bluuebunny/crossref_metadata_2025 huggingface dataset:
Roughness Evolution of Granite Flat Fracture Surfaces during Sliding Processes
Authors: Yang Hengtao , Bai Bing , Lin Hang
Published: July 2024

Roughness is an essential factor affecting the shear process of discontinuous surfaces, and the evolution of roughness is closely related to the mechanical behavior of discontinuous surfaces. In this paper, with the help of granite specimens, a direct shear test was carried out on flat fracture surfaces obtained by sawing in order to study the evolution of roughness with shear slip. During the tests, the roughness evolution was evaluated using the arithmetic mean, root mean square and power spectral density of the roughness. The variation in these parameters all indicate that the friction surface with large slip tends to be rougher, at least under the loading conditions in this paper. And the increase in normal force will enhance this process, while the loading rate seems to have little effect on the roughness evolution. Finally, the analysis of the power spectral density shows that the roughness evolution in the spatial frequency of the profile line is mainly reflected in the middle– and low–frequency part, while the high–frequency part corresponding to the microscopic roughness body does not change much throughout the shear process.
Topology Optimization of Anisotropic Materials with Smooth Fiber Orientation
Authors: Jiang Shaofei , Shang Chaofan , Li Jiquan , Yi Bing , Peng Xiang
Published: July 2024

In the concurrent optimization of topology and fiber orientation, the design of smooth fiber helps to maintain the stability of numerical calculation and the compatibility of the manufacturing process. However, the improvement of fiber continuity is often accompanied by a significant decrease in the overall structural stiffness. Aiming at this problem, this paper proposes a topology optimization method for anisotropic materials with smooth fiber orientation. This method improves the smoothness of fiber orientation and reduces stiffness loss by introducing a fiber angle constraint strategy and adaptive filtering technology. The fiber angle constraint strategy integrates the created angle constraint function into the Method of Moving Asymptotes (MMA) to complete the strong constraint of the angle. This strategy quantifies the continuity of the fiber and effectively improves the continuity of the fiber. At the same time, the application of adaptive filtering technology can adjust a reasonable fiber angle distribution on the basis of smoothing fibers, thereby enhancing the stiffness of the overall structure. In addition, this paper shows the complete optimization process and MATLAB code implementation and verifies the effectiveness of the method through a series of numerical examples, that is, on the basis of improving fiber continuity, the stiffness of the whole structure is guaranteed, and then the effective balance between the two is realized.
A Critical Review of the Status of Current Greenhouse Technology in China and Development Prospects
Authors: Guo Bin , Zhou Biao , Zhang Zhiming , Li Kaidi , Wang Jianye , Chen Jiufa , Papadakis George
Published: July 2024

China’s greenhouse industry has undergone thousands of years of development history, although the development of modern greenhouses arrived late. After decades of development in China, its greenhouse industry is at the global forefront. China’s greenhouse industry is experiencing rapid development, transformation, and upgrading. China ranks first in the world in terms of the greenhouse industry. These greenhouses are mainly used for vegetable cultivation, playing an important role in the utilization of agricultural resources and food production. In 2023, the cumulative area of greenhouses nationwide was 1835.87 million ha. In this paper, we present the latest developments in the greenhouse sector. More specifically, we present an overview of the development of the greenhouse market, greenhouse production, the greenhouse industry, and technology development. Current problems are underpinned, development opportunities and prospects are analyzed, and measures and specific proposals are detailed for the technological development of the greenhouse sector, both for increasing product quantity and quality.
Three Novel Artificial Neural Network Architectures Based on Convolutional Neural Networks for the Spatio-Temporal Processing of Solar Forecasting Data
Authors: Benavides Cesar Llinet , Manso-Callejo Miguel-Ángel , Cira Calimanut-Ionut
Published: July 2024

In this work, three new convolutional neural network models—spatio-temporal convolutional neural network versions 1 and 2 (ST_CNN_v1 and ST_CNN_v2), and the spatio-temporal dilated convolutional neural network (ST_Dilated_CNN)—are proposed for solar forecasting and processing global horizontal irradiance (GHI) data enriched with meteorological and astronomical variables. A comparative analysis of the proposed models with two traditional benchmark models shows that the proposed ST_Dilated_CNN model outperforms the rest in capturing long-range dependencies, achieving a mean absolute error of 31.12 W/m2, a mean squared error of 54.07 W/m2, and a forecast skill of 37.21%. The statistical analysis carried out on the test set suggested highly significant differences in performance (p-values lower than 0.001 for all metrics in all the considered scenarios), with the model with the lowest variability in performance being ST_CNN_v2. The statistical tests applied confirmed the robustness and reliability of the proposed models under different conditions. In addition, this work highlights the significant influence of astronomical variables on prediction performance. The study also highlights the intricate relationship between the proposed models and meteorological and astronomical input characteristics, providing important insights into the field of solar prediction and reaffirming the need for further research into variability factors that affect the performance of models.
Full Digital Workflow for Aesthetic Rehabilitation of the Upper Teeth: A Case Report
Authors: Jorquera Gilbert , Hardan Louis , Bourgi Rim , Arias David , Cuevas-Suárez Carlos Enrique , Pietrzycka Krystyna , Lukomska-Szymanska Monika
Published: July 2024

