bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of New Chitosan-Based Complex with Bioactive Molecules for Regenerative Medicine
Authors: Maurmann Natasha , Machado Gabriela Moraes , Kasper Rafaela Hartmann , Couto Marcos do , Paz Luan , Oliveira Luiza , Girón Bastidas Juliana , Bottezini Paola Arosi , Notargiacomo Lucas Machado , Ferreira Carlos Arthur , Pighinelli Luciano , Bavaresco Caren Serra , Pranke Patricia , Brew Myrian
Published: December 2024

Background/Objectives: The development of new materials incorporating bioactive molecules for tissue regeneration is a growing area of interest. The objective of this study was to develop a new complex specifically designed for bone and skin tissue engineering, combining chitosan, ascorbic acid-2-magnesium phosphate (ASAP), and β-tricalcium phosphate (β-TCP). Methods: Chitosan and the complexes chitosan/ASAP and chitosan/ASAP/β-TCP were prepared in membrane form, macerated to a particulate format, and then subjected to characterization through Fourier transform infrared (FTIR) spectroscopy, optical and scanning electron microscopy (SEM), zeta potential, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Cell viability was evaluated through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and with fluorescein diacetate (FDA) and propidium iodide (PI) staining in stem cells obtained from deciduous teeth. Statistical analyses were performed using analysis of variance (ANOVA), followed by Tukey’s test. Results: The FTIR results indicated the characteristic bands in the chitosan group and the complexation between chitosan, ASAP, and β-TCP. Microscopic characterization revealed a polydisperse distribution of micrometric particles. Zeta potential measurements demonstrated a reduction in surface charge upon the addition of ASAP and β-TCP to the chitosan matrix. TGA and DSC analyses further indicated complexation between the three components and the successful formation of a cross-linked structure in the chitosan matrix. Stem cells cultured with the particulate biomaterials demonstrated their biocompatibility. Statistical analysis revealed a significant increase in cell viability for the chitosan/ASAP and chitosan/ASAP/β-TCP groups compared to the chitosan control. Conclusions: Therefore, the chitosan/ASAP complex demonstrated potential for skin regeneration, while the chitosan/ASAP/β-TCP formulation showed promise as a biomaterial for bone regeneration due to the presence of β-tricalcium phosphate.
Tunable Alginate-Polyvinyl Alcohol Bioinks for 3D Printing in Cartilage Tissue Engineering
Authors: Aitchison Alexandra Hunter , Allen Nicholas B. , Mitra Kishen , Abar Bijan , O’Neill Conor N. , Bagheri Kian , Anastasio Albert T. , Adams Samuel B.
Published: December 2024

This study investigates 3D extrusion bioinks for cartilage tissue engineering by characterizing the physical properties of 3D-printed scaffolds containing varying alginate and polyvinyl alcohol (PVA) concentrations. We systematically investigated the effects of increasing PVA and alginate concentrations on swelling, degradation, and the elastic modulus of printed hydrogels. Swelling decreased significantly with increased PVA concentrations, while degradation rates rose with higher PVA concentrations, underscoring the role of PVA in modulating hydrogel matrix stability. The highest elastic modulus value was achieved with a composite of 5% PVA and 20% alginate, reaching 0.22 MPa, which approaches that of native cartilage. These findings demonstrate that adjusting PVA and alginate concentrations enables the development of bioinks with tailored physical and mechanical properties, supporting their potential use in cartilage tissue engineering and other biomedical applications.
Analyzing Multi-Generational Gathering and Dispersion to and from Ten 19th-Century American Cities
Authors: Otterstrom Samuel , Selander Jane , Deo Rafael
Published: December 2024

Genealogy, with its tying of people to places, allows for the study of migration over multiple generations. In this paper we use family history data from FamilySearch.org to analyze the migration of the ancestors of those born between 1865 and 1875 in ten United States cities followed by the migration of descendants of people born in the same city during that same decade. Other work has followed the ancestors for multiple generations, and we have added in an examination of the migration of descendants from city origins. We calculate a number of statistics and indices and use maps to illustrate the main spatial themes of these migrations and how they vary among the cities. We find that cities have their own unique mixes of migrants that lead to differences in how often the generations were stable in a community; that descendants of those born in our study cities tended to stay close to the city for some time; that the ancestors of migration funneling into a city were more spread out than the descendants of those born in the city; that migration generally proceeded from east to west from the great-great-grandparents to the children, but that the center of migration was more random for the descendants; and that the distance of migration between ancestral generations was highly affected by the share of European ancestors and the regional location of the city. The value of this approach is that genealogical migration research can examine a large number of historical migration questions within one unified framework, which has not been carried out in other studies.
Heritability and Genome-Wide Association Study of Dog Behavioral Phenotypes in a Commercial Breeding Cohort
Authors: Bhowmik Nayan , Cook Shawna R. , Croney Candace , Barnard Shanis , Romaniuk Aynsley C. , Ekenstedt Kari J.
Published: December 2024

