bluuebunny/crossref_metadata_2025 huggingface dataset:
An Energy Focusing-Based Scanning and Localization Method for Shallow Underground Explosive Sources
Authors: Wu Dan , Wang Liming , Li Jian
Published: September 2023

To address the problem of slow speed and low accuracy for recognizing and locating the explosive source in complex shallow underground blind spaces, this paper proposes an energy-focusing-based scanning and localization method. First, the three-dimensional (3D) energy field formed by the source explosion is reconstructed using the energy-focusing properties of the steered response power (SRP) localization model, and the velocity field is calculated based on a multilayered stochastic medium model by considering the random statistical characteristics of the medium. Then, a power function factor is introduced to quantum particle swarm optimization (QPSO) to search for and solve the above energy field and to approach the real location of the energy focus point. Additionally, the initial population is constructed based on the logistic chaos model to realize global traversal. Finally, extensive simulation results based on the real-world dataset show that compared to the baseline algorithm, the focusing accuracy of the energy field of the proposed scheme is improved by 117.20%, the root mean square error (RMSE) is less than 0.0551 m, the triaxial relative error (RE) is within 0.2595%, and the average time cost is reduced by 98.40%. It has strong advantages in global search capability and fast convergence, as well as robustness and generalization.
Sound Event Detection with Perturbed Residual Recurrent Neural Network
Authors: Yuan Shuang , Yang Lidong , Guo Yong
Published: September 2023

Sound event detection (SED) is of great practical and research significance owing to its wide range of applications. However, due to the heavy reliance on dataset size for task performance, there is often a severe lack of data in real-world scenarios. In this study, an improved mean teacher model is utilized to carry out semi-supervised SED, and a perturbed residual recurrent neural network (P-RRNN) is proposed as the SED network. The residual structure is employed to alleviate the problem of network degradation, and pre-training the improved model on the ImageNet dataset enables it to learn information that is beneficial for event detection, thus improving the performance of SED. In the post-processing stage, a customized median filter group with a specific window length is designed to effectively smooth each type of event and minimize the impact of background noise on detection accuracy. Experimental results conducted on the publicly available Detection and Classification of Acoustic Scenes and Events 2019 Task 4 dataset demonstrate that the P-RRNN used for SED in this study can effectively enhance the detection capability of the model. The detection system achieves a Macro Event-based F1 score of 38.8% on the validation set and 40.5% on the evaluation set, indicating that the proposed method can adapt to complex and dynamic SED scenarios.
Flood Disaster Assessment Method Based on a Stacked Denoising Autoencoder
Authors: Chen Yanping , Wang Yilun , Wu Zhize , Zou Le , Li Wenbo
Published: September 2023

In recent years, extreme weather has occurred frequently, and the risk of heavy rainfall and flooding faced by the people has risen. It is therefore an urgent requirement to carry out applied research on heavy rainfall and flooding risk assessment. We took Henan Province, where a major flood disaster occurred in 2021, as an example to analyze the impact factors of urban flooding and conduct a risk assessment. Indicators were first selected from population, housing, and the economy, and correlation analysis was used to optimize the indicator system. Then, a deep clustering network model based on a stacked denoising autoencoder (SDAE) was constructed, the feature information implied in the disaster indicators was abstracted into potential features through the coding and decoding of the network, and a small number of potential features were used to express the complex relationship between the disaster indicators. The results of the study show that the high-risk areas of flood damage in Henan Province in 2021 account for 2.3%, the medium-risk areas account for 9.4%, and the low-risk areas account for 80.3%. These evaluation results are in line with the actual situation in Henan Province, and the division of the grade in some areas is more reasonable compared with the entropy weighting method, which is a commonly used method of disaster assessment. The new model does not need to calculate weights to cope with changes in indicators and disaster conditions. The research results can provide scientific reference for urban flood risk management, disaster prevention and mitigation, and regional planning.
Sliding-Window TD-FrFT Algorithm for High-Precision Ranging of LFM Signals in the Presence of Impulse Noise
Authors: Xiao Bo , Liu Xuelian , Wang Chunyang , Wang Yuchao , Huang Tingsheng
Published: September 2023

To address the performance degradation of the conventional linear frequency modulation signal ranging method in the presence of impulse noise, this paper proposes a novel technique that integrates a sliding-window tracking differentiator (TD) with the fractional Fourier transform (FrFT) ranging method. First, the sliding-window TD filtering algorithm is used to suppress the noise in the echo. Subsequently, the filtered signal is subjected to FrFT to calculate the time delay based on the difference in the peak point positions in the fractional domain for realizing target ranging. The simulation results show that the proposed method can effectively suppress impulse noise of different intensities and achieve an accurate and robust ranging of the target.
Redesigning Graphical User Interface of Open-Source Geospatial Software in a Community-Driven Way: A Case Study of GRASS GIS
Authors: Karlovska Linda , Petrasova Anna , Petras Vaclav , Landa Martin
Published: September 2023

