bluuebunny/crossref_metadata_2025 huggingface dataset:
Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas
Authors: Güvenç Canan , Antoranz Asier , Szumera-Ciećkiewicz Anna , Teterycz Pawel P. , Rutkowski Piotr R. , Rawson Robert V. , Scolyer Richard A. , Thompson John F. , Newton-Bishop Julia , Stas Marguerite , Boecxstaens Veerle , Bechter Oliver , Vercauteren Jurgen , Garmyn Marjan , van den Oord Joost , Bosisio Francesca Maria
Published: September 2021

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5–10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.
Inositols: From Established Knowledge to Novel Approaches
Authors: Dinicola Simona , Unfer Vittorio , Facchinetti Fabio , Soulage Christophe O. , Greene Nicholas D. , Bizzarri Mariano , Laganà Antonio Simone , Chan Shiao-Yng , Bevilacqua Arturo , Pkhaladze Lali , Benvenga Salvatore , Stringaro Annarita , Barbaro Daniele , Appetecchia Marialuisa , Aragona Cesare , Bezerra Espinola Maria Salomè , Cantelmi Tonino , Cavalli Pietro , Chiu Tony T. , Copp Andrew J. , D’Anna Rosario , Dewailly Didier , Di Lorenzo Cherubino , Diamanti-Kandarakis Evanthia , Hernández Marín Imelda , Hod Moshe , Kamenov Zdravko , Kandaraki Eleni , Monastra Giovanni , Montanino Oliva Mario , Nestler John E. , Nordio Maurizio , Ozay Ali C. , Papalou Olga , Porcaro Giuseppina , Prapas Nikos , Roseff Scott , Vazquez-Levin Monica , Vucenik Ivana , Wdowiak Artur
Published: September 2021

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.
Metabolic Remodeling and Implicated Calcium and Signal Transduction Pathways in the Pathogenesis of Heart Failure
Authors: Chaanine Antoine H.
Published: September 2021

The heart is an organ with high-energy demands in which the mitochondria are most abundant. They are considered the powerhouse of the cell and occupy a central role in cellular metabolism. The intermyofibrillar mitochondria constitute the majority of the three-mitochondrial subpopulations in the heart. They are also considered to be the most important in terms of their ability to participate in calcium and cellular signaling, which are critical for the regulation of mitochondrial function and adenosine triphosphate (ATP) production. This is because they are located in very close proximity with the endoplasmic reticulum (ER), and for the presence of tethering complexes enabling interorganelle crosstalk via calcium signaling. Calcium is an important second messenger that regulates mitochondrial function. It promotes ATP production and cellular survival under physiological changes in cardiac energetic demand. This is accomplished in concert with signaling pathways that regulate both calcium cycling and mitochondrial function. Perturbations in mitochondrial homeostasis and metabolic remodeling occupy a central role in the pathogenesis of heart failure. In this review we will discuss perturbations in ER-mitochondrial crosstalk and touch on important signaling pathways and molecular mechanisms involved in the dysregulation of calcium homeostasis and mitochondrial function in heart failure.
Acyl Chain Specificity of Marine Streptomyces klenkii PhosPholipase D and Its Application in Enzymatic Preparation of Phosphatidylserine
Authors: Hu Rongkang , Cui Ruiguo , Lan Dongming , Wang Fanghua , Wang Yonghua
Published: September 2021

