bluuebunny/crossref_metadata_2025_split huggingface dataset:
An in silico framework to visualize how cancer‐associated mutations influence structural plasticity of the chemokine receptor CCR3
Authors: van Aalst Evan J. , Wylie Benjamin J. 
Published: December 2024

AbstractG protein Coupled Receptors (GPCRs) are the largest family of cell surface receptors in humans. Somatic mutations in GPCRs are implicated in cancer progression and metastasis, but mechanisms are poorly understood. Emerging evidence implicates perturbation of intra‐receptor activation pathway motifs whereby extracellular signals are transmitted intracellularly. Recently, sufficiently sensitive methodology was described to calculate structural strain as a function of missense mutations in AlphaFold‐predicted model structures, which was extensively validated on experimental and predicted structural datasets. When paired with Molecular Dynamics (MD) simulations, these tools provide a facile approach to screen mutations in silico. We applied this framework to calculate the structural and dynamic effects of cancer‐associated mutations in the chemokine receptor CCR3, a Class A GPCR involved in cancer and autoimmune disorders. Residue‐residue contact scoring refined effective strain results, highlighting significant remodeling of inter‐ and intra‐motif contacts along the highly conserved GPCR activation pathway network. We then integrated AlphaFold‐derived predicted Local Distance Difference Test scores with per‐residue Root Mean Square Fluctuations and activation pathway Contact Analysis (CONAN) from coarse grain MD simulations to identify statistically significant changes in receptor dynamics upon mutation. Finally, analysis of negative control mutants suggests false positive results in AlphaFold pipelines should be considered but can be mitigated with stricter control of statistical analysis. Our results indicate selected mutants influence structural plasticity of CCR3 related to ligand interaction, activation, and G protein coupling, using a framework that could be applicable to a wide range of biochemically relevant protein targets following further validation.
Allosteric regulation of the tyrosine phosphatase PTP1B by a protein–protein interaction
Authors: Chartier Cassandra A. , Woods Virgil A. , Xu Yunyao , van Vlimmeren Anne E. , Johns Andrew C. , Jovanovic Marko , McDermott Ann E. , Keedy Daniel A. , Shah Neel H. 
Published: December 2024

AbstractThe rapid identification of protein–protein interactions has been significantly enabled by mass spectrometry (MS) proteomics‐based methods, including affinity purification‐MS, crosslinking‐MS, and proximity‐labeling proteomics. While these methods can reveal networks of interacting proteins, they cannot reveal how specific protein–protein interactions alter protein function or cell signaling. For instance, when two proteins interact, there can be emergent signaling processes driven purely by the individual activities of those proteins being co‐localized. Alternatively, protein–protein interactions can allosterically regulate function, enhancing or suppressing activity in response to binding. In this work, we investigate the interaction between the tyrosine phosphatase PTP1B and the adaptor protein Grb2, which have been annotated as binding partners in a number of proteomics studies. This interaction has been postulated to co‐localize PTP1B with its substrate IRS‐1 by forming a ternary complex, thereby enhancing the dephosphorylation of IRS‐1 to suppress insulin signaling. Here, we report that Grb2 binding to PTP1B also allosterically enhances PTP1B catalytic activity. We show that this interaction is dependent on the proline‐rich region of PTP1B, which interacts with the C‐terminal SH3 domain of Grb2. Using NMR spectroscopy and hydrogen‐deuterium exchange mass spectrometry (HDX‐MS) we show that Grb2 binding alters PTP1B structure and/or dynamics. Finally, we use MS proteomics to identify other interactors of the PTP1B proline‐rich region that may also regulate PTP1B function similarly to Grb2. This work presents one of the first examples of a protein allosterically regulating the enzymatic activity of PTP1B and lays the foundation for discovering new mechanisms of PTP1B regulation in cell signaling.
The structural influence of the oncogenic driver mutation N642H in the STAT5B SH2 domain
Authors: Haas‐Neill Liam , Meneksedag‐Erol Deniz , Chaudhry Ayesha , Novoselova Masha , Ashraf Qirat F. , de Araujo Elvin D. , Wilson Derek J. , Rauscher Sarah 
Published: December 2024