Learning to use geographic information system (GIS) software effectively may be intimidating due to the extensive range of features it offers. The GRASS GIS software, in particular, presents additional challenges for first-time users in terms of its complex startup procedure and unique terminology associated with its data structure. On the other hand, a substantial part of the GRASS user community including us as developers recognized and embraced the advantages of the current approach. Given the controversial nature of the whole issue, we decided to actively involve regular users by conducting several formal surveys and by performing usability testing. Throughout this process, we discovered that resolving specific software issues through pure user-centered design is not always feasible, particularly in the context of open-source scientific software where the boundary between users and developers is very fuzzy. To address this challenge, we adopted the user-centered methodology tailored to the requirements of open-source scientific software development, which we refer to as community-driven design. This paper describes the community-driven redesigning process on the GRASS GIS case study and sets a foundation for applying community-driven design in other open-source scientific projects by providing insights into effective software development practices driven by the needs and input of the project’s community.
Tyrosine Kinase Inhibitor Profiling Using Multiple Forskolin-Responsive Reporter Cells
Authors: Kasahara Yamato , Tamamura Sakura , Hiyama Gen , Takagi Motoki , Nakamichi Kazuya , Doi Yuta , Semba Kentaro , Watanabe Shinya , Ishikawa Kosuke
Published: September 2023

We have developed a highly sensitive promoter trap vector system using transposons to generate reporter cells with high efficiency. Using an EGFP/luciferase reporter cell clone responsive to forskolin, which is thought to activate adenylate cyclase, isolated from human chronic myelogenous leukemia cell line K562, we found several compounds unexpectedly caused reporter responses. These included tyrosine kinase inhibitors such as dasatinib and cerdulatinib, which were seemingly unrelated to the forskolin-reactive pathway. To investigate whether any other clones of forskolin-responsive cells would show the same response, nine additional forskolin-responsive clones, each with a unique integration site, were generated and quantitatively evaluated by luciferase assay. The results showed that each clone represented different response patterns to the reactive compounds. Also, it became clear that each of the reactive compounds could be profiled as a unique pattern by the 10 reporter clones. When other TKIs, mainly bcr-abl inhibitors, were evaluated using a more focused set of five reporter clones, they also showed unique profiling. Among them, dasatinib and bosutinib, and imatinib and bafetinib showed homologous profiling. The tyrosine kinase inhibitors mentioned above are approved as anticancer agents, and the system could be used for similarity evaluation, efficacy prediction, etc., in the development of new anticancer agents.
The Hemostatic System in Newborns and the Risk of Neonatal Thrombosis
Authors: Khizroeva Jamilya , Makatsariya Alexander , Vorobev Alexander , Bitsadze Victoria , Elalamy Ismail , Lazarchuk Arina , Salnikova Polina , Einullaeva Sabina , Solopova Antonina , Tretykova Maria , Antonova Alexandra , Mashkova Tamara , Grigoreva Kristina , Kvaratskheliia Margaret , Yakubova Fidan , Degtyareva Natalia , Tsibizova Valentina , Gashimova Nilufar , Blbulyan David
Published: September 2023

Newborns are the most vulnerable patients for thrombosis development among all children, with critically ill and premature infants being in the highest risk group. The upward trend in the rate of neonatal thrombosis could be attributed to progress in the treatment of severe neonatal conditions and the increased survival in premature babies. There are physiological differences in the hemostatic system between neonates and adults. Neonates differ in concentrations and rate of synthesis of most coagulation factors, turnover rates, the ability to regulate thrombin and plasmin, and in greater variability compared to adults. Natural inhibitors of coagulation (protein C, protein S, antithrombin, heparin cofactor II) and vitamin K-dependent coagulation factors (factors II, VII, IX, X) are low, but factor VIII and von Willebrand factor are elevated. Newborns have decreased fibrinolytic activity. In the healthy neonate, the balance is maintained but appears more easily converted into thrombosis. Neonatal hemostasis has less buffer capacity, and almost 95% of thrombosis is provoked. Different triggering risk factors are responsible for thrombosis in neonates, but the most important risk factors for thrombosis are central catheters, fluid fluctuations, liver dysfunction, and septic and inflammatory conditions. Low-molecular-weight heparins are the agents of choice for anticoagulation.
A Comprehensive Genome-Wide Association Study of Carotenoid and Capsaicinoid Contents in Capsicum chinense Germplasm
Authors: Haile Mesfin , Ro Nayoung , Ko Ho-Cheol , Oh Hyeonseok , Lee Gi-An
Published: September 2023

Pepper is a highly important vegetable globally, both economically and nutritionally. However, to efficiently select and identify genetic resources for pepper breeding programs, it is crucial to understand the association between important traits and genetic factors. In this study, we investigated the genetic basis of carotenoid and capsaicinoid content in 160 Capsicum chinense germplasms. The study observed significant variability in carotenoid and capsaicinoid content among the germplasms. Correlation analysis revealed a strong positive correlation between violaxanthin and antheraxanthin. In contrast, capsaicin and dihydrocapsaicin displayed negative correlations with individual carotenoids but exhibited a strong positive correlation between the two compounds (r = 0.90 ***). Genotyping-by-sequencing (GBS) was performed on 160 genotypes of pepper germplasm, which identified 47,810 high-quality SNPs. A comprehensive genome-wide association analysis was performed using these SNPs to identify SNPs associated with carotenoids and capsaicinoids, revealing 193 SNPs that exhibited significant associations. Specifically, 4 SNPs were associated with violaxanthin, 2 with antheraxanthin, 86 with capsorubin, 5 with capsanthin, 63 with zeaxanthin, 3 with β-cryptoxanthin, and 2 with α-carotene. With further studies, the significantly associated SNPs identified in this study have the potential to be utilized for selecting pepper accessions with high carotenoid and capsaicinoid contents. Additionally, the genes associated with these significant SNPs will be used to understand their roles and involvement in the biosynthesis pathway of carotenoids and capsaicinoids. Understanding the function of these genes can provide insights into the molecular mechanisms underlying the production of these bioactive compounds in pepper. The findings of this study hold valuable implications for selecting pepper varieties with desirable traits and developing breeding programs aimed at enhancing the nutritional and medicinal properties of pepper.
Genetic Factors of Teeth Impaction: Polymorphic and Haplotype Variants of PAX9, MSX1, AXIN2, and IRF6 Genes
Authors: Trybek Grzegorz , Jaroń Aleksandra , Gabrysz-Trybek Ewa , Rutkowska Monika , Markowska Aleksandra , Chmielowiec Krzysztof , Chmielowiec Jolanta , Grzywacz Anna
Published: September 2023

