bluuebunny/crossref_metadata_2025 huggingface dataset:
Common-Mode Voltage-Reduction Method of 7-Phase BLDC Motor Control System
Authors: Son Yung-Deug , Kim Dong-Youn , Kim Hyeong-Jin , Kim Jang-Mok
Published: February 2023

This paper describes a method for reducing the common-mode voltage in a seven-phase brushless DC motor (BLDC) drive. The conventional interleaved method used in the three-phase inverter system is extended and applied. The proposed phase-phase interleaved method is studied to apply the six-phase excitation method for controlling the seven-phase BLDC. The six-phase switching functions related with modulation index (MI) and interleaved angle are obtained, and the average of the common-mode voltage is derived mathematically. The proposed control method reduces the common-mode voltage generation by applying the optimal interleaved angle according to MI. The proposed method is verified by experimental results.
Evaluation of Shale Oil Mobility for the Eocene Shahejie Formation in Liutun Sag, Dongpu Depression, Bohai Bay Basin
Authors: Yan Qiang , Ping Hongwei , Yang Xin , Liu Honglin , Chen Honghan
Published: February 2023

Previous studies have shown that shale oil mobility depends on the relative content of free oil and adsorbed oil. However, the research on how to establish a shale oil mobility evaluation is relatively insufficient. This study aims to use pyrolysis data before and after extraction to accurately identify the content of free oil and adsorbed oil, analyze the influencing factors of shale oil mobility, characterize the hydrocarbon generation and expulsion process, and evaluate shale oil mobility. We utilized an integrated mineralogical and geochemical dataset from the PS18-1 well in the Liutun Sag, Dongpu Depression, Bohai Bay Basin. The results show that the adsorption capacity of type I organic matter (OM) on shale oil is greater than that of type II OM, the OM abundance is of great significance to shale oil mobility, and that quartz and feldspar can promote shale oil mobility. The Tmax corresponding to the threshold of hydrocarbon expulsion is 438~440 °C, and the oil saturation index (OSI) is about 158 mg/g TOC. There are four small intervals: a (3257 m~3260 m), b (3262 m~3267 m), c (3273 m~3278 m), and d (3281 m~3282 m) meeting the conditions of hydrocarbon expulsion. Large-scale hydrocarbon expulsion occurred in interval a, a small amount of hydrocarbon expulsion in interval b, a large amount of hydrocarbon expulsion in interval c, and almost no hydrocarbon expulsion in interval d. Based on the crossplot of S1 and TOC, combined with other parameters such as OSI, hydrocarbon generation potential (HGP), and free and adsorbed oil, we established an evaluation chart of shale oil mobility and divided it into five categories: A, B, C, D, and E. While categories A and C have good mobility and great resource potential, categories B and D have relatively poor mobility and medium resource potential, and category E has little mobility and is an invalid resource.
Numerical Analysis of In Situ Conversion Process of Oil Shale Formation Based on Thermo-Hydro-Chemical Coupled Modelling
Authors: Jin Juan , Jiang Weidong , Liu Jiandong , Shi Junfeng , Zhang Xiaowen , Cheng Wei , Yu Ziniu , Chen Weixi , Ye Tingfu
Published: February 2023

The in situ conversion process (ICP) is a retorting method pyrolyzing the kerogen in shale into oil and gas products, which shows great potential to promote the recovery of oil shale resources. In this work, a thermo-hydro-chemical-coupled model for the in situ conversion process is established, considering the temperature dependence of key properties and the transverse isotropy caused by the layered characteristics of oil shale. Based on the proposed model, a series of simulations is conducted to evaluate the production performance of the in situ conversion process of oil shale reservoirs. The results indicate that energy efficiency reaches a maximum of 2.7 around the fifth year of the heating process, indicating the feasibility of in situ conversion technology. Furthermore, the sensitivity analysis shows that the heating temperature should be higher than 300 °C to avoid the energy output being less than the energy input, and the oil/gas ratio decreases with increasing heating temperature. Moreover, thermal conductivity is positively with production while heat capacity is negatively correlated, and the energy efficiency decreases with increasing thermal conductivity and matrix heat capacity. Finally, the heating period should be no longer than 4 years to maximize the heating efficiency.
Probing the Pre-Ignition Behavior of Negative Temperature Coefficient Fuels at Low to High Temperatures: A Case Study of Dimethyl Ether
Authors: Huang Wenlin , Wu Honghuan , Sun Wuchuan , Hong Congjie , Tian Zemin , Yan Yingwen , Huang Zuohua , Zhang Yingjia
Published: February 2023

Pre-ignition, involving complex interactions of physical and chemical processes, occurs not only in actual combustion engines but also in fundamental research equipment such as rapid compression machines and shock tubes. Thus, identifying the combustion conditions prone to pre-ignition is critical for the interpretation of ignition data and fuel design. Shock tube experiments with dimethyl ether (DME) were carried out in this study to investigate the pre-ignition behavior during fuel auto-ignition. The experimental conditions included a wide range of temperatures (620–1370 K), pressures (1–9 atm), and equivalence ratios (0.5–5.0). The results indicate that pre-ignition of DME is prone to occur in the transition region from a high temperature to an intermediate temperature (~1000 K), and the decrease in pressure and equivalency ratio will aggravate the pre-ignition behavior. Theoretical analysis was then performed using four physical-based criteria: temperature perturbation sensitivity of ignition delay times, thermal diffusivity, a dimensionless parameter analogous to the Damköhler number, and the Sankaran number. According to experimental observations and theoretical analysis, it was found that the temperature sensitivity (Stp = 75 μs/K) and Sankaran number (Sap = 1) are the best available criteria for predicting the pre-ignition behavior of negative temperature coefficient (NTC) fuels. The pre-ignition region of non-NTC fuels can be accurately predicted by thermal diffusivity and the Damköhler number, but they deviate greatly when predicting the pre-ignition of NTC fuels. This strategy is expected to provide a feasible method for identifying the critical conditions under which pre-ignition may occur and for revealing the pre-ignition mechanisms for other NTC fuels.
The Design of a Large-Scale Induction Heating Power Source for Organic Waste Digesters to Produce Fertilizer
Authors: Thosdeekoraphat Thanaset , Tanthai Kittisak , Lhathum Kachaporn , Kotchapradit Supawat , Santalunai Samran , Thongsopa Chanchai
Published: February 2023

