bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of Machine Learning‐Based Surrogate Models of Neural Activation Under Electrical Stimulation
Authors: Toni Laura , Pierantoni Luca , Verardo Claudio , Romeni Simone , Micera Silvestro 
Published: December 2024

ABSTRACTElectrical stimulation of peripheral nerves via implanted electrodes has been shown to be a promising approach to restore sensation, movement, and autonomic functions across a wide range of illnesses and injuries. While in principle computational models of neuromodulation can allow the exploration of large parameter spaces and the automatic optimization of stimulation devices and strategies, their high time complexity hinders their use on a large scale. We recently proposed the use of machine learning‐based surrogate models to estimate the activation of nerve fibers under electrical stimulation, producing a considerable speed‐up with respect to biophysically accurate models of fiber excitation while retaining good predictivity. Here, we characterize the performance of four frequently employed machine learning algorithms and provide an illustrative example of their ability to generalize to unseen stimulation protocols, stimulating sites, and nerve sections. We then discuss how the ability to generalize to such scenarios is relevant to different optimization protocols, paving the way for the automatic optimization of neuromodulation applications.
Highly Reliable Organisations and Sustainability Risk Management: Safety Cultures in the Nigerian Oil and Gas Supply Chain Sector
Authors: Egila Ashem Emmanuel , Kamal Muhammad Mustafa , Kumar Mangla Sachin , Rich Nick , Tjahjono Benny 
Published: December 2024

ABSTRACTThis study investigates the environmental consequences of pursuing profits in the oil and gas industry, focusing on Nigeria. It examines the role of top management commitment, safety culture and stakeholder risk prioritisation in the industry. By surveying 441 stakeholders, this study highlights the importance of extensive stakeholder engagement and a systemic supply chain approach in building resilience and shaping sustainable practices. The findings reveal that stakeholder risk perception influences sustainability risk management; however, variations in risk prioritisation between internal and external stakeholders remain a challenge. The study advocates for a paradigm shift and emphasises the crucial role of high‐reliability management in guiding organisations towards effective risk mitigation strategies for the industry's immediate health, communities, environment and future.
Exploring Materiality and Stakeholder Engagement in European Water Utilities' Sustainability Strategies, Organizational Practices, and Reporting
Authors: Giacomini Davide , Rocca Laura , Tonoli Davide 
Published: December 2024

ABSTRACTMateriality is a key principle enabling organizations to determine what information to disclose, serving as both a filtering mechanism and a strategic tool shaped by institutional dynamics. Institutional logics, which inform and legitimize organizational practices, significantly influence accountability and reporting processes, including the application of materiality. Effective water management is essential for sustainable development, making the water industry a key sector for exploring materiality and stakeholder engagement within sustainability strategies. This study explores the integration of the materiality principle, stakeholder engagement, and related organizational practices into the sustainability strategies and reporting of the European water industry between 2020 and 2022. Through content analysis of sustainability reports from 26 European water utilities, the study identifies three primary stakeholder engagement approaches: one‐way communication, dialogic interaction, and multi‐directional dialog. The prevailing trend is a dialogic approach that has evolved over time, though concerns about its relevance and effectiveness remain. Additionally, the study examines disclosed material topics, noting a dominant focus on environmental concerns and health and safety, with economic and governance issues receiving comparatively less attention. It emphasizes the need to improve the materiality process by integrating insights from accounting research into organizational practices and underscores the importance of effective stakeholder engagement for fostering trust and collaboration, particularly in vital sectors like water management. The findings offer valuable perspectives for policymakers, emphasizing the need to design robust mechanisms that promote stakeholder engagement. While progress in this area in recent years is evident, as demonstrated by this research, it must quickly evolve into a fundamental component of effective water management to avoid the risk of becoming merely an organizational façade.
A Clinical Prediction Model for Pathologic Upgrade to Invasive Carcinoma Following Conization of Cervical High‐Grade Squamous Intraepithelial Lesions
Authors: Liu Qiao , Yang Jing , Cheng Hui , Shu Chuqiang , Tang Yi , Zhao Jing 
Published: December 2024

