bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Incretin-Based Treatment on the Diastolic (Dys)Function in Patients with Uncontrolled Type 2 Diabetes Mellitus: A Prospective Study with 1-Year Follow-Up
Authors: Grigorescu Elena-Daniela , Lăcătușu Cristina-Mihaela , Floria Mariana , Cazac Georgiana-Diana , Onofriescu Alina , Sauciuc Livia-Amira , Ceasovschih Alexandr , Crețu Ioana , Mihai Bogdan-Mircea , Șorodoc Laurențiu
Published: August 2023

Left ventricular diastolic dysfunction (DD) is a subclinical cardiac abnormality in patients with type 2 diabetes mellitus (T2DM) that can progress to heart failure (HF) and increase cardiovascular risk. This prospective study evaluated the DD in T2DM patients without atherosclerotic cardiovascular disease after one year of incretin-based drugs added to standard treatment. Of the 138 enrolled patients (49.30% male, mean age 57.86 ± 8.82, mean T2DM history 5 years), 71 were started on dipeptidyl peptidase-4 inhibitor sitagliptin/saxagliptin, 21 on glucagon-like peptide-1 receptor agonist exenatide, and 46 formed the control group (metformin and sulphonylurea/acarbose). At baseline, 71 patients had grade 1 DD, another 12 had grade 2 and 3 DD, and 15 had indeterminate DD. After one year, DD was evidenced in 50 cases. Diastolic function improved in 9 cases, and 27 patients went from grade 1 to indeterminate DD. The active group benefited more, especially patients treated with exenatide; their metabolic and inflammation profiles also improved the most. An in-depth analysis of echocardiographic parameters and paraclinical results in the context of literature data justifies the conclusion that early assessment of diastolic function in T2DM patients is necessary and the benefits of affordable incretin-based treatment may extend to subclinical cardiovascular manifestations such as DD.
Investigation of Feature Engineering Methods for Domain-Knowledge-Assisted Bearing Fault Diagnosis
Authors: Bienefeld Christoph , Becker-Dombrowsky Florian Michael , Shatri Etnik , Kirchner Eckhard
Published: August 2023

The engineering challenge of rolling bearing condition monitoring has led to a large number of method developments over the past few years. Most commonly, vibration measurement data are used for fault diagnosis using machine learning algorithms. In current research, purely data-driven deep learning methods are becoming increasingly popular, aiming for accurate predictions of bearing faults without requiring bearing-specific domain knowledge. Opposing this trend in popularity, the present paper takes a more traditional approach, incorporating domain knowledge by evaluating a variety of feature engineering methods in combination with a random forest classifier. For a comprehensive feature engineering study, a total of 42 mathematical feature formulas are combined with the preprocessing methods of envelope analysis, empirical mode decomposition, wavelet transforms, and frequency band separations. While each single processing method and feature formula is known from the literature, the presented paper contributes to the body of knowledge by investigating novel series connections of processing methods and feature formulas. Using the CWRU bearing fault data for performance evaluation, feature calculation based on the processing method of frequency band separation leads to particularly high prediction accuracies, while at the same time being very efficient in terms of low computational effort. Additionally, in comparison with deep learning approaches, the proposed feature engineering method provides excellent accuracies and enables explainability.
A Multi-Robot-Based Architecture and a Trust Model for Intelligent Fault Management and Control Systems
Authors: Gharbi Atef , Altowaijri Saleh M.
Published: August 2023

One of the most important challenges in robotics is the development of a Multi-Robot-based control system in which the robot can make intelligent decisions in a changing environment. This paper proposes a robot-based control approach for dynamically managing robots in such a widely distributed production system. A Multi-Robot-based control system architecture is presented, and its main features are described. Such architecture facilitates the reconfiguration (either self-reconfiguration ensured by the robot itself or distributed reconfiguration executed by the Multi-Robot-based system). The distributed reconfiguration is facilitated through building a trust model that is based on learning from past interactions between intelligent robots. The Multi-Robot-based control system architecture also addresses other specific requirements for production systems, including fault flexibility. Any out-of-control fault occurring in a production system results in the loss of production time, resources, and money. In these cases, robot trust is critical for successful job completion, especially when the work can only be accomplished by sharing knowledge and resources among robots. This work introduces research on the construction of trust estimation models that experimentally calculate and evaluate the trustworthiness of robots in a Multi-Robot system where the robot can choose to cooperate and collaborate exclusively with other trustworthy robots. We compare our proposed trust model with other models described in the literature in terms of performance based on four criteria, which are time steps analysis, RMSD evaluation, interaction analysis, and variation of total feedback. The contribution of the paper can be summarized as follows: (i) the Multi-Robot-based Control Architecture; (ii) how the control robot handles faults; and (iii) the trust model.
Understanding Soil Respiration Dynamics in Temperate Forests in Northwestern Mexico
Authors: Martínez-Rivas José Alexis , Vargas-Larreta Benedicto , López-Martínez Jorge Omar , Aguirre-Calderón Cristóbal Gerardo , Hernández Francisco Javier , Ángeles-Pérez Gregorio
Published: August 2023