Heating induction is a new environmentally friendly, energy-saving technology that offers a more effective performance than other common heaters. The energy-use efficiency of an inductor circuit is greater than 80 percent, while a biomass tank and tungsten coil have 70 percent and 51.8 percent efficiency, respectively. This method also produces more heat than any other forms of heating using gas or coal. The induction heating method has attracted significant interest and has seen application worldwide. Based on this important source of heating, we have designed and developed a large induction-heating machine with high energy to heat up a tank directly. The aim is to degrade organic waste as much as possible and convert it into an effective fertilizer by adding mesophilic microorganisms; the fertilizer transforming process takes no more than 24 h. The tank featured in our design has a 100-cm radius and is 155 in length; this is very large. The aim of this process is to reduce the amount of organic waste and thereby provide environmental benefits. To this end, we have designed a large, high-energy induction-heating machine (approximately 9.6 kilowatt) and used two machines in order to appropriately heat the tank for a large amount of organic-waste degradation. This research can be effectively applied to many heating methods in industry.
The Contribution of Lean Management—Industry 4.0 Technologies to Improving Energy Efficiency
Authors: Arana-Landín Germán , Uriarte-Gallastegi Naiara , Landeta-Manzano Beñat , Laskurain-Iturbe Iker
Published: February 2023

The current socio-economic and environmental context obliges companies to increase their energy efficiency to be competitive, and the development of Industry 4.0 technologies should contribute to improve it. This article analyses the influence of Industry 4.0 technologies on energy efficiency and the mediation of quality management of production process variables. After a descriptive analysis, a correlation and regression analysis is presented using information from 72 projects for the integration of Industry 4.0 technologies in industrial companies. At a global level, it is confirmed that the four technology groups (Artificial Vision and Artificial Intelligence, Additive Manufacturing and Robotics, Big Data and Advanced Analytics, and Internet of Things) contribute to improving energy efficiency by an average of 15–25% in the processes where they are integrated. In addition, the regression model determines that improved decision-making capabilities strongly mediate the achievement of higher energy efficiency.
A Google Earth Engine Algorithm to Map Phenological Metrics in Mountain Areas Worldwide with Landsat Collection and Sentinel-2
Authors: Orusa Tommaso , Viani Annalisa , Cammareri Duke , Borgogno Mondino Enrico
Published: February 2023

Google Earth Engine has deeply changed the way in which Earth observation data are processed, allowing the analysis of wide areas in a faster and more efficient way than ever before. Since its inception, many functions have been implemented by a rapidly expanding community, but none so far has focused on the computation of phenological metrics in mountain areas with high-resolution data. This work aimed to fill this gap by developing an open-source Google Earth Engine algorithm to map phenological metrics (PMs) such as the Start of Season, End of Season, and Length of Season and detect the Peak of Season in mountain areas worldwide using high-resolution free satellite data from the Landsat collection and Sentinel-2. The script was tested considering the entire Alpine chain. The validation was performed by the cross-computation of PMs using the R package greenbrown, which permits land surface phenology and trend analysis, and the Moderate-Resolution Imaging Spectroradiometer (MODIS) in homogeneous quote and land cover alpine landscapes. MAE and RMSE were computed. Therefore, this algorithm permits one to compute with a certain robustness PMs retrieved from higher-resolution free EO data from GEE in mountain areas worldwide.
Psychological Distress, Depression, and Anxiety in Nursing Students: A Longitudinal Study
Authors: Sonmez Yonca , Akdemir Meltem , Meydanlioglu Ayse , Aktekin Mehmet Rifki
Published: February 2023

The aim of this longitudinal study is to determine how stressful life events, psychological distress, depressive symptoms, and anxiety change in a cohort of students from one nursing faculty during the education process and to document the factors related to psychological distress, depressive symptoms, and anxiety during the fourth year of education. The General Health Questionnaire (GHQ-12), the Beck Depression Inventory (BDI), and the State-Trait Anxiety Inventory (STAI) were applied to students within the faculty of nursing within the first week of the 2018–2019 academic year. All students were asked to answer a questionnaire measuring their possible stressful life events (first timepoint). The process was repeated for the same students again in the fourth year (second timepoint). The changes between the two timepoints were examined. Nursing students’ GHQ-12 and STAI scores and averages increased significantly from first timepoint to second timepoint (p < 0.05). There was a significant increase in the prevalence of depressive symptoms for the ≥21 cut-off point of BDI in the fourth year of the study cohort. A significant increase in perceived stress levels between the two timepoints was also found for numerous stressful life events. As a result of linear regression, “dissatisfaction with major” was found as a determinant on all scale scores. The psychological indicators increased significantly in nursing students during their education. Interventions to reduce stress, anxiety, and psychological distress are needed to improve the mental health status of nursing students.
How Does Organizational Toxicity Affect Depression? A Moderated Mediation Model
Authors: Tekin Ömer Akgün , Üngüren Engin , Doğrucan Ayşegül , Yıldız Sevcan
Published: February 2023