The present case report presents a digital workflow for designing an aesthetic rehabilitation of the upper anterior teeth in an adult male. The patient suffered from a gummy smile resulting from an unfavorable ratio between upper lip length and gingiva/tooth display. In addition, the tooth shapes, color, and position were not accepted by the patient. The treatment planning included gingivectomy based on a digitally designed PMMA guide performed using a soft tissue SOGA laser (Shenzhen Soga Technology Co., Ltd., Shenzhen, China). The preparation was guided by the plastic guides for preparation control created digitally in Exocad software (Rijeka 3.1. Darmstadt, Germany) and printed in three-dimensional plastic. Next, both arches and maximum intercuspation were scanned. The milled lithium disilicate veneers were manufactured using CAD-computer-aided manufacturing (CAM) equipment. The restorations were cemented using a translucent light-cure resin cement (RelyX Universal, 3M ESPE, St. Paul, MN, USA). Next, occlusion adjustment and polishing were executed. Based on the present case report, it can be assumed that the application of digital techniques allows us to achieve an aesthetic and functional result with reduced work time and errors. Emphasizing the clinical impact, these methods enhance patient satisfaction and treatment accuracy in intricate aesthetic rehabilitations.
Reviving Ancient Egypt in the Renaissance Hieroglyph: Humanist Aspirations to Immortality
Authors: Howard Rebecca M.
Published: July 2024

In his On the Art of Building, Renaissance humanist Leon Battista Alberti wrote that the ancient Egyptians believed that alphabetical languages would one day all be lost, but the pictorial method of writing they used could be understood easily by intellectuals everywhere and far into the future. Amidst a renewed appreciation of ancient Egyptian hieroglyphics found on obelisks in Italy and the discovery of Horapollo’s Hieroglyphica, which purported to translate the language, Renaissance humanists like Alberti developed an obsession with this ancient form of non-alphabetical writing. Additionally, a growing awareness of the lost language of their Etruscan ancestors further ignited an anxiety among Italian humanists that their own ideas might one day become unintelligible. As Egyptomania spread through the Italian peninsula, some saw an answer to their fears in the pictorial hieroglyphics of the ancient Egyptians, for they perceived, in Egyptian writing, the potential for a universal language. Thus, many created Renaissance hieroglyphs based on those of the Egyptians. This essay examines the successes and failures of these neo-hieroglyphs, which early modern humanists and artists created hoping that a language divorced from alphabetical text might better convey the memory of their names and contributions to posterity.
Application of the NCAR FastEddy® Microscale Model to a Lake Breeze Front
Authors: Welch Brittany M. , Horel John D. , Sauer Jeremy A.
Published: July 2024

This study investigates how urban environments influence boundary layer processes during the passage of a Great Salt Lake breeze using a multi-scale modeling system, NCAR’s WRF-Coupled GPU-accelerated FastEddy® (FE) model. Motivated by the need for sub-10 m scale decision support tools for uncrewed aerial systems (UAS), the FE model was used to simulate turbulent flows around urban structures at 5 m horizontal resolution with a 9 km × 9 km domain centered on the Salt Lake City International Airport. FE was one-way nested within a 1 km resolution Weather Research and Forecasting (WRF) domain spanning 400 × 400 km. Focused on the late morning lake breeze on 3 June 2022, an FE simulation was compared with WRF outputs and validated using surface and radar observations. The FE simulation revealed low sensible heat flux and cool near-surface temperatures, attributed to a relatively low specification of thermal roughness suitable for previously tested FE applications. Lake breeze characteristics were minimally affected, as FE effectively resolved interactions between the lake breeze and urban-induced turbulent eddies, providing insights into fine-scale boundary layer processes. FE’s GPU acceleration ensured efficient simulations, underscoring its potential for aiding decision support in UAS operations in complex urban environments.
Sundowner Winds at Montecito during the Sundowner Winds Experiment
Authors: Fovell Robert G. , Brewer Matthew J.
Published: July 2024

This study investigates the predictability of downslope windstorms located in Santa Barbara County, California, locally referred to as Sundowner winds, from both observed relationships and a high-resolution, operational numerical weather prediction model. We focus on April 2022, during which the Sundowner Winds Experiment (SWEX) was conducted. We further refine our study area to the Montecito region owing to some of the highest wind measurements occurring at or near surface station MTIC1, situated on the coast-facing slope overlooking the area. Fires are not uncommon in this area, and the difficulty of egress makes the population particularly vulnerable. Area forecasters often use the sea-level pressure difference (ΔSLP) between Santa Barbara Airport (KSBA) and locations to the north such as Bakersfield (KBFL) to predict Sundowner windstorm occurrence. Our analysis indicates that ΔSLP by itself is prone to high false alarm rates and offers little information regarding downslope wind onset, duration, or magnitude. Additionally, our analysis shows that the high-resolution rapid refresh (HRRR) model has limited predictive skill overall for forecasting winds in the Montecito area. The HRRR, however, skillfully predicts KSBA-KBFL ΔSLP, as does GraphCast, a machine learning weather prediction model. Using a logistic regression model we were able to predict the occurrence of winds exceeding 9 m s−1 with a high probability of detection while minimizing false alarm rates compared to other methods analyzed. This provides a refined and easily computed algorithm for operational applications.
Effects of Aluminum/Carbon and Morphology on Optical Characteristics and Radiative Forcing of Alumina Clusters Emitted by Solid Rockets in the Stratosphere
Authors: Xu Yueyuan , Bai Lu , Bai Jingyu , Guo Lixin
Published: July 2024