In recent research, there has been a growing awareness of the role of genetic factors in the positioning and eruption of teeth in the maxilla and mandible. This study aimed to evaluate the potential of specific polymorphic markers of single nucleotide polymorphisms (SNPs) located within the PAX9, MSX1, AXIN2, and IRF6 genes to determine the predisposition to tooth impaction. The study participants were divided into two groups: the first group consisted of individuals with at least one impacted secondary tooth. In contrast, the second group (control group) had no impacted teeth in their jaws. To analyze the genes, real-time PCR (polymerase chain reaction) and TaqMan probes were utilized to detect the selected polymorphisms. The findings suggest that disruptions in the structure and function of the mentioned genetic factors such as polymorphic and haplotype variants of PAX9, MSX1, AXIN2, and IRF6 genes, which play a direct role in tooth and periodontal tissue development, might be significant factors in tooth impaction in individuals with genetic variations. Therefore, it is reasonable to hypothesize that tooth impaction may be influenced, at least in part, by the presence of specific genetic markers, including different allelic variants of the PAX9, AXIN2, and IRF6 genes, and especially MSX1.
Extracellular Vesicles as Source of Biomarkers in Glomerulonephritis
Authors: Bruschi Maurizio , Candiano Giovanni , Angeletti Andrea , Lugani Francesca , Panfoli Isabella
Published: September 2023

Kidney disease is a global health and healthcare burden. Glomerulonephritis (Gn), both primary and secondary, is generally characterized by an inflammatory glomerular injury and may lead to end-stage renal disease. Kidney biopsy is fundamental to the diagnosis; however, kidney biopsy presents some concerns that may partly hamper the clinical process. Therefore, more accurate diagnostic tools are needed. Extracellular vesicles (EVs) are membranous vesicles released by cells and found in bodily fluids, including urine. EVs mediate intercellular signaling both in health and disease. EVs can have both harmful and cytoprotective effects in kidney diseases, especially Gn. Previous findings reported that the specific cargo of urinary EV contains an aerobic metabolic ability that may either restore the recipient cell metabolism or cause oxidative stress production. Here, we provide an overview of the most recent proteomic findings on the role of EVs in several aspects of glomerulopathies, with a focus on this metabolic and redox potential. Future studies may elucidate how the ability of EVs to interfere with aerobic metabolism and redox status can shed light on aspects of Gn etiology which have remained elusive so far.
Complement System Inhibitory Drugs in a Zebrafish (Danio rerio) Model: Computational Modeling
Authors: Fernandes Dayanne Carla , Tambourgi Denise V.
Published: September 2023

The dysregulation of complement system activation usually results in acute or chronic inflammation and can contribute to the development of various diseases. Although the activation of complement pathways is essential for innate defense, exacerbated activity of this system may be harmful to the host. Thus, drugs with the potential to inhibit the activation of the complement system may be important tools in therapy for diseases associated with complement system activation. The synthetic peptides Cp40 and PMX205 can be highlighted in this regard, given that they selectively inhibit the C3 and block the C5a receptor (C5aR1), respectively. The zebrafish (Danio rerio) is a robust model for studying the complement system. The aim of the present study was to use in silico computational modeling to investigate the hypothesis that these complement system inhibitor peptides interact with their target molecules in zebrafish, for subsequent in vivo validation. For this, we analyzed molecular docking interactions between peptides and target molecules. Our study demonstrated that Cp40 and the cyclic peptide PMX205 have positive interactions with their respective zebrafish targets, thus suggesting that zebrafish can be used as an animal model for therapeutic studies on these inhibitors.
Serum Extracellular Vesicle-Derived hsa-miR-2277-3p and hsa-miR-6813-3p Are Potential Biomarkers for Major Depression: A Preliminary Study
Authors: Seki Issei , Izumi Hiroto , Okamoto Naomichi , Ikenouchi Atsuko , Morimoto Yasuo , Horie Seichi , Yoshimura Reiji
Published: September 2023

The aim of the present study was to examine the association between miRNA levels in extracellular vesicles (EVs) from serum and the severity of Major Depression (MD). Patient sera from 16 MD cases were collected at our university hospital. The miRNAs contained in EVs were extracted using a nanofiltration method, and their expression levels were analyzed using miRNA microarrays. Intergroup comparisons were performed to validate the diagnostic performance of miRNAs in EVs. Furthermore, candidate miRNAs in EVs were added to neural progenitor cells, astrocytes, and microglial cells in vitro, and the predicted target genes of the candidate miRNAs were extracted. The predicted target genes underwent enrichment analysis. The expression levels of hsa-miR-6813-3p and hsa-miR-2277-3p were significantly downregulated with increasing depression severity of MD. The pathway enrichment analysis suggests that hsa-miR-6813-3p may be involved in glucocorticoid receptor and gamma-aminobutyric acid receptor signaling. Additionally, hsa-miR-2277-3p was found to be involved in the dopaminergic neural pathway. The analysis of serum miRNAs in EVs suggests that hsa-miR-6813-3p and hsa-miR-2277-3p could serve as novel biomarkers for MD, reflecting its severity. Moreover, these miRNAs in EVs could help understand MD pathophysiology.
Novel Long Non-Coding RNA (lncRNA) Transcript AL137782.1 Promotes the Migration of Normal Lung Epithelial Cells through Positively Regulating LMO7
Authors: Zhang Ying , Wang Weili , Duan Chunchun , Li Min , Gao Liyang
Published: September 2023

