bluuebunny/crossref_metadata_2025 huggingface dataset:
LES and RANS Spray Combustion Analysis of OME3-5 and n-Dodecane
Authors: Wiesmann Frederik , Nguyen Tuan M. , Manin Julien , Pickett Lyle M. , Wan Kevin , Tagliante Fabien , Lauer Thomas
Published: May 2024

Clean-burning oxygenated and synthetic fuels derived from renewable power, so-called e-fuels, are a promising pathway to decarbonize compression–ignition engines. Polyoxymethylene dimethyl ethers (PODEs or OMEs) are one candidate of such fuels with good prospects. Their lack of carbon-to-carbon bonds and high concentration of chemically bound oxygen effectively negate the emergence of polycyclic aromatic hydrocarbons (PAHs) and even their precursors like acetylene (C2H2), enabling soot-free combustion without the soot-NOx trade-off common for diesel engines. The differences in the spray combustion process for OMEs and diesel-like reference fuels like n-dodecane and their potential implications on engine applications include discrepancies in the observed ignition delay, the stabilized flame lift-off location, and significant deviations in high-temperature flame morphology. For CFD simulations, the accurate modeling and prediction of these differences between OMEs and n-dodecane proved challenging. This study investigates the spray combustion process of an OME3 − 5 mixture and n-dodecane with advanced optical diagnostics, Reynolds-Averaged Navier–Stokes (RANS), and Large-Eddy Simulations (LESs) within a constant-volume vessel. Cool-flame and high-temperature combustion were measured simultaneously via high-speed (50 kHz) imaging with formaldehyde (CH2O) planar laser-induced fluorescence (PLIF) representing the former and line-of-sight OH* chemiluminescence the latter. Both RANS and LES simulations accurately describe the cool-flame development process with the formation of CH2O. However, CH2O consumption and the onset of high-temperature reactions, signaled by the rise of OH* levels, show significant deviations between RANS, LES, and experiments as well as between n-dodecane and OME. A focus is set on the quality of the simulated results compared to the experimentally observed spatial distribution of OH*, especially in OME fuel-rich regions. The influence of the turbulence modeling is investigated for the two distinct ambient temperatures of 900 K and 1200 K within the Engine Combustion Network Spray A setup. The capabilities and limitations of the RANS simulations are demonstrated with the initial cool-flame propagation and periodic oscillations of CH2O formation/consumption during the quasi-steady combustion period captured by the LES.
The Optimal Infrastructure Design for Grid-to-Vehicle (G2V) Service: A Case Study Based on the Monash Microgrid
Authors: Yoon Soobok , Dargaville Roger
Published: May 2024

The electrification of the transport sector has emerged as a game changer in addressing the issues of climate change caused by global warming. However, the unregulated expansion and simplistic approach to electric vehicle (EV) charging pose substantial risks to grid stability and efficiency. Intelligent charging techniques using Information and Communication Technology, known as smart charging, enable the transformation of the EV fleets from passive consumers to active participants within the grid ecosystem. This concept facilitates the EV fleet’s contribution to various grid services, enhancing grid functionality and resilience. This paper investigates the optimal infrastructure design for a smart charging system within the Monash microgrid (Clayton campus). We introduce a centralized Grid-to-Vehicle (G2V) algorithm and formulate three optimization problems utilizing linear and least-squares programming methods. These problems address tariff structures between the main grid and microgrid, aiming to maximize aggregator profits or minimize load fluctuations while meeting EV users’ charging needs. Additionally, our framework incorporates network-aware coordination via the Newton–Raphson method, leveraging EVs’ charging flexibility to mitigate congestion and node voltage issues. We evaluate the G2V algorithm’s performance under increasing EV user demand through simulation and analyze the net present value (NPV) over 15 years. The results highlight the effectiveness of our proposed framework in optimizing grid operation management. Moreover, our case study offers valuable insights into an efficient investment strategy for deploying the G2V system on campus.
Model-Predictive-Control-Based Centralized Disturbance Suppression Strategy for Distributed Drive Electric Vehicle
Authors: Tan Aiping , Gao Lixiao , Chen Yanfeng
Published: May 2024

This paper presents a centralized disturbance suppression strategy for distributed drive electric vehicles which is based on model predictive direct motion control. This strategy is capable of addressing issues such as parameter uncertainties and external disturbances in vehicles. Firstly, the paper provides a brief introduction to model predictive direct motion control. Secondly, it analyzes the impact of vehicle parameter uncertainties and external disturbances on the mathematical model. Finally, a centralized disturbance suppression strategy based on a sliding mode observer is proposed. Simulation results demonstrate that this strategy exhibits excellent disturbance rejection capabilities.
Minimum Shear Reinforcement for Reactive Powder Concrete Beams
Authors: Sultan Hussein Kareem , Huseien Ghasan Fahim
Published: May 2024