Background: Canine behavior plays an important role in the success of the human–dog relationship and the dog’s overall welfare, making selection for behavior a vital part of any breeding program. While behaviors are complex traits determined by gene × environment interactions, genetic selection for desirable behavioral phenotypes remains possible. Methods: No genomic association studies of dog behavior to date have been reported on a commercial breeding (CB) cohort; therefore, we utilized dogs from these facilities (n = 615 dogs). Behavioral testing followed previously validated protocols, resulting in three phenotypes/variables [social fear (SF), non-social fear (NSF), and startle response (SR)]. Dogs were genotyped on the 710 K Affymetrix Axiom CanineHD SNP array. Results: Inbreeding coefficients indicated that dogs from CB facilities are statistically less inbred than dogs originating from other breeding sources. Heritability estimates for behavioral phenotypes ranged from 0.042 ± 0.045 to 0.354 ± 0.111. A genome-wide association analysis identified genetic loci associated with SF, NSF, and SR; genes near many of these loci have been previously associated with behavioral phenotypes in other populations of dogs. Finally, genetic risk scores demonstrated differences between dogs that were more or less fearful in response to test stimuli, suggesting that these behaviors could be subjected to genetic improvement. Conclusions: This study confirms several canine genetic behavioral loci identified in previous studies. It also demonstrates that inbreeding coefficients of dogs in CB facilities are typically lower than those in dogs originating from other breeding sources. SF and NSF were more heritable than SR. Risk allele and weighted risk scores suggest that fearful behaviors could be subjected to genetic improvement.
Mutant p53-Mediated Tumor Secretome: Bridging Tumor Cells and Stromal Cells
Authors: Qiu Lei , Ma Zelong , Wu Xiaoming
Published: December 2024

The tumor secretome comprises the totality of protein factors secreted by various cell components within the tumor microenvironment, serving as the primary medium for signal transduction between tumor cells and between tumor cells and stromal cells. The deletion or mutation of the p53 gene leads to alterations in cellular secretion characteristics, contributing to the construction of the tumor microenvironment in a cell non-autonomous manner. This review discusses the critical roles of mutant p53 in regulating the tumor secretome to remodel the tumor microenvironment, drive tumor progression, and influence the plasticity of cancer-associated fibroblasts (CAFs) as well as the dynamics of tumor immunity by focusing on both secreted protein expression and secretion pathways. The aim is to provide new insights for targeted cancer therapies.
Automated Snow Avalanche Monitoring and Alert System Using Distributed Acoustic Sensing in Norway
Authors: Turquet Antoine , Wuestefeld Andreas , Svendsen Guro K. , Nyhammer Finn Kåre , Nilsen Espen Lauvlund , Persson Andreas Per-Ola , Refsum Vetle
Published: December 2024

Avalanches present substantial hazard risk in mountainous regions, particularly when avalanches obstruct roads, either hitting vehicles directly or leaving traffic exposed to subsequent avalanches during cycles. Traditional detection methods often are designed to cover only a limited section of a road stretch, hampering effective risk management. This research introduces a novel approach using Distributed Acoustic Sensing (DAS) for avalanche detection. The monitoring site in Northern Norway is known to be frequently impacted by avalanches. Between 2022–2024, we continuously monitored the road for avalanches blocking the traffic. The automated alert system identifies avalanches affecting the road and estimates accumulated snow. The system provides continuous, real-time monitoring with competitive sensitivity and accuracy over large areas (up to 170 km) and for multiple sites on parallel. DAS powered alert system can work unaffected by visual barriers or adverse weather conditions. The system successfully identified 10 road-impacting avalanches (100% detection rate). Our results via DAS align with the previous works and indicate that low frequency part of the signal (<20 Hz) is crucial for detection and size estimation of avalanche events. Alternative fiber installation methods are evaluated for optimal sensitivity to avalanches. Consequently, this study demonstrates its durability and lower maintenance requirements, especially when compared to the high setup costs and coverage limitations of radar systems, or the weather and lighting vulnerabilities of cameras. Furthermore the system can detect vehicles on the road as important supplemental information for search and rescue operations, and thus the authorities can be alerted, thereby playing a vital role in urgent rescue efforts.
Strain Accumulation Along the Eastern Java Back–Arc Thrust System Inferred from a Dense Global Navigation Satellite System Network
Authors: Widjajanti Nurrohmat , Pratama Cecep , Azizi Iqbal Hanun , Yulaikhah Yulaikhah , Abiyyu Muhammad Farhan , Rahman Sheva Aulia , Cahyadi Mokhamad Nur , Aprianti Evi , Prayoga Oktadi
Published: December 2024

The back–arc thrust region in Eastern Java to Flores is significantly influenced by the arc–continent collision between the Australian Plate and the Eastern Sunda Arc, leading to a tectonic regime characterized by high seismic and volcanic hazards. This area has experienced several major earthquakes. However, back–arc thrust in Eastern Java remains absent from significant shallow earthquakes, which might indicate intense deformation. We conducted an analysis using recent and dense Global Navigation Satellite System (GNSS) observations from both continuous and campaign stations to develop a strain rate model and explore the detailed crustal behavior and strain accumulation within the Eastern Java back–arc thrust system. Our findings revealed varying values of compression and extension throughout the region, with compression values ranging from −2.24 to 0.086 μstrain/year. Additionally, we observed that the maximum shear strain rate and dilatation strain rate were within the ranges of 0.0013 to 1.12 μstrain/year and −2.24 to 0.698 μstrain/year, respectively. These findings could facilitate more informed strategies and improve preparedness for future seismic events.
The Relationship Between Reduced Hand Dexterity and Brain Structure Abnormality in Older Adults
Authors: Manelis Anna , Hu Hang , Satz Skye
Published: December 2024