Mining of phospholipase D (PLD) with altered acyl group recognition except its head group specificity is also useful in terms of specific acyl size phospholipid production and as diagnostic reagents for quantifying specific phospholipid species. Microbial PLDs from Actinomycetes, especially Streptomyces, best fit this process requirements. In the present studies, a new PLD from marine Streptomyces klenkii (SkPLD) was purified and biochemically characterized. The optimal reaction temperature and pH of SkPLD were determined to be 60 °C and 8.0, respectively. Kinetic analysis showed that SkPLD had the relatively high catalytic efficiency toward phosphatidylcholines (PCs) with medium acyl chain length, especially 12:0/12:0-PC (67.13 S−1 mM−1), but lower catalytic efficiency toward PCs with long acyl chain (>16 fatty acids). Molecular docking results indicated that the different catalytic efficiency was related to the increased steric hindrance of long acyl-chains in the substrate-binding pockets and differences in hydrogen-bond interactions between the acyl chains and substrate-binding pockets. The enzyme displayed suitable transphosphatidylation activity and the reaction process showed 26.18% yield with L-serine and soybean PC as substrates. Present study not only enriched the PLD enzyme library but also provide guidance for the further mining of PLDs with special phospholipids recognition properties.
Inhibition of NHE-1 Increases Smoke-Induced Proliferative Activity of Barrett’s Esophageal Cell Line
Authors: Becskeházi Eszter , Korsós Marietta Margaréta , Gál Eleonóra , Tiszlavicz László , Hoyk Zsófia , Deli Mária A. , Köhler Zoltán Márton , Keller-Pintér Anikó , Horváth Attila , Csekő Kata , Helyes Zsuzsanna , Hegyi Péter , Venglovecz Viktória
Published: September 2021

Several clinical studies indicate that smoking predisposes its consumers to esophageal inflammatory and malignant diseases, but the cellular mechanism is not clear. Ion transporters protect esophageal epithelial cells by maintaining intracellular pH at normal levels. In this study, we hypothesized that smoking affects the function of ion transporters, thus playing a role in the development of smoking-induced esophageal diseases. Esophageal cell lines were treated with cigarettesmoke extract (CSE), and the viability and proliferation of the cells, as well as the activity, mRNA and protein expression of the Na+/H+ exchanger-1 (NHE-1), were studied. NHE-1 expression was also investigated in human samples. For chronic treatment, guinea pigs were exposed to tobacco smoke, and NHE-1 activity was measured. Silencing of NHE-1 was performed by using specific siRNA. CSE treatment increased the activity and protein expression of NHE-1 in the metaplastic cells and decreased the rate of proliferation in a NHE-1-dependent manner. In contrast, CSE increased the proliferation of dysplastic cells independently of NHE-1. In the normal cells, the expression and activity of NHE-1 decreased due to in vitro and in vivo smoke exposure. Smoking enhances the function of NHE-1 in Barrett’s esophagus, and this is presumably a compensatory mechanism against this toxic agent.
Achievements and Challenges of Genomics-Assisted Breeding in Forest Trees: From Marker-Assisted Selection to Genome Editing
Authors: Ahmar Sunny , Ballesta Paulina , Ali Mohsin , Mora-Poblete Freddy
Published: September 2021

Forest tree breeding efforts have focused mainly on improving traits of economic importance, selecting trees suited to new environments or generating trees that are more resilient to biotic and abiotic stressors. This review describes various methods of forest tree selection assisted by genomics and the main technological challenges and achievements in research at the genomic level. Due to the long rotation time of a forest plantation and the resulting long generation times necessary to complete a breeding cycle, the use of advanced techniques with traditional breeding have been necessary, allowing the use of more precise methods for determining the genetic architecture of traits of interest, such as genome-wide association studies (GWASs) and genomic selection (GS). In this sense, main factors that determine the accuracy of genomic prediction models are also addressed. In turn, the introduction of genome editing opens the door to new possibilities in forest trees and especially clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). It is a highly efficient and effective genome editing technique that has been used to effectively implement targetable changes at specific places in the genome of a forest tree. In this sense, forest trees still lack a transformation method and an inefficient number of genotypes for CRISPR/Cas9. This challenge could be addressed with the use of the newly developing technique GRF-GIF with speed breeding.
Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis
Authors: Ashraf Jasni Viralippurath , Al Haj Zen Ayman
Published: September 2021

Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease.
Transcriptome and Proteome Analysis Revealed Key Pathways Regulating Final Stage of Oocyte Maturation of the Turkey (Meleagris gallopavo)
Authors: Słowińska Mariola , Paukszto Łukasz , Pardyak Laura , Jastrzębski Jan P. , Liszewska Ewa , Wiśniewska Joanna , Kozłowski Krzysztof , Jankowski Jan , Bilińska Barbara , Ciereszko Andrzej
Published: September 2021

In birds, the zona pellucida (ZP) matrix that surrounds the ovulated oocyte—called the inner perivitelline layer—is involved in sperm–zona interaction and successful fertilization. To identify the important genes and proteins connected with the final step of egg development, next-generation sequencing and two-dimensional electrophoresis, combined with mass spectrometry, were used for the analysis of mature oocytes at the F1 developmental stage. A total of 8161 genes and 228 proteins were annotated. Six subfamilies of genes, with codes ZP, ZP1–4, ZPD, and ZPAX, were identified, with the dominant expression of ZPD. The main expression site for ZP1 was the liver; however, granulosa cells may also participate in local ZP1 secretion. A ubiquitination system was identified in mature oocytes, where ZP1 was found to be the main ubiquitinated protein. Analysis of transcripts classified in estrogen receptor (ESR) signaling indicated the presence of ESR1 and ESR2, as well as a set of estrogen-dependent genes involved in both genomic and nongenomic mechanisms for the regulation of gene expression by estrogen. Oxidative phosphorylation was found to be a possible source of adenosine triphosphate, and the nuclear factor erythroid 2-related factor 2 signaling pathway could be involved in the response against oxidative stress. Oocyte–granulosa cell communication by tight, adherens, and gap junctions seems to be essential for the final step of oocyte maturation.
Mathematical Modelling of p53 Signalling during DNA Damage Response: A Survey
Authors: Eliaš Ján , Macnamara Cicely K.
Published: September 2021

No gene has garnered more interest than p53 since its discovery over 40 years ago. In the last two decades, thanks to seminal work from Uri Alon and Ghalit Lahav, p53 has defined a truly synergistic topic in the field of mathematical biology, with a rich body of research connecting mathematic endeavour with experimental design and data. In this review we survey and distill the extensive literature of mathematical models of p53. Specifically, we focus on models which seek to reproduce the oscillatory dynamics of p53 in response to DNA damage. We review the standard modelling approaches used in the field categorising them into three types: time delay models, spatial models and coupled negative-positive feedback models, providing sample model equations and simulation results which show clear oscillatory dynamics. We discuss the interplay between mathematics and biology and show how one informs the other; the deep connections between the two disciplines has helped to develop our understanding of this complex gene and paint a picture of its dynamical response. Although yet more is to be elucidated, we offer the current state-of-the-art understanding of p53 response to DNA damage.
RNA Modifications and Epigenetics in Modulation of Lung Cancer and Pulmonary Diseases
Authors: Teng Pai-Chi , Liang Yanwen , Yarmishyn Aliaksandr A. , Hsiao Yu-Jer , Lin Ting-Yi , Lin Tzu-Wei , Teng Yuan-Chi , Yang Yi-Ping , Wang Mong-Lien , Chien Chian-Shiu , Luo Yung-Hung , Chen Yuh-Min , Hsu Po-Kuei , Chiou Shih-Hwa , Chien Yueh
Published: September 2021