The aim of this research was to determine the minimal requirements for shear reinforcement for reactive powder concrete (RPC) rectangular cross-sectional beams with a compressive strength of 157 MPa and a steel fiber volume content of 2.0% that remained constant for all the tested beams. Additionally, the recommendations of KCI-2012 and AFGC-2013 for the design of RPC beams as well as the shear design requirements of ACI 314-2014 when applied to RPC beams were studied. Utilizing a three-dimensional finite element program, a computational model was designed for forecasting the deformations and shear strength of the examined RPC beams. Both the shear-span-to-depth relationship (a/d) and the minimal reinforcement web ratio, represented by the distance between stirrups and the diameter of the stirrup bars, are the key study parameters in this regard. According to this study’s experimental findings, increasing the given reinforcement of the web ratio has little influence on both the ultimate shear strength as well as the diagonal cracking strength of the beams. Additionally, the findings demonstrated that the ACI 318-2014 maximum stirrup spacing requirement of 0.5 d can safely be extended to 0.75 d for beams that are relatively short. Compared to what ACI 318-2014 mandates, the suggestions of AFGC-2013 and KCI-2012 are more cautious and safe. According to the AFGC-2013 criteria, the mean proportion of Vfb to projected Vu,AFGC is roughly 58.3%, whereas the mean proportion of vs. and Vc is just 41.7%. The deformation response and ultimate shear strength of the examined RPC beams were well predicted by the designed model using finite elements when metal fibers were taken into account.
Antioxidant Activity and Fatty Acid Profile of Sous-Vide Beef Marinated with Kiwiberry Fruit Pulp: Effects of Level Addition and Refrigerated Storage
Authors: Haraf Gabriela , Goluch Zuzanna , Teleszko Mirosława , Latocha Piotr
Published: May 2024

The purpose of the study was to determine the antioxidant activity (AA) and fatty acid (FA) profile of sous-vide beef previously marinated in brine with a 10, 20 and 30% addition of kiwiberry (Actinidia arguta cv. ‘Ananasnaya’) fruit pulp, as well as changes in the parameters studied after 0, 1, 2 and 3 weeks of refrigerated storage in a vacuum package. The FA profile, FRAP (ferric-reducing antioxidant power assay), ABTS (2,2′-azinobis (3-ethylbenzthiazoline-6-acid)), total polyphenols, chlorophylls and carotenoids were also determined in the fruit pulp. Lipid indices for meat were calculated based on the obtained FA profile. The values of FRAP and ABTS of experimental meat products were significantly (p ≤ 0.05) higher than those of control samples but decreased with storage time. The proportion of unsaturated FA in the lipids of sous-vide meat was higher in samples with pulp than in control samples and insignificantly decreased with storage time. Meat marinated with kiwiberry pulp was characterized by a significantly (p ≤ 0.05) higher proportion of ALA (α-linolenic acid) and LA (linoleic acid), considerably affecting the more favorable value of polyunsaturated FA/saturated FA ratio. A troubling finding was the heightened level of palmitic acid (C16:0) in the lipids of beef subjected to 30% kiwiberry pulp, a factor recognized to play a significant role in the development of various diseases. Beef marinated with 20% kiwiberry pulp addition provides greater nutritional and health benefits than other sample variants because of optimal AA and FA profile changes during refrigerated storage.
Effects of Gnaphalium affine Extract on the Gel Properties of •OH-Induced Oxidation of Myofibrillar Proteins
Authors: Chang Haijun , Hu Yu , Shi Yuanwei , Xiong Jie , Bo Zhaoying
Published: May 2024

