bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic and Pharmacological Inhibition of GCN2 Ameliorates Hyperglycemia and Insulin Resistance in Type 2 Diabetic Mice
Authors: Yuan Juntao , Li Fang , Shen Xiyue , Gao Junling , Yu Zhuoran , Luo Kai , Cui Bingqing , Lu Zhongbing
Published: August 2022

It is well recognized that there is a strong and complex association between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We previously demonstrated that genetic knockout or pharmacological inhibition of general control nondepressible kinase 2 (GCN2), a well-known amino acid sensor, alleviated hepatic steatosis and insulin resistance in obese mice. However, whether GCN2 affects the development of T2D remains unclear. After a high-fat diet (HFD) plus low-dose streptozotocin (STZ) treatments, Gcn2−/− mice developed less hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress than wild-type (WT) mice. Inhibition of GCN2 by intraperitoneal injection of 3 mg/kg GCN2iB (a specific inhibitor of GCN2) every other day for 6 weeks also ameliorated hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress in HFD/STZ- and leptin receptor deletion (db/db)-induced T2D mice. Moreover, depletion of hepatic GCN2 in db/db mice by tail vein injection of an AAV8-shGcn2 vector resulted in similar improvement in those metabolic disorders. The protective mechanism of GCN2 inhibition in T2D mice was associated with regulation of the glucose metabolic pathway, repression of lipogenesis genes, and activation of the Nrf2 pathway. Together, our data provide evidence that strategies to inhibit hepatic GCN2 activity may be novel approaches for T2D therapy.
The Role of Oxidative Stress in Atopic Dermatitis and Chronic Urticaria
Authors: Galiniak Sabina , Mołoń Mateusz , Biesiadecki Marek , Bożek Agnieszka , Rachel Marta
Published: August 2022

Atopic dermatitis (AD) and chronic urticaria (CU) are common skin diseases with an increasing prevalence and pathogenesis that are not fully understood. Emerging evidence suggests that oxidative stress plays a role in AD and CU. The aim of the single-center cross-sectional study was to compare markers of oxidative stress in 21 patients with AD, and 19 CU patients. The products of protein oxidation, total antioxidant capacity (TAC), and markers of lipid peroxidation were estimated in the serum. AD patients had a higher level of advanced protein oxidation products and a lower level of thiol groups than healthy participants. However, CU patients had statistically higher levels of AOPP and 3-nitrotyrosine than healthy subjects. The level of thiol groups and serum TAC decreased significantly in patients with CU. There was no difference in serum concentration of lipid peroxidation products, Amadori products, ratio of reduced to oxidized glutathione, and ability of albumin to binding cobalt between AD or CU patients compared to healthy subjects. We found a moderate positive significant correlation between AOPP and age in patients with AD. In patients with CU, TAC was negatively correlated with age. These results may shed light on the etiopathogenesis of AD or CU, and confirm an oxidative burden in these patients. Furthermore, our study could be useful in developing new therapeutic methods that include using antioxidants in dermatological diseases.
The Impact of Assimilating Winds Observed during a Tropical Cyclone on a Forecasting Model
Authors: Kim Jin-Young , Albers Steve , Sen Purnendranath , Kim Hyun-Goo , Kim Keunhoon , Hwang Su-Jin
Published: August 2022

The accurate and timely depiction of the state of severe weather is critical for enhancing forecaster situational awareness. This study attempted to develop a hurricane forecasting model with a warm-start run and investigated the impact of winds observed during a tropical cyclone on long-term lead times. The Hurricane Research System initialized with the Hurricane Local Analysis Prediction System (HRS/HLAPS) was applied to Hurricanes Katrina and Dennis (2005). The forecasting model used a warm-start run with 7% improved wind data and cloud initialization using the HLAPS. The simulated cyclones were more intense and realistic structures, although the performance varied slightly according to the lead time and cyclone characteristics. The results show that the tropical cyclone development (track and intensity) was significantly affected by initial forcing up to 6–12 h, as well as by the forcing of the limit condition after 6 h. The well-organized spiral bands of convective precipitations were also captured, particularly within the 6 h spin-up time due to vertical wind shear and water vapor trapped in the lower atmosphere. This study demonstrates that aircraft-observed winds and convective initialization can be useful for numerical modeling and operational forecasting.
Valve Endothelial Cell Exposure to High Levels of Flow Oscillations Exacerbates Valve Interstitial Cell Calcification
Authors: Hsu Chia-Pei Denise , Tchir Alexandra , Mirza Asad , Chaparro Daniel , Herrera Raul E. , Hutcheson Joshua D. , Ramaswamy Sharan
Published: August 2022