Organizational toxicity is a key organizational issue today, impacting the success of both employees and organizations negatively alike. Negative working conditions revealed by organizational toxicity pave the way for an organizational atmosphere to arise, which negatively influences the physical and psychological well-being of employees, causing burn-out syndrome and depression. Thus, organizational toxicity is observed to have a destructive impact on employees and can threaten the future of companies. In this framework, this study examines the mediating role of burnout and moderator role of occupational self-efficacy, in the relationship between organizational toxicity and depression. Conducted as cross-sectional, this study adopts a quantitative research approach. To that end, convenience sampling was used to collect data from 727 respondents who are employed at five-star hotels. Data analysis was completed with SPSS 24.0 and AMOS 24 packages. Consequent to the analyses, organizational toxicity was determined to have a positive effect on burnout syndrome and depression. Moreover, burnout syndrome was found to have a mediating effect on the relationship between organizational toxicity and depression. In addition, occupational self-efficacy was found to have a moderator role on the effect of employees’ burnout levels on their depression levels. According to the findings, occupational self-efficacy is an influential variable on reducing the impact that organizational toxicity and burnout have on depression.
Prader–Willi Syndrome and Chromosome 15q11.2 BP1-BP2 Region: A Review
Authors: Butler Merlin G.
Published: February 2023

Prader–Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive, hypogonadism/hypogenitalism and developmental delay during infancy. Hyperphagia, obesity, learning and behavioral problems, short stature with growth and other hormone deficiencies are identified during childhood. Those with the larger 15q11-q13 Type I deletion with the absence of four non-imprinted genes (NIPA1, NIPA2, CYFIP1, TUBGCP5) from the 15q11.2 BP1-BP2 region are more severely affected compared with those with PWS having a smaller Type II deletion. NIPA1 and NIPA2 genes encode magnesium and cation transporters, supporting brain and muscle development and function, glucose and insulin metabolism and neurobehavioral outcomes. Lower magnesium levels are reported in those with Type I deletions. The CYFIP1 gene encodes a protein associated with fragile X syndrome. The TUBGCP5 gene is associated with attention-deficit hyperactivity disorder (ADHD) and compulsions, more commonly seen in PWS with the Type I deletion. When the 15q11.2 BP1-BP2 region alone is deleted, neurodevelopment, motor, learning and behavioral problems including seizures, ADHD, obsessive-compulsive disorder (OCD) and autism may occur with other clinical findings recognized as Burnside–Butler syndrome. The genes in the 15q11.2 BP1-BP2 region may contribute to more clinical involvement and comorbidities in those with PWS and Type I deletions.
Aberrantly Expressed MicroRNAs in Cancer-Associated Fibroblasts and Their Target Oncogenic Signatures in Hepatocellular Carcinoma
Authors: Eun Jung Woo , Ahn Hye Ri , Baek Geum Ok , Yoon Moon Gyeong , Son Ju A , Weon Ji Hyang , Yoon Jung Hwan , Kim Hyung Seok , Han Ji Eun , Kim Soon Sun , Cheong Jae Youn , Kim Bong-wan , Cho Hyo Jung
Published: February 2023

Cancer-associated fibroblasts (CAFs) contribute to tumor progression, and microRNAs (miRs) play an important role in regulating the tumor-promoting properties of CAFs. The objectives of this study were to clarify the specific miR expression profile in CAFs of hepatocellular carcinoma (HCC) and identify its target gene signatures. Small-RNA-sequencing data were generated from nine pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues, respectively. Bioinformatic analyses were performed to identify the HCC-CAF-specific miR expression profile and the target gene signatures of the deregulated miRs in CAFs. Clinical and immunological implications of the target gene signatures were evaluated in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA_LIHC) database using Cox regression and TIMER analysis. The expressions of hsa-miR-101-3p and hsa-miR-490-3p were significantly downregulated in HCC-CAFs. Their expression in HCC tissue gradually decreased as HCC stage progressed in the clinical staging analysis. Bioinformatic network analysis using miRWalks, miRDB, and miRTarBase databases pointed to TGFBR1 as a common target gene of hsa-miR-101-3p and hsa-miR-490-3p. TGFBR1 expression was negatively correlated with miR-101-3p and miR-490-3p expression in HCC tissues and was also decreased by ectopic miR-101-3p and miR-490-3p expression. HCC patients with TGFBR1 overexpression and downregulated hsa-miR-101-3p and hsa-miR-490-3p demonstrated a significantly poorer prognosis in TCGA_LIHC. TGFBR1 expression was positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages in a TIMER analysis. In conclusion, hsa-miR-101-3p and hsa-miR-490-3p were substantially downregulated miRs in CAFs of HCC, and their common target gene was TGFBR1. The downregulation of hsa-miR-101-3p and hsa-miR-490-3p, as well as high TGFBR1 expression, was associated with poor clinical outcome in HCC patients. In addition, TGFBR1 expression was correlated with the infiltration of immunosuppressive immune cells.
Aggregation Limiting Cell-Penetrating Peptides Derived from Protein Signal Sequences
Authors: Porosk Ly , Härk Heleri Heike , Bicev Renata Naporano , Gaidutšik Ilja , Nebogatova Jekaterina , Armolik Eger-Jasper , Arukuusk Piret , da Silva Emerson Rodrigo , Langel Ülo
Published: February 2023