This study aimed to investigate the effect of Gnaphalium affine extract (GAE) (0.04, 0.2 and 1 mg/g protein) on the gel properties of porcine myofibrillar proteins (MPs) in a simulated Fenton oxidation system, using tea polyphenols (TPs) at similar concentrations of 0.04, 0.2, and 1 mg/g protein, respectively, as a contrast. The findings revealed that as the TP concentration increased, the water retention of MP gels decreased significantly (p < 0.05). In contrast, MP gels containing medium and high concentrations of GAE exhibited significantly higher water retention than those with low concentrations of GAE (p < 0.05). When the concentration of GAE was increased to 1 mg/g protein, the strength of MP gels was significantly reduced (p < 0.05) by 33.32% compared with the oxidized control group, suggesting that low and medium GAE concentrations support MP gel formation. A texture profile analysis indicated that an appropriate GAE concentration improved gel structure and texture. Dynamic rheological characterization revealed that low concentrations of TP (0.04 mg/g protein) and low and medium concentrations of GAE (0.04 and 0.2 mg/g protein) strengthened the protein gel system. Conversely, high concentrations of TP and GAE (1.0 mg/g protein) damaged the protein gel system or even promoted the collapse of the gel system. Scanning electron microscopy revealed that higher TP concentrations disrupted the gel, whereas low and medium GAE concentrations maintained a more continuous and complete gel network structure compared with the oxidized control group. This indicates that an appropriate GAE concentration could effectively hinder the destruction of the gel network structure by oxidation. Therefore, based on the obtained results, 0.2 mg/g protein is recommended as the ideal concentration of GAE to be used in actual meat processing to regulate the oxidization and gel properties of meat products.
An Evaluation of the Sensitivity and Applicability of a Droplet Digital Polymerase Chain Reaction Assay to Simultaneously Detect Pseudomonas aeruginosa and Pseudomonas fragi in Foods
Authors: Huang Ju , Zhai Ligong , Wang Junyin , Sun Xiaotian , Wang Baoshi , Wei Zhaohui
Published: May 2024

Achieving effective control over microbial contamination necessitates the precise and concurrent identification of numerous pathogens. As a common bacterium in the environment, Pseudomonas is rich in variety. It not only has pathogenic strains, but also spoilage bacteria that cause food spoilage. In this research, we devised a remarkably sensitive duplex droplet digital PCR (dddPCR) reaction system to simultaneously detect pathogenic Pseudomonas aeruginosa (P. aeruginosa) and spoilage Pseudomonas fragi (P. fragi). By employing comparative genomics, we identified four genes of P. fragi. Through a specific analysis, the RS22680 gene was selected as the detection target for P. fragi, and the lasR gene was chosen for P. aeruginosa, which were applied to construct a dddPCR reaction. In terms of specificity, sensitivity and anti-interference ability, the constructed dddPCR detection system was verified and analyzed. The assay showed excellent sensitivity and applicability, as evidenced by a limit of detection of 100 cfu/mL. When the concentration of natural background bacteria in milk or fresh meat was 100 times that of the target detection bacteria, the method was still capable of completing the absolute quantification. In the simulation of actual sample contamination, P. aeruginosa could be detected after 3 h of enrichment culture, and P. fragi could be detected after 6 h. The established dddPCR detection system exhibits exceptional performance, serving as a foundation for the simultaneous detection of various pathogenic bacteria in food products.
A Novel COL4A5 Pathogenic Variant Joins the Dots in a Family with a Synchronous Diagnosis of Alport Syndrome and Polycystic Kidney Disease
Authors: Graziani Ludovico , Minotti Chiara , Carriero Miriam Lucia , Bengala Mario , Lai Silvia , Terracciano Alessandra , Novelli Antonio , Novelli Giuseppe
Published: May 2024

Alport Syndrome (AS) is the most common genetic glomerular disease, and it is caused by COL4A3, COL4A4, and COL4A5 pathogenic variants. The classic phenotypic spectrum associated with AS ranges from isolated hematuria to chronic kidney disease (CKD) with extrarenal abnormalities. Atypical presentation of the disorder is possible, and it can mislead the diagnosis. Polycystic kidney disease (PKD), which is most frequently associated with Autosomal Dominant PKD (ADPKD) due to PKD1 and PKD2 heterozygous variants, is emerging as a possible clinical manifestation in COL4A3-A5 patients. We describe a COL4A5 novel familial frameshift variant (NM_000495.5: c.1095dup p.(Leu366ValfsTer45)), which was associated with AS and PKD in the hemizygous proband, as well as with PKD, IgA glomerulonephritis and focal segmental glomerulosclerosis (FSGS) in the heterozygous mother. Establishing the diagnosis of AS can sometimes be difficult, especially in the context of misleading family history and atypical phenotypic features. This case study supports the emerging genotypic and phenotypic heterogeneity in COL4A3-A5-associated disorders, as well as the recently described association between PKD and collagen type IV (Col4) defects. We highlight the importance of the accurate phenotyping of all family members and the relevance of next-generation sequencing in the differential diagnosis of hereditary kidney disease.
Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence
Authors: Graziani Andrea , Rocca Maria Santa , Vinanzi Cinzia , Masi Giulia , Grande Giuseppe , De Toni Luca , Ferlin Alberto
Published: May 2024