Alumina (Al2O3) particles, the primary combustion products of solid rockets, can accumulate in the stratosphere, changing the global radiative balance. These Al2O3 particles were usually treated as homogeneous spheres. However, they contain impurities and may form clusters during the combustion process. Models representing Al-containing and C-containing Al2O3 clusters were developed, denoted as Al2O3 shell model (ASM) and Al2O3 core model (ACM), respectively. The superposition T-matrix method (STMM) was applied to examine their optical characteristics. Subsequently, a method to obtain the top-of-atmosphere flux was proposed by integrating the models with the moderate resolution atmospheric transmission code (MODTRAN). With the addition of Al/C, the absorption cross-section enhances by several orders of magnitude at 0.55 μm and increases slightly at 10 μm. The equivalent sphere models will weaken their scattering ability. A 4Tg mass burden of Al2O3 produces radiative forcing of −0.439 Wm−2. However, the addition of Al and C reduces the forcing by up to 15% and 12%, respectively. In summary, the optical characteristics and radiative forcing of Al2O3 clusters are sensitive to Al/C and morphology models. While our findings are impacted by various uncertainties, they contribute valuable insights into the radiative forcing of Al2O3 particles, potential climatic changes by space activities.
Flood Forecasting through Spatiotemporal Rainfall in Hilly Watersheds
Authors: Liu Yuanyuan , Liu Yesen , Liu Yang , Liu Zhengfeng , Yang Weitao , Li Kuang
Published: July 2024

Flood prediction in hilly regions, characterized by rapid flow rates and high destructive potential, remains a significant challenge. This study addresses this problem by introducing a novel machine learning-based approach to enhance flood forecast accuracy and lead time in small watersheds within hilly terrain. The study area encompasses small watersheds of approximately 600 km2. The proposed method analyzes spatiotemporal characteristics in rainfall dynamics to identify historical rainfall–flood events that closely resemble current patterns, effectively “learning from the past to predict the present”. The approach demonstrates notable precision, with an average error of 8.33% for peak flow prediction, 14.27% for total volume prediction, and a lead time error of just 1 h for peak occurrence. These results meet the stringent accuracy requirements for flood forecasting, offering a targeted and effective solution for flood forecasting in challenging hilly terrains. This innovative methodology deviates from conventional techniques by adopting a holistic view of rainfall trends, representing a significant advancement in addressing the complexities of flood prediction in these regions.
Achieving Optimal Order in a Novel Family of Numerical Methods: Insights from Convergence and Dynamical Analysis Results
Authors: Moscoso-Martínez Marlon , Chicharro Francisco I. , Cordero Alicia , Torregrosa Juan R. , Ureña-Callay Gabriela
Published: July 2024

In this manuscript, we introduce a novel parametric family of multistep iterative methods designed to solve nonlinear equations. This family is derived from a damped Newton’s scheme but includes an additional Newton step with a weight function and a “frozen” derivative, that is, the same derivative than in the previous step. Initially, we develop a quad-parametric class with a first-order convergence rate. Subsequently, by restricting one of its parameters, we accelerate the convergence to achieve a third-order uni-parametric family. We thoroughly investigate the convergence properties of this final class of iterative methods, assess its stability through dynamical tools, and evaluate its performance on a set of test problems. We conclude that there exists one optimal fourth-order member of this class, in the sense of Kung–Traub’s conjecture. Our analysis includes stability surfaces and dynamical planes, revealing the intricate nature of this family. Notably, our exploration of stability surfaces enables the identification of specific family members suitable for scalar functions with a challenging convergence behavior, as they may exhibit periodical orbits and fixed points with attracting behavior in their corresponding dynamical planes. Furthermore, our dynamical study finds members of the family of iterative methods with exceptional stability. This property allows us to converge to the solution of practical problem-solving applications even from initial estimations very far from the solution. We confirm our findings with various numerical tests, demonstrating the efficiency and reliability of the presented family of iterative methods.
A Method for Calculating the Reliability of 2-Separable Networks and Its Applications
Authors: Liang Jing , Zhao Haixing , Xie Sun
Published: July 2024

This paper proposes a computational method for the reliability of 2-separable networks. Based on graph theory and probability theory, this method simplifies the calculation process by constructing a network equivalent model and designing corresponding algorithms to achieve the efficient evaluation of reliability. Considering independent random failures of edges with equal probability q, this method can accurately calculate the reliability of 2-separable networks, and its effectiveness and accuracy are verified through examples. In addition, to demonstrate the generality of our method, we have also applied it to other 2-separable networks with fractal structures and proposed linear algorithms for calculating their all-terminal reliability.
The Split Equality Fixed-Point Problem and Its Applications
Authors: Mohammed Lawan Bulama , Kilicman Adem
Published: July 2024

It is generally known that in order to solve the split equality fixed-point problem (SEFPP), it is necessary to compute the norm of bounded and linear operators, which is a challenging task in real life. To address this issue, we studied the SEFPP involving a class of quasi-pseudocontractive mappings in Hilbert spaces and constructed novel algorithms in this regard, and we proved the algorithms’ convergences both with and without prior knowledge of the operator norm for bounded and linear mappings. Additionally, we gave applications and numerical examples of our findings. A variety of well-known discoveries revealed in the literature are generalized by the findings presented in this work.
Experimental Investigation on Thermal Runaway of Lithium-Ion Batteries under Low Pressure and Low Temperature
Authors: Meng Di , Weng Jingwen , Wang Jian
Published: July 2024