Temperate mixed forests in Mexico are considered highly important ecosystems because of their high levels of biodiversity and capacity to store carbon. The aim of this study was to evaluate temporal and between-forest soil respiration (CO2 efflux) variability, and to assess the effect of vegetation diversity metrics on soil CO2 fluxes in mixed-uneven-aged forests in Durango, Northwestern Mexico. Soil CO2 efflux, soil moisture, and soil temperature were measured in three temperate forest types. A generalized linear model (GLM) was fitted to analyze the relationship between soil CO2 fluxes and stand variables, diversity metrics, soil moisture, and soil temperature. Furthermore, a two-way analysis of variance was used to assess the effect of forest type, month of the year, and their interaction on soil respiration. Annual average, minimum, and maximum soil CO2 efflux rate values were 3.81 (±2.94), 2.28 (±1.47), and 7.97 (±2.94) µmol m−2 s−1, respectively. Soil respiration was positively related to species richness, aboveground biomass, and quadratic mean diameter; however, forest type did not contribute to understanding the dynamics of soil CO2 fluxes. The results highlight the importance of seasonality, species diversity and aboveground biomass stocks to preserve the ecosystem processes driving soil respiration in temperate forests.
Large-Scale and High-Accuracy Phenotyping of Populus simonii Leaves Using the Colony Counter and OpenCV
Authors: Zhu Sheng , Zhang Heng , Chen Siyuan , Zhang Lei , Huang Minren
Published: August 2023

Image-based morphometric technology is broadly applicable to generate large-scale phenomic datasets in ecological, genetic and morphological studies. However, little is known about the performance of image-based measuring methods on plant morphological characters. In this study, we presented an automatic image-based workflow to obtain the accurate estimations for basic leaf characteristics (e.g., ratio of length/width, length, width, and area) from a hundred Populus simonii pictures, which were captured on Colony counter Scan1200. The image-based workflow was implemented with Python and OpenCV, and subdivided into three parts, including image pre-processing, image segmentation and object contour detection. Six image segmentation methods, including Chan-Vese, Iterative threshold, K-Mean, Mean, OSTU, and Watershed, differed in the running time, noise sensitivity and accuracy. The image-based estimates and measured values for leaf morphological traits had a strong correlation coefficient (r2 > 0.9736), and their residual errors followed a Gaussian distribution with a mean of almost zero. Iterative threshold, K-Mean, OSTU, and Watershed overperformed the other two methods in terms of efficiency and accuracy. This study highlights the high-quality and high-throughput of autonomous image-based phenotyping and offers a guiding clue for the practical use of suitable image-based technologies in biological and ecological research.
Preparation of Superhydrophobic Wood Surfaces Modified Using MIL-88(Fe) via Solvothermal Method
Authors: Han Yu , Mu Pingxuan , Wang Jinxin , Qi Dawei
Published: August 2023

A superhydrophobic wood surface was produced by employing the solvothermal method to form shuttle-like, well-crystallized MIL-88(Fe) on the surface of wood and assembling a Octadecylphosphonic acid (OPA) reagent. The nanosized MIL-88(Fe) molecule caused the wood’s surface to take on a nano mastoid shape. In addition, MIL-88(Fe) provides metal sites to capture OPA molecules, preventing the long-chain alkane hydrophobic group from contacting the surface of the wood. They both make a considerable difference in the growth of a hydrophobic wood surface. The results of the experiment indicate that the water contact angle (WCA) increases with reactant concentration. The WCA of the samples prepared with 5.0 × 10−2 M FeCl3 was 140.57°. When the reactant concentration was 10.0 × 10−2 M, the greatest WCA = 153.69° reading was obtained. The research’s findings present a novel technique for producing superhydrophobic wood surfaces.
Preparation of Teakwood Bending Components with Excellent Softening Properties by Vacuum Impregnation with Triethanolamine Compounding Solution
Authors: Yao Linghua , Ji Lina , Sun Delin , Wang Zhangheng , Ge Hui , Xu Man , Yu Minggong
Published: August 2023

To study the softening bending properties and mechanism of teakwood, it was extractively pretreated by using superheated steam, the triethanolamine compound was used as a softening solution, which was infiltrated into the wood by vacuum impregnation and synergistically softened through saturated steam to improve the bending properties of teakwood. Analysis by Fourier transform infrared spectroscopy (FTIR), Carbon 13 nuclear magnetic resonance (13C NMR), and X-ray photoelectron spectroscopy (XPS) showed that the synergistic softening treatment elevated the content of O and N elements in the softening solution and together with the C elements in the wood, formed C-NH2 and C-N bonds, which increased the molecular activity and improved the softening properties of teakwood. Scanning electron microscope (SEM) observations revealed that the outer conduits, cell walls, and fibrous tissue structures of the teakwood were stretched after softening and bending, and even microcracks of different degrees were formed between the cell walls. According to the load–deformation relationship of teakwood softening bending, the stress–strain relationship was theoretically derived and the bifold constitutive model of teakwood bending was constructed after fitting the constitutive relationship data, the integrated correlation coefficient R2 was 96.25%, which proved that the present model can better simulate the constitutive relationship of teakwood in bending.
Evaluation of the Deterioration State of Historical Palm Leaf Manuscripts from Burma
Authors: Chu Shimin , Lin Lanying , Tian Xingling
Published: August 2023