The aortic valve facilitates unidirectional blood flow to the systemic circulation between the left cardiac ventricle and the aorta. The valve’s biomechanical function relies on thin leaflets to adequately open and close over the cardiac cycle. A monolayer of valve endothelial cells (VECs) resides on the outer surface of the aortic valve leaflet. Deeper within the leaflet are sublayers of valve interstitial cells (VICs). Valve tissue remodeling involves paracrine signaling between VECs and VICs. Aortic valve calcification can result from abnormal paracrine communication between these two cell types. VECs are known to respond to hemodynamic stimuli, and, specifically, flow abnormalities can induce VEC dysfunction. This dysfunction can subsequently change the phenotype of VICs, leading to aortic valve calcification. However, the relation between VEC-exposed flow oscillations under pulsatile flow to the progression of aortic valve calcification by VICs remains unknown. In this study, we quantified the level of flow oscillations that VECs were exposed to under dynamic culture and then immersed VICs in VEC-conditioned media. We found that VIC-induced calcification was augmented under maximum flow oscillations, wherein the flow was fully forward for half the cardiac cycle period and fully reversed for the other half. We were able to computationally correlate this finding to specific regions of the aortic valve that experience relatively high flow oscillations and that have been shown to be associated with severe calcified deposits. These findings establish a basis for future investigations on engineering calcified human valve tissues and its potential for therapeutic discovery of aortic valve calcification.
Anti-Tumor Effect of Parasitic Protozoans
Authors: Ding Haojie , Wu Songrui , Jin Zi , Zheng Bin , Hu Yuan , He Ke , Lu Shaohong , Zhuo Xunhui
Published: August 2022

The immune system may aberrantly silence when against “altered self”, which consequently may develop into malignancies. With the development of tumor immunology and molecular biology, the deepened understanding of the relationship between parasites and tumors shifts the attitude towards parasitic pathogens from elimination to utilization. In recent years, the antitumor impact implemented by protozoan parasites and the derived products has been confirmed. The immune system is activated and enhanced by some protozoan parasites, thereby inhibiting tumor growth, angiogenesis, and metastasis in many animal models. In this work, we reviewed the available information on the antitumor effect of parasitic infection or induced by parasitic antigen, as well as the involved immune mechanisms that modulate cancer progression. Despite the fact that clinical trials of the protozoan parasites against tumors are limited and the specific mechanisms of the effect on tumors are not totally clear, the use of genetically modified protozoan parasites and derived molecules combined with chemotherapy could be an important element for promoting antitumor treatment in the future.
Combined Effects of Sulfate and Chloride Attack on Steel Reinforced Mortar under Drying–Immersion Cycles
Authors: Sun Hongfang , Zou Hao , Li Xinwei , Memon Shazim Ali , Yuan Binyang , Xing Feng , Zhang Xiaogang , Ren Jie
Published: August 2022

In this study, X-ray microcomputed tomography (XCT) and nanoindentation techniques were used to evaluate the synergistic action between sulfate and chloride ingress under cyclic drying–immersion conditions on steel-reinforced mortars. Three salt solutions, namely 3% NaCl (Sc), 5% Na2SO4 (Ss), and 5% Na2SO4 + 3% NaCl (Scs), were used and 24 drying–immersion cycles were applied. The results showed that the chloride caused more severe corrosion on steel reinforcement than the sulfate while under the influence of Scs, and the presence of sulfate suppressed the steel corrosion caused by chloride. In terms the damage to the mortar cover, after 24 drying–immersion cycles, the sulfate caused the most severe damage (volume loss of approximately 7.1%) while the chloride resulted in the least damage (volume loss of approximately 2.6%). By comparing Ss and Scs, it was also found that chloride suppressed the sulfate attack by reducing the damage to the mortar cover (volume loss of approximately 6.3% for Scs). Moreover, the degradation of mortar specimens was found to be layer-dependent, as was the distribution of micro-mechanics. Regarding the micro-mechanics, the specimens of the three solutions performed differently in terms of the aforementioned properties, depending on which underlying mechanism was analyzed. This research could allow for a more accurate assessment of the factors influencing building structures in a typical aggressive marine environment.
Fragility Functions for Reinforced Concrete Structures Based on Multiscale Approach for Earthquake Damage Criteria
Authors: Kohns Julia , Stempniewski Lothar , Stark Alexander
Published: August 2022

For seismic risk analysis, reliable predictions and estimations of earthquake damage and seismic behaviour of buildings are essential. A common method is the use of fragility curves. In this paper, fragility functions are developed based on various numerical damage criteria for five defined damage grades, from slight to destruction. The proposed new multiscale approach establishes a correlation between observed damage patterns due to foreign earthquakes and the seismic response of the building using thresholds for material-specific and global characteristics. This approach takes into account various possible damage patterns on different scales more comprehensively than the well-known approach of displacement criteria. Moreover, the approach is universal and adaptable for building classes as well as region-specific material and system characteristics. Several damage criteria with their defined limit values are assigned to the five proposed damage grades, whereby quantity and distribution of the exceeded criteria are relevant, since the first occurrence does not always lead to damage. With the new approach, damages that are not evident in the pushover curve in terms of strength degradation can be detected and taken into account for the damage thresholds. The derived displacement values associated with the damage levels are the basis for developing fragility functions. The results—damage criteria, pushover curves with damage grades, capacity curves as well as fragility functions and parameters—are presented for a four-storey reinforced concrete frame building. These results are discussed and validated with data from the literature. Comparisons to existing fragility functions in the literature show that our developed fragility functions are mostly located in the middle range, graphically as well as for the curve parameters. This specific example was chosen to present our multiscale approach, but for general building classes, numerous simulations with varying characteristics are essential and result in a higher standard deviation of the final fragility curves.
Application of Glass Structures in Architectural Shaping of All-Glass Pavilions, Extensions, and Links
Authors: Jóźwik Anna
Published: August 2022