The role of long non-coding RNA (lncRNAs) in biological processes remains poorly understood, despite their significant impact. Our previous research discovered that the expression of AL137782.1, a long transcript of the novel lncRNA ENSG00000261553, is upregulated in lung epithelial cells upon exposure to microbes. Furthermore, the expression of AL137782.1 exhibits variability between para-cancerous and lung adenocarcinoma samples. These findings imply that this lncRNA may play a role in both normal lung epithelial cellular processes and pathophysiology. To elucidate the function of AL137782.1 in lung epithelial cells, we utilized bioinformatics retrieval and analysis to examine its expression. We then analyzed its subcellular localization using fluorescence in situ hybridization (FISH) and subcellular fractionation. Through rapid amplification of cDNA ends (RACE), we confirmed the presence of a 4401 nt lncRNA AL137782.1 in lung epithelial cells. Moreover, we discovered that this lncRNA positively regulates both mRNA and the protein expression of LMO7, a protein that may regulate the cell migration of normal lung epithelial cells. Although the overexpression of AL137782.1 has been shown to enhance the migration of both normal lung epithelial cells and lung adenocarcinoma cells in vitro, our study revealed that the expression of this lncRNA was significantly decreased in lung cancers compared to adjacent tissues. This suggests that the cell migration pattern regulated by the AL137782.1–LMO7 axis is more likely to occur in normal lung epithelial cells, rather than being a pathway that promotes lung cancer cell migration. Therefore, our study provides new insights into the mechanism underlying cell migration in human lung epithelial cells. This finding may offer a potential strategy to enhance normal lung epithelial cell migration after lung injury.
The P2X7 Receptor in Oncogenesis and Metastatic Dissemination: New Insights on Vesicular Release and Adenosinergic Crosstalk
Authors: Adinolfi Elena , De Marchi Elena , Grignolo Marianna , Szymczak Bartosz , Pegoraro Anna
Published: September 2023

The tumor niche is an environment rich in extracellular ATP (eATP) where purinergic receptors have essential roles in different cell subtypes, including cancer, immune, and stromal cells. Here, we give an overview of recent discoveries regarding the role of probably the best-characterized purinergic receptor in the tumor microenvironment: P2X7. We cover the activities of the P2X7 receptor and its human splice variants in solid and liquid cancer proliferation, dissemination, and crosstalk with immune and endothelial cells. Particular attention is paid to the P2X7-dependent release of microvesicles and exosomes, their content, including ATP and miRNAs, and, in general, P2X7-activated mechanisms favoring metastatic spread and niche conditioning. Moreover, the emerging role of P2X7 in influencing the adenosinergic axis, formed by the ectonucleotidases CD39 and CD73 and the adenosine receptor A2A in cancer, is analyzed. Finally, we cover how antitumor therapy responses can be influenced by or can change P2X7 expression and function. This converging evidence suggests that P2X7 is an attractive therapeutic target for oncological conditions.
The Apoptotic and Anti-Warburg Effects of Brassinin in PC-3 Cells via Reactive Oxygen Species Production and the Inhibition of the c-Myc, SIRT1, and β-Catenin Signaling Axis
Authors: Kwon Hyeon Hee , Ahn Chi-Hoon , Lee Hyo-Jung , Sim Deok Yong , Park Ji Eon , Park Su-Yeon , Kim Bonglee , Shim Bum-Sang , Kim Sung-Hoon
Published: September 2023

Though Brassinin is known to have antiangiogenic, anti-inflammatory, and antitumor effects in colon, prostate, breast, lung, and liver cancers, the underlying antitumor mechanism of Brassinin is not fully understood so far. Hence, in the current study, the apoptotic mechanism of Brassinin was explored in prostate cancer. Herein, Brassinin significantly increased the cytotoxicity and reduced the expressions of pro-Poly ADP-ribose polymerase (PARP), pro-caspase 3, and B-cell lymphoma 2 (Bcl-2) in PC-3 cells compared to DU145 and LNCaP cells. Consistently, Brassinin reduced the number of colonies and increased the sub-G1 population and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL)-positive cells in the PC-3 cells. Of note, Brassinin suppressed the expressions of pyruvate kinase-M2 (PKM2), glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and lactate dehydrogenase (LDH) as glycolytic proteins in the PC-3 cells. Furthermore, Brassinin significantly reduced the expressions of SIRT1, c-Myc, and β-catenin in the PC-3 cells and also disrupted the binding of SIRT1 with β-catenin, along with a protein–protein interaction (PPI) score of 0.879 and spearman’s correlation coefficient of 0.47 being observed between SIRT1 and β-catenin. Of note, Brassinin significantly increased the reactive oxygen species (ROS) generation in the PC-3 cells. Conversely, ROS scavenger NAC reversed the ability of Brassinin to attenuate pro-PARP, pro-Caspase3, SIRT1, and β-catenin in the PC-3 cells. Taken together, these findings support evidence that Brassinin induces apoptosis via the ROS-mediated inhibition of SIRT1, c-Myc, β-catenin, and glycolysis proteins as a potent anticancer candidate.
Starving the Beast: Limiting Coenzyme A Biosynthesis to Prevent Disease and Transmission in Malaria
Authors: Riske Brendan F. , Luckhart Shirley , Riehle Michael A.
Published: September 2023