Palm leaf manuscripts were a prevalent literary medium from South Asia and Southeast Asia prior to the widespread use of paper. This study focuses on the analysis of historical palm leaf manuscripts from South and Southeast Asia. Sample palm leaf manuscripts from Burma were used as a case study; simulated palm leaf manuscripts were also created as a reference for comparison. The anatomy, chemical composition, and mechanical properties of the manuscripts were analyzed to find various forms of deterioration, including damage, fractures, pollution, acidification, and microbial deterioration. Specifically, the S1–S3 layers of the cell walls exhibited complete cracking, and the S2 layer showed numerous circular or nearly circular cavities caused by microbial erosion, while the middle lamella remained intact. The severe degradation of polysaccharides and pectin, accompanied by an increase in the relative content of lignin, caused the historical manuscripts to become more brittle. Additionally, the tensile strengths of historical palm leaf manuscripts were markedly reduced; their longitudinal tensile strength was significantly greater than their transverse tensile strength. This study can contribute to a better understanding of the deterioration process of historical palm leaf manuscripts and provide valuable insights for their restoration and preservation.
Forest Cover Change Monitoring Using Sub-Pixel Mapping with Edge-Matching Correction
Authors: Xia Siran , Yang Zhigao , Zhang Gui , Wu Xin
Published: August 2023

Sentinel-2 serves as a crucial data source for monitoring forest cover change. In this study, a sub-pixel mapping of forest cover is performed on Sentinel-2 images, downscaling the spatial resolution of the positioned results to 2.5 m, enabling sub-pixel-level forest cover monitoring. A novel sub-pixel mapping with edge-matching correction is proposed on the basis of the Sentinel-2 images, combining edge-matching technology to extract the forest boundary of Jilin-1 images at sub-meter level as spatial constraint information for sub-pixel mapping. This approach enables accurate mapping of forest cover, surpassing traditional pixel-level monitoring in terms of accuracy and robustness. The corrected mapping method allows more spatial detail to be restored at forest boundaries, monitoring forest changes at a smaller scale, which is highly similar to actual forest boundaries on the surface. The overall accuracy of the modified sub-pixel mapping method reaches 93.15%, an improvement of 1.96% over the conventional Sub-pixel-pixel Spatial Attraction Model (SPSAM). Additionally, the kappa coefficient improved by 0.15 to reach 0.892 during the correction. In summary, this study introduces a new method of forest cover monitoring, enhancing the accuracy and efficiency of acquiring forest resource information. This approach provides a fresh perspective in the field of forest cover monitoring, especially for monitoring small deforestation and forest degradation activities.
Allometric Model of Crown Length for Pinus sylvestris L. Stands in South-Western Poland
Authors: Sporek Monika , Sporek Kazimierz
Published: August 2023

The growth of a tree depends on the size, shape, and functioning of the crown. The length of the crown is a somewhat subjective value because the base of the crown is often difficult to determine. The aim of this study was to develop an allometric model to calculate the crown length of Pinus sylvestris L., which might serve as an alternative to the current equations used especially for stands of variable density. The model used three predictive variables, i.e., diameter at breast height, tree height, and density. The developed crown length model showed high compatibility with empirical data within the studied stands differing in diameter at breast height, height, age, biosocial position, and, above all, density (SD = 1.786). The correlation coefficient between the empirical crown length for the stand (Hemp*) and the calculated model (Hcal*) was r = 0.974, with a discrepancy of (±) 3.17%. The derived crown length model can be one of the components used to estimate the mass of needles or leaf area index (LAI) and, consequently, the amount of transpiration or the amount of carbon dioxide bound, which is crucial in the context of climate change.
Biofuel Policy-Making Based on Outdated Modelling? The Cost of Road Transport Decarbonisation in EU
Authors: Szabó Zoltán
Published: August 2023

The cost of transport decarbonisation matters, yet little information is available. Policies need to reflect the costs to society. The European Union relies on the PRIMES model, a private model with limited transparency. Our research revealed its methodological deficiencies. Based on a revised PRIMES model, modelling was carried out and compared with an official impact assessment prepared for a key EU policy. Our modelling results indicate that crop-based bioethanol has negative abatement costs, biodiesel and biomethane have costs below 100 EUR/tCO2eq, electromobility falls in the range of 100–150 EUR/tCO2eq, cellulosic ethanol has costs above 200 EUR/tCO2eq, while advanced biodiesel has costs above 300 EUR/tCO2eq. Our results on carbon abatement costs suggest that policy-making has often been based on outdated modelling in the EU. With regard to transport decarbonisation policies, a large number of recent energy and climate proposals by the European Commission seem to have been misguided.
Comparative Plastomes of Curcuma alismatifolia (Zingiberaceae) Reveal Diversified Patterns among 56 Different Cut-Flower Cultivars
Authors: Wang Jie , Liao Xuezhu , Li Yongyao , Ye Yuanjun , Xing Guoming , Kan Shenglong , Nie Liyun , Li Sen , Tembrock Luke R. , Wu Zhiqiang
Published: August 2023