This article covers the issues of applying structural glass in shaping all-glass architectural objects. Glass, as a transparent material, is a source of inspiration for new architectural solutions. With the development of technology and the increasing knowledge of glass’s mechanical and strength properties, the possibility of using the material for construction purposes has also been acknowledged. Structural elements and building envelope elements can create a uniform material structure of all-glass objects. This observation contributed to the analysis presented in the article. The research was mainly aimed at investigating the architectural and structural-related conditions in shaping all-glass structures in buildings. In this paper, we specify criteria and typology in terms of the applied design solutions. The criteria investigated in the study included functional-spatial aspects, the form, and the structure. All-glass objects were divided into pavilions, extensions, and links in terms of functional and spatial aspects. Architectural forms were specified and characterised as cubic, cuboid, cylindrical, and free-forms. Regarding structural solutions, frames, grillages, beam-wall, and plate-wall systems were indicated as the main load-bearing structures implemented in the buildings under study. The results have been obtained to describe the architectural and structural shaping of all-glass objects. One of the main results of the work is the indication between functional-spatial aspects, the form, and the structure. This correlation confirms the close relationship in architecture between art and engineering.
Experimental Hybrid Simulation of Severe Aftershocks Chains on Buildings Equipped with Curved Surface Slider Devices
Authors: Furinghetti Marco , Lanese Igor , Pavese Alberto
Published: August 2022

In this research work the outcomes of a hybrid experimental campaign are analyzed, in order to evaluate the influence of aftershock events on the frictional response of sliding-based isolation devices for buildings. To achieve this, a hybrid testing framework was accordingly defined, by considering a numerical substructure, in terms of a simplified analytical model of a case study structure, and a physical substructure, as a full-scale Curved Surface Slider device, tested within the Bearing Tester System of the EUCENTRE Foundation Laboratory in Pavia (Italy). The tested isolator was equipped with a special sliding material, made up of a Poly-Tetra-Fluoro-Ethylene-based compound (PTFE), filled with carbon fibers and with a solid lubrication. The hybrid tests were performed, in terms of earthquake simulations, and the response of the base-isolated structural system was computed, by applying single-events, rather than aftershock chains. Results lead to a better understanding of the behavior of sliding-based seismic isolation systems, characterized by medium-to-high tribological properties, in terms of peak and residual displacements for both the single-event and the mean responses. Specifically, this work provides hybrid experimental evidence of the influence of an initial displacement offset on the overall behavior of the considered structural system.
Does the Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer Patients Predict the Site of First Metastasis—Results from the Adjuvant SUCCESS A Trial
Authors: Trapp Elisabeth K. , Fasching Peter A. , Fehm Tanja , Schneeweiss Andreas , Mueller Volkmar , Harbeck Nadia , Lorenz Ralf , Schumacher Claudia , Heinrich Georg , Schochter Fabienne , de Gregorio Amelie , Tzschaschel Marie , Rack Brigitte , Janni Wolfgang , Friedl Thomas W. P.
Published: August 2022

The prognostic relevance of circulating tumor cells (CTCs) in breast cancer is well established. However, little is known about the association of CTCs and site of first metastasis. In the SUCCESS A trial, 373 out of 3754 randomized high-risk breast cancer patients developed metastatic disease. CTC status was assessed by the FDA-approved CellSearch®-System (Menarini Silicon Biosystems, Bologna, Italy) in 206 of these patients before chemotherapy and additionally in 159 patients after chemotherapy. CTCs were detected in 70 (34.0%) of 206 patients before (median 2 CTCs, 1–827) and in 44 (27.7%) of 159 patients after chemotherapy (median 1 CTC, 1–124); 16 (10.1%) of 159 patients were CTC-positive at both timepoints. The site of first distant disease was bone-only, visceral-only, and other-site-only in 44 (21.4%), 60 (29.1%), and 74 (35.9%) patients, respectively, while 28 (13.6%) patients had multiple sites of first metastatic disease. Patients with CTCs at both timepoints more often showed bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs before and/or after chemotherapy (p = 0.027). In conclusion, the presence of CTCs before and after chemotherapy is associated with multiple-site or bone-only first-distant disease and may trigger intensified follow-up and perhaps further treatment.
Pre-Training on In Vitro and Fine-Tuning on Patient-Derived Data Improves Deep Neural Networks for Anti-Cancer Drug-Sensitivity Prediction
Authors: Prasse Paul , Iversen Pascal , Lienhard Matthias , Thedinga Kristina , Herwig Ralf , Scheffer Tobias
Published: August 2022

Large-scale databases that report the inhibitory capacities of many combinations of candidate drug compounds and cultivated cancer cell lines have driven the development of preclinical drug-sensitivity models based on machine learning. However, cultivated cell lines have devolved from human cancer cells over years or even decades under selective pressure in culture conditions. Moreover, models that have been trained on in vitro data cannot account for interactions with other types of cells. Drug-response data that are based on patient-derived cell cultures, xenografts, and organoids, on the other hand, are not available in the quantities that are needed to train high-capacity machine-learning models. We found that pre-training deep neural network models of drug sensitivity on in vitro drug-sensitivity databases before fine-tuning the model parameters on patient-derived data improves the models’ accuracy and improves the biological plausibility of the features, compared to training only on patient-derived data. From our experiments, we can conclude that pre-trained models outperform models that have been trained on the target domains in the vast majority of cases.
Transcriptomic Profiling Analysis of Castration-Resistant Prostate Cancer Cell Lines Treated with Chronic Intermittent Hypoxia
Authors: Lee Chung Lyul , Lee Minji , Lee Ji Yong , Hong Sin-hyoung , Yang Seung Woo , Min Ji-hyeon , Lee Dong-eon , Baek Joonyoung , Kim Chanseul , Lim Jae Sung , Song Ki Hak , Shin Ju Hyun , Kim Gun-Hwa
Published: August 2022