ABSTRACTObjectiveTo explore the risk factors associated with the pathological progression to invasive carcinoma following the conization of cervical high‐grade squamous intraepithelial lesions (HSIL) and to construct a risk prediction model to guide preoperative risk assessment and optimize the selection of surgical approaches.MethodsA retrospective analysis was conducted on the clinical data of 3337 patients who underwent cervical conization for HSIL at Hunan Provincial Maternal and Child Health Care Hospital from December 2016 to March 2022. The patients were categorized into the pathological progression group (398 cases) and the nonprogression group (2939 cases) based on postconization pathology results. Statistical significance factors were selected by least absolute shrinkage and selection operator regression and then multivariate logistic regression was utilized to build predictive models, which were presented as a nomogram and evaluated for discriminability, calibration, and decision curves. The Bootstrap method was utilized for internal validation. A total of 277 patients were enrolled from April 2022 to October 2022 for external validation.ResultsThe percentage of pathologic upgrades to invasive carcinoma following cervical conization was 11.9%. The predictive model included age, contact bleeding symptoms, HPV16/18 infection, HSIL cytology, cervical biopsy pathology diagnosis level, suspicious stromal infiltration in the biopsy pathology diagnosis, and endocervical curettage HSIL. The model demonstrated good overall discrimination in predicting the risk of HSIL progression to early invasive cancer, and internal validation confirmed its reliability (C‐index = 0.787). Area under the curve analysis indicated good model discriminability across external datasets. The decision curve analysis also suggested that this model is clinically useful.ConclusionWe developed and validated a nomogram incorporating multiple clinically relevant variables to better identify cases of HSIL progressing to early cervical cancer, providing a basis for individualized treatment and surgical approach selection.
Efficacy and Safety of Chemotherapy or EGFR‐TKIs as First‐Line Therapy in NSCLC Patients Harboring Non‐Ex 20 Ins Uncommon EGFR Mutations: A Retrospective Study in China
Authors: Liao Chen , Bai Li , He Tingting , Liang Qingle , Hu Defeng , Lei Shipeng , He Yong , Wang Yubo 
Published: December 2024

ABSTRACTBackgroundUncommon EGFR mutations are a kind of heterogeneous group of mutations with various responses to EGFR‐TKIs and are often excluded from most prospective clinical trials. In this real‐world retrospective study, we retrospectively compared the efficacy and safety of chemotherapy or various generations of EGFR‐TKIs as first‐line therapy in NSCLC Chinese patients harboring non‐ex 20 ins uncommon EGFR mutations.MethodsWe enrolled 139 NSCLC patients with non‐ex 20 ins uncommon EGFR mutations in this study retrospectively. Patients' clinical characteristics and the efficacy and safety of different first‐line therapies were analyzed and compared.ResultsOur data reviewed that for first‐line therapy, NSCLC patients harboring non‐ex 20 ins uncommon EGFR mutations benefited more from EGFR‐TKIs compared with chemotherapy. Afatinib performed with great efficacy for the majority of non‐ex 20 ins uncommon EGFR mutations (N = 43, ORR = 41.86%, mPFS = 13.5 months, mOS = 20.8 months), especially in L861Q mutation (mPFS = 18.4 months). Osimertinib also demonstrated efficacy in patients harboring non‐ex 20 ins uncommon EGFR mutations (N = 36, ORR = 27.78%, mPFS = 10.0 months, mOS = 21.0 months), especially in those without L861Q and G719X mutations (mPFS = 12.1 months). When treated with afatinib, patients harboring non‐ex 20 ins uncommon EGFR mutations should pay attention to the management of safety, especially for gastrointestinal‐related AE and rash, while osimertinib was safer.ConclusionTaking into account both efficacy and safety, afatinib and osimertinib are better choices than chemotherapy and first‐generation EGFR‐TKIs for NSCLC patients with non‐ex 20 ins uncommon EGFR mutations. L861Q showed a trend toward a better response to afatinib, while in those without L861Q and G719X mutations, osimertinib might be a better choice. Safety also should be a concern when choosing EGFR‐TKI for treatment, patients should pay attention to the management of safety when using afatinib while osimertinib is safer.
Phase I Trial of Upamostat Combined With Gemcitabine in Locally Unresectable or Metastatic Pancreatic Cancer: Safety and Preliminary Efficacy Assessment
Authors: Lai Xiuping , Cheng Di , Xu Huixin , Wang Jingshu , Lv Xiaozhi , Yao Herui , Li Liuning , Wu Junyan , Ye Suiwen , Li Zhihua 
Published: December 2024

