bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of Nuclear Factor Erythroid 2-Related Factor 2 Transcriptionally Upregulates Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 Expression and Inhibits Ectopic Calcification in Mice
Authors: Tomomi Tomomi , Kanzaki Hiroyuki , Shimoyama Miho , Tohyama Syunnosuke , Ishikawa Misao , Katsumata Yuta , Arai Chihiro , Wada Satoshi , Manase Shugo , Tomonari Hiroshi
Published: July 2024

Calcification plays a key role in biological processes, and breakdown of the regulatory mechanism results in a pathological state such as ectopic calcification. We hypothesized that ENPP1, the enzyme that produces the calcification inhibitor pyrophosphate, is transcriptionally regulated by Nrf2, and that Nrf2 activation augments ENPP1 expression to inhibit ectopic calcification. Cell culture experiments were performed using mouse osteoblastic cell line MC3T3-E1. Nrf2 was activated by 5-aminolevulinic acid and sodium ferrous citrate. Nrf2 overexpression was induced by the transient transfection of an Nrf2 expression plasmid. ENPP1 expression was monitored by real-time RT-PCR. Because the promoter region of ENPP1 contains several Nrf2-binding sites, chromatin immunoprecipitation using an anti-Nrf2 antibody followed by real-time PCR (ChIP-qPCR) was performed. The relationship between Nrf2 activation and osteoblastic differentiation was examined by alkaline phosphatase (ALP) and Alizarin red staining. We used mice with a hypomorphic mutation in ENPP1 (ttw mice) to analyze whether Nrf2 activation inhibits ectopic calcification. Nrf2 and Nrf2 overexpression augmented ENPP1 expression and inhibited osteoblastic differentiation, as indicated by ALP expression and calcium deposits. ChIP-qPCR showed that some putative Nrf2-binding sites in the ENPP1 promoter region were bound by Nrf2. Nrf2 activation inhibited ectopic calcification in mice. ENPP1 gene expression was transcriptionally regulated by Nrf2, and Nrf2 activation augmented ENPP1 expression, leading to the attenuation of osteoblastic differentiation and ectopic calcification in vitro and in vivo. Nrf2 activation has a therapeutic potential for preventing ectopic calcification.
Hub-and-Spoke Network Design Considering Congestion and Flow-Based Cost Function
Authors: Khosravi Shahrzad , Bozorgi Ali , Zahedi-Seresht Mazyar
Published: July 2024

This paper presents a model for a “hub-and-spoke network design considering congestion and flow-based cost function”. The number of hubs and spokes is unknown, and the objective is to minimize the cost (including the transportation cost, lost demand, and facility setup cost). In the post-pandemic era, it is expected to have government-imposed restrictions on the congestion of airports, as a measure of health and safety. Unlike the current literature which considers a monetary penalty for congestion, we consider congestion as an externally imposed factor, which should be modeled as a constraint. We take a gravity-based modeling approach to obtain the desirability of a facility and calculate the demand matrix of the network. To solve the model, a Benders decomposition approach is proposed. Without the Benders decomposition approach, only instances with up to ten nodes were solved within a reasonable time, but with the Benders decomposition approach, instances with up to forty nodes were solved. A heuristic algorithm is developed to have a mechanism for dealing with larger instances. A set of experiments are conducted using data from the Turkish Network dataset to study various aspects of the proposed formulation and different parameters’ effects on the performance of the model.
Efficacy and Safety Assessment of Topical Omega Fatty Acid Product in Experimental Model of Irritant Contact Dermatitis: Randomized Controlled Trial
Authors: Ivic Magdalena , Slugan Ana , Leskur Dario , Rusic Doris , Seselja Perisin Ana , Modun Darko , Durdov Toni , Bozic Josko , Vukovic Dubravka , Bukic Josipa
Published: July 2024

Contact dermatitis is a common inflammatory skin disease that often requires prescription therapy and is associated with adverse reactions. Omega fatty acids have been recognized for their anti-inflammatory effect and could serve as a safer option in contact dermatitis treatment. Therefore, the aim of this randomized controlled study, conducted at the University of Split School of Medicine, was to evaluate the efficacy and safety of omega fatty acids containing topical products in an experimental model of irritant contact dermatitis. This study was registered with ClinicalTrials (NCT06189144) and is closed. The primary outcomes were levels of transepidermal water loss, skin hydration, and skin erythema, all measured using an MPA6 device in 25 healthy participants. A significant difference was observed between the hydration values of the intervention (45.7 ± 12.4) and control groups (31.6 ± 12.3) (p < 0.05) on final measurements (day 10). Moreover, higher erythema levels were observed in participants who were smokers, compared to non-smokers. No adverse drug reactions were observed during the study period. In conclusion, omega fatty acids topical product use shows promise in the treatment of irritant contact dermatitis, and further studies are needed to evaluate efficacy in a larger sample of patients.
A Bibliometric Analysis of Soccer Biomechanics
Authors: Plakias Spyridon , Tsatalas Themistoklis , Mina Minas A. , Kokkotis Christos , Kellis Eleftherios , Giakas Giannis
Published: July 2024