Alzheimer’s disease (AD) is the most common neurodegenerative disease (ND) and the leading cause of dementia. It is characterized by non-linear, genetic-driven pathophysiological dynamics with high heterogeneity in the biological alterations and the causes of the disease. One of the hallmarks of the AD is the progression of plaques of aggregated amyloid-β (Aβ) or neurofibrillary tangles of Tau. Currently there is no efficient treatment for the AD. Nevertheless, several breakthroughs in revealing the mechanisms behind progression of the AD have led to the discovery of possible therapeutic targets. Some of these include the reduction in inflammation in the brain, and, although highly debated, limiting of the aggregation of the Aβ. In this work we show that similarly to the Neural cell adhesion molecule 1 (NCAM1) signal sequence, other Aβ interacting protein sequences, especially derived from Transthyretin, can be used successfully to reduce or target the amyloid aggregation/aggregates in vitro. The modified signal peptides with cell-penetrating properties reduce the Aβ aggregation and are predicted to have anti-inflammatory properties. Furthermore, we show that by expressing the Aβ-EGFP fusion protein, we can efficiently assess the potential for reduction in aggregation, and the CPP properties of peptides in mammalian cells.
Inter-Regional Proteomic Profiling of the Human Brain Using an Optimized Protein Extraction Method from Formalin-Fixed Tissue to Identify Signaling Pathways
Authors: Davidson Jennilee M. , Rayner Stephanie L. , Liu Sidong , Cheng Flora , Di Ieva Antonio , Chung Roger S. , Lee Albert
Published: February 2023

Proteomics offers vast potential for studying the molecular regulation of the human brain. Formalin fixation is a common method for preserving human tissue; however, it presents challenges for proteomic analysis. In this study, we compared the efficiency of two different protein-extraction buffers on three post-mortem, formalin-fixed human brains. Equal amounts of extracted proteins were subjected to in-gel tryptic digestion and LC-MS/MS. Protein, peptide sequence, and peptide group identifications; protein abundance; and gene ontology pathways were analyzed. Protein extraction was superior using lysis buffer containing tris(hydroxymethyl)aminomethane hydrochloride, sodium dodecyl sulfate, sodium deoxycholate, and Triton X-100 (TrisHCl, SDS, SDC, Triton X-100), which was then used for inter-regional analysis. Pre-frontal, motor, temporal, and occipital cortex tissues were analyzed by label free quantification (LFQ) proteomics, Ingenuity Pathway Analysis and PANTHERdb. Inter-regional analysis revealed differential enrichment of proteins. We found similarly activated cellular signaling pathways in different brain regions, suggesting commonalities in the molecular regulation of neuroanatomically-linked brain functions. Overall, we developed an optimized, robust, and efficient method for protein extraction from formalin-fixed human brain tissue for in-depth LFQ proteomics. We also demonstrate herein that this method is suitable for rapid and routine analysis to uncover molecular signaling pathways in the human brain.
Electronic Cigarette Exposure Increases the Severity of Influenza a Virus Infection via TRAIL Dysregulation in Human Precision-Cut Lung Slices
Authors: Agraval Hina , Crue Taylor , Schaunaman Niccolette , Numata Mari , Day Brian J. , Chu Hong Wei
Published: February 2023

The use of electronic nicotine dispensing systems (ENDS), also known as electronic cigarettes (ECs), is common among adolescents and young adults with limited knowledge about the detrimental effects on lung health such as respiratory viral infections and underlying mechanisms. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a protein of the TNF family involved in cell apoptosis, is upregulated in COPD patients and during influenza A virus (IAV) infections, but its role in viral infection during EC exposures remains unclear. This study was aimed to investigate the effect of ECs on viral infection and TRAIL release in a human lung precision-cut lung slices (PCLS) model, and the role of TRAIL in regulating IAV infection. PCLS prepared from lungs of nonsmoker healthy human donors were exposed to EC juice (E-juice) and IAV for up to 3 days during which viral load, TRAIL, lactate dehydrogenase (LDH), and TNF-α in the tissue and supernatants were determined. TRAIL neutralizing antibody and recombinant TRAIL were utilized to determine the contribution of TRAIL to viral infection during EC exposures. E-juice increased viral load, TRAIL, TNF-α release and cytotoxicity in IAV-infected PCLS. TRAIL neutralizing antibody increased tissue viral load but reduced viral release into supernatants. Conversely, recombinant TRAIL decreased tissue viral load but increased viral release into supernatants. Further, recombinant TRAIL enhanced the expression of interferon-β and interferon-λ induced by E-juice exposure in IAV-infected PCLS. Our results suggest that EC exposure in human distal lungs amplifies viral infection and TRAIL release, and that TRAIL may serve as a mechanism to regulate viral infection. Appropriate levels of TRAIL may be important to control IAV infection in EC users.
Atf7ip Inhibits Osteoblast Differentiation via Negative Regulation of the Sp7 Transcription Factor
Authors: Hu Guoqin , Shi Xian , Qu Xiuxia , Han Chunqing , Hu Anran , Jia Zhongtang , Yang Jiatao , Liu Huanliang , Wu Yu
Published: February 2023