AbstractThe point mutation N642H of the signal transducer and activator of transcription 5B (STAT5B) protein is associated with aggressive and drug‐resistant forms of leukemia. This mutation is thought to promote cancer due to hyperactivation of STAT5B caused by increased stability of the active, parallel dimer state. However, the molecular mechanism leading to this stabilization is not well understood as there is currently no structure of the parallel dimer. To investigate the mutation's mechanism of action, we conducted extensive all‐atom molecular dynamics simulations of multiple oligomeric forms of both STAT5B and STAT5BN642H, including a model for the parallel dimer. The N642H mutation directly affects the hydrogen bonding network within the phosphotyrosine (pY)‐binding pocket of the parallel dimer, enhancing the pY‐binding interaction. The simulations indicate that apo STAT5B is highly flexible, exploring a diverse conformational space. In contrast, apo STAT5BN642H accesses two distinct conformational states, one of which resembles the conformation of the parallel dimer. The simulation predictions of the effects of the mutation on structure and dynamics are supported by the results of hydrogen‐deuterium exchange (HDX) mass spectrometry measurements carried out on STAT5B and STAT5BN642H in which a phosphopeptide was used to mimic the effects of parallel dimerization on the SH2 domain. The molecular‐level information uncovered in this work contributes to our understanding of STAT5B hyperactivation by the N642H mutation and could help pave the way for novel therapeutic strategies targeting this mutation.
A Phase I Dose‐Finding Design Incorporating Intra‐Patient Dose Escalation
Authors: Guo Beibei , Liu Suyu 
Published: December 2024

ABSTRACTConventional Phase I trial designs assign a single dose to each patient, necessitating a minimum number of patients per dose to reliably identify the maximum tolerated dose (MTD). However, in many clinical trials, such as those involving pediatric patients or patients with rare cancers, recruiting an adequate number of patients can pose challenges, limiting the applicability of standard trial designs. To address this challenge, we propose a new Phase I dose‐finding design, denoted as IP‐CRM, that integrates intra‐patient dose escalation with the continual reassessment method (CRM). In the IP‐CRM design, intra‐patient dose escalation is allowed, guided by both individual patients' toxicity outcomes and accumulated data across patients, and the starting dose for each cohort of patients is adaptively updated. We further extend the IP‐CRM design to address carryover effects and/or intra‐patient correlations. Due to the potential for each patient to contribute multiple data points at varying doses owing to intra‐patient dose escalation, the IP‐CRM design offers the advantage of determining the MTD with a considerably reduced sample size compared to standard Phase I dose‐finding designs. Simulation studies show that our IP‐CRM design can efficiently reduce sample size while concurrently enhancing the probability of identifying the MTD when compared with standard CRM designs and the 3 + 3 design.
Fractional Approach for Diffusion Equations Arising From Oil Pollution Using the Fractional Natural Decomposition Method
Authors: Düşünceli Faruk , Çelik Ercan 
Published: December 2024

ABSTRACTThe main goal is to use the fractional natural decomposition approach to solve diffusion equations related to oil pollution. We examine a model that depicts the evolution of chemical processes in a network that burns helium. Elegant consolidations of nature transform with Adomian decomposition method are made possible by the Caputo operator with fractional order taken into consideration and hired algorithm. We looked at the expected model in a different sequence using fraction to show the expected algorithm's proficiency. Moreover, plots for various arbitrary orders have taken use of the physical characteristics of the obtained results. The obtained findings verify that the algorithm under consideration is highly efficient, methodical, straightforward to use, and accurate in examining the characteristics of the fractional differential system connected to related fields.
Time Dependent Clinical Predictive Model of Maternal Complications, Based on Placental Angiogenic Biomarkers: A Prospective Multicenter Study
Authors: Di Martino Daniela D. , Sabattini Elisa , Giardini Valentina , Tine Gabriele , Sterpi Vittoria , Lonardoni Maria Chiara , Acampora Eleonora , Zaccone Elena , Radaelli Tatjana , Ossola Manuela W. , Vergani Patrizia , Ferrazzi Enrico , Stampalija Tamara 
Published: December 2024