Understanding the thermal runaway mechanism of lithium-ion batteries under low pressure and low temperature is paramount for their application and transportation in the aviation industry. This work investigated the coupling effects of ambient pressure (100 kPa, 70 kPa, 40 kPa) and ambient temperature (−15 °C, 0 °C, 25 °C) on thermal behaviors in an altitude temperature chamber. The experimental results indicate that lowering ambient pressure and temperature could attenuate the thermal runaway intensity, which is mainly attributable to the reduction in oxygen concentration and the increase in heat loss. Such a dual effect leads to the maximum temperature decreasing from 811.9 °C to 667.5 °C, and the maximum temperature rate declines up to 2.6 times. Correspondingly, the whole thermal runaway process is deferred, the total time increases from 370 s to 503 s, and the time interval, Δt, from safety venting gains by 32.3% as the ambient pressure and temperature decrease. This work delivers an in-depth understanding of the thermal characteristics under low pressure and low temperature and provides meritorious guidance for the safety of cell transportation in aviation.
Reshaping Bioacoustics Event Detection: Leveraging Few-Shot Learning (FSL) with Transductive Inference and Data Augmentation
Authors: Ijaz Nouman , Banoori Farhad , Koo Insoo
Published: July 2024

Bioacoustic event detection is a demanding endeavor involving recognizing and classifying the sounds animals make in their natural habitats. Traditional supervised learning requires a large amount of labeled data, which are hard to come by in bioacoustics. This paper presents a few-shot learning (FSL) method incorporating transductive inference and data augmentation to address the issues of too few labeled events and small volumes of recordings. Here, transductive inference iteratively alters class prototypes and feature extractors to seize essential patterns, whereas data augmentation applies SpecAugment on Mel spectrogram features to augment training data. The proposed approach is evaluated by using the Detecting and Classifying Acoustic Scenes and Events (DCASE) 2022 and 2021 datasets. Extensive experimental results demonstrate that all components of the proposed method achieve significant F-score improvements of 27% and 10%, for the DCASE-2022 and DCASE-2021 datasets, respectively, compared to recent advanced approaches. Moreover, our method is helpful in FSL tasks because it effectively adapts to sounds from various animal species, recordings, and durations.
The Involvement of microRNAs in Bone Remodeling Signaling Pathways and Their Role in the Development of Osteoporosis
Authors: Jiménez-Ortega Rogelio F. , Ortega-Meléndez Alejandra I. , Patiño Nelly , Rivera-Paredez Berenice , Hidalgo-Bravo Alberto , Velázquez-Cruz Rafael
Published: July 2024

Bone remodeling, crucial for maintaining the balance between bone resorption and formation, relies on the coordinated activity of osteoclasts and osteoblasts. During osteoclastogenesis, hematopoietic stem cells (HSCs) differentiate into the osteoclast lineage through the signaling pathways OPG/RANK/RANKL. On the other hand, during osteoblastogenesis, mesenchymal stem cells (MSCs) differentiate into the osteoblast lineage through activation of the signaling pathways TGF-β/BMP/Wnt. Recent studies have shown that bone remodeling is regulated by post-transcriptional mechanisms including microRNAs (miRNAs). miRNAs are small, single-stranded, noncoding RNAs approximately 22 nucleotides in length. miRNAs can regulate virtually all cellular processes through binding to miRNA-response elements (MRE) at the 3’ untranslated region (3′UTR) of the target mRNA. miRNAs are involved in controlling gene expression during osteogenic differentiation through the regulation of key signaling cascades during bone formation and resorption. Alterations of miRNA expression could favor the development of bone disorders, including osteoporosis. This review provides a general description of the miRNAs involved in bone remodeling and their significance in osteoporosis development.
Biosynthesis and Pharmacological Activities of the Bioactive Compounds of White Mulberry (Morus alba): Current Paradigms and Future Challenges
Authors: Fatima Maryam , Dar Mudasir A. , Dhanavade Maruti J. , Abbas Syed Zaghum , Bukhari Mohd Nadeem , Arsalan Abdullah , Liao Yangzhen , Wan Jingqiong , Shah Syed Bukhari Jehangir , Ouyang Zhen
Published: July 2024

Traditional natural products have been the focus of research to explore their medicinal properties. One such medicinally important plant is the white mulberry, Morus alba, widely distributed in the Asian subcontinent. It is one of the most cultivated species of mulberry tree and has attracted more focus from researchers because of its abundance in phytochemicals as well as multipurpose uses. The leaves, fruits and other parts of the white mulberry plant act as a source of valuable bioactive compounds like flavonoids, phenolic acids, terpenoids and alkaloids. These secondary metabolites have manifold healthy uses as they possess antioxidant, anti-inflammatory, antidiabetic, neutrotrophic, and anticancer properties. Despite the increasing scientific interest in this plant, there are very few reviews that highlight the phytochemistry and biological potential of white mulberry for biomedical research. To this end, this review elaborates the phytochemistry, biosynthetic pathways and pharmacological activities of the glycoside flavonoids of Morus alba. A comprehensive analysis of the available literature indicates that Morus alba could emerge as a promising natural agent to combat diverse conditions including diabetes, cancer, inflammation and infectious diseases. To achieve such important objectives, it is crucial to elucidate the biosynthesis and regulation mechanisms of the bioactive compounds in white mulberry as well as the multifaceted pharmacological effects attributed to this plant resource. The present review paper is intended to present a summary of existing scientific data and a guide for further research in the phytochemistry and pharmacology of white mulberry. Further, a biosynthetic pathway analysis of the glycoside flavonoid in mulberry is also given. Lastly, we discuss the pros and cons of the current research to ensure the prudent and effective therapeutic value of mulberry for promoting human and animal health.
OCRL1 Deficiency Affects the Intracellular Traffic of ApoER2 and Impairs Reelin-Induced Responses
Authors: Fuentealba Luz M. , Pizarro Héctor , Marzolo María-Paz
Published: July 2024