Curcuma alismatifolia (Zingiberaceae) is an ornamental species with high economic value due to its recent rise in popularity among floriculturists. Cultivars within this species have mixed genetic backgrounds from multiple hybridization events and can be difficult to distinguish via morphological and histological methods alone. Given the need to improve identification resources, we carried out the first systematic study using plastomic data wherein genomic evolution and phylogenetic relationships from 56 accessions of C. alismatifolia were analyzed. The newly assembled plastomes were highly conserved and ranged from 162,139 bp to 164,111 bp, including 79 genes that code for proteins, 30 tRNA genes, and 4 rRNA genes. The A/T motif was the most common of SSRs in the assembled genomes. The Ka/Ks values of most genes were less than 1, and only two genes had Ka/Ks values above 1, which were rps15 (1.15), and ndhl (1.13) with petA equal to 1. The sequence divergence between different varieties of C. alismatifolia was large, and the percentage of variation in coding regions was lower than that in the non-coding regions. Such data will improve cultivar identification, marker assisted breeding, and preservation of germplasm resources.
The Stability and Evolution of Genes and Genomes
Authors: Viggiano Luigi , Marsano René Massimiliano
Published: August 2023

The existence of current species can be attributed to a dynamic interplay between evolutionary forces and the maintenance of genetic information [...]
Association between Physical Activity Habits with Cardiometabolic Variables, Body Composition, and Physical Performance in Chilean Older Women
Authors: Hernandez-Martinez Jordan , González-Castillo Camila , Herrera-Valenzuela Tomás , Muñoz-Vásquez Cristopher , Magnani Branco Braulio Henrique , Valdés-Badilla Pablo
Published: August 2023

This study aimed to associate physical activity habits with cardiometabolic variables (blood pressure, fasting glucose, HDL cholesterol, and triglycerides), body composition (body fat percentage and fat-free mass), and physical performance (handgrip strength (HGS), timed up-and-go (TUG), and walking speed) in Chilean older women. An analytical cross-sectional study analyzed 179 older women with a mean age of 75.4 years distributed into physically inactive (PI) older women (n = 74) and physically active (PA) older women (n = 105). A logistic regression showed that PI older women presented an increased risk of hyperglycemia (OR = 4.70; p = 0.000), high blood pressure (OR = 3.83; p = 0.000), low HDL cholesterol levels (OR = 2.13; p = 0.03), hypertriglyceridemia (OR = 2.54; p = 0.01), excess body fat percentage (OR = 4.33; p = 0.000), low fat-free mass (OR = 2.22; p = 0.02), low HGS in their dominant hand (OR = 3.37; p = 0.001) and non-dominant hand (OR = 3.60; p = 0.0001), and poor performance in TUG (OR = 5.60; p = 0.000) and walking speed (OR = 5.52; p = 0.000). In conclusion, physical inactivity was associated with increased cardiometabolic risk, excess body fat percentage, lower fat-free mass, and poorer physical performance in Chilean older women. At the same time, PA older women showed a lower cardiometabolic risk, better body composition, and better physical performance than PI older women.
Prenatal Alcohol Exposure Impairs the Placenta–Cortex Transcriptomic Signature, Leading to Dysregulation of Angiogenic Pathways
Authors: Sautreuil Camille , Lecointre Maryline , Derambure Céline , Brasse-Lagnel Carole , Leroux Philippe , Laquerrière Annie , Nicolas Gaël , Gil Sophie , Savage Daniel D. , Marret Stéphane , Marguet Florent , Falluel-Morel Anthony , Gonzalez Bruno J.
Published: August 2023

Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician’s difficulties achieving early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta–cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic “placenta–cortex” signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ “placenta–cortex” signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta–cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein–protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that “intercellular communication” was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand–receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta–cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD.
A Case of Curative Treatment with Apatinib and Camrelizumab Following Liver Resection for Advanced Hepatocellular Carcinoma
Authors: Huang Julu , Liang Rong , Lu Cheng , Lu Lu , Li Shuanghang , Tang Minchao , Huang Xi , Huang Shilin , Mai Rongyun , Gao Xing , Li Shizhuo , Zeng Can , Lin Yan , Ye Jiazhou
Published: August 2023

Hepatocellular carcinoma (HCC), a highly malignant digestive system tumor, poses substantial challenges due to its intricate underlying causes and pronounced post-surgery recurrence. Consequently, the prognosis for HCC remains notably unfavorable. The endorsement of sorafenib and PD-L1 inhibitors for HCC signifies the onset of a new era embracing immunotherapy and targeted treatment approaches for this condition. Hence, comprehending the mechanisms underpinning targeted immune combination therapy has become exceedingly vital for the prospective management of HCC patients. This article initially presents a triumphant instance of curative treatment involving the combination of TKI and PD-1 inhibitor subsequent to liver resection, targeting an advanced stage HCC as classified by the BCLC staging system. The case patient carries a decade-long history of hepatitis B, having undergone a regimen of 20 courses of treatments involving apatinib and camrelizumab. Throughout the treatment period, no occurrences of grade 3 or 4 adverse events (AE) were noted. Subsequently, the patient underwent a left hepatectomy. Following the hepatectomy, their serum AFP levels have consistently remained within normal limits, and CT imaging has indicated the absence of tumor recurrence over a span of 36 months. The patient had been reviewed on time for two years after the operation. The last time a CT was performed for this patient in our hospital was 7 May 2021, and no new tumors were found. Follow-up is still ongoing. When applying combined targeted immune transformation therapy using TKI and ICI for a patient with BCLC advanced stage HCC, apatinib treatment serves a dual purpose. It inhibits the survival and angiogenesis of tumor cells, while also enhancing the efficacy of camrelizumab in obstructing the interaction between PD-1 and PD-L1. This restoration of T cell cytotoxicity subsequently facilitates the elimination of tumor cells, leading to an enhanced anticancer effect.
Recurrent Implantation Failure: Bioinformatic Discovery of Biomarkers and Identification of Metabolic Subtypes
Authors: Fan Yuan , Shi Cheng , Huang Nannan , Fang Fang , Tian Li , Wang Jianliu
Published: August 2023