Epigenetic modifications are critical for cell differentiation and growth. As a regulator of H3K9 methylation, Setdb1 is implicated in osteoblast proliferation and differentiation. The activity and nucleus localization of Setdb1 are regulated by its binding partner, Atf7ip. However, whether Atf7ip is involved in the regulation of osteoblast differentiation remains largely unclear. In the present study, we found that Atf7ip expression was upregulated during the osteogenesis of primary bone marrow stromal cells and MC3T3-E1 cells, and was induced in PTH-treated cells. The overexpression of Atf7ip impaired osteoblast differentiation in MC3T3-E1 cells regardless of PTH treatment, as measured by the expression of osteoblast differentiation markers, Alp-positive cells, Alp activity, and calcium deposition. Conversely, the depletion of Atf7ip in MC3T3-E1 cells promoted osteoblast differentiation. Compared with the control mice, animals with Atf7ip deletion in the osteoblasts (Oc-Cre;Atf7ipf/f) showed more bone formation and a significant increase in the bone trabeculae microarchitecture, as reflected by μ-CT and bone histomorphometry. Mechanistically, Atf7ip contributed to the nucleus localization of Setdb1 in MC3T3-E1, but did not affect Setdb1 expression. Atf7ip negatively regulated Sp7 expression, and through specific siRNA, Sp7 knockdown attenuated the enhancing role of Atf7ip deletion in osteoblast differentiation. Through these data, we identified Atf7ip as a novel negative regulator of osteogenesis, possibly via its epigenetic regulation of Sp7 expression, and demonstrated that Atf7ip inhibition is a potential therapeutic measure for enhancing bone formation.
Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies
Authors: Sandonà Martina , Cavioli Giorgia , Renzini Alessandra , Cedola Alessia , Gigli Giuseppe , Coletti Dario , McKinsey Timothy A. , Moresi Viviana , Saccone Valentina
Published: February 2023

Histone deacetylases (HDACs) are enzymes that regulate the deacetylation of numerous histone and non-histone proteins, thereby affecting a wide range of cellular processes. Deregulation of HDAC expression or activity is often associated with several pathologies, suggesting potential for targeting these enzymes for therapeutic purposes. For example, HDAC expression and activity are higher in dystrophic skeletal muscles. General pharmacological blockade of HDACs, by means of pan-HDAC inhibitors (HDACi), ameliorates both muscle histological abnormalities and function in preclinical studies. A phase II clinical trial of the pan-HDACi givinostat revealed partial histological improvement and functional recovery of Duchenne Muscular Dystrophy (DMD) muscles; results of an ongoing phase III clinical trial that is assessing the long-term safety and efficacy of givinostat in DMD patients are pending. Here we review the current knowledge about the HDAC functions in distinct cell types in skeletal muscle, identified by genetic and -omic approaches. We describe the signaling events that are affected by HDACs and contribute to muscular dystrophy pathogenesis by altering muscle regeneration and/or repair processes. Reviewing recent insights into HDAC cellular functions in dystrophic muscles provides new perspectives for the development of more effective therapeutic approaches based on drugs that target these critical enzymes.
circRNA from APP Gene Changes in Alzheimer’s Disease Human Brain
Authors: Urdánoz-Casado Amaya , Sánchez-Ruiz de Gordoa Javier , Robles Maitane , Roldan Miren , Macías Conde Mónica , Acha Blanca , Blanco-Luquin Idoia , Mendioroz Maite
Published: February 2023

Alzheimer’s disease (AD) is the most common cause of age-related dementia. Amyloid precursor protein (APP) is the precursor of Aβ peptides, and its role in AD has been widely investigated. Recently, it has been reported that a circular RNA (circRNA) originated from APP gene can serve as a template for Aβ synthesis, postulating it as an alternative pathway for the Aβ biogenesis. Moreover, circRNAs play important roles in brain development and in neurological diseases. Therefore, our aim was to study the expression of a circAPP (hsa_circ_0007556) and its linear cognate in AD human entorhinal cortex, a brain region most vulnerable to AD pathology. First, we confirmed the presence of circAPP (hsa_circ_0007556) in human entorhinal cortex samples using RT-PCR and Sanger sequencing of PCR products. Next, a 0.49-fold decrease in circAPP (hsa_circ_0007556) levels was observed in entorhinal cortex of AD cases compared to controls (p-value < 0.05) by qPCR. In contrast, APP mRNA expression did not show changes in the entorhinal cortex between AD cases and controls (Fold-change = 1.06; p-value = 0.81). A negative correlation was found between Aβ deposits and circAPP (hsa_circ_0007556) and APP expression levels (Rho Spearman = −0.56, p-value < 0.001 and Rho Spearman = −0.44, p-values < 0.001, respectively). Finally, by using bioinformatics tools, 17 miRNAs were predicted to bind circAPP (hsa_circ_0007556), and the functional analysis predicted that they were involved in some pathways, such as the Wnt-signaling pathway (p = 3.32 × 10−6). Long-term potentiation (p = 2.86 × 10−5), among others, is known to be altered in AD. To sum up, we show that circAPP (hsa_circ_0007556) is deregulated in the entorhinal cortex of AD patients. These results add to the notion that circAPP (hsa_circ_0007556) could be playing a role in the pathogenesis of AD disease.
Glucokinase Inactivation Ameliorates Lipid Accumulation and Exerts Favorable Effects on Lipid Metabolism in Hepatocytes
Authors: Xie Ziyan , Xie Ting , Liu Jieying , Zhang Qian , Xiao Xinhua
Published: February 2023