Malaria parasites must acquire all necessary nutrients from the vertebrate and mosquito hosts to successfully complete their life cycle. Failure to acquire these nutrients can limit or even block parasite development and presents a novel target for malaria control. One such essential nutrient is pantothenate, also known as vitamin B5, which the parasite cannot synthesize de novo and is required for the synthesis of coenzyme A (CoA) in the parasite. This review examines pantothenate and the CoA biosynthesis pathway in the human–mosquito–malaria parasite triad and explores possible approaches to leverage the CoA biosynthesis pathway to limit malaria parasite development in both human and mosquito hosts. This includes a discussion of sources for pantothenate for the mosquito, human, and parasite, examining the diverse strategies used by the parasite to acquire substrates for CoA synthesis across life stages and host resource pools and a discussion of drugs and alternative approaches being studied to disrupt CoA biosynthesis in the parasite. The latter includes antimalarial pantothenate analogs, known as pantothenamides, that have been developed to target this pathway during the human erythrocytic stages. In addition to these parasite-targeted drugs, we review studies of mosquito-targeted allosteric enzymatic regulators known as pantazines as an approach to limit pantothenate availability in the mosquito and subsequently deprive the parasite of this essential nutrient.
Selected miRNA and Psoriasis—Cardiovascular Disease (CVD)—Overweight/Obesity Network—A Pilot Study
Authors: Michalak-Stoma Anna , Walczak Katarzyna , Adamczyk Michał , Kowal Małgorzata , Krasowska Dorota
Published: September 2023

Psoriasis is nowadays recognized as a multifactorial systemic disease with complex and not fully understood pathogenesis. In psoriatic patients, the increased cardiovascular disease (CVD) risk and frequent comorbidities like obesity are observed. The aim of this study was to investigate differences in miRNA (miR-22-3p, miR-133a-3p, miR-146a-5p, miR-369-3p, and Let-7b-5p) involved in CVD risk among psoriatic patients with overweight/obesity and with normal weight. The study comprised 28 male psoriatic patients and 16 male healthy controls. miRNA isolated from peripheral blood mononuclear cells was reverse-transcribed and RT-qPCR was performed. We have found decreased levels of miR-22, miR-133a, miR-146a, and miR-369 among the psoriatic patients. There was a statistically significant difference in miR-22 and miR-146a levels between psoriatic patients with overweight/obesity and with normal weight. There were positive correlations between miR-22 and miR-146a levels and psoriatic arthritis (PsA) in psoriatic patients with normal weight and between the miR-133a level and PsA in the overweight/obese patients. The decreased levels of selected miRNA are consistent with the levels observed in CVD indicating their impact on the CVD risk in psoriatic patients. miR-22 and miR-146 may be recognized as one of the contributing factors in the obesity-CVD-psoriasis network.
Conditional Deletion of Foxg1 Delayed Myelination during Early Postnatal Brain Development
Authors: Cao Guangliang , Sun Congli , Shen Hualin , Qu Dewei , Shen Chuanlu , Lu Haiqin
Published: September 2023

FOXG1 (forkhead box G1) syndrome is a neurodevelopmental disorder caused by variants in the Foxg1 gene that affect brain structure and function. Individuals affected by FOXG1 syndrome frequently exhibit delayed myelination in neuroimaging studies, which may impair the rapid conduction of nerve impulses. To date, the specific effects of FOXG1 on oligodendrocyte lineage progression and myelination during early postnatal development remain unclear. Here, we investigated the effects of Foxg1 deficiency on myelin development in the mouse brain by conditional deletion of Foxg1 in neural progenitors using NestinCreER;Foxg1fl/fl mice and tamoxifen induction at postnatal day 0 (P0). We found that Foxg1 deficiency resulted in a transient delay in myelination, evidenced by decreased myelin formation within the first two weeks after birth, but ultimately recovered to the control levels by P30. We also found that Foxg1 deletion prevented the timely attenuation of platelet-derived growth factor receptor alpha (PDGFRα) signaling and reduced the cell cycle exit of oligodendrocyte precursor cells (OPCs), leading to their excessive proliferation and delayed maturation. Additionally, Foxg1 deletion increased the expression of Hes5, a myelin formation inhibitor, as well as Olig2 and Sox10, two promoters of OPC differentiation. Our results reveal the important role of Foxg1 in myelin development and provide new clues for further exploring the pathological mechanisms of FOXG1 syndrome.
Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer’s Disease
Authors: Wang Hoau-Yan , Cecon Erika , Dam Julie , Pei Zhe , Jockers Ralf , Burns Lindsay H.
Published: September 2023