Background: Hand dexterity is affected by normal aging and neuroinflammatory processes in the brain. Understanding the relationship between hand dexterity and brain structure in neurotypical older adults may be informative about prodromal pathological processes, thus providing an opportunity for earlier diagnosis and intervention to improve functional outcomes. Methods: this study investigates the associations between hand dexterity and brain measures in neurotypical older adults (≥65 years) using the Nine-Hole Peg Test (9HPT) and magnetic resonance imaging (MRI). Results: Elastic net regularized regression revealed that reduced hand dexterity in dominant and non-dominant hands was associated with an enlarged volume of the left choroid plexus, the region implicated in neuroinflammatory and altered myelination processes, and reduced myelin content in the left frontal operculum, the region implicated in motor imagery, action production, and higher-order motor functions. Distinct neural mechanisms underlying hand dexterity in dominant and non-dominant hands included the differences in caudate and thalamic volumes as well as altered cortical myelin patterns in frontal, temporal, parietal, and occipital regions supporting sensorimotor and visual processing and integration, attentional control, and eye movements. Although elastic net identified more predictive features for the dominant vs. non-dominant hand, the feature stability was higher for the latter, thus indicating higher generalizability for the non-dominant hand model. Conclusions: Our findings suggest that the 9HPT for hand dexterity might be a cost-effective screening tool for early detection of neuroinflammatory and neurodegenerative processes. Longitudinal studies are needed to validate our findings in a larger sample and explore the potential of hand dexterity as an early clinical marker.
Limitations of Drawdown Doline Development on Mountainous Glaciokarst
Authors: Veress Márton
Published: December 2024

In this study, we look for a relationship between the lack of drawdown dolines and the karren formation taking place on the bare surfaces of glaciokarsts. Along the profiles, the specific width and density of the most common karren such as rinnenkarren, grikes, and pits were studied, while in three mapped areas, the depth and depth change in rinnenkarren were investigated in various environments. Mainly, carbonate dissolution of a low degree takes place at atmospheric CO2. Therefore, in the case of carbonate dissolution taking place on the bare surfaces of glaciokarsts, the chance of cavity formation in the epikarst is analysed at karren of percolation origin (grike, pit) and at karren of flow origin (rinnenkarren). Vertical infiltration and local cavity formation are only possible at pits (the CO2 quantity increases due to the soil effect in them). Therefore, below the bare surfaces of glaciokarsts, as a result of low dissolution capacity and infiltration of low degree, there is no cavity formation, or it is weakly developed. The piezometric surface is absent or it is local, its surface is not deflected. Drainage is not heterogeneous, but it is local, which does not favour drawdown doline development since drawdown dolines develop in the case of epikarst with well-developed, heterogeneous cavitation and deflected piezometric surface.
“Vill ‘Hem’, Men Vet ej var Hemmet Ligger”: Migration and the Aesthetics of Estrangement in Verner von Heidenstam’s Formative Art and Prose
Authors: Brandsma Elliott J.
Published: December 2024

This essay argues that Nobel laureate Verner von Heidenstam’s campaign against naturalist aesthetics in late nineteenth-century Swedish literature was motivated, in part, by the sense of estrangement he developed from Swedish cultural life during his adolescent years as a migrant. It also contends that the aesthetic discontent he experienced in his early career foreshadowed a wider sense of alienation from place and nation that would accompany the rise of globalization and normalized migration in the twentieth century. While recent scholarship on Heidenstam’s early oeuvre situates the writer’s bibliography within the fin de siècle, this project refocuses the discussion on the contemporaneous artistic debates Heidenstam addresses in his polemic Renässans, as well as the migratory themes he explores in his 1892 novel, Hans Alienus. This approach illuminates how Heidenstam’s youthful quest for aesthetic reinvention upended the notion that artists and writers can be tethered to singular points of origin, offering new pathways for understanding the emergence of a distinct migrant literature and visual art in Sweden. Although Heidenstam’s later works took a sharp nationalistic turn and have receded from popular consciousness in contemporary times, reexamining his earliest paintings and prose as products of a migrant imagination can help scholars more firmly affix his legacy to modern and Modernist traditions, inviting fresh perspectives on his paradigm-shifting aesthetic of estrangement.
Self-Reported Dyspnea Is Associated with Reduced Health-Related Quality of Life in Quaternary Hospital Workers 1 Year Post Mild COVID-19 Infection
Authors: Macedo Junior Humberto Batista de , Mediano Mauro Felippe Felix , Kasal Daniel Arthur Barata
Published: December 2024