Glucokinase-maturity onset diabetes of the young (GCK-MODY) is a kind of rare diabetes with low incidence of vascular complications caused by GCK gene inactivation. This study aimed to investigate the effects of GCK inactivation on hepatic lipid metabolism and inflammation, providing evidence for the cardioprotective mechanism in GCK-MODY. We enrolled GCK-MODY, type 1 and 2 diabetes patients to analyze their lipid profiles, and found that GCK-MODY individuals exhibited cardioprotective lipid profile with lower triacylglycerol and elevated HDL-c. To further explore the effects of GCK inactivation on hepatic lipid metabolism, GCK knockdown HepG2 and AML-12 cell models were established, and in vitro studies showed that GCK knockdown alleviated lipid accumulation and decreased the expression of inflammation-related genes under fatty acid treatment. Lipidomic analysis indicated that the partial inhibition of GCK altered the levels of several lipid species with decreased saturated fatty acids and glycerolipids including triacylglycerol and diacylglycerol, and increased phosphatidylcholine in HepG2 cells. The hepatic lipid metabolism altered by GCK inactivation was regulated by the enzymes involved in de novo lipogenesis, lipolysis, fatty acid β-oxidation and the Kennedy pathway. Finally, we concluded that partial inactivation of GCK exhibited beneficial effects in hepatic lipid metabolism and inflammation, which potentially underlies the protective lipid profile and low cardiovascular risks in GCK-MODY patients.
A Nanoenzyme Constructed from Manganese and Strandberg-Type Phosphomolybdate with Versatility in Antioxidant and Modulating Conformation of Aβ Protein Misfolding Aggregates In Vitro
Authors: Hua Jiai , Wang Feng , Wei Xueman , Qin Yuxin , Lian Jiameng , Wu Jianhong , Ma Pengtao , Ma Xiang
Published: February 2023

Amyloid β-peptide (Aβ) misfolding aggregates with β-sheet structures and surplus reactive oxygen species (ROS) are both considered to be the culprit of neuronal toxicity in Alzheimer’s disease (AD). Therefore, modulating the misfolding mode of Aβ and inhibiting ROS simultaneous has become an important method for anti-AD. Herein, a nanoscale manganese-substituted polyphosphomolybdate (H2en)3[Mn(H2O)4][Mn(H2O)3]2[P2Mo5O23]2·14.5H2O (abbreviated as MnPM) (en = ethanediamine) was designed and synthesized by single crystal to single crystal transformation method. MnPM can modulate the β-sheet rich conformation of Aβ aggregates, and thus reduce the formation of toxic species. Moreover, MnPM also possesses the ability to eliminate the free radicals produced by Cu2+-Aβ aggregates. It can inhibit the cytotoxicity of β-sheet-rich species and protect synapses of PC12 cells. MnPM combines the conformation modulating ability of Aβ and anti-oxidation ability, which makes a promising multi-funcational molecular with a composite mechanism for the new conceptual designing in treatment of such protein-misfolding diseases.
Pathways of Coagulopathy and Inflammatory Response in SARS-CoV-2 Infection among Type 2 Diabetic Patients
Authors: Akácsos-Szász Orsolya-Zsuzsa , Pál Sándor , Nyulas Kinga-Ilona , Nemes-Nagy Enikő , Fárr Ana-Maria , Dénes Lóránd , Szilveszter Mónika , Bán Erika-Gyöngyi , Tilinca Mariana Cornelia , Simon-Szabó Zsuzsánna
Published: February 2023

Chronic inflammation and endothelium dysfunction are present in diabetic patients. COVID-19 has a high mortality rate in association with diabetes, partially due to the development of thromboembolic events in the context of coronavirus infection. The purpose of this review is to present the most important underlying pathomechanisms in the development of COVID-19-related coagulopathy in diabetic patients. The methodology consisted of data collection and synthesis from the recent scientific literature by accessing different databases (Cochrane, PubMed, Embase). The main results are the comprehensive and detailed presentation of the very complex interrelations between different factors and pathways involved in the development of arteriopathy and thrombosis in COVID-19-infected diabetic patients. Several genetic and metabolic factors influence the course of COVID-19 within the background of diabetes mellitus. Extensive knowledge of the underlying pathomechanisms of SARS-CoV-2-related vasculopathy and coagulopathy in diabetic subjects contributes to a better understanding of the manifestations in this highly vulnerable group of patients; thus, they can benefit from a modern, more efficient approach regarding diagnostic and therapeutic management.
Transcriptome Analysis of Retinal and Choroidal Pathologies in Aged BALB/c Mice Following Systemic Neonatal Murine Cytomegalovirus Infection
Authors: Zhang Xinyan , Xu Jinxian , Marshall Brendan , Dong Zheng , Liu Yutao , Espinosa-Heidmann Diego G. , Zhang Ming
Published: February 2023