Recurrent implantation failure (RIF) is a challenging scenario from different standpoints. This study aimed to investigate its correlation with the endometrial metabolic characteristics. Transcriptomics data of 70 RIF and 99 normal endometrium tissues were retrieved from the Gene Expression Omnibus database. Common differentially expressed metabolism-related genes were extracted and various enrichment analyses were applied. Then, RIF was classified using a consensus clustering approach. Three machine learning methods were employed for screening key genes, and they were validated through the RT-qPCR experiment in the endometrium of 10 RIF and 10 healthy individuals. Receiver operator characteristic (ROC) curves were generated and validated by 20 RIF and 20 healthy individuals from Peking University People’s Hospital. We uncovered 109 RIF-related metabolic genes and proposed a novel two-subtype RIF classification according to their metabolic features. Eight characteristic genes (SRD5A1, POLR3E, PPA2, PAPSS1, PRUNE, CA12, PDE6D, and RBKS) were identified, and the area under curve (AUC) was 0.902 and the external validated AUC was 0.867. Higher immune cell infiltration levels were found in RIF patients and a metabolism-related regulatory network was constructed. Our work has explored the metabolic and immune characteristics of RIF, which paves a new road to future investigation of the related pathogenic mechanisms.
ZmHMA3, a Member of the Heavy-Metal-Transporting ATPase Family, Regulates Cd and Zn Tolerance in Maize
Authors: Liao Changjian , Li Youqiang , Wu Xiaohong , Wu Wenmei , Zhang Yang , Zhan Penglin , Meng Xin , Hu Gaojiao , Yang Shiqi , Lin Haijian
Published: August 2023

The pollution of heavy metals is extremely serious in China, including zinc (Zn), copper (Cu), lead (Pb), and cadmium (Cd). Heavy-metal-transporting ATPase (HMA) belongs to a subfamily of the P-ATPase family, which absorbs and transports Zn, Cu, Pb, and Cd in plants. Here, we describe a ZmHMA-encoding HMA family protein that positively regulates Cd and Zn tolerance. The real-time fluorescence quantification (RT-PCR) results revealed that ZmHMA3 had a high expression in B73, and the expression of ZmHMA3 was sensitive to Cd in yeast cells, which was related to Cd accumulation in yeast. Additionally, the Arabidopsis thaliana homologous mutants of AtHMA2 showed Cd sensitivity compared with WT. The overexpressing ZmHMA3 plants showed higher tolerance under Cd and Zn stresses than the wild type. The overexpression of ZmHMA3 led to higher Cd and Zn accumulation in tissues based on the subcellular distribution analysis. We propose that ZmHMA3 improves maize tolerance to Cd and Zn stresses by absorbing and transporting Cd and Zn ions. This study elucidates the gene function of the ZmHMA3 response to Cd and Zn stress and provides a reference for improving the characteristics of heavy metals enrichment in existing maize varieties and the plant remediation technology of heavy-metal-contaminated soil.
Application of Novel Transcription Factor Machine Learning Model and Targeted Drug Combination Therapy Strategy in Triple Negative Breast Cancer
Authors: Pang Jianyu , Li Huimin , Zhang Xiaoling , Luo Zhengwei , Chen Yongzhi , Zhao Haijie , Lv Handong , Zheng Hongan , Fu Zhiqian , Tang Wenru , Sheng Miaomiao
Published: August 2023

Transcription factors (TFs) have been shown to play a key role in the occurrence and development of tumors, including triple-negative breast cancer (TNBC), with a worse prognosis. Machine learning is widely used for establishing prediction models and screening key tumor drivers. Current studies lack TF integration in TNBC, so targeted research on TF prognostic models and targeted drugs is beneficial to improve clinical translational application. The purpose of this study was to use the Least Absolute Shrinkage and Selection Operator to build a prognostic TFs model after cohort normalization based on housekeeping gene expression levels. Potential targeted drugs were then screened on the basis of molecular docking, and a multi-drug combination strategy was used for both in vivo and in vitro experimental studies. The machine learning model of TFs built by E2F8, FOXM1, and MYBL2 has broad applicability, with an AUC value of up to 0.877 at one year. As a high-risk clinical factor, its abnormal disorder may lead to upregulation of the activity of pathways related to cell proliferation. This model can also be used to predict the adverse effects of immunotherapy in patients with TNBC. Molecular docking was used to screen three drugs that target TFs: Trichostatin A (TSA), Doxorubicin (DOX), and Calcitriol. In vitro and in vivo experiments showed that TSA + DOX was able to effectively reduce DOX dosage, and TSA + DOX + Calcitriol may be able to effectively reduce the toxic side effects of DOX on the heart. In conclusion, the machine learning model based on three TFs provides new biomarkers for clinical and prognostic diagnosis of TNBC, and the combination targeted drug strategy offers a novel research perspective for TNBC treatment.
Ethanol Kinetics in the Human Brain Determined by Magnetic Resonance Spectroscopy
Authors: Thierauf-Emberger Annette , Schuldis Dominik , Dacko Michael , Lange Thomas
Published: August 2023