Lowe Syndrome (LS) is a rare X-linked disorder characterized by renal dysfunction, cataracts, and several central nervous system (CNS) anomalies. The mechanisms underlying the neurological dysfunction in LS remain unclear, albeit they share some phenotypic characteristics similar to the deficiency or dysfunction of the Reelin signaling, a relevant pathway with roles in CNS development and neuronal functions. In this study, we investigated the role of OCRL1, an inositol polyphosphate 5-phosphatase encoded by the OCRL gene, mutated in LS, focusing on its impact on endosomal trafficking and receptor recycling in human neuronal cells. Specifically, we tested the effects of OCRL1 deficiency in the trafficking and signaling of ApoER2/LRP8, a receptor for the ligand Reelin. We found that loss of OCRL1 impairs ApoER2 intracellular trafficking, leading to reduced receptor expression and decreased levels at the plasma membrane. Additionally, human neurons deficient in OCRL1 showed impairments in ApoER2/Reelin-induced responses. Our findings highlight the critical role of OCRL1 in regulating ApoER2 endosomal recycling and its impact on the ApoER2/Reelin signaling pathway, providing insights into potential mechanisms underlying the neurological manifestations of LS.
Forces Bless You: Mechanosensitive Piezo Channels in Gastrointestinal Physiology and Pathology
Authors: Guo Jing , Li Li , Chen Feiyi , Fu Minhan , Cheng Cheng , Wang Meizi , Hu Jun , Pei Lixia , Sun Jianhua
Published: July 2024

The gastrointestinal (GI) tract is an organ actively involved in mechanical processes, where it detects forces via a mechanosensation mechanism. Mechanosensation relies on specialized cells termed mechanoreceptors, which convert mechanical forces into electrochemical signals via mechanosensors. The mechanosensitive Piezo1 and Piezo2 are widely expressed in various mechanosensitive cells that respond to GI mechanical forces by altering transmembrane ionic currents, such as epithelial cells, enterochromaffin cells, and intrinsic and extrinsic enteric neurons. This review highlights recent research advances on mechanosensitive Piezo channels in GI physiology and pathology. Specifically, the latest insights on the role of Piezo channels in the intestinal barrier, GI motility, and intestinal mechanosensation are summarized. Additionally, an overview of Piezo channels in the pathogenesis of GI disorders, including irritable bowel syndrome, inflammatory bowel disease, and GI cancers, is provided. Overall, the presence of mechanosensitive Piezo channels offers a promising new perspective for the treatment of various GI disorders.
HL156A, an AMP-Activated Protein Kinase Activator, Inhibits Cyst Growth in Autosomal Dominant Polycystic Kidney Disease
Authors: Seo Sujung , Kim Hyunho , Hwang Jung-Taek , Kim Jin Eop , Kim Jisu , Jeon Sohyun , Song Young-jin , Choi Kwang-ho , Sim Gwangeon , Cho Myunkyu , Yoon Jong-woo , Kim Hyunsuk
Published: July 2024

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disorder. While metformin has demonstrated the ability to inhibit cyst growth in animal models of ADPKD via activation of adenosine monophosphate-activated protein kinase (AMPK), its effectiveness in humans is limited due to its low potency. This study explored the impact of HL156A, a new and more potent AMPK activator, in a mouse model of ADPKD. Methods: To investigate whether HL156A inhibits the proliferation of renal cyst cells in ADPKD in vitro, exogenous human telomerase reverse transcriptase (hTERT)-immortalized renal cyst cells from ADPKD patients were treated with HL156A, and an MTT (dimethylthiazol-diphenyltetrazolium bromide) assay was performed. To assess the cyst-inhibitory effect of HL156A in vivo, we generated Pkd1 conditional knockout (KO) mice with aquaporin 2 (AQP2)-Cre, which selectively expresses Cre recombinase in the collecting duct. The effectiveness of HL156A in inhibiting cyst growth and improving renal function was confirmed by measuring the number of cysts and blood urea nitrogen (BUN) levels in the collecting duct-specific Pkd1 KO mice. Results: When cyst cells were treated with up to 20 µM of metformin or HL156A, HL156A reduced cell viability by 25% starting at a concentration of 5 µM, whereas metformin showed no effect. When AQP2-Cre male mice were crossed with Pkd1flox/flox female mice, and when AQP2-Cre female mice were crossed with Pkd1flox/flox male mice, the number of litters produced by both groups was comparable. In collecting duct-specific Pkd1 KO mice, HL156A was found to inhibit cyst growth, reducing both the number and size of cysts. Furthermore, it was confirmed that kidney function improved as HL156A treatment led to a reduction in elevated BUN levels. Lastly, it was observed that the increase in AMPK phosphorylation induced by HL156A decreased ERK phosphorylation and α-SMA expression. Conclusion: HL156A has potential as a drug that can restore kidney function in ADPKD patients by inhibiting cyst growth.
Isolation and Characterization of Milk Exosomes for Use in Advanced Therapies
Authors: Medel-Martinez Ana , Redrado-Osta Ana , Crespo-Barreda Alejandra , Sancho-Albero Maria , Sánchez Lourdes , Sebastián Víctor , Pardo María , de la Vieja Antonio , Martín-Duque Pilar
Published: July 2024