Background/Objectives: The COVID-19 pandemic had significant implications for healthcare workers (HWs), especially those that work in hospitals. This study evaluated health related quality of life (HRQOL) and its relationship with dyspnea approximately one year after COVID-19 infection in HWs. Methods: HWs with previous COVID-19 infections were interviewed, and the EuroQol five-dimensional three-level questionnaire (EQ-5D-3L) with a visual analog scale (VAS) was used to evaluate HRQOL. Self-reported clinical and sociodemographic data were also obtained. Data were stratified by the presence of self-reported dyspnea in the moment of the study interview. The association between self-reported dyspnea and HRQOL was evaluated by regression models, either unadjusted or adjusted for potential confounders (for age and sex, marital status, work category, number of comorbidities, and number of days between diagnosis and evaluation). Results: A total of 109 HWs were interviewed; the median number of days post COVID-19 diagnosis for this group was 400 (IIQ 25–75% 321–428). The majority were women (67.9%); the median age was 44 (IIQ 25–75% 38–52) years. Overall, the median EQ-5D-3L score was 0.79 (IIQ 25–75% 0.74–0.85), and the median VAS score was 80 (IIQ 25–75% 70–90). Self-reported dyspnea was indicated by 22 individuals (20.2%). Self-reported dyspnea was associated with lower EQ-5D-3L and VAS scores, both in adjusted and non-adjusted models. In addition, self-reported dyspnea was associated with more problems in carrying out usual activities in both the non-adjusted and adjusted models (p < 0.01). Conclusions: Our results underscore the long-term implications of COVID-19, based on persistent perceptions of self-reported dyspnea and its relationship with HRQOL in HWs. Future studies, with extended follow-up and the employment of cardiopulmonary and mental health testing, may help to elucidate the nature and extent of COVID-19 sequelae.
Trends in Avoidable Hospitalizations for Heart Failure in Switzerland (1998–2018): A Cross-Sectional Analysis
Authors: Gaillard Lionel , Maung Ko Ko , Mauron Charlène , Marques-Vidal Pedro , Gouveia Alexandre
Published: December 2024

Background/Objectives: Timely and appropriate outpatient care can prevent potentially avoidable hospitalizations (PAHs) for heart failure (HF). We analyzed the trends, determinants, and consequences of PAHs for HF in Switzerland over two decades.; Methods: Hospital discharge data of Switzerland from 1998 to 2018 were utilized. PAH was defined according to the Organization for Economic Cooperation and Development (OECD) criteria.; Results: Data from 206,000 PAHs for HF were included (49.1% women, 55.8% aged over 80). Admission rates for PAHs represented 54.5 per 10,000 admissions in 1999, and they increased to 117.6 per 10,000 admissions in 2018. Similarly, age-standardized admission rates were 107.8 per 100,000 inhabitants in 1999, and they increased to 220.7 per 100,000 inhabitants in 2018. Between 1999 and 2018, patients admitted with PAHs for HF became older (% of patients aged over 80: 60.4% in 2018 vs. 49.2% in 1999), presented more frequently with a Charlson index < 4 (65% vs. 35%), were admitted more frequently as an emergency (89.0% vs. 60.7%), by the patient’s own initiative (31.5% vs. 13.9%), while ICU admission increased only slightly (8.6% vs. 7.6%) and length of stay decreased—median and (interquartile range) 8 (6–13) vs. 12 (8–18) days. In 2018, the costs related to PAHs for HF were estimated at over CHF 170 million, and the corresponding number of occupied beds at 407 per year; Conclusions: In Switzerland, the number of PAHs for HF has increased steadily. The medical and financial burden due to PAH for HF could still be reduced with timely and appropriate outpatient care.
Alloantibody Identification: The Importance of Temperature, Strength Reaction and Enzymes—A Practical Approach
Authors: Manduzio Palma
Published: December 2024

Red blood cell (RBC) alloimmunization and antibodies formation against non-self antigens on red cells may occur after blood transfusion, pregnancies or other exposures. The RBC alloimmunization rate varies from 2% to 6% according to recent studies. The antibody screen is performed to identify or confirm the presence of antibodies in patient’s serum or plasma, as a preoperative or pretransfusion test. The antibody identification process and major crossmatch are critical steps of risk management in transfusion medicine. The aim of this article is to describe a flow chart of the antibody identification. I report three educational examples of case studies associated with the negative direct antiglobulin test and clinically significant single and multiple alloantibodies using the gel method, Anti-M, Anti-c and Anti-E, Anti-Jka and Anti-s. Furthermore, I provide a critical analysis of the current literature on the topic. The flow chart of the antibody identification may simplify the process and possibly reduce errors in routine workflow.
Association Between Lead Exposure and Red Blood Cell Folate Concentrations in U.S. Children Aged 2–17 Years: An Analysis of Data from NHANES 2007–2018
Authors: Hu Wenping , LeBlanc Tanya Telfair , Ruckart Perri Zeitz , Brooks-Griffin Quanza Shavonne , Allwood Paul
Published: December 2024