In many parts of the world, ethanol is a widely consumed substance that displays its effect in the brain, the target organ for desired, but also negative impact. In a previous study, the ethanol concentrations were analyzed in different regions of the brain by magnetic resonance spectroscopy (MRS). In this study, the same method is used to demonstrate the kinetics of the ethanol concentration in the human brain after oral ethanol uptake. A drinking study was performed with 10 healthy participants. After the uptake of ethanol in a calculated amount leading to a plasma ethanol concentration of 0.92 g/L (19.95 mM corresponding to a blood ethanol concentration of 0.7 g/kg), brain ethanol concentrations were continuously measured by means of MRS on a 3 Tesla human magnetic resonance imaging (MRI) system. For the data acquisition a single-voxel sLASER sequence was used, with the volume of interest located in the occipital cortex. Intermittently, blood samples were taken and plasma was analyzed for ethanol using headspace gas chromatography with flame ionization detection (HS-GC-FID). The obtained MRS brain ethanol curves showed distinct inter-individual differences; however, a good intra-individual correlation of plasma and brain ethanol concentrations was observed. The results suggest a rapid equilibration between blood and brain. The ethanol concentrations measured in the brain were substantially lower than the measured plasma ethanol results, suggesting an MRS visibility of about 63% for ethanol in brain tissue. The maximum individual ethanol concentrations in the brain (normalized to water content) ranged between 7.1 and 14.1 mM across the cohort, while the highest measured plasma concentrations were in the range between 0.35 g/L (9.41 mM) and 0.95 g/L (20.52 mM).
Small Molecules Targeting Viral RNA
Authors: Mathez Gregory , Cagno Valeria
Published: August 2023

The majority of antivirals available target viral proteins; however, RNA is emerging as a new and promising antiviral target due to the presence of highly structured RNA in viral genomes fundamental for their replication cycle. Here, we discuss methods for the identification of RNA-targeting compounds, starting from the determination of RNA structures either from purified RNA or in living cells, followed by in silico screening on RNA and phenotypic assays to evaluate viral inhibition. Moreover, we review the small molecules known to target the programmed ribosomal frameshifting element of SARS-CoV-2, the internal ribosomal entry site of different viruses, and RNA elements of HIV.
Macrophage-Myofibroblast Transition Contributes to Myofibroblast Formation in Proliferative Vitreoretinal Disorders
Authors: Abu El-Asrar Ahmed M. , De Hertogh Gert , Allegaert Eef , Nawaz Mohd I. , Abouelasrar Salama Sara , Gikandi Priscilla W. , Opdenakker Ghislain , Struyf Sofie
Published: August 2023

Inflammation and fibrosis are key features of proliferative vitreoretinal disorders. We aimed to define the macrophage phenotype and investigate the role of macrophage-myofibroblast transition (MMT) in the contribution to myofibroblast populations present in epiretinal membranes. Vitreous samples from proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR) and nondiabetic control patients, epiretinal fibrovascular membranes from PDR patients and fibrocellular membranes from PVR patients, human retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied by ELISA, immunohistochemistry and flow cytometry analysis. Myofibroblasts expressing α-SMA, fibroblast activation protein-α (FAP-α) and fibroblast-specific protein-1 (FSP-1) were present in all membranes. The majority of CD68+ monocytes/macrophages co-expressed the M2 macrophage marker CD206. In epiretinal membranes, cells undergoing MMT were identified by co-expression of the macrophage marker CD68 and myofibroblast markers α-SMA and FSP-1. Further analysis revealed that CD206+ M2 macrophages co-expressed α-SMA, FSP-1, FAP-α and ß-catenin. Soluble (s) CD206 and sFAP-α levels were significantly higher in vitreous samples from PDR and PVR patients than in nondiabetic control patients. The proinflammatory cytokine TNF-α and the hypoxia mimetic agent cobalt chloride induced upregulation of sFAP-α in culture media of Müller cells but not of HRMECs. The NF-ĸß inhibitor BAY11-7085 significantly attenuated TNF-α-induced upregulation of sFAP-α in Müller cells. Our findings suggest that the process of MMT might contribute to myofibroblast formation in epiretinal membranes, and this transition involved macrophages with a predominant M2 phenotype. In addition, sFAP-α as a vitreous biomarker may be derived from M2 macrophages transitioned to myofibroblasts and from Müller cells.
Dysregulation of Lipid Metabolism in Aging Meibomian Glands and Its Molecular Markers
Authors: Butovich Igor A. , Wilkerson Amber , Yuksel Seher
Published: August 2023