Castration-resistant prostate cancer (CRPC) is still a major concern in men’s health, with 375,000 cancer deaths annually. Hypoxia, which is a marked characteristic of advanced solid tumors, has been suggested to induce prostate cancer towards CRPC, metastasis and treatment resistance. To evaluate the effect of hypoxia on prostate cancer, two and five cycles of hypoxia and reoxygenation were administered using 22Rv1 cell lines and denominated as 22Rv1-CI and 22Rv1-PCI, respectively. Cancer cell migration was promoted in 22Rv1-CI compared to controls, and the expression of COL13A1 was significantly up-regulated in 22Rv1-CI according to differentially expressed gene analysis of RNA sequencing among groups. Cancer cell migration was impeded in a wound healing assay after transfecting si-COL13A1. Moreover, the expression of COL13A1 was also higher in the cell line originating from bone metastatic prostate cancer compared to other cell lines. Using the open database GEO, we also confirmed that the expression of COL13A1 was higher in bone metastatic prostate cancer tissue than in localized prostate cancer tissue in patients. Therefore, COL13A1 may be closely related to the bony metastasis of prostate cancer, and our findings may provide valuable information on the pathophysiology of the metastatic niche induced by hypoxia in patients with CRPC.
Potential of a Non-Contrast-Enhanced Abbreviated MRI Screening Protocol (NC-AMRI) in High-Risk Patients under Surveillance for HCC
Authors: Willemssen François , de Lussanet de la Sablonière Quido , Bos Daniel , IJzermans Jan , De Man Robert , Dwarkasing Roy
Published: August 2022

Purpose: To evaluate NC-AMRI for the detection of HCC in high-risk patients. Methods: Patients who underwent yearly contrast-enhanced MRI (i.e., full MRI protocol) of the liver were included retrospectively. For all patients, the sequences that constitute the NC-AMRI protocol, namely diffusion-weighted imaging (DWI), T2-weighted (T2W) imaging with fat saturation, and T1-weighted (T1W) in-phase and opposed-phase imaging, were extracted, anonymized, and uploaded to a separate research server and reviewed independently by three radiologists with different levels of experience. Reader I and III held a mutual training session. Levels of suspicion of HCC per patient were compared and the sensitivity, specificity, and area under the curve (AUC) using the Mann–Whitney U test were calculated. The reference standard was a final diagnosis based on full liver MRI and clinical follow-up information. Results: Two-hundred-and-fifteen patients were included, 36 (16.7%) had HCC and 179 (83.3%) did not. The level of agreement between readers was reasonable to good and concordant with the level of expertise and participation in a mutual training session. Receiver operating characteristics (ROC) analysis showed relatively high AUC values (range 0.89–0.94). Double reading showed increased sensitivity of 97.2% and specificity of 87.2% compared with individual results (sensitivity 80.1%–91.7%–97.2%; specificity 91.1%–72.1%–82.1%). Only one HCC (2.8%) was missed by all readers. Conclusion: NC-AMRI presents a good potential surveillance imaging tool for the detection of HCC in high-risk patients. The best results are achieved with two observers after a mutual training session.
Sorbent and Photocatalytic Potentials of Local Clays for the Removal of Organic Xenobiotic: Case of Crystal Violet
Authors: Dalhatou Sadou , Sali Mouhamadou , Tetteh Samuel , Boubakari Abdoulaye , Talami Bouba , Zeghioud Hicham , Kane Abdoulaye , El Jery Atef , Assadi Aymen Amin , Obada David Olubiyi
Published: August 2022

Natural materials are widely used in the field of environmental remediation and are appreciated for their surface physical and chemical properties. Clay constitutes a typical example. In this work, we report the evaluation of sorbent and photocatalytic potentials of local clay of two irrigated rice field waters in the degradation of crystal violet. The structural, textural and compositional properties of the local clay were investigated by Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD) and X-ray Fluorescence (XRF) analysis. The analysis results showed that these materials were composed mainly of quartz and kaolinite. The efficiency of these adsorbents (Y. Clay and L. Clay) to eliminate crystal violet dye from aqueous medium was examined at different initial concentrations, pH, contact time, adsorbent dose and the possible interference of inorganic salts from fertilizers. Kinetic studies showed that the adsorption process was well described by the pseudo-second order model and the equilibrium modelling results fitted adequately to the Freundlich model. The maximum amount of uptake capacity achieved at pH 2.0 was 18.40 (mg·g−1) and 20.40 (mg·g−1), respectively, for Y. Clay and L. Clay. The evaluation of the photocatalytic potential showed that the raw clay samples do not show photocatalytic activities during the 30 min of exposure to UV light. On the other hand, their photocatalytic potential is manifested when loaded with titanium dioxide (TiO2). Clays coupled with TiO2 under UV light showed an improvement in the degradation of the crystal violet dye by 15%. The synergistic effects between the high photocatalytic activity of TiO2 and the strong adsorption capacity of clays can be one promising technique for in situ remediation of contaminated soaked rice field.
Integrated Multi-Omics Signature Predicts Survival in Head and Neck Cancer
Authors: Ribeiro Ilda Patrícia , Esteves Luísa , Caramelo Francisco , Carreira Isabel Marques , Melo Joana Barbosa
Published: August 2022