The objective of this study is to evaluate the impact of low blood lead levels (BLLs) on the red blood cell folate concentrations in U.S. children aged 2–17 years. All data were obtained from the National Health and Nutrition Examination Survey (NHANES) over six consecutive cycles from 2007–2008 to 2017–2018. A total of 12,739 children with BLLs lower than 10 µg/dL (geometric mean: 0.66 µg/dL) were included in the dataset. BLLs were categorized into three tertiles (tertile 1: <0.55 µg/dL; tertile 2: 0.55–0.95 µg/dL; and tertile 3: ≥0.95 µg/dL). The multivariate linear regression model analysis indicates a negative relationship between BLLs and red blood cell folate concentrations. After adjusting for potential confounding factors, red blood cell folate concentrations were lower in children in the BLL tertile 2 (β-coefficient = −0.0450; 95% CI: −0.0676, −0.0224) and BLL tertile 3 groups (β-coefficient = −0.0775; 95% CI: −0.1032, −0.0517) compared to children in the BLL tertile 1 group. When stratified by age, gender, and race/Hispanic origin, the subgroup analysis consistently revealed a negative relationship between BLLs and red blood cell folate concentrations, with red blood cell folate concentrations being lower (p < 0.05) in children in the BLL tertile 3 group compared to children in the tertile 1 group. Further investigation is needed to explore the mechanism underlying the potential relationship between BLLs and red blood cell folate concentrations and determine whether folate plays an active role beneficial for preventing the harmful effects of lead on children.
Virtual Care Appointments and Experience Among Older Rural Patients with Chronic Conditions in New South Wales: An Analysis of Existing Survey Data
Authors: Price Eloise A. B. , Hamiduzzaman Mohammad , McLennan Vanette , Williams Christopher , Flood Victoria
Published: December 2024

This retrospective, descriptive study, conducted in 2024, analysed Virtual Care Survey (2020–2022) data of patients’ self-reported reflections on use and experiences to investigate relationships between demographics, the number of chronic conditions, and virtual care use among older rural patients (≥65 years with at least one chronic condition) living in New South Wales, and their satisfaction with virtual care. Associations between categorical variables were assessed using chi-squared tests, and Kruskal–Wallis tests were used for continuous variables. Qualitative feedback was analysed thematically. The study included 264 patients (median age 74 years; 51.1% women). Most virtual care appointments (65.3%) were for consultations, check-ups, or review of test results. Over one-third (38.3%) of the patients had multimorbidity and were 1.8 times more likely to have five or more virtual care appointments compared to the patients with one chronic condition. The oldest age group (≥80 years) preferred telephone over online mediums (Skype or Zoom) (p < 0.05). Patient satisfaction was high (65.8%), with 60.9% finding virtual care comparable to in-person consultations. Technological issues correlated with more negative experiences (p < 0.05). Key themes were enhanced accessibility and convenience, quality and safety of virtual care, and recommendations for equitable access. Despite positive responses, addressing technological complexities is important for optimising virtual care models for older rural Australians with chronic conditions.
Site Selection of Elderly Care Facilities Based on Multi-Source Spatial Big Data and Integrated Learning
Authors: Zhang Yin , Zhu Junhong , Li Fangyi , Wang Yingjie
Published: December 2024

This study explores a method to improve the site selection for elderly care facilities in an aging region, using Hefei City, China, as the study area. It combines topographic conditions, population distribution, economic development status, and other multi-source spatial big data at a 500 m grid scale; constructs a prediction model for the suitability of sites for elderly care facilities based on integrated learning; and carries out a comprehensive evaluation and feature importance analysis. Finally, it uses trained random forest (RF) and gradient boosting decision tree (GBDT) models to predict preliminary site selection results for elderly care facilities. A second screening that compares three degrees of population aging is conducted to obtain the final site selection results. The results show the following: (1) The comprehensive evaluation indexes of the two integrated learning models, RF and GBDT, are above or below 80% as needed, which is better than the four single learning models. (2) The prediction results of the RF and GBDT models have 87.9% and 78.4% fit to existing elderly facilities, respectively, which indicates that the methods are reasonable and reliable. (3) The results of both the RF and GBDT models indicate that the closest distance to healthcare facilities and the size of the population distribution are the two most important factors affecting the location of elderly care facilities. (4) The results of the preliminary site selection show an overall spatial distribution of higher suitability in the main urban area and lower suitability in the suburban counties. The secondary screening finds that priority needs to be given to the periphery of the main urban area and to Lujiang County and other surrounding townships that have a more serious degree of aging as soon as possible in the site selection of new elderly care facilities.
Schema Retrieval for Korean Geographic Knowledge Base Question Answering Using Few-Shot Prompting
Authors: Lee Seokyong , Yu Kiyun
Published: December 2024

Geographic Knowledge Base Question Answering (GeoKBQA) has garnered increasing attention for its ability to process complex geographic queries. This study focuses on schema retrieval, a critical step in GeoKBQA that involves extracting relevant schema items (classes, relations, and properties) to generate accurate operational queries. Current GeoKBQA studies primarily rely on rule-based approaches for schema retrieval. These predefine words or descriptions for each schema item. This rule-based method has three critical limitations: (1) poor generalization to undefined schema items, (2) failure to consider the semantic meaning of user queries, and (3) an inability to adapt to languages not used in the predefined step. In this study, we present a schema retrieval model by using few-shot prompting on GPT-4 Turbo to address these issues. Using the SKRE dataset, we searched for the best prompt in terms of enabling the model to handle Korean geographic questions across various generalization levels. Notably, this method outperformed fine-tuning in zero-shot scenarios, underscoring its adaptability to unseen data. To our knowledge, this is the first attempt to develop a schema retrieval model for GeoKBQA that purely utilizes a language model and is capable of processing Korean geographic questions.
A Two-Phase and Bi-Level Spatial Configuration Methodology of Shelters Based on a Circular Assignment Model and Evacuation Traffic Flow Allocation
Authors: Zhang Yujia , Chen Wei , Zhong Guangchun , Zhai Guofang , Zhai Wei
Published: December 2024