The main function of exocrine Meibomian glands (MGs) is to produce a lipid-rich secretion called meibum which plays a critical role in maintaining the ocular surface homeostasis of humans and most mammals. The chemical composition of meibum, and its quantity produced by MGs, largely determine whether it can fulfill its role successfully. Aging was frequently associated with the onset of various MG-related pathologies. The goal of this study was to determine how aging affects the chemical composition and quantity of meibum in mice, and identify possible molecular markers of aging. Unbiased, untargeted and targeted lipidomic evaluation of mouse MG lipids was conducted using liquid chromatography—high-resolution mass spectrometry, and the results were analyzed using Principal Component, Orthogonal Projections to Latent Structures Discriminant, and Partial Least Square Discriminant Analyses. We found that aging leads to dysregulation of lipid metabolism in MGs, changing the ratios of major classes of MG lipids (such as wax esters, triacylglycerols, and phospholipids) in a progressive manner. Several lipid species that belong to these groups of MG lipids are proposed as clear markers of aging in a mouse model.
Studying the Interaction between Bendamustine and DNA Molecule with SERS Based on AuNPs/ZnCl2/NpAA Solid-State Substrate
Authors: Yao Lina , Li Yanjie , Zuo Zhenzhong , Gong Ziyi , Zhu Jie , Feng Xiaoqiang , Sun Dan , Wang Kaige
Published: August 2023

Bendamustine (BENDA) is a bifunctional alkylating agent with alkylating and purinergic antitumor activity, which exerts its anticancer effects by direct binding to DNA, but the detailed mechanism of BENDA–DNA interaction is poorly understood. In this paper, the interaction properties of the anticancer drug BENDA with calf thymus DNA (ctDNA) were systematically investigated based on surface-enhanced Raman spectroscopy (SERS) technique mainly using a novel homemade AuNPs/ZnCl2/NpAA (NpAA: nano porous anodic alumina) solid-state substrate and combined with ultraviolet–visible spectroscopy and molecular docking simulation to reveal the mechanism of their interactions. We experimentally compared and studied the SERS spectra of ctDNA, BENDA, and BENDA–ctDNA complexes with different molar concentrations (1:1, 2:1, 3:1), and summarized their important characteristic peak positions, their peak position differences, and hyperchromic/hypochromic effects. The results showed that the binding modes include covalent binding and hydrogen bonding, and the binding site of BENDA to DNA molecules is mainly the N7 atom of G base. The results of this study help to understand and elucidate the mechanism of BENDA at the single-molecule level, and provide guidance for the further development of effective new drugs with low toxicity and side effects.
Synergistic Effect, Improved Cell Selectivity, and Elucidating the Action Mechanism of Antimicrobial Peptide YS12
Authors: Suchi Suzia Aktar , Lee Dae Young , Kim Young Kyun , Kang Seong Soo , Bilkis Tahmina , Yoo Jin Cheol
Published: August 2023

Antimicrobial peptides (AMPs) have attracted considerable attention as potential substitutes for traditional antibiotics. In our previous research, a novel antimicrobial peptide YS12 derived from the Bacillus velezensis strain showed broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria. In this study, the fractional inhibitory concentration index (FICI) indicated that combining YS12 with commercial antibiotics produced a synergistic effect. Following these findings, the combination of YS12 with an antibiotic resulted in a faster killing effect against bacterial strains compared to the treatment with the peptide YS12 or antibiotic alone. The peptide YS12 maintained its antimicrobial activity under different physiological salts (Na+, Mg2+, and Fe3+). Most importantly, YS12 exhibited no cytotoxicity towards Raw 264.7 cells and showed low hemolytic activity, whereas positive control melittin indicated extremely high toxicity. In terms of mode of action, we found that peptide YS12 was able to bind with LPS through electrostatic interaction. The results from fluorescent measurement revealed that peptide YS12 damaged the integrity of the bacterial membrane. Confocal laser microscopy further confirmed that the localization of peptide YS12 was almost in the cytoplasm of the cells. Peptide YS12 also exhibited anti-inflammatory activity by reducing the release of LPS-induced pro-inflammatory mediators such as TNF-α, IL-1β, and NO. Collectively, these properties strongly suggest that the antimicrobial peptide YS12 may be a promising candidate for treating microbial infections and inflammation.
JNK Cascade-Induced Apoptosis—A Unique Role in GqPCR Signaling
Authors: Nadel Guy , Maik-Rachline Galia , Seger Rony
Published: August 2023