ABSTRACTObjectiveTo develop a prediction model for maternal adverse outcomes in high‐risk pregnant populations based on clinical history, biophysical parameters, and placental angiogenic biomarkers.DesignProspective, observational, and multicenter study.SettingTwo university hospitals in Northern Italy.PopulationWomen affected by hypertensive disorder of pregnangy (HDP) and/or foetal growth restriction (FGR).MethodsFms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF) were measured at recruitment. First, the whole cohort was stratified according to sFlt‐1/PlGF ratio risk categories. Second, the Cox Model was adapted with sFlt‐1/PlGF ratio integrated as a continuous variable together with demographic, clinical and biophysical risk factors to develop a prediction model for the maternal adverse outcomes (severe pre‐eclampsia, HELLP syndrome, abruptio placenta and liver haematoma).ResultsWe recruited 335 consecutive singleton high‐risk pregnancies (109 with HDP, 95 with HDP‐FGR, and 131 with FGR). Seventy‐one of these developed severe‐pre‐eclampsia, 11 suffered from placental abruption and seven developed HELLP syndrome. At survival analysis, the probability to develop adverse outcomes was significantly different between patients with medium (38–85, 38–110) to very high (> 85/110) sFlt‐1/PlGF ratio compared to those with low sFlt‐1/PlGF ratio (< 38). The Cox multivariable clinical model was significantly associated with maternal complications: the area under the curve was 89.5% after 1 week, 93.8% after 2 weeks, 93.7% after 4 weeks and 96.1% after 8 weeks.ConclusionsIn a cohort of women with HDP and/or FGR, a prediction model, based on demographic, clinical, biophysical risk factors and sFlt‐1/PlGF ratio, can predict the risk of developing maternal complications from the time at diagnosis and up to 1, 2, 4, and 8 weeks. The inclusion of sFlt‐1/PlGF ratio, as a continuous variable, significantly improved the risk prediction.
Adaptive Fuzzy Fault‐Tolerant Control for CSTR With State Constraints Dependent on Temperature and Concentration
Authors: Ma Yinqiao , Liu Lei , Li Dapeng , Li Dongjuan 
Published: December 2024

ABSTRACTThe indispensable experimental equipment of the continuous stirred tank reactor (CSTR) is crucial in chemical production processes. This paper presents a novel adaptive state‐dependent constraint control method for nonlinear CSTR system. The CSTR system is transformed into the nonlinear system with a pure feedback structure begins with the mean value theorem. Subsequently, the Fuzzy logic systems (FLS) is used to approximate unknown dynamics. Reactant concentration and mixture temperature are crucial variables in CSTR system. When these variables surpass the specified constraints, it can lead to a decrease in product quality and yield. The constraint boundaries considered in this paper are dependent on both state and time. Therefore, the time‐varying asymmetric Barrier Lyapunov Function (BLF) is proposed to deal with state‐dependent constraints. Additionally, the actuator fault is resolved in this paper, by considering fault‐tolerant control strategy. Lyapunov stability analysis shows that all signals in a closed‐loop system are bounded. Finally, the effectiveness of the control scheme is verified by the simulation of CSTR system.
Frequency Shaping for Improving a Trade‐Off Between Control and Privacy Performance: Beyond Differential Privacy
Authors: Watanabe Rintaro , Kawano Yu , Wada Nobutaka , Cao Ming 
Published: December 2024

ABSTRACTIn privacy protection of control systems, a trade‐off between control performance and privacy level is often pointed out. Our goal in this paper is to improve this trade‐off by shaping the frequency of noise added for privacy protection when the control objective is to track a reference signal, which is taken as a piece of information whose privacy needs to be preserved. Frequency shaping of noise is achieved by passing it through a filter, thus generating noise via a dynamical system. To deal with such noise in privacy analysis, we provide a novel condition related to differential privacy, which shows that differential privacy is less effective in evaluating privacy performance in the frequency domain. To demonstrate privacy protection using frequency information, we discuss filter design in terms of the power spectrum of an estimation of private information, enabling us to obscure its power spectrum in order to preserve privacy. Furthermore, taking control performance into account, we formulate filter design to balance the trade‐off as a standard control problem. The effectiveness of the proposed method, compared with simply adding i.i.d. noise, is illustrated by numerical simulation.
A Unified Topological Representation for Robotic Fleets in Agricultural Applications
Authors: Das Gautham , Cielniak Grzegorz , Heselden James , Pearson Simon , Duchetto Francesco Del , Zhu Zuyuan , Dichtl Johann , Hanheide Marc , Fentanes Jaime Pulido , Binch Adam , Hutchinson Michael , From Pal 
Published: December 2024