With the continued recognition of the devastating effects of natural hazards, the construction of shelters has become essential in urban disaster preparedness planning systems. After analyzing the deficiency of the conventional spatial allocation model of shelters and the hierarchy of evacuation assignments, this study proposes a bi-level and two-phase spatial configuration methodology of shelters. The first hierarchy aims to evacuate refugees from demand blocks to both emergency shelters and resident emergency congregate shelters. The second hierarchy aims to transfer refugees from selected shelters in the first hierarchy to resident emergency congregate shelters. Each hierarchy contains two phases of optimizing calculations. The optimization objects for the first phase and second phase are minimizing the number of new shelters and the evacuation time, respectively. A genetic algorithm and exhaustive approach are programmed to determine the solution of the model in the first and second phases, respectively. The evacuation assignment rule is proposed based on the gravity model, which distributes evacuees proportionally to nearby shelters. This study uses the deterministic user equilibrium problem to present the evacuation traffic flow allocation, which improves the scientificity of the location model of shelters. The refuge demands differentiate the population between daytime and nighttime through mobile signaling data and improve the accuracy from the plot scale to the building scale. Using mobile signaling data to differentiate refuge demands between day and night populations enhances the model’s precision. Finally, to validate the proposed methodology, this study selected the main area of Changshu City, Jiangsu Province, China, which has a population of 1.6 million, as a case study area.
Adipose Tissue as a Major Launch Spot for Circulating Extracellular Vesicle-Carried MicroRNAs Coordinating Tissue and Systemic Metabolism
Authors: Diez-Roda Paula , Perez-Navarro Elena , Garcia-Martin Ruben
Published: December 2024

Circulating microRNAs (miRNAs), especially transported by extracellular vesicles (EVs), have recently emerged as major new participants in interorgan communication, playing an important role in the metabolic coordination of our tissues. Among these, adipose tissue displays an extraordinary ability to secrete a vast list of EV-carried miRNAs into the circulation, representing new hormone-like factors. Despite the limitations of current methodologies for the unequivocal identification of the origin and destination of EV-carried miRNAs in vivo, recent investigations clearly support the important regulatory role of adipose-derived circulating miRNAs in shaping the metabolism and function of other tissues including the liver, muscle, endocrine pancreas, cardiovascular system, gastrointestinal tract, and brain. Here, we review the most recent findings regarding miRNAs transported by adipose-derived EVs (AdEVs) targeting other major metabolic organs and the implications of this dialog for physiology and pathology. We also review here the current and potential future diagnostic and therapeutic applications of AdEV-carried miRNAs.
Impact of T Cell Exhaustion and Stroma Senescence on Tumor Cell Biology and Clinical Outcome of Head and Neck Squamous Cell Carcinomas
Authors: Brust Lukas A. , Vorschel Meike , Körner Sandrina , Knebel Moritz , Kühn Jan Philipp , Wemmert Silke , Smola Sigrun , Wagner Mathias , Schick Bernhard , Linxweiler Maximilian
Published: December 2024

Head and neck squamous cell carcinomas (HNSCC) have an overall poor prognosis, especially in locally advanced and metastatic stages. In most cases, multimodal therapeutic approaches are required and show only limited cure rates with a high risk of tumor recurrence. Anti-PD-1 antibody treatment was recently approved for recurrent and metastatic cases but to date, response rates remain lower than 25%. Therefore, the investigation of the immunological tumor microenvironment and the identification of novel immunotherapeutic targets in HNSCC is of paramount importance. In our study, we used tissue samples of n = 116 HNSCC patients for the immunohistochemical detection of the intratumoral and peritumoral expression of T cell exhaustion markers (PD-1, LAG-3, TIM-3) on tumor infiltration leukocytes (TIL), as well as the expression level of stromal senescence markers (IL-8, MMP-3) on tumor-associated fibroblasts. The clinical parameter of the vitamin D serum status as well as the histopathological HPV infection status of the tumor was correlated with the expression rates of the biomarkers and the overall patient survival. An increased peritumoral and intratumoral expression of the biomarkers PD-1 and TIM-3 significantly correlated with improved overall patient survival. A high peritumoral expression of LAG-3 correlated with better overall survival. A positive HPV tumor status correlated with a significantly elevated expression of PD-1 and TIM-3. Biomarkers of stromal senescence showed no influence on the patient outcome. However, the vitamin D serum status showed no influence on patient outcomes or biomarker expressions. Our study identified PD-1, LAG-3, and TIM-3 as promising targets of a therapeutic strategy targeting the tumor microenvironment in HNSCC, particularly among HPV-positive patients, where a higher expression of these checkpoints correlated with an improved overall survival. These findings support the potential of antibodies targeting these immune checkpoints to enhance treatment efficacy, especially in the context of bispecific targeting.
Cancer Cell’s Achilles Heels: Considerations for Design of Anti-Cancer Drug Combinations
Authors: Gahramanov Valid , Vizeacoumar Frederick S. , Morales Alain Morejon , Bonham Keith , Sakharkar Meena K. , Kumar Santosh , Vizeacoumar Franco J. , Freywald Andrew , Sherman Michael Y.
Published: December 2024