Several genes are implicated in spermatogenesis and fertility regulation, and these genes are presently being analysed in clinical practice due to their involvement in male factor infertility (MFI). However, there are still few genetic analyses that are currently recommended for use in clinical practice. In this manuscript, we reviewed the genetic causes of qualitative sperm defects. We distinguished between alterations causing reduced sperm motility (asthenozoospermia) and alterations causing changes in the typical morphology of sperm (teratozoospermia). In detail, the genetic causes of reduced sperm motility may be found in the alteration of genes associated with sperm mitochondrial DNA, mitochondrial proteins, ion transport and channels, and flagellar proteins. On the other hand, the genetic causes of changes in typical sperm morphology are related to conditions with a strong genetic basis, such as macrozoospermia, globozoospermia, and acephalic spermatozoa syndrome. We tried to distinguish alterations approved for routine clinical application from those still unsupported by adequate clinical studies. The most important aspect of the study was related to the correct identification of subjects to be tested and the correct application of genetic tests based on clear clinical data. The correct application of available genetic tests in a scenario where reduced sperm motility and changes in sperm morphology have been observed enables the delivery of a defined diagnosis and plays an important role in clinical decision-making. Finally, clarifying the genetic causes of MFI might, in future, contribute to reducing the proportion of so-called idiopathic MFI, which might indeed be defined as a subtype of MFI whose cause has not yet been revealed.
Scientific Utility of Selected Latin American Global Geoparks: A Literature-Based Case Study
Authors: Ruban Dmitry A. , Yashalova Natalia N.
Published: May 2024

Global geoparks, i.e., the members of the UNESCO Global Geopark (UGGp) network, possess highly valuable geoheritage resources, which can be used for the purposes of not only education and tourism, but also science. Five examples from four Latin American countries (Chile, Ecuador, Mexico, and Peru) were employed to realize the importance of these global geoparks as facilitators of international research. Journal articles devoted to these geoparks were selected with the major bibliographical databases, and the information from them was analyzed quantitatively. Particularly, the numbers of articles published before and after the UGGp membership, paying significant and marginal attention to geoparks, and published by international teams were calculated; the general themes of the articles were outlined. It was established that the total number of publications grew after the UGGp membership of these geoparks, but not steadily. The established dynamics of publishing are unstable and differ between the geoparks. Geoparks of Mexico (Mixteca Alta) and Peru (Colca y Volcanes de Andagua) are notable examples because they started to facilitate international research before the UGGp membership. Many articles consider geoparks only marginally (nonetheless, there are also articles paying significant attention to geoparks, especially in the cases of two Mexican geoparks). The author teams are often not restricted to Latin America. The research themes are rather diverse (geoheritage, geology, ecology, innovations, society, technology), although the majority of the publications are geoheritage-focused. Of special interest is the Colca y Volcanes de Andagua global geopark, which has been considered in the innovation-focused article. Generally, our results indicate a moderate importance of the considered global geoparks to international research activity and the incomplete exploitation of their scientific potential. Two Mexican geoparks (Comarca Minera and Mixteca Alta) seem to be the most successful in the facilitation of international research. Indeed, the scientific utility of global geoparks should be strengthened.
Family Caregivers’ Experiences during the COVID-19 Pandemic: Qualitative Study
Authors: Rico-Blázquez Milagros , Sánchez-Ruano Raquel , Oter-Quintana Cristina , Polentinos-Castro Elena , Martín-García Ángel , Otones-Reyes Pedro , González-Beltrán Damián , Martínez-Marcos Mercedes
Published: May 2024

Background: The COVID-19 pandemic imposed lockdown measures that affected caregiving. Understanding caregivers’ context provides reveals their adaptive strategies to continue caring in this situation of uncertainty and isolation. Objective: To better understand the caregiving experiences of caregivers looking after dependent individuals living in the community during the pandemic. Design: Qualitative research, phenomenological approach. Setting: Primary healthcare centers in Madrid region (Spain). Participants: 21 family caregivers. Methods: Purposive and theoretical sampling was used to recruit caregivers across nurses from primary healthcare centers. Participants were interviewed using a semi-structured interview guide to explore the caring experience. Interview transcripts were evaluated using thematic analysis. Results: The findings were categorized into two themes: “Caregivers during lockdown—providing care in a time of adversity” and “Caregiving toward normality”. The sub-themes identified were the re-structuring of before-care services and the introduction of new care approaches, managing the dependent person’s health problems, looking after oneself, and dealing with adversity. To adapt to the new normal, strategies were put in place designed to recover confidence and trust, reincorporate assistance, and reconnect with others. Conclusions: Care intensified during the pandemic. Caregivers took on the task without assistance, focusing on preventing contagion and protecting themselves to be able to continue giving care.
Integrated Approach of Historical Landscape Characterisation Techniques and Remote Sensing for the Definition of Predictive Models and Scenario Analysis in the Planning of Archaeological Areas
Authors: Quattrone Giuliana
Published: May 2024