Soccer biomechanics is a field that applies principles of mechanics to improve performance and reduce the risk of injury for soccer players. The purpose of this research is to perform a mapping review of the existing knowledge in the current literature, identify leading researchers and institutions, and explore emerging research topics. After conducting a mini literature review, a bibliometric analysis was carried out using the VOSviewer software. The data imported into VOSviewer was obtained from the Scopus database and included 951 records. The analysis performed included: (a) performance analysis to calculate the number of records per year and the authors with the most citations; (b) science mapping analysis (co-authorship, co-citation, and bibliographic coupling); and (c) clustering analysis through the co-occurrence analysis of author keywords. Our findings highlight a significant growth in research publications on soccer biomechanics over the past few decades, with a notable increase in the number of articles published in high-impact journals. Additionally, the clustering analysis resulted in seven clusters, with each cluster providing valuable insights into different aspects of soccer biomechanics, which clearly reflects the multifaceted nature of the field.
Using Enhanced Representations to Predict Medical Procedures from Clinician Notes
Authors: Móstoles Roberto , Araque Oscar , Iglesias Carlos Á.
Published: July 2024

Nowadays, most health professionals use electronic health records to keep track of patients. To properly use and share these data, the community has relied on medical classification standards to represent patient information. However, the coding process is tedious and time-consuming, often limiting its application. This paper proposes a novel feature representation method that considers the distinction between diagnoses and procedure codes, and applies this to the task of medical procedure code prediction. Diagnosis codes are combined with text annotations, and the result is then used as input to a downstream procedure code prediction task. Various diagnosis code representations are considered by exploiting a code hierarchy. Furthermore, different text representation strategies are also used, including embeddings from language models. Finally, the method was evaluated using the MIMIC-III database. Our experiments showed improved performance in procedure code prediction when exploiting the diagnosis codes, outperforming state-of-the-art models.
Environmental-Impact-Based Multi-Agent Reinforcement Learning
Authors: Alamiyan-Harandi Farinaz , Ramazi Pouria
Published: July 2024

To promote cooperation and strengthen the individual impact on the collective outcome in social dilemmas, we propose the Environmental-impact Multi-Agent Reinforcement Learning (EMuReL) method where each agent estimates the “environmental impact” of every other agent, that is, the difference in the current environment state compared to the hypothetical environment in the absence of that other agent. Inspired by the inequity aversion model, the agent then compares its own reward with that of its fellows multiplied by their environmental impacts. If its reward exceeds the scaled reward of one of its fellows, the agent takes “social responsibility” toward that fellow by reducing its own reward. Therefore, the less influential an agent is in reaching the current state, the more social responsibility is taken by other agents. Experiments in the Cleanup (resp. Harvest) test environment demonstrated that agents trained based on EMuReL learned to cooperate more effectively and obtained 54% (39%) and 20% (44%) more total rewards while preserving the same cooperation levels compared to when they were trained based on the two state-of-the-art reward reshaping methods: inequity aversion and social influence.
Modeling and Parameter Optimization of Multi-Step Horizontal Salt Cavern Considering Heat Transfer for Energy Storage
Authors: Wang Jinchao , Wang Zhiming , Zeng Quanshu , Wang Jun , Li Binwang
Published: July 2024

Horizontal salt caverns represent a prime choice for energy storage within bedded salt formations. Constructing multi-step horizontal salt caverns involves intricate fluid and chemical dynamics, including salt boundary dissolution, cavern development, brine flow, heat transfer, and species transportation. In this paper, the influence of heat transfer and turbulent flow is considered in developing a 3D multi-physics coupled flow model for the construction of multi-step horizontal salt caverns. The feasibility and accuracy of the model are verified by comparisons with the field data of the Volgograd horizontal salt cavern. The effects of turbulent flow and heat transfer on the dissolution process are thoroughly analyzed. By analyzing the characteristics of the flow field, the brine concentration distribution, and cavern expansion, the results indicate a steady rise in cavity brine concentrations throughout the leaching phases, with the previously formed cavities continuing to enlarge during subsequent leaching stages, albeit at a diminishing rate of expansion. Furthermore, the results reveal that a larger injection flow rate results in a larger cavern volume, whereas higher injection concentrations result in smaller cavern volumes. While the step distance has a minimal impact on cavern volume, identifying the optimal step distance remains crucial. This analysis of construction parameters aims to provide valuable insights into the design and engineering practices involved in developing multi-step horizontal salt caverns for energy storage purposes.
Functionality of Muffins Fortified with Apple Pomace: Nutritional, Textural, and Sensory Aspects
Authors: Mureșan Andruța E. , Man Simona , Socaci Sonia A. , Pușcaș Andreea , Tanislav Anda Elena , Pall Emoke , Mureșan Vlad , Cerbu Constantin G.
Published: July 2024

Apple pomace resulting from juice processing and thermal processing (50 °C/12 h and 80 °C/5 h) were optimized in order to obtain apple pomace powders with an organoleptic profile suitable as ingredients in food products. Proximate composition (moisture, titratable acidity, ash, soluble substances, and fat content) was analyzed using ISO standard methods. The Folin–Ciocâlteu method, a DPPH (2,2-Diphenyl-1-picrylhydrazyl) test, and flavonoid determination were used to assess antioxidant potential and bioactive compound contents. Antimicrobial potential and cytotoxic and anti-proliferative potential were also assessed. Aroma was characterized by a volatile compound analysis performed using ITEX/GC-MS for the by-products, the powder, and some muffins developed with the proposed functional ingredient. For the sensory analysis of muffins, the acceptability was evaluated using the hedonic test and texture analysis was done using the CT3 Texture Analyzer. The cytotoxic potential of the methanol extracts of the by-products ranged between 70.42 and 78.80%. The hedonic test revealed that the evaluators highly appreciated the aroma, which was attributed to the volatile compounds responsible for the pleasant aroma. The addition of 20% apple pomace powder led to similar texture and sensory scores to the reference samples.
Free Vibration Analysis of Curvilinearly Tapered Axially Functionally Graded Material Beams
Authors: Burlayenko Vyacheslav N. , Kouhia Reijo , Dimitrova Svetlana D.
Published: July 2024