Loss of function screens using shRNA (short hairpin RNA) and CRISPR (clustered regularly interspaced short palindromic repeats) are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA (Gene Set Enrichment Analysis) and CMAP (Connectivity Map) analyses of multiple published shRNA screens, we identified a core set of pathways that affect responses to multiple drugs with diverse mechanisms of action. This suggests that these pathways represent “weak points” or “Achilles heels”, whose mild disturbance should make cancer cells vulnerable to a variety of treatments. These “weak points” include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junction-related pathways. Therefore, inhibitors of these pathways are expected to sensitize cancer cells to a variety of drugs. This hypothesis was tested by analyzing the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and Akt-mTOR pathways. Indeed, the quantitative evaluation indicates that inhibitors of any of these signaling pathways can synergize with a more diverse set of pharmaceuticals, compared to compounds inhibiting targets distinct from the “weak points” pathways. Our findings described here imply that inhibitors of the “weak points” pathways should be considered as primary candidates in a search for synergistic drug combinations.
Preeclampsia Treatment Aspirin/Clampsilin: Oxidative Stress, sFlt-1/PIGF Soluble Tyrosine Kinase 1, and Placental Growth Factor Monitoring
Authors: Kostadinova-Slavova Denitsa , Petkova-Parlapanska Kamelia , Koleva Irina , Angelova Mariya , Sadi J. Al-Dahwi Rafaah , Georgieva Ekaterina , Karamalakova Yanka , Nikolova Galina
Published: December 2024

The present study aimed to investigate and compare oxidative stress biomarkers and antioxidant enzyme activity in the serum of women at risk of developing preeclampsia (PE) to prevent adverse pregnancy outcomes through early intervention. Changes in soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) levels were measured between 11 and 13 gestational weeks (gw.) before the onset of preeclampsia and its associated complications. This study evaluated the feasibility of the sFlt-1/PlGF biomarker ratio in predicting preeclampsia and adverse pregnancy outcomes, with the goal of preventive therapy with acetylsalicylic acid (150 mg daily), with acetylsalicylic acid (75 mg daily) and Clampsilin. For this purpose, the following were evaluated: (1) the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as parameters of oxidative stress; (2) lipid oxidation; (3) antioxidant enzyme activity; and (4) cytokine production. Analysis of the results showed that pregnant women at risk of preeclampsia had significantly higher levels of ROS, lipid oxidation, and superoxide anion radical (•O2−) levels compared to normal pregnancies. In PE, depleted levels of nitric oxide (NO), impaired NO synthase system (NOS), and reduced antioxidant enzyme activity (p < 0.03) suggest that PE patients cannot compensate for oxidative stress (OS). In conclusion, oxidative stress in PE plays a key role, which arises from placental problems and affects both mother and baby. The groups with acetylsalicylic acid therapy (150 mg and 75 mg) were better affected compared to those on Clampsillin.
Galectin Plasmatic Levels Reveal a Cluster Associated with Disease Aggressiveness and Kidney Damage in Multiple Myeloma Patients
Authors: Carvalho Lidiane Vasconcelos do Nascimento , Assis Reijane Alves , Montenegro Claudio , da Rosa Michelle Melgarejo , Pereira Michelly Cristiny , Pitta Maira Galdino da Rocha , de Melo Rêgo Moacyr Jesus Barreto
Published: December 2024

Multiple myeloma (MM) is a malignant disease characterized by the proliferation of plasma cells, primarily in the bone marrow. It accounts for approximately 1% of all cancers and 10% of hematologic malignancies. Clinical manifestations include hypercalcemia, anemia, renal failure, and bone lesions. The pathogenesis of MM involves complex interactions between myeloma cells and their microenvironment. Galectins, a family of β-galactoside-binding proteins, particularly galectin-1, -3, -4, -7, and -9, have been implicated in MM development. This study aimed to assess the plasma levels of these galectins in newly diagnosed MM patients and explore their correlation with clinical parameters. Peripheral blood samples were collected from patients at the Oncohematology Service of the Hospital de Câncer de Pernambuco, and galectin levels were measured using ELISA. Plasma levels of galectins-3, -7, and -9 were significantly higher in MM patients compared to the control group. Three clusters of MM patients were identified based on galectin plasma levels, with cluster 3, characterized by high levels of galectin-1, -4, and -7, being associated with a worse prognosis. A strong positive correlation was found between galectin-1, -4, and -7 levels and markers of kidney function (urea, creatinine, and β2-microglobulin), while negative correlations were observed with hematocrit and hemoglobin. Additionally, galectin-9 showed high accuracy in distinguishing MM patients from healthy controls (AUC = 0.931). Elevated galectin levels were indicative of disease aggressiveness and renal impairment in MM patients. Overall, our findings suggest that galectins-1, -4, -7, and -9 could serve as potential biomarkers for MM progression and severity, warranting further investigation into their utility in MM diagnosis and treatment.
Metabolomic and Lipidomic Profiling for Pre-Transplant Assessment of Delayed Graft Function Risk Using Chemical Biopsy with Microextraction Probes
Authors: Warmuzińska Natalia , Łuczykowski Kamil , Stryjak Iga , Wojtal Emilia , Woderska-Jasińska Aleksandra , Masztalerz Marek , Włodarczyk Zbigniew , Bojko Barbara
Published: December 2024