This study explores the synergistic integration of remote sensing (RS) and Historical Landscape Characterisation (HLC) methodology as an innovative, multi-scalar and holistic approach to enhance archaeological planning. The goal is to maximize the effectiveness of the investigations, optimizing data collection and improving the contextual understanding of the sites. In fact, these methodologies can significantly contribute to the documentation, conservation, planning and valorisation of archaeological areas. By integrating RS data with features detected by HLC, a complete picture is obtained that facilitates a deeper understanding of the landscape and historical dynamics. This article will explain the combined approach of RS and HLC, presenting some methodologies key to improving the precision and effectiveness of archaeological planning. This integration facilitates the sustainable preservation of archaeological resources and contributes to the conscious management of cultural heritage in the context of contemporary development. The paper demonstrates, through a case study, how the application of the two methodologies (RS and HLC) in an integrated form can provide an exhaustive interpretation of the territory in which the archaeological area is located, which can represent an exhaustive knowledge base on which to set up effective processes for the strategic territorial planning of archaeological areas.
Phenolic Compounds of Six Unexplored Asteraceae Species from Asia: Comparison of Wild and Cultivated Plants
Authors: Olennikov Daniil N. , Chirikova Nadezhda K.
Published: May 2024

The Asteraceae family in Siberian Asia exhibits remarkable biodiversity and has long served as a valuable resource for domesticating various beneficial plants with medicinal, therapeutic, and industrial significance to humanity. In this work, we studied for the first time the chemical composition of six understudied or previously unexplored plant species, Artemisia jacutica (AJ), Carduus nutans subsp. leiophyllus (CL), Cirsium heterophyllum (CH), Echinops davuricus (ED), Ixeris chinensis subsp. versicolor (IV), and Lactuca sibirica (LS), which were successfully cultivated under open-field conditions as biennial or perennial crops. We profiled these species, employing a liquid chromatography–mass spectrometry approach, identifying over 100 phenolic compounds. Among these compounds were hydroxybenzoic acid glucosides, hydroxybenzoyl/p-coumaroyl/feruloyl quinic acids, hydroxycoumarin O-glucosides, caffeoyl/p-coumaroyl/feruloyl glucaric/tartaric acids, O- and C-glucosides of apigenin, acacetin, luteolin, chrysoeriol, 6-hydroxyluteolin, pectolinarigenin, kaempferol, quercetin, isorhamnetin, and tri-/tetra-O-p-coumaroyl spermines and spermidines. All examined species exhibited a significant accumulation of phenolic compounds throughout the experimental period, reaching levels comparable to or exceeding those found in wild samples (WSs), with the best total phenolic content for AJ at 26.68 mg/g (vs. 26.68 mg/g in WS; second year), CL at 50.23 mg/g (vs. 38.32 mg/g in WS; second year), CH at 51.14 mg/g (vs. 40.86 mg/g in WS; sixth year), ED at 86.12 mg/g (vs. 78.08 mg/g in WS; seventh year), IV at 102.49 mg/g (vs. 88.58 mg/g in WS; fourth year), and LS at 127.34 mg/g (vs. 110.64 mg/g in WS; fifth year). Notably, in the first year of cultivation, approximately 40–60% of the wild-level target compounds accumulated in the plants, with even higher levels detected in subsequent years, particularly in the second and third years. This study highlights the potential of cultivation to produce new Asteraceae plants rich in bioactive phenolics.
Total Least Squares Estimation in Hedonic House Price Models
Authors: Zhan Wenxi , Hu Yu , Zeng Wenxian , Fang Xing , Kang Xionghua , Li Dawei
Published: May 2024

In real estate valuation using the Hedonic Price Model (HPM) estimated via Ordinary Least Squares (OLS) regression, subjectivity and measurement errors in the independent variables violate the Gauss–Markov theorem assumption of a non-random coefficient matrix, leading to biased parameter estimates and incorrect precision assessments. In this contribution, the Errors-in-Variables model equipped with Total Least Squares (TLS) estimation is proposed to address these issues. It fully considers random errors in both dependent and independent variables. An iterative algorithm is provided, and posterior accuracy estimates are provided to validate its effectiveness. Monte Carlo simulations demonstrate that TLS provides more accurate solutions than OLS, significantly improving the root mean square error by over 70%. Empirical experiments on datasets from Boston and Wuhan further confirm the superior performance of TLS, which consistently yields a higher coefficient of determination and a lower posterior variance factor, which shows its more substantial explanatory power for the data. Moreover, TLS shows comparable or slightly superior performance in terms of prediction accuracy. These results make it a compelling and practical method to enhance the HPM.
The Role of Methylation Analysis in Distinguishing Cellular Myxoma from Low-Grade Myxofibrosarcoma
Authors: Henzinger Hanna , Brčić Iva , Igrec Jasminka , Godschachner Theresa Marie , Scheipl Susanne , Szkandera Joanna , Jurmeister Philipp , Liegl-Atzwanger Bernadette
Published: May 2024