The study focuses on the free vibration analysis of beams made of axially functionally graded materials (AFGM) with curvilinear variable cross-sections along their length. The beams encompass various shapes, including concave and convex conic sections, with axial material properties varying according to polynomial and exponential laws. The equations of motion are derived using Hamilton’s principle within the framework of Timoshenko beam theory. These governing equations, subjected to various boundary conditions, are solved using the differential transform method (DTM). The proposed solution technique is validated by comparing computed natural frequencies with the existing literature and results obtained using three-dimensional finite element analysis in ABAQUS. The incorporation of material gradients into the beam finite element models was achieved using the user-defined material subroutine (UMAT). Additionally, a comprehensive study is conducted to examine the influence of various factors on the natural frequencies of functionally graded beams. These factors include parameters of material laws, types of variable beam shapes, slenderness ratio, and specific boundary conditions. This study provides a thorough understanding of the modal dynamics of the considered beams, offering valuable insights into the behavior of FGM structures.
Numerical and Theoretical Analyses of Laminated Veneer Lumber Beams Strengthened with Fiber-Reinforced Polymer Sheets
Authors: Bakalarz Michał Marcin , Kossakowski Paweł Grzegorz
Published: July 2024

This study outlines a method of utilizing the finite element method and a simple mathematical model to predict the behavior of laminated veneer lumber (LVL) beams strengthened with composite sheets. The numerical models were created using the Abaqus 2017 software. The LVL was considered as a linearly elastic or elastic–plastic material, factoring in Hill’s yield criterion. The composites were simulated as linearly elastic–ideally plastic materials. The mathematical models were predicated on the methodology of transformed cross-section. The theoretical and numerical outcomes were juxtaposed with previous empirical investigations. The comparison encompassed load-bearing capacity, stiffness, and deformation under peak force. Furthermore, presentations of normal stress maps in the LVL and composite have been illustrated. The derived maps were juxtaposed with the delineations of failure modes. An adequate correlation was identified between the theoretical, numerical, and empirical values in the case of beams reinforced with aramid, glass, and carbon sheets. The relative deviation varied from several to multiple percentages. This technique is not applicable for evaluating load-bearing capacity and deformation when only dealing with sheets with low elongation of rupture. This is a consequence of their premature failure. The proposed models may be utilized by researchers and engineers in the design of reinforcements for timber structures.
Highly Efficient Hybrid Reconfigurable Intelligent Surface Approach for Power Loss Reduction and Coverage Area Enhancement in 6G Networks
Authors: Ahmed Aya Kh. , Al-Raweshidy Hamed S.
Published: July 2024

This paper introduces a novel efficient hybrid reconfigurable intelligent surface (RIS) approach designed to significantly reduce power loss and enhance coverage area in 6G networks. The core innovation of this approach lies in an advanced iterative algorithm introduced as the Hybrid reconfigurable intelligent surface decision-making algorithm (HRIS-DMA) that integrates precise user location data into the RIS configuration process. By dynamically adjusting RIS elements to reflect and direct signals based on real-time user positions, this method minimises signal attenuation and optimises signal propagation. The mechanism driving the performance gains includes precise beamforming and intelligent reflection, continuously refined through iterative updates. This technique ensures robust signal strength and expanded coverage, addressing the challenges of dense and diverse deployment scenarios in 6G networks. The proposed scheme’s application in 6G networks demonstrates substantial improvements in signal quality and network reliability, paving the way for enhanced user experiences and efficient communication infrastructures. This novel approach was tested using MATLAB R2023a, and its performance was evaluated using three downlink scenarios: zero to few, few to moderate, and moderate to many obstacles. The three scenarios show higher coverages than conventional simultaneous transmitting and reflecting reconfigurable intelligent surfaces (STAR-RISs) and base station (BS) handover. Based on the evaluation metrics, the analysis results of the novel HRIS-DMA show 70% less signal power loss, 0.17 μs less system delay, 25 dB and 12 dB channel gain compared with the conventional STAR-RIS and BS handover, respectively, and 95% improvement in the overall system’s efficiency compared to STAR-RIS and 13% compared to BS-BS handover.
BESO and SESO: Comparative Analysis of Spatial Structures Considering Self-Weight and Structural Reliability
Authors: Simonetti Hélio Luiz , Almeida Valério S. , Neves Francisco de Assis das , Azar Sina Zhian , Silva Márcio Maciel da
Published: July 2024