Lung cancer is the leading cause of cancer-related mortality worldwide, and its tumorigenesis involves the accumulation of genetic and epigenetic events in the respiratory epithelium. Epigenetic modifications, such as DNA methylation, RNA modification, and histone modifications, have been widely reported to play an important role in lung cancer development and in other pulmonary diseases. Whereas the functionality of DNA and chromatin modifications referred to as epigenetics is widely characterized, various modifications of RNA nucleotides have recently come into prominence as functionally important. N6-methyladosine (m6A) is the most prevalent internal modification in mRNAs, and its machinery of writers, erasers, and readers is well-characterized. However, several other nucleotide modifications of mRNAs and various noncoding RNAs have also been shown to play an important role in the regulation of biological processes and pathology. Such epitranscriptomic modifications play an important role in regulating various aspects of RNA metabolism, including transcription, translation, splicing, and stability. The dysregulation of epitranscriptomic machinery has been implicated in the pathological processes associated with carcinogenesis including uncontrolled cell proliferation, migration, invasion, and epithelial-mesenchymal transition. In recent years, with the advancement of RNA sequencing technology, high-resolution maps of different modifications in various tissues, organs, or disease models are being constantly reported at a dramatic speed. This facilitates further understanding of the relationship between disease development and epitranscriptomics, shedding light on new therapeutic possibilities. In this review, we summarize the basic information on RNA modifications, including m6A, m1A, m5C, m7G, pseudouridine, and A-to-I editing. We then demonstrate their relation to different kinds of lung diseases, especially lung cancer. By comparing the different roles RNA modifications play in the development processes of different diseases, this review may provide some new insights and offer a better understanding of RNA epigenetics and its involvement in pulmonary diseases.
Engineering Efficient Self-Assembled Plasmonic Nanostructures by Configuring Metallic Nanoparticle’s Morphology
Authors: Devaraj Vasanthan , Lee Jong-Min , Kim Ye-Ji , Jeong Hyuk , Oh Jin-Woo
Published: September 2021

We reveal the significance of plasmonic nanoparticle’s (NP) shape and its surface morphology en route to an efficient self-assembled plasmonic nanoparticle cluster. A simplified model is simulated in the form of free-space dimer and trimer nanostructures (NPs in the shape of a sphere, cube, and disk). A ~200% to ~125% rise in near-field strength (gap mode enhancement) is observed for spherical NPs in comparison with cubical NPs (from 2 nm to 8 nm gap sizes). Full-width three-quarter maximum reveals better broad-spectral optical performance in a range of ~100 nm (dimer) and ~170 nm (trimer) from spherical NPs as compared to a cube (~60 nm for dimer and trimer). These excellent properties for sphere-based nanostructures are merited from its dipole mode characteristics.
Imatinib Regulates miR-483-3p and Mitochondrial Respiratory Complexes in Gastrointestinal Stromal Tumors
Authors: Huang Wen-Kuan , Shi Hao , Akçakaya Pinar , Zeljic Katarina , Gangaev Anastasia , Caramuta Stefano , Yeh Chun-Nan , Bränström Robert , Larsson Catharina , Lui Weng-Onn
Published: September 2021

Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the efficacy of imatinib. In this study, we explored the role of microRNAs in regulating OXPHOS in GIST upon imatinib treatment. Using a microarray approach, we found that miR-483-3p was one of the most downregulated miRNAs in imatinib-treated tumors compared to untreated tumors. Using an extended series of GIST samples, we further validated the downregulation of miR-483-3p in imatinib-treated GIST samples by RT-qPCR. Using both gain- and loss-of-function experiments, we showed that miR-483-3p could regulate mitochondrial respiratory Complex II expression, suggesting its role in OXPHOS regulation. Functionally, miR-483-3p overexpression could rescue imatinib-induced cell death. These findings provide the molecular link for imatinib-induced OXPHOS expression and the biological role of miR-483-3p in regulating cell viability upon imatinib treatment.
Comparative Analysis of Phenolic Composition of Six Commercially Available Chamomile (Matricaria chamomilla L.) Extracts: Potential Biological Implications
Authors: Catani Maria Valeria , Rinaldi Federica , Tullio Valentina , Gasperi Valeria , Savini Isabella
Published: September 2021