Our previous studies have shown that systemic neonatal murine cytomegalovirus (MCMV) infection of BALB/c mice spread to the eye with subsequent establishment of latency in choroid/RPE. In this study, RNA sequencing (RNA-Seq) analysis was used to determine the molecular genetic changes and pathways affected by ocular MCMV latency. MCMV (50 pfu per mouse) or medium as control were injected intra-peritoneally (i.p.) into BALB/c mice at <3 days after birth. At 18 months post injection, the mice were euthanized, and the eyes were collected and prepared for RNA-Seq. Compared to three uninfected control eyes, we identified 321 differentially expressed genes (DEGs) in six infected eyes. Using the QIAGEN Ingenuity Pathway Analysis (QIAGEN IPA), we identified 17 affected canonical pathways, 10 of which function in neuroretinal signaling, with the majority of DEGs being downregulated, while 7 pathways function in upregulated immune/inflammatory responses. Retinal and epithelial cell death pathways involving both apoptosis and necroptosis were also activated. MCMV ocular latency is associated with upregulation of immune and inflammatory responses and downregulation of multiple neuroretinal signaling pathways. Cell death signaling pathways are also activated and contribute to the degeneration of photoreceptors, RPE, and choroidal capillaries.
Topical Diacerein Decreases Skin and Splenic CD11c+ Dendritic Cells in Psoriasis
Authors: Brunner Susanne M. , Ramspacher Andrea , Rieser Caroline , Leitner Julia , Heil Hannah , Ablinger Michael , Tevini Julia , Wimmer Monika , Koller Andreas , Piñón Hofbauer Josefina , Felder Thomas K. , Bauer Johann W. , Kofler Barbara , Lang Roland , Wally Verena
Published: February 2023

Psoriasis is an inflammatory skin disease characterized by increased neo-vascularization, keratinocyte hyperproliferation, a pro-inflammatory cytokine milieu and immune cell infiltration. Diacerein is an anti-inflammatory drug, modulating immune cell functions, including expression and production of cytokines, in different inflammatory conditions. Therefore, we hypothesized that topical diacerein has beneficial effects on the course of psoriasis. The current study aimed to evaluate the effect of topical diacerein on imiquimod (IMQ)-induced psoriasis in C57BL/6 mice. Topical diacerein was observed to be safe without any adverse side effects in healthy or psoriatic animals. Our results demonstrated that diacerein significantly alleviated the psoriasiform-like skin inflammation over a 7-day period. Furthermore, diacerein significantly diminished the psoriasis-associated splenomegaly, indicating a systemic effect of the drug. Remarkably, we observed significantly reduced infiltration of CD11c+ dendritic cells (DCs) into the skin and spleen of psoriatic mice with diacerein treatment. As CD11c+ DCs play a pivotal role in psoriasis pathology, we consider diacerein to be a promising novel therapeutic candidate for psoriasis.
Carbonic Anhydrase IX in Tumor Tissue and Plasma of Breast Cancer Patients: Reliable Biomarker of Hypoxia and Prognosis
Authors: Rezuchova Ingeborg , Bartosova Maria , Belvoncikova Petra , Takacova Martina , Zatovicova Miriam , Jelenska Lenka , Csaderova Lucia , Meciarova Iveta , Pohlodek Kamil
Published: February 2023

Carbonic anhydrase IX (CA IX) is recognized as an excellent marker of hypoxia and an adverse prognostic factor in solid tumors, including breast cancer (BC). Clinical studies confirm that soluble CA IX (sCA IX), shed into body fluids, predicts the response to some therapeutics. However, CA IX is not included in clinical practice guidelines, possibly due to a lack of validated diagnostic tools. Here, we present two novel diagnostic tools—a monoclonal antibody for CA IX detection by immunohistochemistry and an ELISA kit for the detection of sCA IX in the plasma—validated on a cohort of 100 patients with early BC. We confirm that tissue CA IX positivity (24%) correlates with tumor grading, necrosis, negative hormone receptor status, and the TNBC molecular subtype. We show that antibody IV/18 can specifically detect all subcellular forms of CA IX. Our ELISA test provides 70% sensitivity and 90% specificity. Although we showed that this test could detect exosomes in addition to shed CA IX ectodomain, we could not demonstrate a clear association of sCA IX with prognosis. Our results indicate that the amount of sCA IX depends on subcellular CA IX localization, but more strictly on the molecular composition of individual molecular subtypes of BC, particularly on metalloproteinases inhibitor expression.
Accelerating the Discovery of Anticancer Peptides through Deep Forest Architecture with Deep Graphical Representation
Authors: Yao Lantian , Li Wenshuo , Zhang Yuntian , Deng Junyang , Pang Yuxuan , Huang Yixian , Chung Chia-Ru , Yu Jinhan , Chiang Ying-Chih , Lee Tzong-Yi
Published: February 2023

Cancer is one of the leading diseases threatening human life and health worldwide. Peptide-based therapies have attracted much attention in recent years. Therefore, the precise prediction of anticancer peptides (ACPs) is crucial for discovering and designing novel cancer treatments. In this study, we proposed a novel machine learning framework (GRDF) that incorporates deep graphical representation and deep forest architecture for identifying ACPs. Specifically, GRDF extracts graphical features based on the physicochemical properties of peptides and integrates their evolutionary information along with binary profiles for constructing models. Moreover, we employ the deep forest algorithm, which adopts a layer-by-layer cascade architecture similar to deep neural networks, enabling excellent performance on small datasets but without complicated tuning of hyperparameters. The experiment shows GRDF exhibits state-of-the-art performance on two elaborate datasets (Set 1 and Set 2), achieving 77.12% accuracy and 77.54% F1-score on Set 1, as well as 94.10% accuracy and 94.15% F1-score on Set 2, exceeding existing ACP prediction methods. Our models exhibit greater robustness than the baseline algorithms commonly used for other sequence analysis tasks. In addition, GRDF is well-interpretable, enabling researchers to better understand the features of peptide sequences. The promising results demonstrate that GRDF is remarkably effective in identifying ACPs. Therefore, the framework presented in this study could assist researchers in facilitating the discovery of anticancer peptides and contribute to developing novel cancer treatments.
Synergic Action of Insulin-like Growth Factor-2 and miRNA-483 in Pterygium Pathogenesis
Authors: Maxia Cristina , Isola Michela , Grecu Eleonora , Cuccu Alberto , Scano Alessandra , Orrù Germano , Di Girolamo Nick , Diana Andrea , Murtas Daniela
Published: February 2023