ABSTRACTAimThis study aimed to determine the maximum tolerated dose (MTD) of the urokinase plasminogen activator (uPA) inhibitor upamostat (LH011) in combination with gemcitabine for locally advanced unresectable or metastatic pancreatic cancer.MethodSeventeen patients were enrolled and received escalating doses of oral LH011 (100, 200, 400, or 600 mg) daily alongside 1000 mg/m2 of gemcitabine. Safety profiles, tumor response (including response rate and progression‐free survival), pharmacokinetics, and changes in CA199 and D‐dimer levels were assessed.ResultsDuring the study period (Day0–Day49), no patients achieved partial response. Stable disease (SD) was observed in 12 patients (70.6%), while four patients (23.5%) experienced progressive disease (PD). One patient withdrew due to a serious adverse event (SAE) on D47. Pharmacokinetic analysis revealed a dose‐related increase in LH011 and its metabolite WX‐UK1 exposure from 100 to 400 mg but not in the 600 mg group. Hematological toxicity, mainly attributable to gemcitabine, was the predominant grade 3 or 4 adverse event, with additional occurrences of loss of appetite, rash, and interstitial lung disease. Sinus bradycardia possibly linked to LH011 rather than gemcitabine was noted. The MTD was not reached.ConclusionCombining LH011 at doses ranging from 100 to 600 mg with gemcitabine every 21 days demonstrated manageable safety and tolerability. However, tumor response did not significantly differ among the dose groups, suggesting the need for further investigation.Trial RegistrationNCT05329597
Hit Selection of Dipeptidyl Peptidase‐4 Inhibitors Bearing Thieno[2,3‐d]Pyrimidine Scaffold
Authors: Pavlović Katarina Tomović , Ilić Budimir S. , Dimov Stefan , Yancheva Denitsa , Mavrova Anelia Ts , Šmelcerović Andrija 
Published: December 2024

ABSTRACTThe thieno[2,3‐d]pyrimidine fragment is in the structure of many drug‐like candidate derivatives with a wide range of biological activities. However, very few dipeptidyl peptidase‐4 (DPP‐4) inhibitors with this building block are currently known. Here, the selection of a novel DPP‐4 inhibitor based on the thienopyrimidine scaffold is reported. In the performed study, ethyl 4‐amino‐5‐methyl‐2‐(3‐(trifluoromethyl)phenyl)thieno[2,3‐d]pyrimidine‐6‐carboxylate (compound 22) demonstrated DPP‐4 inhibitory potential about twice higher than that of the reference inhibitor diprotin A. The manner of inhibition is noncompetitive, a rare type among DPP‐4 inhibitors. The molecular docking highlighted the importance of Ser349, Asn377, Glu378, Phe396, and Asp588 in forming the inhibitor/DPP‐4 complex. Compound 22 might be useful as a source of ideas contributing to the design and further changes and optimizations of thieno[2,3‐d]pyrimidine‐based DPP‐4 inhibitors.
Phytochemical Profiling and Biological Activities of Nigella sativa Vinegar Extract: An Insight Into Hypoglycemic Potential Using In Vivo and In Silico Studies
Authors: Akhtar Muhammad Tahir , Qadir Rahman , Altaf Uzma , Almas Tahira , Batool Sajida , Ikram Muhammad Salman , Meor Hussin Anis Shobirin , Perveen Kahkashan , Alshaikh Najla A. , Saadia Mubshara 
Published: December 2024

ABSTRACTThe current study was conducted to characterize the vinegar extract of Nigella sativa and evaluate its biological activities using in vitro and in vivo studies. The N. sativa extract (NSE) was prepared by macerating seeds in a mixture of water and synthetic vinegar (1:10). The antioxidant potential of NSE was assessed, revealing high total phenolic contents (431.66 mg/100 g), total flavonoid contents (73.45 mg/100 g), total antioxidant capacity (118.55 mg/100 g), and strong radical scavenging potential (89.67%). The anticancer activity of NSE showed insignificant cytotoxic effects on HepG2 liver cell lines (96.61 ± 3.00). An in vivo animal trial was performed, and NSE significantly (p < 0.05) lowered the blood glucose (−47.71%), total cholesterol (−37.86%), total glycerides (39.42%), low‐density lipoproteins (−29.36%), and very low‐density lipoproteins (−30.60%), while increasing the high‐density lipoproteins (26.92%) in alloxan‐induced diabetic rats. GC–MS analysis of NSE revealed a diverse range of bioactive compounds, including alkaloids, phenolics, and flavonoids. In silico studies using molecular docking simulations showed that pyrrolo[1,2‐a] pyrazine‐1,4‐dione, hexahydro‐3‐(2‐methylpropyl) demonstrated a strong inhibitory action (6.6 kcal/mol) against alpha‐amylase enzyme. These findings suggest that NSE is a promising natural remedy for managing diabetes and related metabolic disorders, and its potential as a nutraceutical ingredient in functional food applications is significant.
Inhibition of Clinical Multidrug‐Resistant Pseudomonas aeruginosa Biofilms by Cinnamaldehyde and Eugenol From Essential Oils: In Vitro and In Silico Analysis
Authors: Benaissa Asma , Bouali Wafaa , Ngenge Tamfu Alfred , Ammara Bousselham , Kucukaydin Selcuk , Latti Nawel , Khadir Abdelmounaim , Bendahou Mourad , Anouar El Hassane , Ceylan Ozgur 
Published: December 2024