Simufilam is a novel oral drug candidate in Phase 3 clinical trials for Alzheimer’s disease (AD) dementia. This small molecule binds an altered form of filamin A (FLNA) that occurs in AD. This drug action disrupts FLNA’s aberrant linkage to the α7 nicotinic acetylcholine receptor (α7nAChR), thereby blocking soluble amyloid beta1–42 (Aβ42)’s signaling via α7nAChR that hyperphosphorylates tau. Here, we aimed to clarify simufilam’s mechanism. We now show that simufilam reduced Aβ42 binding to α7nAChR with a 10-picomolar IC50 using time-resolved fluorescence resonance energy transfer (TR-FRET), a robust technology to detect highly sensitive molecular interactions. We also show that FLNA links to multiple inflammatory receptors in addition to Toll-like receptor 4 (TLR4) in postmortem human AD brains and in AD transgenic mice: TLR2, C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 5 (CCR5), and T-cell co-receptor cluster of differentiation 4 (CD4). These aberrant FLNA linkages, which can be induced in a healthy control brain by Aβ42 incubation, were disrupted by simufilam. Simufilam reduced inflammatory cytokine release from Aβ42-stimulated human astrocytes. In the AD transgenic mice, CCR5–G protein coupling was elevated, indicating persistent activation. Oral simufilam reduced both the FLNA–CCR5 linkage and the CCR5–G protein coupling in these mice, while restoring CCR5′s responsivity to C-C chemokine ligand 3 (CCL3). By disrupting aberrant FLNA–receptor interactions critical to AD pathogenic pathways, simufilam may promote brain health.
The Illustration of Altered Glucose Dependency in Drug-Resistant Cancer Cells
Authors: Bishayee Kausik , Lee Seung-Hee , Park Yong Soo
Published: September 2023

A chemotherapeutic approach is crucial in malignancy management, which is often challenging due to the development of chemoresistance. Over time, chemo-resistant cancer cells rapidly repopulate and metastasize, increasing the recurrence rate in cancer patients. Targeting these destined cancer cells is more troublesome for clinicians, as they share biology and molecular cross-talks with normal cells. However, the recent insights into the metabolic profiles of chemo-resistant cancer cells surprisingly illustrated the activation of distinct pathways compared with chemo-sensitive or primary cancer cells. These distinct metabolic dynamics are vital and contribute to the shift from chemo-sensitivity to chemo-resistance in cancer. This review will discuss the important metabolic alterations in cancer cells that lead to drug resistance.
Microfluidic Isolation of Disseminated Tumor Cells from the Bone Marrow of Breast Cancer Patients
Authors: Volmer Léa L. , Önder Cansu E. , Volz Barbara , Singh Anjali R. , Brucker Sara Y. , Engler Tobias , Hartkopf Andreas D. , Koch André
Published: September 2023

Disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer (BC) patients are putative precursors of metastatic disease, and their presence is associated with an adverse clinical outcome. To achieve the personalization of therapy on a clinical routine level, the characterization of DTCs and in vitro drug testing on DTCs are of great interest. Therefore, biobanking methods, as well as novel approaches to DTC isolation, need to be developed. In this study, we established a protocol for the biobanking of BM samples and evaluated a microfluidic-based separation system (Parsortix®) for the enrichment of cryopreserved DTCs. We were able to successfully isolate viable DTCs after the prior cryopreservation of BM samples. We calculated a significant increase of up to 90-fold in harvested DTCs with the proposed method compared to the current standard techniques, opening up new analysis possibilities for DTCs. Our advanced method further presents options for 3D DTC cultures, enabling the individualized testing of targeted therapies for BC patients. In conclusion, we present a novel approach for DTC enrichment, with possibilities for future clinical implications.
Defining the Basal and Immunomodulatory Mediator-Induced Phosphoprotein Signature in Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL) Diagnostic Samples
Authors: Khanolkar Aaruni , Liu Guorong , Simpson Schneider Bridget M.
Published: September 2023

It is theorized that dysregulated immune responses to infectious insults contribute to the development of pediatric B-ALL. In this context, our understanding of the immunomodulatory-mediator-induced signaling responses of leukemic blasts in pediatric B-ALL diagnostic samples is rather limited. Hence, in this study, we defined the signaling landscape of leukemic blasts, as well as normal mature B cells and T cells residing in diagnostic samples from 63 pediatric B-ALL patients. These samples were interrogated with a range of immunomodulatory-mediators within 24 h of collection, and phosflow analyses of downstream proximal signaling nodes were performed. Our data reveal evidence of basal hyperphosphorylation across a broad swath of these signaling nodes in leukemic blasts in contrast to normal mature B cells and T cells in the same sample. We also detected similarities in the phosphoprotein signature between blasts and mature B cells in response to IFNγ and IL-2 treatment, but significant divergence in the phosphoprotein signature was observed between blasts and mature B cells in response to IL-4, IL-7, IL-10, IL-21 and CD40 ligand treatment. Our results demonstrate the existence of both symmetry and asymmetry in the phosphoprotein signature between leukemic and non-leukemic cells in pediatric B-ALL diagnostic samples.
Taxonomic Identification of the Arctic Strain Nocardioides Arcticus Sp. Nov. and Global Transcriptomic Analysis in Response to Hydrogen Peroxide Stress
Authors: Cong Bailin , Zhang Hui , Li Shuang , Liu Shenghao , Lin Jing , Deng Aifang , Liu Wenqi , Yang Yan
Published: September 2023