Cellular myxoma is a benign soft tissue tumor frequently associated with GNAS mutation that may morphologically resemble low-grade myxofibrosarcoma. This study aimed to identify the undescribed methylation profile of cellular myxoma and compare it to myxofibrosarcoma. We performed molecular analysis on twenty cellular myxomas and nine myxofibrosarcomas and analyzed the results using the methylation-based DKFZ sarcoma classifier. A total of 90% of the cellular myxomas had GNAS mutations (four loci had not been previously described). Copy number variations were found in all myxofibrosarcomas but in none of the cellular myxomas. In the classifier, none of the cellular myxomas reached the 0.9 threshold. Unsupervised t-SNE analysis demonstrated that cellular myxomas form their own clusters, distinct from myxofibrosarcomas. Our study shows the diagnostic potential and the limitations of molecular analysis in cases where morphology and immunohistochemistry are not sufficient to distinguish cellular myxoma from myxofibrosarcoma, particularly regarding GNAS wild-type tumors. The DKFZ sarcoma classifier only provided a valid prediction for one myxofibrosarcoma case; this limitation could be improved by training the tool with a more considerable number of cases. Additionally, the classifier should be introduced to a broader spectrum of mesenchymal neoplasms, including benign tumors like cellular myxoma, whose distinct methylation pattern we demonstrated.
Multi-Omics Characterization of Colon Mucosa and Submucosa/Wall from Crohn’s Disease Patients
Authors: Jin Liang , Macoritto Michael , Wang Jing , Bi Yingtao , Wang Fei , Suarez-Fueyo Abel , Paez-Cortez Jesus , Hu Chenqi , Knight Heather , Mascanfroni Ivan , Staron Matthew M. , Schwartz Sterman Annette , Houghton Jean Marie , Westmoreland Susan , Tian Yu
Published: May 2024

Crohn’s disease (CD) is a subtype of inflammatory bowel disease (IBD) characterized by transmural disease. The concept of transmural healing (TH) has been proposed as an indicator of deep clinical remission of CD and as a predictor of favorable treatment endpoints. Understanding the pathophysiology involved in transmural disease is critical to achieving these endpoints. However, most studies have focused on the intestinal mucosa, overlooking the contribution of the intestinal wall in Crohn’s disease. Multi-omics approaches have provided new avenues for exploring the pathogenesis of Crohn’s disease and identifying potential biomarkers. We aimed to use transcriptomic and proteomic technologies to compare immune and mesenchymal cell profiles and pathways in the mucosal and submucosa/wall compartments to better understand chronic refractory disease elements to achieve transmural healing. The results revealed similarities and differences in gene and protein expression profiles, metabolic mechanisms, and immune and non-immune pathways between these two compartments. Additionally, the identification of protein isoforms highlights the complex molecular mechanisms underlying this disease, such as decreased RTN4 isoforms (RTN4B2 and RTN4C) in the submucosa/wall, which may be related to the dysregulation of enteric neural processes. These findings have the potential to inform the development of novel therapeutic strategies to achieve TH.
Microgravity-like Crystallization of Paramagnetic Species in Strong Magnetic Fields
Authors: Samsonenko Arkady A. , Artiukhova Natalia A. , Letyagin Gleb A. , Kiryutin Alexey S. , Zhukov Ivan V. , Veber Sergey L.
Published: May 2024