ABSTRACTPseudomonas aeruginosa causes nosocomial infections and chronic diseases. Cinnamomum cassia and Syzygium aromaticum are used natural antimicrobials. Essential oil (EO) from C. cassia (CCEO) and S. aromaticum (CEO) was characterized using GC‐MS analysis. Eugenol (82.31%), eugenol acetate (10.57%), and β‐caryophyllene (3.41%) were major constituents in CEO while cinnamaldehyde (88.18%), cinnamyl acetate (2.85%) and 2‐methoxy cinnamaldehyde (1.77%) were main components in CCEO. The EOs and major constituents exhibited good antimicrobial activity against clinical strains of P. aeruginosa. Cinnamaldehyde exhibited the best antimicrobial effect with minimal inhibitory concentration (MIC) as low as 0.031% ± 0.07% (v/v) and inhibition zones reaching 30 ± 0.5 mm diameter. Test samples showed antibiofilm activities against two culture types and seven clinical strains of P. aeruginosa at concentrations of 2MIC to MIC/4. CCEO and its major constituent cinnamaldehyde were more active, compared to CEO and its major constituent eugenol. Scanning electron microscopy images showed untreated colonies with well‐developed biofilms while there was significant reduction of biofilms with distorted architecture and cell shrinkage upon treatment with test samples. In silico studies indicated great interactions between the major compounds, eugenol and cinnamaldehyde, with the receptor proteins of P. aeruginosa revealed by negative binding energies. Eugenol and cinnamaldehyde exhibited appreciable druglikeness.
Application of Cas9‐Based Gene Editing to Engineering of Nonribosomal Peptide Synthetases
Authors: Hashimoto Takuya , Suenaga Hikaru , Shin‐ya Kazuo 
Published: December 2024

AbstractEngineering of nonribosomal peptide synthetases (NRPSs) could transform the production of bioactive natural product derivatives. A number of recent reports have described the engineering of NRPSs without marked reductions in yield. Comparative analysis of evolutionarily related NRPSs can provide insights regarding permissive fusion sites for engineering where recombination may occur during evolutionary processes. Studies involving engineering of NRPSs using these recombination sites showed that they have great potential. Moreover, we highlight recent advances in engineering of NRPSs using CRISPR‐associated protein 9 (Cas9)‐based gene editing technology. The use of Cas9 facilitates the editing of even larger biosynthetic gene clusters (BGCs) close to or over 100 kb in size by precisely targeting and digesting DNA sequences at specific sites. This technology combined with growing understanding of potential fusion sites from large‐scale informatics analyses will accelerate the scalable exploration of engineered NRPS assembly lines to obtain bioactive natural product derivatives in high yields.
Molecular Insights into the Heme‐Binding Potential of Plant NCR247‐Derived Peptides
Authors: Vaidya Sonali M. , Rathod Dhruv C. , Ramoji Anuradha , Neugebauer Ute , Imhof Diana 
Published: December 2024