Head and Neck Cancer (HNC) is characterized by phenotypic, biological, and clinical heterogeneity. Despite treatment modalities, approximately half of all patients will die of the disease. Several molecular biomarkers have been investigated, but until now, without clinical translation. Here, we identified an integrative nine-gene multi-omics signature correlated with HNC patients’ survival independently of relapses or metastasis development. This prognosis multi-omic signature comprises genes mapped in the chromosomes 1q, 3p, 8q, 17q, 19p, and 19q and encompasses alterations at copy number, gene expression, and methylation. Copy number alterations in LMCD1-A1S and GRM7, the methylation status of CEACAM19, KRT17, and ST18, and the expression profile of RPL29, UBA7, FCGR2C, and RPSAP58 can predict the HNC patients’ survival. The difference higher than two years observed in the survival of HNC patients that harbor this nine-gene multi-omics signature can represent a significant step forward to improve patients’ management and guide new therapeutic targets development.
The Properties of Proinflammatory Ly6Chi Monocytes Are Differentially Shaped by Parasitic and Bacterial Liver Infections
Authors: Hoenow Stefan , Yan Karsten , Noll Jill , Groneberg Marie , Casar Christian , Lory Niels Christian , Vogelsang Malte , Hansen Charlotte , Wolf Vincent , Fehling Helena , Sellau Julie , Mittrücker Hans-Willi , Lotter Hannelore
Published: August 2022

In the past, proinflammatory CD11b+Ly6Chi monocytes were predominantly considered as a uniform population. However, recent investigations suggests that this population is far more diverse than previously thought. For example, in mouse models of Entamoeba (E.) histolytica and Listeria (L.) monocytogenes liver infections, it was shown that their absence had opposite effects. In the former model, it ameliorated parasite-dependent liver injury, whereas in the listeria model it exacerbated liver pathology. Here, we analyzed Ly6Chi monocytes from the liver of both infection models at transcriptome, protein, and functional levels. Paralleled by E. histolytica- and L. monocytogenes-specific differences in recruitment-relevant chemokines, both infections induced accumulation of Ly6C+ monocytes at infection sites. Transcriptomic analysis revealed a high similarity between monocytes from naïve and parasite-infected mice and a clear proinflammatory phenotype of listeria-induced monocytes. This was further reflected by the upregulation of M2-related transcription factors (e.g., Mafb, Nr4a1, Fos) and higher CD14 expression by Ly6Chi monocytes in the E. histolytica infection model. In contrast, monocytes from the listeria infection model expressed M1-related transcription factors (e.g., Irf2, Mndal, Ifi204) and showed higher expression of CD38, CD74, and CD86, as well as higher ROS production. Taken together, proinflammatory Ly6Chi monocytes vary considerably depending on the causative pathogen. By using markers identified in the study, Ly6Chi monocytes can be further subdivided into different populations.
Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis
Authors: Nagel David J. , Rackow Ashley R. , Ku Wei-Yao , Bell Tyler J. , Sime Patricia J. , Kottmann Robert Matthew
Published: August 2022

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in extracellular pH activates latent TGF-β1, and that TGF-β1 then drives its own activation, creating a feed-forward mechanism that propagates myofibroblast differentiation. Given the important roles of extracellular pH in the progression of pulmonary fibrosis, we sought to identify whether pH mediates other cellular phenotypes independent of TGF-β1. Proton-sensing G-protein coupled receptors are activated by acidic environments, but their role in fibrosis has not been studied. Here, we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68) has dual roles in both promoting and mitigating pulmonary fibrosis. We demonstrate that OGR1 protein expression is significantly reduced in lung tissue from patients with IPF and that TGF-β1 decreases OGR1 expression. In fibroblasts, OGR1 inhibits myofibroblast differentiation and does not contribute to inflammation. However, in epithelial cells, OGR1 promotes epithelial to mesenchymal transition (EMT) and inflammation. We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible for the differential effect of OGR1 in each cell type. Our results suggest that strategies to selectively target OGR1 expression may represent a novel therapeutic strategy for pulmonary fibrosis.
Oxidative Stress Is Associated with Overgrowth in Drosophila l(3)mbt Mutant Imaginal Discs
Authors: Climent-Cantó Paula , Molnar Cristina , Santabárbara-Ruiz Paula , Prieto Cristina , Abril Josep F. , Serras Florenci , Gonzalez Cayetano
Published: August 2022

The loss-of-function conditions for an l(3)malignant brain tumour (l(3)mbt) in larvae reared at 29 °C results in malignant brain tumours and hyperplastic imaginal discs. Unlike the former that have been extensively characterised, little is known about the latter. Here we report the results of a study of the hyperplastic l(3)mbt mutant wing imaginal discs. We identify the l(3)mbt wing disc tumour transcriptome and find it to include genes involved in reactive oxygen species (ROS) metabolism. Furthermore, we show the presence of oxidative stress in l(3)mbt hyperplastic discs, even in apoptosis-blocked conditions, but not in l(3)mbt brain tumours. We also find that chemically blocking oxidative stress in l(3)mbt wing discs reduces the incidence of wing disc overgrowths. Our results reveal the involvement of oxidative stress in l(3)mbt wing discs hyperplastic growth.
Stem Cells from Healthy and Tendinopathic Human Tendons: Morphology, Collagen and Cytokines Expression and Their Response to T3 Thyroid Hormone
Authors: Ciardulli Maria Camilla , Scala Pasqualina , Giudice Valentina , Santoro Antonietta , Selleri Carmine , Oliva Francesco , Maffulli Nicola , Porta Giovanna Della
Published: August 2022