A comparative analysis between Bidirectional Evolutionary Structural Optimization (BESO) and Smoothing-ESO (SESO), simultaneously considering Reliability-Based Topology Optimization (RBTO) and the structure’s self-weight in the case of three-dimensional elasticity, is presented in this study. Due to the important role of the existence of uncertainties in making the structural design more realistic, geometry, volumetric fraction, modulus of elasticity, compliance, and loading are considered random variables with normal probability distribution. When adopting the First Order Reliability Method (FORM), the failure probability is calculated based on the reliability index. Furthermore, considering the influence of self-weight in problems involving large structures in civil engineering, especially in the case of bridges, this makes the optimal configuration more reliable for design. A series of examples are covered to validate the methods presented, showing their efficiency and robustness.
A Multi-Plant Height Detection Method Based on Ruler-Free Monocular Computer Vision
Authors: Tian Haitao , Song Mengmeng , Xie Zhiming , Li Yuqiang
Published: July 2024

Plant height is an important parameter of plant phenotype as one indicator of plant growth. In view of the complexity and scale limitation in current measurement systems, a scaleless method is proposed for the automatic measurement of plant height based on monocular computer vision. In this study, four peppers planted side by side were used as the measurement objects. Two color images of the measurement object were obtained by using a monocular camera at different shooting heights. Binary images were obtained as the images were processed by super-green grayscale and the Otsu method. The binarized images were transformed into horizontal one-dimensional data by the statistical number of vertical pixels, and the boundary points of multiple plants in the image were found and segmented into single-plant binarized images by filtering and searching for valleys. The pixel height was extracted from the segmented single plant image and the pixel displacement of the height was calculated, which was substituted into the calculation together with the reference height displacement to obtain the realistic height of the plant and complete the height measurements of multiple plants. Within the range of 2–3 m, under the light condition of 279 lx and 324 lx, this method can realize the rapid detection of multi-plant phenotypic parameters with a high precision and obtain more accurate plant height measurement results. The absolute error of plant height measurement is not more than ±10 mm, and the absolute proportion error is not more than ±4%.
Computerized Cognitive Training in the Older Workforce: Effects on Cognition, Life Satisfaction, and Productivity
Authors: Milič Kavčič Zdenka , Kavcic Voyko , Giordani Bruno , Marusic Uros
Published: July 2024

Background: The accelerated aging of the world’s population will lead to an increase in the number of older people in the workforce. Computerized Cognitive Training (CCT) is effective in improving cognitive outcomes, but its benefits for older workers remain controversial. We investigate the real-world efficacy of CCT in the workplace, focusing on employees aged 50+ years from a public sector agency. Methods: Case managers (n = 82) were randomized to either an intervention group (24 40 min CCT sessions two times per week) or a waiting list passive control group. Cognitive ability, well-being, job satisfaction, and productivity outcome measures were collected and assessed before and after CCT or the comparable control wait time. Results: Participants undergoing CCT improved on a task of executive functioning (p = 0.04). There was a trend toward a change in work productivity after CCT (p = 0.09), with the control group showing a significant decrease (p = 0.02), while the intervention group remained stable. Conclusions: CCT during office hours has a positive effect on cognition and well-being without affecting productivity among white-collar office workers. CCT could be considered as an intervention to support the older workforce in managing the cognitive and behavioral challenges of changing workplace demands.
Estimation of Particulate Matter (PM10) Over Middle Indo-Gangetic Plain (Patna) of India: Seasonal Variation and Source Apportionment
Authors: Devi Ningombam Linthoingambi , Chandra Yadav Ishwar , Kumar Amrendra
Published: July 2024

Despite extensive research on particulate matter (PM) pollution in India’s Indo-Gangetic Plain (IGP), source apportionment remains challenging. This study investigates the effect of particulate matter (PM10)-associated water soluble inorganic ions (WSIIs) on ambient air concentration across the middle IGP from January to December 2018. Moreover, the seasonal fluctuation and chemical characterization of PM10 were assessed for the year 2018. The results revealed a high concentration of PM10 (156 µg/m3), exceeding the WHO and National Ambient Air Quality Standard (NAAQS) limits. The highest PM10 levels were observed during autumn, winter, summer, and the rainy season. The study identified SO42− and NH4+ as the most common WSIIs, constituting 46% and 23% of the total WSIIs. Source apportionment analysis indicated that street dust, biomass burning, and vehicle and industrial emissions together with secondary formation significantly contributed to IGP’s PM pollution. Additionally, the investigation of air mass back trajectory suggests that air quality in IGP is largely influenced by eastern and western Maritime air masses originated from the Arabian Sea, the Bay of Bengal, Gujarat, Afghanistan, Pakistan, and Bangladesh.
Evaluating the Impact of Increased Heavy Oil Consumption on Urban Pollution Levels through Isotope (δ13C, δ34S, 14C) Composition
Authors: Bučinskas Laurynas , Garbarienė Inga , Mašalaitė Agnė , Šapolaitė Justina , Ežerinskis Žilvinas , Jasinevičienė Dalia , Garbaras Andrius
Published: July 2024