Organ shortage remains a significant challenge in transplantology, prompting efforts to maximize the use of available organs and expand the donor pool, including through extended criteria donors (ECDs). However, ECD kidney recipients often face poorer outcomes, including a higher incidence of delayed graft function (DGF), which is linked to worse graft performance, reduced long-term survival, and an increased need for interventions like dialysis. This underscores the urgent need for strategies to improve early DGF risk assessment and optimize post-transplant management for high-risk patients. This study conducted multi-time point metabolomic and lipidomic analyses of donor kidney tissue and recipient plasma to identify compounds predicting DGF risk and assess the translational potential of solid-phase microextraction (SPME) for graft evaluation and early complication detection. The SPME-based chemical biopsy enabled a direct kidney analysis, while thin-film microextraction facilitated high-throughput plasma preparation. Following high-performance liquid chromatography coupled with a mass spectrometry analysis, the random forest algorithm was applied to identify compounds with predictive potential for assessing DGF risk before transplantation. Additionally, a comparison of metabolomic and lipidomic profiles of recipient plasma during the early post-operative days identified metabolites that distinguish between DGF and non-DGF patients. The selected compounds primarily included amino acids and their derivatives, nucleotides, organic acids, peptides, and lipids, particularly phospholipids and triacylglycerols. In conclusion, this study highlights the significant translational potential of chemical biopsies and plasma metabolite analyses for risk assessments and the non-invasive monitoring of DGF. The identified metabolites provide a foundation for developing a comprehensive DGF assessment and monitoring method, with potential integration into routine clinical practice.
Novel Tripeptides as Tyrosinase Inhibitors: In Silico and In Vitro Approaches
Authors: Dymek Michał , Warszycki Dawid , Podlewska Sabina , Sikora Elżbieta
Published: December 2024

Tyrosinase is a key enzyme responsible for the formation of melanin (a natural skin pigment with ultraviolet-protection properties). However, some people experience melanin overproduction, so new, safe, and biocompatible enzyme inhibitors are sought. New tripeptide tyrosinase inhibitors were developed using molecular modeling. A combinatorial library of tripeptides was prepared and docked to the mushroom tyrosinase crystal structure and investigated with molecular dynamics. Based on the results of calculations and expert knowledge, the three potentially most active peptides (CSF, CSN, CVL) were selected. Their in vitro properties were examined, and they achieved half-maximal inhibitory concentration (IC50) values of 136.04, 177.74, and 261.79 µM, respectively. These compounds attach to the binding pocket of tyrosinase mainly through hydrogen bonds and salt bridges. Molecular dynamics simulations demonstrated the stability of the peptid–tyrosinase complexes and highlighted the persistence of key interactions throughout the simulation period. The ability of these peptides to complex copper ions was also confirmed. The CSF peptide showed the highest chelating activity with copper. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay confirmed that none of the test tripeptides showed cytotoxicity toward the reconstructed human epidermis. Our results indicated that the developed tripeptides were non-toxic and effective tyrosinase inhibitors. They could be applied as raw materials in skin-brightening or anti-aging cosmetic products.
Etiology-Dependent Microbiome Differences in Hepatocellular Carcinoma Development
Authors: Todorovic Nevena , Martinelli Serena , Nannini Giulia , Weiskirchen Ralf , Amedei Amedeo
Published: December 2024

Chronic liver disease is characterised by persistent inflammation, tissue damage, and regeneration, which leads to steatosis, fibrosis, and, lastly, cirrhosis and hepatocellular carcinoma (HCC). HCC, the most prevalent form of primary liver cancer, is one of the leading causes of cancer-related mortality worldwide. The gut microbiota plays a fundamental role in human physiology, and disturbances in its critical balance are widely recognised as contributors to various pathological conditions, including chronic liver diseases, both infectious and non-infectious in nature. Growing interest in microbiota research has recently shifted the focus towards the study of intratumoural microbiota, referred to as the “oncobiome”, which can significantly impact the development and progression of HCC. In this review, we discuss existing research and provide an overview of the microbiota influence on viral hepatitis, particularly in shaping the progression of liver disease caused by the hepatitis B and hepatitis C viruses. We also explore microbial dysbiosis and its contribution to the silent and dangerous progression of non-alcoholic fatty liver disease. Additionally, we address the impact of alcohol on the liver and its interaction with the microbiota, tracing the pathway from inflammation to cirrhosis and cancer. The review emphasises the most common etiologies of hepatocellular carcinoma.