Microorganisms living in polar regions rely on specialized mechanisms to adapt to extreme environments. The study of their stress adaptation mechanisms is a hot topic in international microbiology research. In this study, a bacterial strain (Arc9.136) isolated from Arctic marine sediments was selected to implement polyphasic taxonomic identification based on factors such as genetic characteristics, physiological and biochemical properties, and chemical composition. The results showed that strain Arc9.136 is classified to the genus Nocardioides, for which the name Nocardioides arcticus sp. nov. is proposed. The ozone hole over the Arctic leads to increased ultraviolet (UV-B) radiation, and low temperatures lead to increased dissolved content in seawater. These extreme environmental conditions result in oxidative stress, inducing a strong response in microorganisms. Based on the functional classification of significantly differentially expressed genes under 1 mM H2O2 stress, we suspect that Arc9.136 may respond to oxidative stress through the following strategies: (1) efficient utilization of various carbon sources to improve carbohydrate transport and metabolism; (2) altering ion transport and metabolism by decreasing the uptake of divalent iron (to avoid the Fenton reaction) and increasing the utilization of trivalent iron (to maintain intracellular iron homeostasis); (3) increasing the level of cell replication, DNA repair, and defense functions, repairing DNA damage caused by H2O2; (4) and changing the composition of lipids in the cell membrane and reducing the sensitivity of lipid peroxidation. This study provides insights into the stress resistance mechanisms of microorganisms in extreme environments and highlights the potential for developing low-temperature active microbial resources.
Use of Cells, Supplements, and Peptides as Therapeutic Strategies for Modulating Inflammation after Spinal Cord Injury: An Update
Authors: Garcia Elisa , Buzoianu-Anguiano Vinnitsa , Silva-Garcia Raúl , Esparza-Salazar Felipe , Arriero-Cabañero Alejandro , Escandon Adela , Doncel-Pérez Ernesto , Ibarra Antonio
Published: September 2023

Spinal cord injury is a traumatic lesion that causes a catastrophic condition in patients, resulting in neuronal deficit and loss of motor and sensory function. That loss is caused by secondary injury events following mechanical damage, which results in cell death. One of the most important events is inflammation, which activates molecules like proinflammatory cytokines (IL-1β, IFN-γ, and TNF-α) that provoke a toxic environment, inhibiting axonal growth and exacerbating CNS damage. As there is no effective treatment, one of the developed therapies is neuroprotection of the tissue to preserve healthy tissue. Among the strategies that have been developed are the use of cell therapy, the use of peptides, and molecules or supplements that have been shown to favor an anti-inflammatory environment that helps to preserve tissue and cells at the site of injury, thus favoring axonal growth and improved locomotor function. In this review, we will explain some of these strategies used in different animal models of spinal cord injury, their activity as modulators of the immune system, and the benefits they have shown.
Role of Lnc-RNAs in the Pathogenesis and Development of Diabetic Retinopathy
Authors: Perisset Sofia , Potilinski M. Constanza , Gallo Juan E.
Published: September 2023

Important advances in diabetic retinopathy (DR) research and management have occurred in the last few years. Neurodegenerative changes before the onset of microvascular alterations have been well established. So, new strategies are required for earlier and more effective treatment of DR, which still is the first cause of blindness in working age. We describe herein gene regulation through Lnc-RNAs as an interesting subject related to DR. Long non-coding RNAs (Lnc-RNAs) are non-protein-coding transcripts larger than 200 nucleotides. Lnc-RNAs regulate gene expression and protein formation at the epigenetic, transcriptional, and translational levels and can impact cell proliferation, apoptosis, immune response, and oxidative stress. These changes are known to take part in the mechanism of DR. Recent investigations pointed out that Lnc-RNAs might play a role in retinopathy development as Metastasis-Associated Lung Adenocarcinoma Transcript (Lnc-MALAT1), Maternally expressed gene 3 (Lnc-MEG3), myocardial-infarction-associated transcript (Lnc-MIAT), Lnc-RNA H19, Lnc-RNA HOTAIR, Lnc-RNA ANRIL B-Raf proto-oncogene (Lnc-RNA BANCR), small nucleolar RNA host gene 16 (Lnc-RNA SNHG16) and others. Several molecular pathways are impacted. Some of them play a role in DR pathophysiology, including the PI3K-Akt signaling axis, NAD-dependent deacetylase sirtuin-1 (Sirti1), p38 mitogen-activated protein kinase (P38/mapk), transforming growth factor beta signaling (TGF-β) and nuclear factor erythroid 2-related factor 2 (Nrf2). The way Lnc-RNAs affect diabetic retinopathy is a question of great relevance. Performing a more in-depth analysis seems to be crucial for researchers if they want to target Lnc-RNAs. New knowledge on gene regulation and biomarkers will enable investigators to develop more specialized therapies for diabetic retinopathy, particularly in the current growing context of precision medicine.
Magnolol Supplementation Alters Serum Parameters, Immune Homeostasis, Amino Acid Profiles, and Gene Expression of Amino Acid Transporters in Growing Pigs
Authors: Liu Yanchen , Li Yuanfei , Yu Miao , Tian Zhimei , Deng Jinping , Ma Xianyong , Yin Yulong
Published: September 2023