The impact of heavy fuel oil (HFO) on the chemical and isotopic composition of submicron particulate matter (PM1) was investigated. For this purpose, we conducted an analysis of water-soluble inorganic ions (WSIIs) and multiple isotopes (δ34S, δ13C, 14C) of PM1 and SO2 collected during two heating periods: before (2021–2022) and during the use of HFO (2022–2023) in Vilnius, Lithuania. The results showed that the combustion of HFO increased the concentrations of SO2 (by 94%) and PM1-related sulfate (by 30%). It also altered the chemical composition of PM1, with sulfate becoming the predominant component (~40%) of WSIIs. The stable sulfur isotope ratios of SO2 (δ34SSO2) and sulfate (δ34SPM1) shifted significantly to more negative values (δ34SSO2 = 0.4‰, δ34SPM1 = −0.3‰) compared to the previous heating period. Anticorrelation between δ13C and δ34S values indicated increased contributions of 13C-enriched fossil fuel sources (coal and HFO) in EC, although the share of fossil fuels in elemental carbon (EC) slightly decreased during the HFO period. The combustion of HFO affected the concentrations of PM1 chemical components and substantially impacted the isotopic composition and source contributions of sulfate and EC.
Some Results on the Free Poisson Distribution
Authors: Alanzi Ayed. R. A. , Alqasem Ohud A. , Elwahab Maysaa Elmahi Abd , Fakhfakh Raouf
Published: July 2024

Let K+(μi)={Qsiμi,si∈(m0μi,m+μi)}, i=1,2, be two CSK families generated by the nondegenerate probability measures μ1 and μ2 with support bounded from above. Define the set of measures L=K+(μ1)•K+(μ2)={Qs1μ1•Qs2μ2,s1∈(m0μ1,m+μ1)ands2∈(m0μ2,m+μ2)}, where Qs1μ1•Qs2μ2 denotes the Fermi convolution of Qs1μ1 and Qs2μ2. We prove that if L is still a CSK family (that is, L=K+(σ) for some nondegenerate probability measure ()σ), then the probability measures σ, μ1 and μ2 are of the free Poisson type and follow the free Poisson law up to affinity. The same result, regarding the free Poisson measure, is obtained if we consider the t-deformed free convolution t replacing the Fermi convolution • in the family of measures L.
Motor Learning in a Complex Motor Task Is Unaffected by Three Consecutive Days of Transcranial Alternating Current Stimulation
Authors: Wilkins Erik W. , Pantovic Milan , Noorda Kevin J. , Premyanov Mario I. , Boss Rhett , Davidson Ryder , Hagans Taylor A. , Riley Zachary A. , Poston Brach
Published: July 2024

Transcranial alternating current stimulation (tACS) delivered to the primary motor cortex (M1) can increase cortical excitability, entrain neuronal firing patterns, and increase motor skill acquisition in simple motor tasks. The primary aim of this study was to assess the impact of tACS applied to M1 over three consecutive days of practice on the motor learning of a challenging overhand throwing task in young adults. The secondary aim was to examine the influence of tACS on M1 excitability. This study implemented a double-blind, randomized, SHAM-controlled, between-subjects experimental design. A total of 24 healthy young adults were divided into tACS and SHAM groups and performed three identical experimental sessions that comprised blocks of overhand throwing trials of the right dominant arm concurrent with application of tACS to the left M1. Performance in the overhand throwing task was quantified as the endpoint error. Motor evoked potentials (MEPs) were assessed in the right first dorsal interosseus (FDI) muscle with transcranial magnetic stimulation (TMS) to quantify changes in M1 excitability. Endpoint error was significantly decreased in the post-tests compared with the pre-tests when averaged over the three days of practice (p = 0.046), but this decrease was not statistically significant between the tACS and SHAM groups (p = 0.474). MEP amplitudes increased from the pre-tests to the post-tests (p = 0.003), but these increases were also not different between groups (p = 0.409). Overall, the main findings indicated that tACS applied to M1 over multiple days does not enhance motor learning in a complex task to a greater degree than practice alone (SHAM).
Explore the Value of Multi-Parameter MRI in Non-Invasive Assessment of Prognostic Risk and Oxford Classification in Children with IgAN or IgAVN
Authors: Liao Zhouyan , Yuan Guanjie , He Kangwen , Li Shichao , Gao Mengmeng , Liang Ping , Xu Chuou , Zhang Yu , Li Zhen
Published: July 2024

Purpose: To explore the Oxford classification and prognostic risk stratification of the non-invasive evaluation of immunoglobulin A nephropathy (IgAN) or immunoglobulin A vasculitis with nephritis (IgAVN) in children using multiparametric magnetic resonance imaging (MRI). Materials and Methods: Forty-four children diagnosed with IgAN or IgAVN were included. Patients with 80-month risk scores >10% were categorized as the high-risk group, while others constituted the low-risk group. The T2* and apparent diffusion coefficient (ADC) values of the renal cortex and medulla were measured. Clinical and pathological parameters were also assessed. Univariate and multivariate logistic regression analyses were performed to identify the indicators associated with the high-risk group. Receiver operating characteristic (ROC) curves were drawn and the areas under the curve (AUCs) were calculated to evaluate the diagnostic performance variables for differentiating the high-risk group from the low-risk group. Results: Only the T2*Cortex and mean arterial pressure (MAP) were independently reliable in both the univariate and multivariate analyses. The AUCs for differentiating the high-risk group from the low-risk group of T2*Cortex, MAP, and their combination model were 0.907, 0.881, and 0.947, respectively. Conclusions: Multiparametric MRI parameters, especially T2* values, could be used as new biomarkers to provide a new dimension in chronic kidney disease-related research and could play an important role in the non-invasive prognosis of children with IgAN or IgAVN.
Therapeutic Target Identification and Drug Discovery Driven by Chemical Proteomics
Authors: Zou Mingjie , Zhou Haiyuan , Gu Letian , Zhang Jingzi , Fang Lei
Published: July 2024