AbstractHeme is involved in many critical processes in pathogenic bacteria as iron acquisition by these microorganisms is achieved by either direct uptake of heme or use of heme‐binding proteins called hemophores. Exploring the underlying mechanisms on a molecular level can open new avenues in understanding the host‐pathogen interactions. Any imbalance of the heme concentration has a direct impact on the bacterial growth and survival. Thus, heme‐regulated proteins that are involved in heme homeostasis poise to be promising targets for research. Similarly, naturally occurring compounds, including cysteine‐rich peptides from either plant secondary metabolites or venom toxins from vertebrates and invertebrates, have been studied for their therapeutic potential. NCR247 is such a cysteine‐rich peptide, known to be crucial for nitrogenase activity in M. truncatula and its symbiotic relation with S. meliloti. NCR247‐derived peptides were suggested to serve as high‐affinity heme‐binding molecules with remarkable heme‐capturing properties. A comprehensive biochemical and computational analysis of NCR247‐derived peptides, however, redefines their heme‐binding capacity and consequently their potential therapeutic role.
Advances in Drug Delivery Systems for Atopic Dermatitis Treatment
Authors: Yang Jingyi , Jin Ling , Li Yuhao , Deng Dan , Miao Yuqing 
Published: December 2024

AbstractAtopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by pruritus and impaired skin barrier function. Advances in drug delivery systems have transformed AD treatment by enhancing drug stability, bioavailability, and targeted delivery. Drug delivery systems such as liposomes, hydrogels, and microneedles enable deeper skin penetration, prolonged drug retention, and controlled release, reducing side effects and treatment frequency. Liposomes improve drug absorption and stability, while hydrogels offer high water content and responsive drug release. Microneedles facilitate painless, localized drug delivery, enhancing patient compliance. These systems address the limitations of traditional therapies like topical corticosteroids and systemic immunosuppressants, which are associated with adverse effects and poor patient adherence. Recent innovations include Janus kinase (JAK) inhibitors and biologics targeting immune pathways, demonstrating significant efficacy in reducing inflammation and symptoms. Drug delivery systems offer a safer, more efficient alternative for delivering these advanced therapies. By improving therapeutic outcomes and patient experience, drug delivery systems represent a crucial advancement in AD management.
Intramolecular Inhibition by Imidazole in Acid‐Catalyzed Hydrolysis of Protected Carbohydrates
Authors: Szaniszló Szebasztián , Csizmadia Imre G. , Jákli Imre , Farkas Viktor , Láng András , Sulyok‐Eiler Máté , Harmat Veronika , Pintér István , Perczel András 
Published: December 2024

AbstractThe present study reveals an unexpected anomaly observed in the acid‐catalyzed hydrolysis of the 5,6‐O‐isopropylidene group in 3‐O‐protected D‐gluco‐ and D‐allofuranose derivatives. Although the removal of the 5,6‐O‐isopropylidene protecting group is typically rapid and quantitative under acidic conditions, an unexpected inhibition of this reaction is observed for the two C3‐epimers, 3‐O‐imidazole sulfonyl moiety. X‐ray data show a two‐faced imidazole ring orientation in the crystal, while solution state NOE data reveal a critical interaction type between the isopropylidene and the imidazole rings. Advanced conformational searches coupled with ab initio molecular modeling illuminate and explain the NMR and kinetic data and lay the groundwork for the most plausible mechanism of this unprecedented inhibition. These results provide valuable insights into the cross‐coupling of carbohydrate O‐protecting groups and shed light on how specific ring orientations and steric effects can trigger the inhibition of an otherwise easily feasible reaction, such as an acid‐catalyzed hydrolysis.
Anodic Activation of Prussian Blue Analog Leads to Highly Active Cobalt‐Doped Nickel (Oxy)Hydroxide for Organic Oxidation Reactions
Authors: Ansari Toufik , Bagchi Debabrata , Ghosh Suptish , Niklas Hausmann Jan , Indra Arindam , Menezes Prashanth W. 
Published: December 2024

AbstractWater‐assisted electrocatalytic oxidation of alcohols into valuable chemicals is a promising strategy to circumvent the sluggish kinetics of water oxidation, while also reducing cell voltage and improving energy efficiency. Recently, transition metal (TM)‐based catalysts have been investigated for anodic alcohol oxidation, but success has been limited due to competition from the oxygen evolution reaction (OER) within the working regime. In this study, NiCo‐based Prussian blue analog (PBA) was electrochemically activated at the anodic potential to produce a Co−Ni(O)OH active catalyst with a nanosheet‐like architecture. This catalyst was further employed for the selective oxidation of benzyl alcohol (PhCH2OH) to benzoic acid (PhCOOH), achieving a 97 % Faradaic efficiency (FE). The electrochemical activity of Co−Ni(O)OH was also compared with hydrothermally prepared CoNi‐LDH, demonstrating that the PBA‐derived Co−Ni(O)OH was more effective.