This study investigated whether dietary supplementation with magnolol affects growth performance, anti-inflammatory abilities, serum and muscle amino acid profiles, and metabolisms in growing pigs. A total of 42 seventy-days-old growing barrows (Duroc × Landrace × Yorkshire) were randomly allocated into two dietary groups: Con, control group (basal diet); and Mag, magnolol group (basal diet supplemented with 400 mg/kg of magnolol). The results revealed that dietary supplementation with magnolol had no effect (p > 0.05) on growth performance. However, magnolol supplementation remarkably increased (p < 0.05) the serum content of albumin, total protein, immunoglobulin G, immunoglobulin M, and interleukin-22. In addition, dietary magnolol supplementation altered the amino acid (AA) profiles in serum and dorsal muscle and particularly increased (p < 0.05) the serum content of arginine and muscle glutamate. Simultaneously, the mRNA expression of genes associated with AA transport in jejunum (SLC38A2, SLC1A5, and SLC7A1) and ileum (SLC1A5 and SLC7A1) was higher (p < 0.05) in the Mag group than in the Con group. Additionally, the serum metabolomics analysis showed that the addition of magnolol significantly enhanced (p < 0.05) arginine biosynthesis, as well as D-glutamine and D-glutamate metabolism. Overall, these results suggested that dietary supplementation with magnolol has the potential to improve the accumulation of AAs, protein synthesis, immunity, and body health in growing pigs by increasing intestinal absorption and the transport of AAs.
An Updated Review on Developing Small Molecule Kinase Inhibitors Using Computer-Aided Drug Design Approaches
Authors: Li Linwei , Liu Songtao , Wang Bi , Liu Fei , Xu Shu , Li Pirui , Chen Yu
Published: September 2023

Small molecule kinase inhibitors (SMKIs) are of heightened interest in the field of drug research and development. There are 79 (as of July 2023) small molecule kinase inhibitors that have been approved by the FDA and hundreds of kinase inhibitor candidates in clinical trials that have shed light on the treatment of some major diseases. As an important strategy in drug design, computer-aided drug design (CADD) plays an indispensable role in the discovery of SMKIs. CADD methods such as docking, molecular dynamic, quantum mechanics/molecular mechanics, pharmacophore, virtual screening, and quantitative structure–activity relationship have been applied to the design and optimization of small molecule kinase inhibitors. In this review, we provide an overview of recent advances in CADD and SMKIs and the application of CADD in the discovery of SMKIs.
Targeted Radiation Exposure Induces Accelerated Aortic Valve Remodeling in ApoE−/− Mice
Authors: Rucher Guillaume , Prigent Kevin , Simard Christophe , Frelin Anne-Marie , Coquemont-Guyot Maëlle , Elie Nicolas , Delcroix Nicolas , Perzo Nicolas , Guinamard Romain , Berger Ludovic , Manrique Alain ,   on behalf of the STOP-AS Investigators
Published: September 2023

Thoracic radiation therapy may result in accelerated atherosclerosis and in late aortic valve stenosis (AS). In this study, we assessed the feasibility of inducing radiation-induced AS using a targeted aortic valve irradiation (10 or 20 Grays) in two groups of C57Bl6/J (WT) and ApoE−/− mice compared to a control (no irradiation). Peak aortic jet velocity was evaluated by echocardiography to characterize AS. T2*-weighted magnetic resonance imaging after injection of MPIO-αVCAM-1 was used to examine aortic inflammation resulting from irradiation. A T2* signal void on valve leaflets and aortic sinus was considered positive. Valve remodeling and mineralization were assessed using von Kossa staining. Finally, the impact of radiation on cell viability and cycle from aortic human valvular interstitial cells (hVICs) was also assessed. The targeted aortic valve irradiation in ApoE−/− mice resulted in an AS characterized by an increase in peak aortic jet velocity associated with valve leaflet and aortic sinus remodeling, including mineralization process, at the 3-month follow-up. There was a linear correlation between histological findings and peak aortic jet velocity (r = 0.57, p < 0.01). In addition, irradiation was associated with aortic root inflammation, evidenced by molecular MR imaging (p < 0.01). No significant effect of radiation exposure was detected on WT animals. Radiation exposure did not affect hVICs viability and cell cycle. We conclude that targeted radiation exposure of the aortic valve in mice results in ApoE−/−, but not in WT, mice in an aortic valve remodeling mimicking the human lesions. This preclinical model could be a useful tool for future assessment of therapeutic interventions.
Efficacy and Safety of Self-Expandable Metallic Stent Placement for Malignant Esophageal Fistula
Authors: Izumi Atsuko , Yoshio Toshiyuki , Sasaki Takashi , Ishioka Mitsuaki , Kizawa Atsuko , Ikenoyama Yohei , Namikawa Ken , Tokai Yoshitaka , Yoshimizu Shoichi , Horiuchi Yusuke , Ishiyama Akiyoshi , Hirasawa Toshiaki , Chin Keisho , Ogura Mariko , Sasahira Naoki , Fujisaki Junko
Published: September 2023

Patients with malignant esophageal fistulas often experience dysphagia and infection, resulting in poor prognoses. Self-expandable metallic stent (SEMS) placement is a palliative treatment option; however, its efficacy and safety are unclear. We aimed to determine the efficacy and safety of SEMS placement for malignant esophageal fistulas. We retrospectively investigated patients who underwent SEMS placement for malignant esophageal fistulas between 2013 and 2022 at the Cancer Institute Hospital. Dysphagia scores (DSs) before and after SEMS placement, adverse events, and overall survival from SEMS placement until death were evaluated. A total of 17 patients underwent SEMS placement, including 12 and 5 patients with esophageal and lung cancers, respectively. Prior treatments included chemoradiotherapy (n = 11), radiotherapy (n = 4), and chemotherapy (n = 4); two patients underwent palliative radiotherapy after chemotherapy. All procedures were technically successful. After SEMS placement, 14 (82.4%) patients were able to consume semisolid or solid food (DS ≤ 2). Major adverse events were encountered in only one case. The median survival time after SEMS placement was 71 days (range 17–247 days). SEMS placement allowed most patients to resume oral intake with a low rate of major adverse events. SEMS placement is a reasonable palliative treatment option for patients with malignant fistulas who have poor prognoses.