Throughout the human lifespan, from conception to the end of life, small molecules have an intrinsic relationship with numerous physiological processes. The investigation into small-molecule targets holds significant implications for pharmacological discovery. The determination of the action sites of small molecules provide clarity into the pharmacodynamics and toxicological mechanisms of small-molecule drugs, assisting in the elucidation of drug off-target effects and resistance mechanisms. Consequently, innovative methods to study small-molecule targets have proliferated in recent years, with chemical proteomics standing out as a vanguard development in chemical biology in the post-genomic age. Chemical proteomics can non-selectively identify unknown targets of compounds within complex biological matrices, with both probe and non-probe modalities enabling effective target identification. This review attempts to summarize methods and illustrative examples of small-molecule target identification via chemical proteomics. It delves deeply into the interactions between small molecules and human biology to provide pivotal directions and strategies for the discovery and comprehension of novel pharmaceuticals, as well as to improve the evaluation of drug safety.
The Neurotrophin System in the Postnatal Brain—An Introduction
Authors: von Bohlen und Halbach Oliver , Klausch Monique
Published: July 2024

Neurotrophins can bind to and signal through specific receptors that belong to the class of the Trk family of tyrosine protein kinase receptors. In addition, they can bind and signal through a low-affinity receptor, termed p75NTR. Neurotrophins play a crucial role in the development, maintenance, and function of the nervous system in vertebrates, but they also have important functions in the mature nervous system. In particular, they are involved in synaptic and neuronal plasticity. Thus, it is not surprisingly that they are involved in learning, memory and cognition and that disturbance in the neurotrophin system can contribute to psychiatric diseases. The neurotrophin system is sensitive to aging and changes in the expression levels correlate with age-related changes in brain functions. Several polymorphisms in genes coding for the different neurotrophins or neurotrophin receptors have been reported. Based on the importance of the neurotrophins for the central nervous system, it is not surprisingly that several of these polymorphisms are associated with psychiatric diseases. In this review, we will shed light on the functions of neurotrophins in the postnatal brain, especially in processes that are involved in synaptic and neuronal plasticity.
Mitochondrial Genome-Encoded Long Noncoding RNA Cytochrome B (LncCytB) and Mitochondrial Ribonucleases in Diabetic Retinopathy
Authors: Kumar Jay , Malaviya Pooja , Kowluru Renu A.
Published: July 2024

Aim: Hyperglycemia damages mitochondria and downregulates transcription of mtDNA-encoded genes and the long noncoding RNA LncCytB, causing mitochondrial genomic instability. The genes encoded by mtDNA are transcribed as large polycistronic transcripts, and the 5′ ends of precursor tRNAs are processed by mitochondrial-targeted ribonuclease P (MRPPs). Our aim was to investigate the role of MRPP1 in the downregulation of LncCytB in diabetic retinopathy. Methods: Using human retinal endothelial cells incubated in 20 mM D-glucose for 96 h, the gene expression and mitochondrial localization (immunofluorescence) of MRPP1 and the interaction between MRPP1 and LncCytB (determined by RNA-FISH and RNA immunoprecipitation) were quantified. The results were confirmed in retinal microvessels from streptozotocin-induced diabetic mice and from human donors with documented diabetic retinopathy. Results: Compared to normal glucose, high glucose decreased mRNA and mitochondrial localization of MRPP1 and its interaction with LncCytB. While MRPP1 overexpression prevented glucose-induced decrease in MRPP1–LncCytB interaction, LncCytB expression and mitochondrial damage (reduction in protective nucleoids in mtDNA), MRPP1-siRNA further worsened them. Similar results were obtained from retinal microvessels from diabetic mice and from human donors with diabetic retinopathy. Conclusions: Downregulation of MRPP1 in diabetes suppresses LncCytB transcription, resulting in mitochondrial functional and genomic instability, ultimately leading to the development of diabetic retinopathy. Thus, preventing MRPP1 downregulation has the potential to inhibit retinopathy and prevent the fear of vision loss in diabetic patients.
New Indicator of Arterial Stiffness START—Is There a Prognostic Value of Its Dynamics in Patients with Coronary Artery Disease?
Authors: Sumin Alexey N. , Shcheglova Anna V. , Barbarash Olga L.
Published: July 2024