Exosomes are cell-derived extracellular vesicles (EVs) with diameters between 30 and 120 nm. In recent years, several studies have evaluated the therapeutic potential of exosomes derived from different fluids due to their low immunogenicity and high biocompatibility. However, producing exosomes on a large scale is still challenging. One of the fluids from which they could be isolated in large quantities is milk. Moreover, regeneration is a well-known property of milk. The present work seeks to optimize a method for isolating exosomes from bovine and human milk, comparing different storage conditions and different extraction protocols. We found differences in the yield extraction associated with pre-storage milk conditions and observed some differences according to the processing agent. When we removed milk fat globules and added rennet before freezing, we obtained a cleaner final fraction. In summary, we attempted to optimize a rennet-based new milk–exosome isolation method and concluded that pre-treatment, followed by freezing of samples, yielded the best exosome population.
The Cell-Penetrating Peptide GV1001 Enhances Bone Formation via Pin1-Mediated Augmentation of Runx2 and Osterix Stability
Authors: Piao Meiyu , Lee Sung Ho , Hwang Jin Wook , Kim Hyung Sik , Han Youn Ho , Lee Kwang Youl
Published: July 2024

Peptide-based drug development is a promising direction due to its excellent biological activity, minimal immunogenicity, high in vivo stability, and efficient tissue penetrability. GV1001, an amphiphilic peptide, has proven effective as an anti-cancer vaccine, but its effect on osteoblast differentiation is unknown. To identify proteins interacting with GV1001, biotin-conjugated GV1001 was constructed and confirmed by mass spectrometry. Proteomic analyses were performed to determine GV1001’s interaction with osteogenic proteins. GV1001 was highly associated with peptidyl-prolyl isomerase A and co-immunoprecipitation assays revealed that GV1001 bound to peptidyl-prolyl cis-trans isomerase 1 (Pin1). GV1001 significantly increased alkaline phosphatase (ALP) activity, bone nodule formation, and the expression of osteogenic gene markers. GV1001-induced osteogenic activity was enhanced by Pin1 overexpression and abolished by Pin1 knockdown. GV1001 increased the protein stability and transcriptional activity of Runx2 and Osterix. Importantly, GV1001 administration enhanced bone mass density in the OVX mouse model, as verified by µCT analysis. GV1001 demonstrated protective effects against bone loss in OVX mice by upregulating osteogenic differentiation via the Pin1-mediated protein stabilization of Runx2 and Osterix. GV1001 could be a potential candidate with anabolic effects for the prevention and treatment of osteoporosis.
Impact of Different Red Blood Cell Storage Solutions and Conditions on Cell Function and Viability: A Systematic Review
Authors: Tran Linh Nguyen T. , González-Fernández Cristina , Gomez-Pastora Jenifer
Published: July 2024

Red blood cell (RBC) storage solutions have evolved significantly over the past decades to optimize the preservation of cell viability and functionality during hypothermic storage. This comprehensive review provides an in-depth analysis of the effects of various storage solutions and conditions on critical RBC parameters during refrigerated preservation. A wide range of solutions, from basic formulations such as phosphate-buffered saline (PBS), to advanced additive solutions (ASs), like AS-7 and phosphate, adenine, glucose, guanosine, saline, and mannitol (PAGGSM), are systematically compared in terms of their ability to maintain key indicators of RBC integrity, including adenosine triphosphate (ATP) levels, morphology, and hemolysis. Optimal RBC storage requires a delicate balance of pH buffering, metabolic support, oxidative damage prevention, and osmotic regulation. While the latest alkaline solutions enable up to 8 weeks of storage, some degree of metabolic and morphological deterioration remains inevitable. The impacts of critical storage conditions, such as the holding temperature, oxygenation, anticoagulants, irradiation, and processing methods, on the accumulation of storage lesions are also thoroughly investigated. Personalized RBC storage solutions, tailored to individual donor characteristics, represent a promising avenue for minimizing storage lesions and enhancing transfusion outcomes. Further research integrating omics profiling with customized preservation media is necessary to maximize post-transfusion RBC survival and functions. The continued optimization of RBC storage practices will not only enhance transfusion efficacy but also enable blood banking to better meet evolving clinical needs.
A Mini-Review of Diagnostic Methods for the Antigen and Antibody Detection of Rocky Mountain and Brazilian Spotted Fever
Authors: Silva Kamila Alves , Prado Vanesa Borges do , Silva Rafael Rodrigues , Rocha Marcelo van Petten , de Oliveira Rafael Almeida Ribeiro , Falcão Tarumim de Jesus Rodrigues , Serpa Clara Cristina , Rocha Marina Andrade , Pereira Sabrina Paula , Silva Líria Souza , Machado Juliana Martins , Machado-de-Ávila Ricardo Andrez , Fujiwara Ricardo Toshio , Chávez-Fumagalli Miguel Angel , Coelho Eduardo Antônio Ferraz , Giunchetti Rodolfo Cordeiro , Campos-da-Paz Mariana , Gonçalves Ana Alice Maia , Galdino Alexsandro Sobreira
Published: July 2024