The aim of this study was to investigate the effect of triiodothyronine (T3) on tendon specific markers and cytokines expression of stem cells extracted from human tendons. Indeed, thyroid hormones have been reported to be protective factors, maintaining tendons’ homeostasis, whereas tendinopathy is believed to be related to a failed healing response. Healthy and tendinopathic human tendons were harvested to isolate tendon stem/progenitor cells (TSPCs). TSPCs obtained from pathological samples showed gene expression and morphological modifications at baseline in comparison with cells harvested from healthy tissues. When cells were maintained in a medium supplemented with T3 (10−6 M), only pathological populations showed a significant upregulation of tenogenic markers (DCN, TNC, COL1A1, COL3A1). Immunostaining revealed that healthy cells constantly released type I collagen, typical of tendon matrix, whereas pathological ones overexpressed and secreted type III collagen, typical of scarred and impaired tissue. Pathological cells also overexpressed pro- and anti-inflammatory cytokines, suggesting an impaired balance in the presence of T3, without STAT3 activation. Moreover, DKK-1 was significantly high in the culture medium of pathological cell cultures and was reversed by T3. This study opens perspectives on the complex biochemical alteration of cells from pathological tendons, which may lead to the chronic disease context with an impaired extracellular matrix.
MAGED2 Is Required under Hypoxia for cAMP Signaling by Inhibiting MDM2-Dependent Endocytosis of G-Alpha-S
Authors: Seaayfan Elie , Nasrah Sadiq , Quell Lea , Kleim Maja , Weber Stefanie , Meyer Hemmo , Laghmani Kamel , Kömhoff Martin
Published: August 2022

Mutations in MAGED2 cause transient Bartter syndrome characterized by severe renal salt wasting in fetuses and infants, which leads to massive polyhydramnios causing preterm labor, extreme prematurity and perinatal death. Notably, this condition resolves spontaneously in parallel with developmental increase in renal oxygenation. MAGED2 interacts with G-alpha-S (Gαs). Given the role of Gαs in activating adenylyl cyclase at the plasma membrane and consequently generating cAMP to promote renal salt reabsorption via protein kinase A (PKA), we hypothesized that MAGED2 is required for this signaling pathway under hypoxic conditions such as in fetuses. Consistent with that, under both physical and chemical hypoxia, knockdown of MAGED2 in renal (HEK293) and cancer (HeLa) cell culture models caused internalization of Gαs, which was fully reversible upon reoxygenation. In contrast to Gαs, cell surface expression of the β2-adrenergic receptor, which is coupled to Gαs, was not affected by MAGED2 depletion, demonstrating specific regulation of Gαs by MAGED2. Importantly, the internalization of Gαs due to MAGED2 deficiency significantly reduced cAMP generation and PKA activity. Interestingly, the internalization of Gαs was blocked by preventing its endocytosis with dynasore. Given the role of E3 ubiquitin ligases, which can be regulated by MAGE-proteins, in regulating endocytosis, we assessed the potential role of MDM2-dependent ubiquitination in MAGED2 deficiency-induced internalization of Gαs under hypoxia. Remarkably, MDM2 depletion or its chemical inhibition fully abolished Gαs-endocytosis following MAGED2 knockdown. Moreover, endocytosis of Gαs was also blocked by mutation of ubiquitin acceptor sites in Gαs. Thus, we reveal that MAGED2 is essential for the cAMP/PKA pathway under hypoxia to specifically regulate Gαs endocytosis by blocking MDM2-dependent ubiquitination of Gαs. This may explain, at least in part, the transient nature of Bartter syndrome caused by MAGED2 mutations and opens new avenues for therapy in these patients.
Corneal Regeneration Using Adipose-Derived Mesenchymal Stem Cells
Authors: Alió del Barrio Jorge L. , De la Mata Ana , De Miguel María P. , Arnalich-Montiel Francisco , Nieto-Miguel Teresa , El Zarif Mona , Cadenas-Martín Marta , López-Paniagua Marina , Galindo Sara , Calonge Margarita , Alió Jorge L.
Published: August 2022

Adipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular lineages, to show immunomodulatory properties, and to promote tissue regeneration by a paracrine action through the secretion of extracellular vesicles containing trophic factors. This secretome is currently being investigated as a potential source for a cell-free based regenerative therapy for human tissues, which would significantly reduce the involved costs, risks and law regulations, allowing for a broader application in real clinical practice. In the current article, we will review the existing preclinical and human clinical evidence regarding the use of such adipose-derived mesenchymal stem cells for the regeneration of the three main layers of the human cornea: the epithelium (derived from the surface ectoderm), the stroma (derived from the neural crest mesenchyme), and the endothelium (derived from the neural crest cells).
Investigation of Healthcare Professionals’ Knowledge of Evidence-Based Clinical Practices for Preterm Neonatal Skin Care—A Pilot Study
Authors: Metallinou Dimitra , Nanou Christina , Tsafonia Panagiota , Karampas Grigorios , Lykeridou Katerina
Published: August 2022