The crystallization of paramagnetic species in a magnetic field gradient under microgravity-like conditions is an area of interest for both fundamental and applied science. In this paper, a setup for the crystallization of paramagnetic species in the magnetic field up to 7 T generated by a superconducting magnet is described. The research includes calculations of the conditions necessary to compensate for the gravitational force for several types of paramagnetic substances using the magnetic field of superconducting magnets (4.7 T, 7 T, 9.4 T, and 16.4 T). Additionally, for the first time, the crystallization of copper sulfate and cobalt sulfate, as well as a mixture of copper sulfate and cobalt sulfate under gravitational force compensation in a superconducting magnet, was performed. This paper experimentally demonstrates the feasibility of growing paramagnetic crystals within the volume of a test tube on the example of copper and cobalt sulfate crystals. A comparison of crystals grown from the solution of a mixture of copper and cobalt sulfates under the same conditions, with and without the presence of a magnetic field, showed changes in both the number and size of crystals.
Effect of Garlic Extract on the Erythrocyte as a Simple Model Cell
Authors: Furdak Paulina , Bartosz Grzegorz , Stefaniuk Ireneusz , Cieniek Bogumił , Bieszczad-Bedrejczuk Edyta , Soszyński Mirosław , Sadowska-Bartosz Izabela
Published: May 2024

Garlic is known to have diverse effects on mammalian cells, being cytotoxic, especially to cancer cells, but also protect against oxidative stress. Mammalian erythrocyte is a simple cell devoid of intracellular organelles, protein synthesis ability, and most signaling pathways. Therefore, examination of the effects of garlic on erythrocytes allows for revealing primary events in the cellular action of garlic extract. In this study, human erythrocytes or erythrocyte membranes were exposed to garlic extract at various dilutions. Hemoglobin oxidation to methemoglobin, increased binding of hemoglobin to the membrane, and formation of Heinz bodies were observed. Garlic extract depleted acid-soluble thiols, especially glutathione, and induced a prooxidative shift in the cellular glutathione redox potential. The extract increased the osmotic fragility of erythrocytes, induced hemolysis, and inhibited hemolysis in isotonic ammonium chloride, indicative of decreased membrane permeability for Cl− and increased the membrane fluidity. Fluorescent probes indicated an increased level of reactive oxygen species and induction of lipid peroxidation, but these results should be interpreted with care since the extract alone induced oxidation of the probes (dichlorodihydrofluorescein diacetate and BODIPY C11). These results demonstrate that garlic extract induces oxidative changes in the erythrocyte, first of all, thiol and hemoglobin oxidation.
Skeletal Muscle Injury in Chronic Kidney Disease—From Histologic Changes to Molecular Mechanisms and to Novel Therapies
Authors: Heitman Kylie , Alexander Matthew S. , Faul Christian
Published: May 2024

Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.
The Species Effect: Differential Sphingosine-1-Phosphate Responses in the Bone in Human Versus Mouse
Authors: Frost Kathryn , Lewis Jonathan W. , Jones Simon W. , Edwards James R. , Naylor Amy J. , McGettrick Helen M.
Published: May 2024

The deterioration of osteoblast-led bone formation and the upregulation of osteoclast-regulated bone resorption are the primary causes of bone diseases, including osteoporosis. Numerous circulating factors play a role in bone homeostasis by regulating osteoblast and osteoclast activity, including the sphingolipid—sphingosine-1-phosphate (S1P). However, to date no comprehensive studies have investigated the impact of S1P activity on human and murine osteoblasts and osteoclasts. We observed species-specific responses to S1P in both osteoblasts and osteoclasts, where S1P stimulated human osteoblast mineralisation and reduced human pre-osteoclast differentiation and mineral resorption, thereby favouring bone formation. The opposite was true for murine osteoblasts and osteoclasts, resulting in more mineral resorption and less mineral deposition. Species-specific differences in osteoblast responses to S1P were potentially explained by differential expression of S1P receptor 1. By contrast, human and murine osteoclasts expressed comparable levels of S1P receptors but showed differential expression patterns of the two sphingosine kinase enzymes responsible for S1P production. Ultimately, we reveal that murine models may not accurately represent how human bone cells will respond to S1P, and thus are not a suitable model for exploring S1P physiology or potential therapeutic agents.
Peposertib, a DNA-PK Inhibitor, Enhances the Anti-Tumor Efficacy of Topoisomerase II Inhibitors in Triple-Negative Breast Cancer Models
Authors: Revia Steffie , Neumann Felix , Jabs Julia , Orio Florian , Sirrenberg Christian , Zimmermann Astrid , Amendt Christiane , Albers Joachim
Published: May 2024

Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.
Characterizing Glomerular Barrier Dysfunction with Patient-Derived Serum in Glomerulus-on-a-Chip Models: Unveiling New Insights into Glomerulonephritis
Authors: Kim Shin Young , Choi Yun Yeong , Kwon Eun Jeong , Seo Seungwan , Kim Wan Young , Park Sung Hyuk , Park Seokwoo , Chin Ho Jun , Na Ki Young , Kim Sejoong
Published: May 2024

Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy.
Prediction of Drug-Target Affinity Using Attention Neural Network
Authors: Tang Xin , Lei Xiujuan , Zhang Yuchen
Published: May 2024