The aim of the study was to evaluate the prognostic value of the one-year dynamics of the new index START in patients with coronary artery disease after coronary artery bypass grafting (CABG). Methods. Patients with coronary artery disease (n = 196) whose START index was assessed before CABG and one year after surgery. Depending on the dynamics of the stiffness index, three groups of patients were identified: 1st—with a decrease in haSTART (n = 79, 40.3%), 2nd—without dynamics (n = 52, 26.5%), and 3rd. Patients were followed for 10 years, and groups were compared for all-cause death, myocardial infarction, stroke/transient ischemic attack, and a composite endpoint. Results. In the group with an increase in the haSTART index, type D personality was identified more often (53.8%) than in the group without changes in haSTAR (26.9%) or with a decrease in the haSTAR index (34.2%) (p = 0.008). In the long-term follow-up period, death from all causes was significantly more common in the group with an increase in haSTART (33.9%) and in the group without changes in haSTART (23.1%) than in the group with a decrease in haSTART (11.4%, p = 0.005). Patients with an increase in haSTART more often had MACE (death, MI, stroke/TIA)—in 47.7% of cases (p = 0.01), compared with patients with a decrease in haSTART (in 24.1% of cases) and without change in haSTART (by 30.8%). Kaplan–Meier curves revealed better long-term survival rates in the group with a decrease in the haSTART index (p = 0.024). Multivariate analysis showed that a decrease in the haSTART index one year after CABG was associated with a decrease in mortality (HR 0.462; 95% CI 0.210–1.016; p = 0.055). Conclusions. The dynamics of the haSTART arterial stiffness index one year after CABG has prognostic significance in the long-term follow-up period. In addition, in the group with an increase in the haSTART index, personality type D is more common. Further studies need to study which interventions in patients with coronary artery disease can cause favorable dynamics in the haSTART index and to what extent psychological characteristics can influence these dynamics.
Evaluation of Anti-CAR Linker mAbs for CAR T Monitoring after BiTEs/bsAbs and CAR T-Cell Pretreatment
Authors: Grahnert Anja , Seiffert Sabine , Wenk Kerstin , Schmiedel Dominik , Boldt Andreas , Vucinic Vladan , Merz Maximilian , Platzbecker Uwe , Klemann Christian , Koehl Ulrike , Friedrich Maik
Published: July 2024

For the monitoring of chimeric antigen receptor (CAR) T-cell therapies, antigen-based CAR detection methods are usually applied. However, for each target-antigen, a separate detection system is required. Furthermore, when monitored CAR T-cells in the blood of patients treated with bispecific antibodies or T-cell engagers (bsAbs/BiTEs) recognize the same antigen, these methods produce false-positive results in clinical diagnostics. Anti-CAR-linker monoclonal antibodies (mAbs) targeting the linker sequence between the variable domains of the antigen binding CAR fragment promise a universal and unbiased CAR detection. To test this, we analyzed clinical specimens of all BCMA- and CD19-targeting CAR T-cell products currently approved for clinical use. We found a highly specific and sensitive CAR detection using anti-CAR-linker mAb in blood cells from patients treated with Ide-cel, Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. For Ide-cel and Tisa-cel, the sensitivity was significantly lower compared to that for antigen-based CAR detection assays. Strikingly, the specificity of anti-CAR linker mAb was not affected by the simultaneous presence of bispecific blinatumomab or teclistamab for Axi-cel, Brexu-cel, Liso-cel, or Ide-cel, respectively. Cilta-cel (containing a monomeric G4S-CAR linker) could not be detected by anti-CAR linker mAb. In conclusion, anti-CAR-linker mAbs are highly specific and useful for CAR T-cell monitoring but are not universally applicable.
Osteopontin: A Versatile Biomarker—Insights and Innovations from Three Decades of Research
Authors: Abreu Hugo , Cappellano Giuseppe
Published: July 2024

This second Biomedicines Special Issue—“30 Years of osteopontin (OPN) Milestones and Future Avenues 2 [...]
Constitutive, Muscle-Specific Orai1 Knockout Results in the Incomplete Assembly of Ca2+ Entry Units and a Reduction in the Age-Dependent Formation of Tubular Aggregates
Authors: Di Fonso Alessia , Serano Matteo , He Miao , Leigh Jennifer , Rastelli Giorgia , Dirksen Robert T. , Protasi Feliciano , Pietrangelo Laura
Published: July 2024

Store-operated Ca2+ entry (SOCE) is a ubiquitous cellular mechanism that cells use to activate extracellular Ca2+ entry when intracellular Ca2+ stores are depleted. In skeletal muscle, SOCE occurs within Ca2+ entry units (CEUs), intracellular junctions between stacks of SR membranes containing STIM1 and transverse tubules (TTs) containing ORAI1. Gain-of-function mutations in STIM1 and ORAI1 are linked to tubular aggregate (TA) myopathy, a disease characterized by the atypical accumulation of tubes of SR origin. Moreover, SOCE and TAs are increased in the muscles of aged male mice. Here, we assessed the longitudinal effects (from 4–6 months to 10–14 months of age) of constitutive, muscle-specific Orai1 knockout (cOrai1 KO) on skeletal muscle structure, function, and the assembly of TAs and CEUs. The results from these studies indicate that cOrai1 KO mice exhibit a shorter lifespan, reduced body weight, exercise intolerance, decreased muscle-specific force and rate of force production, and an increased number of structurally damaged mitochondria. In addition, electron microscopy analyses revealed (i) the absence of TAs with increasing age and (ii) an increased number of SR stacks without adjacent TTs (i.e., incomplete CEUs) in cOrai1 KO mice. The absence of TAs is consistent with TAs being formed as a result of excessive ORAI1-dependent Ca2+ entry.
Remnant Pancreas Volume Affects New-Onset Impaired Glucose Homeostasis Secondary to Pancreatic Cancer
Authors: Yang Jie , Tan Chunlu , Liu Ya , Zheng Zhenjiang , Liu Xubao , Chen Yonghua
Published: July 2024