Pterygium is a multifactorial disease in which UV-B is speculated to play a key role by inducing oxidative stress and phototoxic DNA damage. In search for candidate molecules that are useful for justifying the intense epithelial proliferation observed in pterygium, our attention has been focused on Insulin-like Growth Factor 2 (IGF-2), mainly detected in embryonic and fetal somatic tissues, which regulate metabolic and mitogenic functions. The binding between IGF-2 and its receptor Insulin-like Growth Factor 1 Receptor (IGF-1R) activates the PI3K-AKT pathway, which leads to the regulation of cell growth, differentiation, and the expression of specific genes. Since IGF2 is regulated by parental imprinting, in different human tumors, the IGF2 Loss of Imprinting (LOI) results in IGF-2- and IGF2-derived intronic miR-483 overexpression. Based on these activities, the purpose of this study was to investigate the overexpression of IGF-2, IGF-1R, and miR-483. Using an immunohistochemical approach, we demonstrated an intense colocalized epithelial overexpression of IGF-2 and IGF-1R in most pterygium samples (Fisher’s exact test, p = 0.021). RT-qPCR gene expression analysis confirmed IGF2 upregulation and demonstrated miR-483 expression in pterygium compared to normal conjunctiva (253.2-fold and 12.47-fold, respectively). Therefore, IGF-2/IGF-1R co-expression could suggest their interplay through the two different paracrine/autocrine IGF-2 routes for signaling transfer, which would activate the PI3K/AKT signaling pathway. In this scenario, miR-483 gene family transcription might synergically reinforce IGF-2 oncogenic function through its boosting pro-proliferative and antiapoptotic activity.
A Novel Combination of Sotorasib and Metformin Enhances Cytotoxicity and Apoptosis in KRAS-Mutated Non-Small Cell Lung Cancer Cell Lines through MAPK and P70S6K Inhibition
Authors: Barrios-Bernal Pedro , Lucio-Lozada José , Ramos-Ramírez Maritza , Hernández-Pedro Norma , Arrieta Oscar
Published: February 2023

Novel inhibitors of KRAS with G12C mutation (sotorasib) have demonstrated short-lasting responses due to resistance mediated by the AKT-mTOR-P70S6K pathway. In this context, metformin is a promising candidate to break this resistance by inhibiting mTOR and P70S6K. Therefore, this project aimed to explore the effects of the combination of sotorasib and metformin on cytotoxicity, apoptosis, and the activity of the MAPK and mTOR pathways. We created dose–effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin in three lung cancer cell lines; A549 (KRAS G12S), H522 (wild-type KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by an MTT assay, apoptosis induction through flow cytometry, and MAPK and mTOR pathways were assessed by Western blot. Our results showed a sensitizing effect of metformin on sotorasib effect in cells with KRAS mutations and a slight sensitizing effect in cells without K-RAS mutations. Furthermore, we observed a synergic effect on cytotoxicity and apoptosis induction, as well as a notable inhibition of the MAPK and AKT-mTOR pathways after treatment with the combination, predominantly in KRAS-mutated cells (H23 and A549). The combination of metformin with sotorasib synergistically enhanced cytotoxicity and apoptosis induction in lung cancer cells, regardless of KRAS mutational status.
Construction of Two Independent RAB Family-Based Scoring Systems Based on Machine Learning Algorithms and Definition of RAB13 as a Novel Therapeutic Target for Hepatocellular Carcinoma
Authors: Jiang Chenhao , Liu Zijian , Yuan Jingsheng , Wu Zhenru , Kong Lingxiang , Yang Jiayin , Lv Tao
Published: February 2023

Hepatocellular carcinoma (HCC) remains a global health challenge with a low early diagnosis rate and high mortality. The Rab GTPase (RAB) family plays an essential role in the occurrence and progression of HCC. Nonetheless, a comprehensive and systematic investigation of the RAB family has yet to be performed in HCC. We comprehensively assessed the expression landscape and prognostic significance of the RAB family in HCC and systematically correlated these RAB family genes with tumor microenvironment (TME) characteristics. Then, three RAB subtypes with distinct TME characteristics were determined. Using a machine learning algorithm, we further established a RAB score to quantify TME features and immune responses of individual tumors. Moreover, to better evaluate patient prognosis, we established a RAB risk score as an independent prognostic factor for patients with HCC. The risk models were validated in independent HCC cohorts and distinct HCC subgroups, and their complementary advantages guided clinical practice. Furthermore, we further confirmed that the knockdown of RAB13, a pivotal gene in risk models, suppressed HCC cell proliferation and metastasis by inhibiting the PI3K/AKT signaling pathway, CDK1/CDK4 expression, and epithelial-mesenchymal transition. In addition, RAB13 inhibited the activation of JAK2/STAT3 signaling and the expression of IRF1/IRF4. More importantly, we confirmed that RAB13 knockdown enhanced GPX4-dependent ferroptosis vulnerability, highlighting RAB13 as a potential therapeutic target. Overall, this work revealed that the RAB family played an integral role in forming HCC heterogeneity and complexity. RAB family-based integrative analysis contributed to enhancing our understanding of the TME and guided more effective immunotherapy and prognostic evaluation.