Studying drug-target interactions (DTIs) is the foundational and crucial phase in drug discovery. Biochemical experiments, while being the most reliable method for determining drug-target affinity (DTA), are time-consuming and costly, making it challenging to meet the current demands for swift and efficient drug development. Consequently, computational DTA prediction methods have emerged as indispensable tools for this research. In this article, we propose a novel deep learning algorithm named GRA-DTA, for DTA prediction. Specifically, we introduce Bidirectional Gated Recurrent Unit (BiGRU) combined with a soft attention mechanism to learn target representations. We employ Graph Sample and Aggregate (GraphSAGE) to learn drug representation, especially to distinguish the different features of drug and target representations and their dimensional contributions. We merge drug and target representations by an attention neural network (ANN) to learn drug-target pair representations, which are fed into fully connected layers to yield predictive DTA. The experimental results showed that GRA-DTA achieved mean squared error of 0.142 and 0.225 and concordance index reached 0.897 and 0.890 on the benchmark datasets KIBA and Davis, respectively, surpassing the most state-of-the-art DTA prediction algorithms.
New Case of Spinocerebellar Ataxia, Autosomal Recessive 4, Due to VPS13D Variants
Authors: Kistol Denis , Tsygankova Polina , Bostanova Fatima , Orlova Maria , Zakharova Ekaterina
Published: May 2024

Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The VPS13D gene, part of the VPS13 family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of VPS13D-associated disease with two variants in the VPS13D gene in an adult female. This case contributes to our evolving understanding of VPS13D-related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions.
Acetate Alleviates Gut Microbiota Depletion-Induced Retardation of Skeletal Muscle Growth and Development in Young Mice
Authors: Yang Guitao , Zhang Jinwei , Liu Yan , Sun Jing , Ge Liangpeng , Lu Lu , Long Keren , Li Xuewei , Xu Dengfeng , Ma Jideng
Published: May 2024

The normal growth and development of skeletal muscle is essential for the health of the body. The regulation of skeletal muscle by intestinal microorganisms and their metabolites has been continuously demonstrated. Acetate is the predominant short-chain fatty acids synthesized by gut microbiota through the fermentation of dietary fiber; however, the underlying molecular mechanisms governing the interaction between acetate and skeletal muscle during the rapid growth stage remains to be further elucidated. Herein, specific pathogen-free (SPF) mice, germ-free (GF) mice, and germ-free mice supplemented with sodium acetate (GS) were used to evaluate the effects of acetate on the skeletal muscle growth and development of young mice with gut microbiota deficiency. We found that the concentration of serum acetate, body mass gain, succinate dehydrogenase activity, and expression of the myogenesis maker gene of skeletal muscle in the GS group were higher than those in the GF group, following sodium acetate supplementation. Furthermore, the transcriptome analysis revealed that acetate activated the biological processes that regulate skeletal muscle growth and development in the GF group, which are otherwise inhibited due to a gut microbiota deficiency. The in vitro experiment showed that acetate up-regulated Gm16062 to promote skeletal muscle cell differentiation. Overall, our findings proved that acetate promotes skeletal muscle growth and development in young mice via increasing Gm16062 expression.
Increased H19/miR-675 Expression in Adult T-Cell Leukemia Is Associated with a Unique Notch Signature Pathway
Authors: Bellon Marcia , Nicot Christophe
Published: May 2024

The Notch pathway is a key cancer driver and is important in tumor progression. Early research suggested that Notch activity was highly dependent on the expression of the intracellular cleaved domain of Notch-1 (NICD). However, recent insights into Notch signaling reveal the presence of Notch pathway signatures, which may vary depending on different cancer types and tumor microenvironments. Herein, we perform a comprehensive investigation of the Notch signaling pathway in adult T-cell leukemia (ATL) primary patient samples. Using gene arrays, we demonstrate that the Notch pathway is constitutively activated in ATL patient samples. Furthermore, the activation of Notch in ATL cells remains elevated irrespective of the presence of activating mutations in Notch itself or its repressor, FBXW7, and that ATL cells are dependent upon Notch-1 expression for proliferation and survival. We demonstrate that ATL cells exhibit the expression of pivotal Notch-related genes, including notch-1, hes1, c-myc, H19, and hes4, thereby defining a critical Notch signature associated with ATL disease. Finally, we demonstrate that lncRNA H19 is highly expressed in ATL patient samples and ATL cells and contributes to Notch signaling activation. Collectively, our results shed further light on the Notch pathway in ATL leukemia and reveal new therapeutic approaches to inhibit Notch activation in ATL cells.