The response of cells to extracellular signals is mediated by a variety of intracellular signaling pathways that determine stimulus-dependent cell fates. One such pathway is the cJun-N-terminal Kinase (JNK) cascade, which is mainly involved in stress-related processes. The cascade transmits its signals via a sequential activation of protein kinases, organized into three to five tiers. Proper regulation is essential for securing a proper cell fate after stimulation, and the mechanisms that regulate this cascade may involve the following: (1) Activatory or inhibitory phosphorylations, which induce or abolish signal transmission. (2) Regulatory dephosphorylation by various phosphatases. (3) Scaffold proteins that bring distinct components of the cascade in close proximity to each other. (4) Dynamic change of subcellular localization of the cascade’s components. (5) Degradation of some of the components. In this review, we cover these regulatory mechanisms and emphasize the mechanism by which the JNK cascade transmits apoptotic signals. We also describe the newly discovered PP2A switch, which is an important mechanism for JNK activation that induces apoptosis downstream of the Gq protein coupled receptors. Since the JNK cascade is involved in many cellular processes that determine cell fate, addressing its regulatory mechanisms might reveal new ways to treat JNK-dependent pathologies.
Inhibition of NLRP3 Inflammasome Activation by 3H-1,2-Dithiole-3-Thione: A Potential Therapeutic Approach for Psoriasis Treatment
Authors: Shih Meng-Chieh , Li Chia-Ling , Liao En-Chih , Yen Chung-Yang , Yen Ling-Jung , Wang Kai-Chun , Lu Ling-Ying , Chou Ting-Yu , Chen Ying-Chin , Yu Sheng-Jie
Published: August 2023

Psoriasis is a chronic autoimmune skin disease with a significant impact on quality of life and potential for severe comorbidities. Inflammation in the skin is induced by immune cells that overexpress pro-inflammatory cytokines, with the Th17 cell playing a crucial role. NLRP3 inflammasome activation is associated with inflammatory diseases and abnormal T cell differentiation. 3H-1,2-dithiole-3-thione (D3T), isolated from cruciferous vegetables, has anti-inflammatory effects and inhibits Th17 differentiation. This study aimed to investigate how D3T reduces skin inflammation and modulates Th17 cell differentiation by inhibiting NLRP3 inflammasome activation. In an imiquimod-induced psoriasis mouse model, D3T treatment demonstrated significant reductions in ear thickness, skin redness, and scaling compared to a control group. Our study also observed decreased expression of ki-67, NLRP3 inflammasome, and cleaved caspase-1 in skin samples, reduced levels of IL-6 and IL-17A in serum samples, and inhibition of Th17 differentiation after D3T application. D3T could also inhibit the expression of NLRP3, caspase-1, and IL-1β in TNF-α stimulated HaCaT cells. The mechanical study also revealed that D3T could inhibit NLRP3 inflammasome activation by inhibiting the JNK pathway in HaCaT cells. These results indicate that targeting NLRP3 inflammasome activation is a promising strategy in the treatment of psoriasis.
Alzheimer’s Disease: Causal Effect between Obesity and APOE Gene Polymorphisms
Authors: Zhao Tianyu , Zhong Tangsheng , Zhang Meishuang , Xu Yang , Zhang Ming , Chen Li
Published: August 2023

Currently studies on the correlation between obesity and Alzheimer’s disease (AD) are still unclear. In addition, few indicators have been used to evaluate obesity, which has failed to comprehen-sively study the correlations between body fat mass, body fat distribution, and AD. Thus, this study innovatively utilized bioinformatics and Mendelian randomization (MR) to explore the key targets of obesity-induced AD, and investigate the causal associations between different types of obesity and key targets. The common targets of obesity and AD were screened using the GeneCards database, and functional and pathway annotations were carried out, thereby revealing the key target. MR analysis was conducted between body anthropometric indexes of obesity and the key target using an IVW model. Bioinformatics analysis revealed Apolipoprotein E (APOE) as the key target of obesity-induced AD. MR results showed that body mass index (BMI) had a negative causal association with APOE2, while body fat percentage (BFP) and trunk fat percentage (TFP) had no significant causal association with APOE2; BMI, BFP, and TFP had a negative causal association with APOE3, and none had any significant causal association with APOE4. In conclusion, there is a correlation between obesity and AD, which is mainly due to the polymorphism of the APOE gene rather than adipose tissue distribution. APOE3 carriers may be more susceptible to obesity, while the risk of AD caused by APOE2 and APOE4 may not be induced by obesity. This study sheds new light on current disputes. At the same time, it is suggested to regulate the body fat mass of APOE3 carriers in the early stage, and to reduce the risk of AD.
Advancement from Small Peptide Pharmaceuticals to Orally Active Piperazine-2,5-dion-Based Cyclopeptides
Authors: Deigin Vladislav , Linkova Natalia , Volpina Olga
Published: August 2023

The oral delivery of peptide pharmaceuticals has long been a fundamental challenge in drug development. A new chemical platform was designed based on branched piperazine-2,5-diones for creating orally available biologically active peptidomimetics. The platform includes a bio-carrier with “built-in” functionally active peptide fragments or bioactive molecules that are covalently attached via linkers. The developed platform allows for a small peptide to be taken with a particular biological activity and to be transformed into an orally stable compound displaying the same activity. Based on this approach, various peptidomimetics exhibiting hemostimulating, hemosuppressing, and adjuvant activity were prepared. In addition, new examples of a rare phenomenon when enantiomeric molecules demonstrate reciprocal biological activity are presented. Finally, the review summarizes the evolutionary approach of the short peptide pharmaceutical development from the immunocompetent organ separation to orally active cyclopeptides and peptidomimetics.