Neonatal skin care practices are considered crucial for a neonate’s survival and are closely related to healthcare professionals’ (HPs) knowledge and skills in delivering scientifically valid neonatal care interventions. In this descriptive cross-sectional pilot study, conducted in 2022, we aimed to assess HPs’ basic theoretical knowledge of neonatal vernix caseosa, skin microbiota, and bathing as well as knowledge regarding evidence-based clinical practices (referred to as “clinical knowledge”) for preterm neonatal skin care. Eligible participants were neonatologists, pediatricians, obstetricians, midwives and nurses working in the Greek setting. The research instrument was an online questionnaire designed by the research team. Finally, 123 HPs took part in the study. The theoretical, clinical and total knowledge scores were all significantly associated with age, healthcare profession and the sources used for education. Participants’ theoretical and clinical knowledge scores were compared and found not to differ significantly (p = 0.566). A significant and positive correlation was found between theoretical and clinical knowledge scores. Thus, it is concluded that HPs should be updated with the latest evidence-based knowledge and clinical guidelines in order to provide neonatal skin care with high-quality standards.
Acceptability of Prednisolone in an Open-Label Randomised Cross-Over Study—Focus on Formulation in Children
Authors: Haslund-Krog Sissel Sundell , Jørgensen Inger Merete , Dalhoff Kim , Holst Helle
Published: August 2022

Developing acceptable medicines for children is a complicated task. Several factors must be considered, including age, physiology, texture preference, formulation, and legal framework among others. In the development of new paediatric medicines, these factors are assessed. However, for older medicines, e.g., prednisolone, acceptability is still a challenge. This study was an open-label randomised three-arm cross-over study investigating different formulations of prednisolone (crushed tablets, whole tablets, and oral solution) in paediatric patients with asthma and asthma-like symptoms. Participants were randomised into two different formulations on two consecutive days. For each formulation, the child or caregiver was asked to evaluate acceptability using a modified five-point Wong Baker Face scale. An analysis of variance (ANOVA) model was used to test for significance. For the 41 children, included mean age was 4.7 years (SD ± 3.6), and mean weight was 21 kg (SD ± 10.8). Sixty-one percent were boys. The participants were divided accordingly into three age groups: 6 to 23 months (N = 11), 2 to 5 years (N = 14), and 6–11 years (N = 16). The overall acceptability was low, with only 23 out of 71 scores rating the treatment either 1 or 2 (32%). The ANOVA test showed a significant difference in acceptability score between crushed tablets and whole tablets (p < 0.003). The mean acceptability score for the crushed tablet was the least favourable at 3.9 compared to oral solution (3.1), oro-dispersible tablet (2.8), and whole tablets (2.4). This is problematic in long-term treatment and for the youngest children who cannot swallow tablets. The improvement of age-appropriate and acceptable formulations is necessary.
Structural and Optical Characteristics of Flexible Optically Rewritable Electronic Paper
Authors: Kudreyko Aleksey , Chigrinov Vladimir
Published: August 2022

A comprehensive theory of light-reflective characteristics and experimental technique of liquid crystal layer thickness control for flexible optically rewritable electronic paper is presented. Cylindrical pillars were used to control the gap between flexible substrates. The introduced prototype of optically rewritable electronic paper has shown very promising performance. In this regard, we report theoretical results of structural photosensitive alignment of nematic liquid crystals on flexible substrate. The focus of theoretical study is on understanding the self-assembled complex structure, governed by the interplay between surface anchoring and liquid crystal elasticity. Mueller matrix spectroscopic ellipsometry was used to study light-reflecting characteristics and polarization properties of the twisted nematic film.
Eucalyptus globulus Extract-Assisted Fabrication of Copper Oxide/Zinc Oxide Nanocomposite for Photocatalytic Applications
Authors: Hafeez Muhammad , Ghazal Arooba , Khan Jahanzeb , Ahmad Pervaiz , Khandaker Mayeen Uddin , Osman Hamid , Alamri Sultan
Published: August 2022

In this work, we report the engineering of sub 30 nm nanoparticles of copper oxide (CuO) and Zinc oxide (ZnO) and their nanocomposite, using a green method, to degrade an organic dye (methyl orange) that is responsible for water pollution. The plant extract of Eucalyptus globulus was used as a capping and stabilizing agent, as it is non-toxic, easy to use, and affordable. The percent purity and composition of the samples were found using Energy Dispersive Spectroscopy (EDS), which confirmed the formation of 75% CuO nanoparticles, 77.81% ZnO nanoparticles, and 77.34% ZnO/CuO nanocomposite in respective samples. Morphological analysis was achieved using Scanning Electron Microscopy (SEM). FTIR investigations revealed that the vibrations of CuO and ZnO nanoparticles and CuO/ZnO nanocomposite were observed at 568 cm−1, 617.9 cm−1, and 475 cm−1, respectively. The bandgap of the synthesized CuO and ZnO nanoparticles, and ZnO/CuO nanocomposite was analyzed using Diffuse Reflectance Spectroscopy (DRS), and found to be 3.36 eV, 1.83 eV, and 1.48 eV, respectively. Best photocatalytic activity confirmed that favorable conditions for the maximum degradation of methyl orange are at pH 12 and 0.02 g of the photocatalyst is required.
Laser Additive Manufacturing of Bulk Silicon Nitride Ceramic: Modeling versus Integral Transform Technique with Experimental Correlation
Authors: Mihailescu Cristian N. , Oane Mihai , Sava Bogdan A. , Popescu Andrei C. , Elisa Mihail , Mahmood Muhammad Arif , Mihailescu Natalia , Filip Ana V. , Anghel Sinziana Andreea , Mihailescu Ion N. , Ristoscu Carmen
Published: August 2022