Rocky Mountain or Brazilian spotted fever, caused by Rickettsia rickettsii, is a fulminant, seasonal, and neglected disease that occurs in focal points of North America and South America. Its rapid detection is essential for the better prognosis and survival rate of infected individuals. However, disease diagnosis still faces challenges as the accuracy of many of the available laboratory tests fluctuates. This review aimed to analyze methods for antibody or antigen detection, their gaps, and their evolution over time. A search was conducted to find all studies in the Pubmed database that described the antibody or antigen detection of R. rickettsii infections. Initially, a total of 403 articles were screened. Of these articles, only 17 fulfilled the pre-established inclusion criteria and were selected. Among the different methods applied, the IFA technique was the one most frequently found in the studies. However, it presented varied results such as a low specificity when using the indirect method. Other techniques, such as ELISA and immunohistochemistry, were also found, although in smaller numbers and with their own limitations. Although some studies showed promising results, there is a pressing need to find new techniques to develop a rapid and effective diagnosis of R. rickettssi infection.
Reducing Oxidative Stress-Mediated Alcoholic Liver Injury by Multiplexed RNAi of Cyp2e1, Cyp4a10, and Cyp4a14
Authors: Zhang Qi , Wu Shuang , Chen Qiubing , Zhang Yahong , Zhang Cai , Yin Runting , Ouyang Zhen , Wei Yuan
Published: July 2024

The prevalence of excessive drinking-related alcoholic liver disease (ALD) is rising, yet therapeutic options remain limited. High alcohol consumption and consequent oxidative metabolism by cytochrome P450 (CYP) can lead to extremely high levels of reactive oxygen species, which overwhelm cellular defenses and harm hepatocytes. Our previous investigations showed that inhibiting Cyp2e1 using RNA interference reduced the incidence of ALD. However, compensatory mechanisms other than CYP2E1 contribute to oxidative stress in the liver. Therefore, we coupled triple siRNA lipid nanoparticles (LNPs) targeting Cyp2e1 with two isoenzymes Cyp4a10 and Cyp4a14 to treat ALD mouse models fed with Lieber–Decarli ethanol liquid diet for 12 weeks at the early (1st week), middle (5th week), and late (9th week) stages. The administration of triple siRNA LNPs significantly ameliorated chronic alcoholic liver injury in mice, and early treatment achieved the most profound effects. These effects can be attributed to a reduction in oxidative stress and increased expression of antioxidant genes, including Gsh-Px, Gsh-Rd, and Sod1. Moreover, we observed the alleviation of inflammation, evidenced by the downregulation of Il-1β, Il-6, Tnf-α, and Tgf-β, and the prevention of excessive lipid synthesis, evidenced by the restoration of the expression of Srebp1c, Acc, and Fas. Finally, triple siRNA treatment maintained normal metabolism in lipid oxidation. In brief, our research examined the possible targets for clinical intervention in ALD by examining the therapeutic effects of triple siRNA LNPs targeting Cyp2e1, Cyp4a10, and Cyp4a14. The in vivo knockdown of the three genes in this study is suggested as a promising siRNA therapeutic approach for ALD.
Impact of SGLT2 Inhibitors on Very Elderly Population with Heart Failure with Reduce Ejection Fraction: Real Life Data
Authors: Balaguer Germán Jorge , Cortés García Marcelino , Rodríguez López Carlos , Romero Otero Jose María , Esteban Chapel Jose Antonio , Bollas Becerra Antonio José , Nieto Roca Luis , Taibo Urquía Mikel , Pello Lázaro Ana María , Tuñón Fernández José
Published: July 2024

(1) Background: The validation of new lines of therapy for the elderly is required due to the progressive ageing of the world population and scarce evidence in elderly patients with HF with reduced ejection fraction (HFrEF). The purpose of our study is to analyze the effect of SGLT2 inhibitors (SGLT2i) in this subgroup of patients. (2) Methods: A single-center, real-world observational study was performed. We consecutively enrolled all patients aged ≥ 75 years diagnosed with HFrEF and for treatment with SGLT2i, and considered the theoretical indications. (3) Results: A total of 364 patients were recruited, with a mean age of 84.1 years. At inclusion, the mean LVEF was 29.8%. Median follow-up was 33 months, and there were 122 deaths. A total of 55 patients were under SGLT2i treatment. A multivariate Cox logistic regression test for all-cause mortality was performed, and only SGLT2i (HR 0.39 [0.19–0.82]) and glomerular filtration rate (HR 0.98 [0.98–0.99]) proved to be protective factors. In parallel, we conducted a propensity-score-matched analysis, where a significant reduction in all-cause mortality was associated with the use of SGLT2i treatment (HR 0.39, [0.16–0.97]). (4) Conclusions: Treatment with SGLT2i in elderly patients with HFrEF was associated with a lower rate of all-cause mortality. Our data show that SGLT2i therapy could improve prognosis in the elderly with HFrEF in a real-world study.
MUC1-C Dependence for the Progression of Pancreatic Neuroendocrine Tumors Identifies a Druggable Target for the Treatment of This Rare Cancer
Authors: Ozawa Hiroki , Haratake Naoki , Nakashoji Ayako , Daimon Tatsuaki , Bhattacharya Atrayee , Wang Keyi , Shigeta Keisuke , Fushimi Atsushi , Fukuda Kazumasa , Masugi Yohei , Yamaguchi Ryo , Kitago Minoru , Kawakubo Hirofumi , Kitagawa Yuko , Kufe Donald
Published: July 2024

Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.
Design of Alginate/Gelatin Hydrogels for Biomedical Applications: Fine-Tuning Osteogenesis in Dental Pulp Stem Cells While Preserving Other Cell Behaviors
Authors: Ferjaoui Zied , López-Muñoz Roberto , Akbari Soheil , Chandad Fatiha , Mantovani Diego , Rouabhia Mahmoud , D. Fanganiello Roberto
Published: July 2024

Alginate/gelatin (Alg-Gel) hydrogels have been used experimentally, associated with mesenchymal stromal/stem cells (MSCs), to guide bone tissue formation. One of the main challenges for clinical application is optimizing Alg-Gel stiffness to guide osteogenesis. In this study, we investigated how Alg-Gel stiffness could modulate the dental pulp stem cell (DPSC) attachment, morphology, proliferation, and osteogenic differentiation, identifying the optimal conditions to uncouple osteogenesis from the other cell behaviors. An array of Alg-Gel hydrogels was prepared by casting different percentages of alginate and gelatin cross-linked with 2% CaCl2. We have selected two hydrogels: one with a stiffness of 11 ± 1 kPa, referred to as “low-stiffness hydrogel”, formed by 2% alginate and 8% gelatin, and the other with a stiffness of 55 ± 3 kPa, referred to as “high-stiffness hydrogel”, formed by 8% alginate and 12% gelatin. Hydrogel analyses showed that the average swelling rates were 20 ± 3% for the low-stiffness hydrogels and 35 ± 2% for the high-stiffness hydrogels. The degradation percentage was 47 ± 5% and 18 ± 2% for the low- and high-stiffness hydrogels, respectively. Both hydrogel types showed homogeneous surface shape and protein (Alg-Gel) interaction with CaCl2 as assessed by physicochemical characterization. Cell culture showed good adhesion of the DPSCs to the hydrogels and proliferation. Furthermore, better osteogenic activity, determined by ALP activity and ARS staining, was obtained with high-stiffness hydrogels (8% alginate and 12% gelatin). In summary, this study confirms the possibility of characterizing and optimizing the stiffness of Alg-Gel gel to guide osteogenesis in vitro without altering the other cellular properties of DPSCs.
Exploring the Role of Neutrophil-Related Genes in Osteosarcoma via an Integrative Analysis of Single-Cell and Bulk Transcriptome
Authors: Lu Jing , Rui Jiang , Xu Xiao-Yu , Shen Jun-Kang
Published: July 2024

Background: The involvement of neutrophil-related genes (NRGs) in patients with osteosarcoma (OS) has not been adequately explored. In this study, we aimed to examine the association between NRGs and the prognosis as well as the tumor microenvironment of OS. Methods: The OS data were obtained from the TARGET-OS and GEO database. Initially, we extracted NRGs by intersecting 538 NRGs from single-cell RNA sequencing (scRNA-seq) data between aneuploid and diploid groups, as well as 161 up-regulated differentially expressed genes (DEGs) from the TARGET-OS datasets. Subsequently, we conducted Least Absolute Shrinkage and Selection Operator (Lasso) analyses to identify the hub genes for constructing the NRG-score and NRG-signature. To assess the prognostic value of the NRG signatures in OS, we performed Kaplan–Meier analysis and generated time-dependent receiver operating characteristic (ROC) curves. Gene enrichment analysis (GSEA) and gene set variation analysis (GSVA) were utilized to ascertain the presence of tumor immune microenvironments (TIMEs) and immunomodulators (IMs). Additionally, the KEGG neutrophil signaling pathway was evaluated using ssGSEA. Subsequently, PCR and IHC were conducted to validate the expression of hub genes and transcription factors (TFs) in K7M2-induced OS mice. Results: FCER1G and C3AR1 have been identified as prognostic biomarkers for overall survival. The findings indicate a significantly improved prognosis for OS patients. The effectiveness and precision of the NRG signature in prognosticating OS patients were validated through survival ROC curves and an external validation dataset. The results clearly demonstrate that patients with elevated NRG scores exhibit decreased levels of immunomodulators, stromal score, immune score, ESTIMATE score, and infiltrating immune cell populations. Furthermore, our findings substantiate the potential role of SPI1 as a transcription factor in the regulation of the two central genes involved in osteosarcoma development. Moreover, our analysis unveiled a significant correlation and activation of the KEGG neutrophil signaling pathway with FCER1G and C3AR1. Notably, PCR and IHC demonstrated a significantly higher expression of C3AR1, FCER1G, and SPI1 in Balb/c mice induced with K7M2. Conclusions: Our research emphasizes the significant contribution of neutrophils within the TIME of osteosarcoma. The newly developed NRG signature could serve as a good instrument for evaluating the prognosis and therapeutic approach for OS.