ABSTRACTAgricultural robots offer a viable solution to the critical challenges of productivity and sustainability of modern agriculture. The widespread deployment of agricultural robotic fleets, however, is still hindered by the overall system's complexity, requiring the integration of several nontrivial components for the operation of each robot but also the orchestration of robots working with each other and human workers. This paper proposes a topological map as the unifying representation and computational model to facilitate the smooth deployment of robotic fleets in agriculture. This topological abstraction of the system state (probabilistic estimates of the functional states and locations of the agents in the environment abstracted to the topological map representations—e.g., human picker at a node and robot traversing on edge ) results in an efficient representation of large‐scale environments (in many hectares), but also offers the scalable and efficient operation of the entire fleet and allows for ex situ modeling and analysis of operations. The practical use of the proposed framework is demonstrated in a horticultural use case with a fleet of robots supporting the work of human fruit pickers. The critical components of the system are analyzed and evaluated in deployment in both realistic digital twin and real‐life soft fruit farms of different scales, demonstrating the scalability and effectiveness of the proposed framework. The presented framework is general and should be easy to adopt in other multirobot/multihuman scenarios, such as warehouse logistics, cleaning, and maintenance of public spaces.
Political and Institutional Dynamics of Global Female Labor Force Participation: Discovering the Role of Women Political Participation
Authors: Saha Tanaya , Singh Prakash 
Published: December 2024

ABSTRACTThe global nonattainment of the Sustainable Development Goal (SDG) 5 indicates the issue of rising gender inequality. The educated women shying away from the labor force is worsening it. The institutional and political dynamics of an economy might shape the female labor force participation. A gender‐inclusive policy environment involving these factors should drive the educated women in joining the labor force. The female political representation might shape this policy dynamics. However, the absence of a benchmark policy framework is restraining the realization of this objective. The present study has attempted to develop this policy framework by analyzing the aforesaid dynamics across 125 countries over 1990–2020. The study outcomes obtained via elasticity modeling show that realigning the institutional and political dynamics is necessary to ensure the labor force participation of educated women. The women political participation is found to catalyze this policy objective. The study outcomes are utilized to develop a policy framework for attaining the objectives of SDG 5.
Computational and Spectroscopic Study of Newly Synthesized Bio‐Active Azo Dyes: DFT, Solvatochromism, and Preferential Solvation
Authors: U. Renuka , Nehal Subhani Khanam , N. M. Mallikarjuna , K. Vibha , S. M. Arun Kumar , H. M. Suresh Kumar , Javuku Thipperudrappa 
Published: December 2024

AbstractThe computational, solvatochromism, and preferential solvation studies have been carried out on newly synthesized bio‐active azo dye molecules, namely 5‐[(E)‐(1,5‐dimethyl‐3‐oxo‐2‐phenyl‐2,3‐dihydro‐1H‐pyrazol‐4‐yl)diazenyl]‐6‐hydroxy‐4‐methyl‐2‐oxo‐1,2‐dihydropyridine‐3‐carbonitrile (A1) and 5‐[(E)‐(1,5‐dimethyl‐3‐oxo‐2‐phenyl‐2,3‐dihydro‐1H‐pyrazol‐4‐yl)diazenyl]‐6‐hydroxy‐1,4‐dimethyl‐2‐oxo‐1,2‐dihydropyridine‐3‐carbonitrile (A2). The electronic properties, chemical reactivity, and optical characteristics of the dye molecules have been computed using density functional theory (DFT). These findings suggest that the dye molecules are chemically active and show their suitability in NLO applications. The computations related to light‐harvesting properties have been carried out on the dye molecules. The ADME properties of the dye molecules have been evaluated using SwissADME and PreADMET online tools. The solvatochromic behavior of dye molecules has been investigated using Lippert's and Reichardt's solvent polarity parameters. The dye molecules' dielectric interactions and hydrogen bonding characteristics are analyzed using the Catalan multiple regression approach. The findings of the solvatochromic studies suggest the potentiality of the molecules in polarity sensing applications. Additionally, the solvatochromic data has been exploited to determine the excited state dipole moments using various solvatochromic approaches. The HOMO‐LUMO energy values, absorption wavelengths, light‐harvesting properties, and excited state dipole moments of the synthesized dye molecules indicate their suitability in dye‐sensitized solar cell applications. The preferential solvation studies of dye molecules have been conducted in a DCM–DMSO solvent mixture.
Vilsmeier–Haack Reagent‐Catalyzed C4(sp2)─H Formylation in Thiophene Derivatives: Insights into Unexpected Fluorescence Properties
Authors: Missoum Hadjer , Datoussaid Yazid , Ziani‐Cherif Chewki , Seijas Julio A. , Vázquez‐Tato M. Pilar , Choukchou‐Braham Noureddine 
Published: December 2024