A semi-analytical-numerical solution is theorized to describe the laser additive manufacturing via laser-bulk ceramic interaction modeling. The Fourier heat equation was used to infer the thermal distribution within the ceramic sample. Appropriate boundary conditions, including convection and radiation, were applied to the bulk sample. It was irradiated with a Gaussian spatial continuous mode fiber laser (λ = 1.075 µm) while a Lambert-Beer law was assumed to describe the laser beam absorption. A close correlation between computational predictions versus experimental results was validated in the case of laser additive manufacturing of silicon nitride bulk ceramics. The thermal field value rises but stays confined within the irradiated zone due to heat propagation with an infinite speed, a characteristic of the Fourier heat equation. An inverse correlation was observed between the laser beam scanning speed and thermal distribution intensity. Whenever the laser scanning speed increases, photons interact with and transfer less energy to the sample, resulting in a lower thermal distribution intensity. This model could prove useful for the description and monitoring of low-intensity laser beam-ceramic processing.
Biogeographic Patterns and Richness of the Meconopsis Species and Their Influence Factors across the Pan-Himalaya and Adjacent Regions
Authors: Shi Ning , Wang Chunya , Wang Jinniu , Wu Ning , Naudiyal Niyati , Zhang Lin , Wang Lihua , Sun Jian , Du Wentao , Wei Yanqiang , Chen Wenkai , Wu Yan
Published: August 2022

Understanding the potential habitat of Meconopsis, their species richness distribution patterns, and their influencing factors are critical for the conservation and rational exploitation of this valuable resource. In this study, we applied the MaxEnt model to predict their potential distribution, mapped the distribution pattern of species richness, and analyzed the variation of species richness along environmental gradients. Finally, we calculated the landscape fragmentation indices between the five subregions. Our results found that: (1) the medium- and high-suitable habitats of Meconopsis were mainly distributed in the central and eastern Himalaya, the Hengduan Mountains, and the southeast edge of the plateau platform, with suitable habitats ranged from 3200 m to 4300 m, whose most important factor is precipitation of the warmest quarter; (2) species richness showed a hump pattern along the environmental gradients except for longitude that showed an increasing trend, mainly concentrated in the south and southeast; and (3) the subregions are in the descending order of species richness: plateau platform, Hengduan Mountains, central, eastern, and western Himalaya; the highest and lowest degree of landscape fragmentation were in the western Himalaya and eastern Himalaya, respectively. Our study provides a theoretical background for the conservation and sustainable exploitation of Meconopsis in the wild.
Challenges in MRI-Guided Breast Biopsy and Some Suggested Strategies: Case Based Review
Authors: Niketa Chotai , Pang Kathleen Ann , Lim Joon Wei
Published: August 2022

With the increasing use of MRI in clinical practice, the need for MRI-guided intervention is also increasing. Indeterminate lesions identified on MRI without mammographic or sonographic correlates will need to be approached under MRI guidance. MRI-guided biopsy is a skill that can be acquired with proper training and guidance. These procedures have their own set of challenges and issues; some of them are specific to the patient habitus in this region. Adequate knowledge and understanding of the challenges can help the radiologist to be better equipped to face these issues and solve them promptly during the procedure, thus increasing the overall success rate of the procedure. Not much local data from Asian countries is available on this front. This paper aims to share common challenges one may face while performing MRI-guided biopsy and share some tips and tricks to address these problems. Hopefully, this will help the readers achieve a higher success rate for MRI-guided interventions in their clinical practice.
Cause of Death in Charred Bodies: Reflections and Operational Insights Based on a Large Cases Study
Authors: Maiese Aniello , Ciallella Costantino , dell’Aquila Massimiliano , De Matteis Alessandra , Toni Chiara , Scatena Andrea , La Russa Raffaele , Mezzetti Eleonora , Di Paolo Marco , Turillazzi Emanuela , Frati Paola , Fineschi Vittorio
Published: August 2022

Our study aims to demonstrate the experience of analyzing fully or partially charred corpses to offer a proper implementation protocol for determining the cause of death. In this study, we present a total of 103 cases obtained from the University of Rome La Sapienza and the University of Pisa archives. All cases were classified based on the extent and severity of burns using a visual method. We divided all cases into two groups. The first group included grade I–II burns (21 cases) without the need for identification. The second group (82 cases) included injuries worse than grade burns II, so all cases were analyzed using an analytical method. For each case, we have documented which of the following analyses have been used and the corresponding findings: inspection, autopsy examination, imaging examination, genetic and toxicological examinations, and histological examination. The results describe the main diagnostic findings and show that only the application of all the above systematic analyses can provide greater accuracy and reliability in describing the causes of death or solving problems, such as identification. In conclusion, we propose an available protocol that defines the main steps of a complete diagnostic pathway that pathologists should follow daily in studying charred bodies.