(5), 574; https://doi.org/10.3390/life14050574 - 30 Apr 2024
Cited by 1 | Viewed by 2205
Abstract
Desmoplastic melanoma accounts for 5% of all cases of melanoma, but its diagnosis can be difficult due to its frequent clinical presentation with amelanotic lesions. Histologically, spindled melanocytes surrounded by a collagenous stroma are observed. Compared with other types of melanoma, the desmoplastic [...] Read more.
Desmoplastic melanoma accounts for 5% of all cases of melanoma, but its diagnosis can be difficult due to its frequent clinical presentation with amelanotic lesions. Histologically, spindled melanocytes surrounded by a collagenous stroma are observed. Compared with other types of melanoma, the desmoplastic types presents greater local aggression, and is more prone to local recurrence, but has a lower risk of lymph node metastasis. Early detection, accurate staging, and proper surgical management are the main factors associated with higher survival rates in melanoma patients. Reflectance confocal microscopy (RCM) has proven to be a valuable imaging tool in the diagnosis of skin neoplasms, being useful for orientating practitioners towards the diagnosis of melanoma and indicating the necessity of performing a diagnostic biopsy. We present the case of 52-year-old woman, who presented to the dermatology department with an irregular, dark-colored plaque in the right deltoid region. Dermoscopy showed asymmetry with an atypical network and some areas of regression. RCM revealed pagetoid cells in the upper epidermis, cell atypia, non-edged papillae, dermal inflammation, and nucleated cells in the dermis, which are highly suggestive of melanoma. A biopsy was also performed. A histopathology exam confirmed the diagnosis of superficially spreading melanoma with a desmoplastic component, and revealed a Breslow index of 0.9 mm, Clark level IV, an absence of mitoses, angiolymphatic invasion and regression, and complete excision. The CT and PET-CT scans were negative. A biopsy of the axillary sentinel lymph node was conducted, with a negative result obtained, establishing the IB stage of the disease. The patient will remain under follow-up to look for a recurrence or a new primary melanoma. Full article
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16 pages, 6321 KB  
Review
Phase Separation as a Driver of Stem Cell Organization and Function during Development
by Amalia S. Parra and Christopher A. Johnston
J. Dev. Biol. 2023, 11(4), 45; https://doi.org/10.3390/jdb11040045 - 12 Dec 2023
Cited by 9 | Viewed by 4883
Abstract
A properly organized subcellular composition is essential to cell function. The canonical organizing principle within eukaryotic cells involves membrane-bound organelles; yet, such structures do not fully explain cellular complexity. Furthermore, discrete non-membrane-bound structures have been known for over a century. Liquid–liquid phase separation [...] Read more.
A properly organized subcellular composition is essential to cell function. The canonical organizing principle within eukaryotic cells involves membrane-bound organelles; yet, such structures do not fully explain cellular complexity. Furthermore, discrete non-membrane-bound structures have been known for over a century. Liquid–liquid phase separation (LLPS) has emerged as a ubiquitous mode of cellular organization without the need for formal lipid membranes, with an ever-expanding and diverse list of cellular functions that appear to be regulated by this process. In comparison to traditional organelles, LLPS can occur across wider spatial and temporal scales and involves more distinct protein and RNA complexes. In this review, we discuss the impacts of LLPS on the organization of stem cells and their function during development. Specifically, the roles of LLPS in developmental signaling pathways, chromatin organization, and gene expression will be detailed, as well as its impacts on essential processes of asymmetric cell division. We will also discuss how the dynamic and regulated nature of LLPS may afford stem cells an adaptable mode of organization throughout the developmental time to control cell fate. Finally, we will discuss how aberrant LLPS in these processes may contribute to developmental defects and disease. Full article
(This article belongs to the Special Issue The 10th Anniversary of JDB: Feature Papers)
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21 pages, 6889 KB  
Article
Inducing Mitotic Catastrophe as a Therapeutic Approach to Improve Outcomes in Ewing Sarcoma
by Soumya M. Turaga, Vikalp Vishwakarma, Stacey L. Hembruff, Benjamin K. Gibbs, Priya Sabu, Rajni V. Puri, Harsh B. Pathak, Glenson Samuel and Andrew K. Godwin
Cancers 2023, 15(20), 4911; https://doi.org/10.3390/cancers15204911 - 10 Oct 2023
Cited by 4 | Viewed by 3142
Abstract
Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including [...] Read more.
Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora kinase A (AURKA) and kinesin family member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical-grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911) given that phosphorylation of KIF15S1169 by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥ 10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1–3%) and increased percentage accumulation of cells in the G2/M phase with the combination treatment (45–52%) upon cell cycle analysis, indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs. vehicle control (p ≤ 0.01), SB-743921 (p ≤ 0.01) and VIC-1911 (p ≤ 0.05). Kaplan–Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p ≤ 0.0001). Full article
(This article belongs to the Special Issue Targeted Therapy of Pediatric Cancer)
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17 pages, 1593 KB  
Review
When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex
by Chenchen Li, Emma E. Furth, Anil K. Rustgi and Peter S. Klein
Cells 2023, 12(18), 2256; https://doi.org/10.3390/cells12182256 - 12 Sep 2023
Cited by 24 | Viewed by 6389
Abstract
The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a “canonical” Wnt pathway that is initiated by [...] Read more.
The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a “canonical” Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is β-catenin, which is stabilized by inhibition of GSK-3, allowing β-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of β-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer)
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14 pages, 4340 KB  
Article
A Novel Error Sensitivity Analysis Method for a Parallel Spindle Head
by Liping Wang, Mengyu Li and Guang Yu
Robotics 2023, 12(5), 129; https://doi.org/10.3390/robotics12050129 - 11 Sep 2023
Cited by 5 | Viewed by 2308
Abstract
Geometric errors are the main factors affecting the output accuracy of the parallel spindle head, and it is necessary to perform a sensitivity analysis to extract the critical geometric errors. The traditional sensitivity analysis method analyzes the output position and orientation errors independently, [...] Read more.
Geometric errors are the main factors affecting the output accuracy of the parallel spindle head, and it is necessary to perform a sensitivity analysis to extract the critical geometric errors. The traditional sensitivity analysis method analyzes the output position and orientation errors independently, defining multiple sensitivity indices and making it difficult to determine critical geometric errors. In this paper, we propose sensitivity indices that can comprehensively consider position and orientation errors. First, the configuration of the hybrid machine tool is introduced, and the TCP position error model is derived. Then, the tool radius and the effective cutting length are introduced, and the sensitivity indices are defined. After that, the sensitivity analysis of the 3-DOF parallel spindle head is performed using the proposed sensitivity indices, and six critical geometric errors are extracted. The machining accuracy of the parallel spindle head can be greatly improved by improving the critical geometric errors. The proposed sensitivity analysis method can provide important guidance for machine tool accuracy design. Full article
(This article belongs to the Special Issue Kinematics and Robot Design VI, KaRD2023)
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