AbstractA simple and efficient method was developed to prepare the novel fluorescent tetra‐substituted thiophene derivatives. This method involves using the Gewald's conditions, followed by the Vilsmeier–Haack–Arnold (VHA) formylation. By judiciously controlling the use of the VHA reagent, we have selectively introduced a formyl group into position 5 of the thiophene. This had a direct impact on its fluorescence properties. The resulting compounds have showed an intense fluorescence in the emission wavelength range of 420–500 nm with a 10−6 M concentration. All new products have been structurally confirmed by spectroscopic data. The structure of compound 2g was confirmed by single‐crystal X‐ray diffraction.
Harnessing ROS Amplification and GSH Depletion Using a Carrier‐Free Nanodrug to Enhance Ferroptosis‐Based Cancer Therapy
Authors: Zhang Huiru , Shan Guisong , Liu Mengyu , Sun Qiuting , Yang Tianhao , Peng Rui , Li Xueqian , Mei Yuxiao , He Xiaoyan , Qiao Lei 
Published: December 2024

AbstractFerroptosis, a non‐apoptotic form of cell death characterized by the production of reactive oxygen species (ROS) and massive accumulation of lipid peroxidation (LPO), shows significant promise in cancer therapy. However, the overexpression of glutathione (GSH) at the tumor site and insufficient ROS often result in unsatisfactory therapeutic efficacy. A multistage, GSH‐consuming, and ROS‐providing carrier‐free nanodrug capable of efficiently loading copper ions (Cu2+), sorafenib (SRF), and chlorogenic acid (CGA) (Cu2+‐CGA‐SRF, CCS‐NDs) is developed to mediate enhanced ferroptosis therapy. Through a reductive intracellular environment, Cu2+ in the CCS‐NDs reacted with intracellular GSH, alleviating the antioxidant capacity of tumor tissues and triggering the release of drugs. Meanwhile, the released SRF inhibited system xc−, thereby blocking cystine uptake and reducing GSH synthesis in tumor cells. By depleting stored GSH and inhibiting its synthesis, CCS‐NDs achieved efficient GSH depletion and increased accumulation of toxic LPO. More importantly, the high concentration of CGA in the CCS‐NDs induced ROS generation, further promoting ferroptosis. Both in vitro and in vivo results demonstrated that CCS‐NDs effectively triggered ferroptosis in tumor cells by inactivating glutathione peroxidase 4 and inducing LPO. Overall, the carrier‐free nanodrug CCS‐NDs offer a promising strategy for regulating GSH and LPO levels in ferroptosis‐based cancer therapy.
Scalable Top‐Down Approach for Recycling Highly Degraded Spent LiFePO4 via Lattice Fragmentation‐Regeneration
Authors: Wang Junwei , Ji Shuaijing , Zhao Yuzhen , Han Qigao , Wang Fengqian , Sha Wuxin , Cheng Danpeng , Zhang Weixin , Tang Shun , Cao Yuan‐Cheng , Cheng Shijie 
Published: December 2024

AbstractDesigning efficient, scalable, and eco‐friendly recycling technologies is crucial for addressing the widespread decommissioning of spent lithium‐ion batteries. Here, an innovative top‐down regeneration method is introduced to rejuvenate highly degraded LiFePO4. Initially, the crystal structure of spent LiFePO4 is destroyed via the oxidation process, followed by the reconstruction of the LiFePO4 lattice through the reduction process. The regenerated LiFePO4 features a uniform particle size and an intact crystal lattice, leading to substantial improvements in electrochemical performance. Specifically, it achieves a capacity of 142.6 mAh g−1 at 1 C, significantly surpassing the spent LiFePO4 (only 55.6 mAh g−1 at 1 C). Furthermore, it demonstrates an exceptional retention of 86.7% after 450 cycles, in contrast to 55.8% retention of commercial LiFePO4. More importantly, spent LiFePO4 with varying degrees of degradation is successfully regenerated using this technology, confirming its scalability. Therefore, this research highlights a transformative and sustainable approach to LiFePO4 regeneration, achieving splendid advancements in both electrochemical performance and cycle stability, and offers a novel pathway for the effective recycling of LiFePO4‐based energy storage systems.