Background: New-onset diabetes (NOD) has been identified as a high-risk factor for the early detection of pancreatic ductal adenocarcinoma (PDAC). The role of tumor volume and remnant pancreas volume (RPV) in the progression from normal to NOD in PDAC patients is not fully illustrated yet. Methods: In this cross-sectional study, glycemic metabolism traits of 95 PDAC patients before pancreatic surgery were described and compared with chronic pancreatitis and type 2 diabetes mellitus patients based on the oral glucose tolerance test. The remnant RPV and tumor volume, calculated by three-dimensional reconstruction of radiological images, were included in the ordinal logistic regression models. Results: The prevalence of NOD was high among PDAC patients (38.9%). However, normal glucose tolerance (NGT) or prediabetes mellitus status were present as more than half (24/44) of advanced tumor stage patients. Indexes reflecting beta-cell function but not insulin sensitivity gradually worsened from NGT to NOD patients (all p < 0.05). The remnant pancreas volume (RPV) was identified as a potential protective factor for diabetes secondary to PDAC (odds ratio 0.95, 95% CI [0.92, 0.97], p < 0.001). Conclusions: Reduced RPV causing beta-cell dysfunction might be one of the mechanisms of NOD secondary to PDAC. Subjects with sufficient pancreas volume could not be detected earlier when regarding patients with NOD as the population at risk for PDAC.
The Association of Metformin, Other Antidiabetic Medications, and Statins with the Prognosis of Hepatocellular Carcinoma in Patients with Type 2 Diabetes: A Retrospective Cohort Study
Authors: Tuunanen Iida , Hautakoski Ari , Huhtamäki Heikki , Arffman Martti , Sund Reijo , Puistola Ulla , Karihtala Peeter , Jukkola Arja , Urpilainen Elina
Published: July 2024

This study aimed to explore whether the prediagnostic use of metformin and statins is associated with the prognosis of patients with hepatocellular carcinoma (HCC) and type 2 diabetes. We identified 1383 eligible individuals who had both type 2 diabetes and HCC diagnosed between 1998 and 2017 from several Finnish registers. Cox models were fitted for cause-specific and all-cause mortality in relation to the use of antidiabetic medications and statins prior to the HCC diagnosis. Prediagnostic metformin use was associated with decreased overall mortality (hazard ratio 0.84, 95% confidence interval 0.74–0.94) compared with nonuse in patients with type 2 diabetes. Similarly, slightly decreased HCC mortality and other-cause mortality were observed among metformin users. The results were inconclusive regarding metformin use and both overall and HCC mortality among patients with localized HCC. No discernible contrast between statin users and nonusers was found in overall mortality nor HCC mortality in either the whole cohort or patients with localized cancer.
Efficient Mako Shark-Inspired Aerodynamic Design for Concept Car Bodies in Underground Road Tunnel Conditions
Authors: Venegas Ignacio , Oñate Angelo , Pierart Fabián G. , Valenzuela Marian , Narayan Sunny , Tuninetti Víctor
Published: July 2024

The automotive industry continuously enhances vehicle design to meet the growing demand for more efficient vehicles. Computational design and numerical simulation are essential tools for developing concept cars with lower carbon emissions and reduced costs. Underground roads are proposed as an attractive alternative for reducing surface congestion, improving traffic flow, reducing travel times and minimizing noise pollution in urban areas, creating a quieter and more livable environment for residents. In this context, a concept car body design for underground tunnels was proposed, inspired by the mako shark shape due to its exceptional operational kinetic qualities. The proposed biomimetic-based method using computational fluid dynamics for engineering design includes an iterative process and car body optimization in terms of lift and drag performance. A mesh sensitivity and convergence analysis was performed in order to ensure the reliability of numerical results. The unique surface shape of the shark enabled remarkable aerodynamic performance for the concept car, achieving a drag coefficient value of 0.28. The addition of an aerodynamic diffuser improved downforce by reducing 58% of the lift coefficient to a final value of 0.02. Benchmark validation was carried out using reported results from sources available in the literature. The proposed biomimetic design process based on computational fluid modeling reduces the time and resources required to create new concept car models. This approach helps to achieve efficient automotive solutions with low aerodynamic drag for a low-carbon future.
Stability and Controller Research of Double-Wing FMAV System Based on Controllable Tail
Authors: Zhang Yichen , Xiao Yiming , Guo Qingcheng , Cui Feng , Zhao Jiaxin , Wu Guangping , Wu Chaofeng , Liu Wu
Published: July 2024

This study aimed to enhance the stability and response speed of a passive stabilized double-wing flapping micro air vehicle (FMAV) by implementing a feedback-controlled biomimetic tail. A model for flapping wings accurately calculated the lift force with only a 2.4% error compared to the experimental data. Experimental tests established the relationship between control torque and tail area, swing angle, and wing–tail spacing. A stability model for the double-wing FMAV was developed, incorporating stabilizing sails. Linearization of the hovering state facilitated the design of a simulation controller to improve response speed. By adjusting the feedback loops of velocity, angle, and angular velocity, the tail controller reduced the angle simulation response time from 4 s to 0.1 s and the velocity response time from 5.64 s to 0.1 s. In take-off experiments, a passive stabilized prototype with an adjustable tail angle exhibited enhanced flight stability compared to fixed tails, reducing standard deviation by 72.96% at a 0° take-off angle and 56.85% at a 5° take-off angle. The control axis standard deviation decreased by 38.06% compared to the passive stability axis, confirming the effectiveness of the designed tail angle controller in reducing angular deflection and improving flight stability.