Several phytochemical-containing herbal extracts are increasingly marketed as health-promoting products. In particular, chamomile (Matricaria recutita L.) is well known for its anti-inflammatory, analgesic, and antitumor properties. Here, we evaluated differences in chemical composition among six commercially available products and their potential impact on biological activity in human immortalized colonocytes. Our investigation encompassed: (i) preparation of dry extracts and yield evaluation; (ii) qualitative and quantitative analysis of phenol content; (iii) modulation of redox state; and (iv) bioavailability of main bioactive compounds. We demonstrated that apparently identical products showed huge heterogeneity, in terms of yield extraction, chemical composition, and antioxidant effects. All samples contained high amounts of flavonoids and cinnamic acid derivatives, but differentially concentrated in the six extracts. Depending on polyphenol content, chamomile samples possessed variable antioxidant potential, in terms of decreased radical generation and increased reduced glutathione levels. The observed effects might be ascribed to flavones (apigenin, luteolin, and their glycones) highly represented in the six extracts. Nonetheless, chamomile extracts exerted cytotoxic effects at high concentrations, suggesting that a herbal medicine is not always safe. In conclusion, due to the complexity and variability of plant matrices, studies evaluating effectiveness of chamomile should always be accompanied by preliminary characterization of phytochemical composition.
Interferons Are Pro-Inflammatory Cytokines in Sheared-Stressed Human Aortic Valve Endothelial Cells
Authors: Parra-Izquierdo Iván , Sánchez-Bayuela Tania , López Javier , Gómez Cristina , Pérez-Riesgo Enrique , San Román J. Alberto , Sánchez Crespo Mariano , Yacoub Magdi , Chester Adrian H. , García-Rodríguez Carmen
Published: September 2021

Calcific aortic valve disease (CAVD) is an athero-inflammatory process. Growing evidence supports the inflammation-driven calcification model, mediated by cytokines such as interferons (IFNs) and tumor necrosis factor (TNF)-α. Our goal was investigating IFNs’ effects in human aortic valve endothelial cells (VEC) and the potential differences between aortic (aVEC) and ventricular (vVEC) side cells. The endothelial phenotype was analyzed by Western blot, qPCR, ELISA, monocyte adhesion, and migration assays. In mixed VEC populations, IFNs promoted the activation of signal transducers and activators of transcription-1 and nuclear factor-κB, and the subsequent up-regulation of pro-inflammatory molecules. Side-specific VEC were activated with IFN-γ and TNF-α in an orbital shaker flow system. TNF-α, but not IFN-γ, induced hypoxia-inducible factor (HIF)-1α stabilization or endothelial nitric oxide synthase downregulation. Additionally, IFN-γ inhibited TNF-α–induced migration of aVEC. Also, IFN-γ triggered cytokine secretion and adhesion molecule expression in aVEC and vVEC. Finally, aVEC were more prone to cytokine-mediated monocyte adhesion under multiaxial flow conditions as compared with uniaxial flow. In conclusion, IFNs promote inflammation and reduce TNF-α–mediated migration in human VEC. Moreover, monocyte adhesion was higher in inflamed aVEC sheared under multiaxial flow, which may be relevant to understanding the initial stages of CAVD.
Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress
Authors: Trnovska Jaroslava , Svoboda Petr , Pelantova Helena , Kuzma Marek , Kratochvilova Helena , Kasperova Barbora Judita , Dvorakova Iveta , Rosolova Katerina , Malinska Hana , Huttl Martina , Markova Irena , Oliyarnyk Olena , Melcova Magdalena , Skop Vojtech , Mraz Milos , Stemberkova-Hubackova Sona , Haluzik Martin
Published: September 2021

(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics; quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence; glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.
Intranasal Administration of Codium fragile Polysaccharide Elicits Anti-Cancer Immunity against Lewis Lung Carcinoma
Authors: Wang Yuhua , An Eun-Koung , Kim So-Jung , You SangGuan , Jin Jun-O
Published: September 2021

Natural polysaccharides have shown promising effects on the regulation of immunity in animals. In this study, we examined the immune stimulatory effect of intranasally administered Codium fragile polysaccharides (CFPs) in mice. Intranasal administration of CFPs in C57BL/6 mice induced the upregulation of surface activation marker expression in macrophages and dendritic cells (DCs) in the mediastinal lymph node (mLN) and the production of interleukin-6 (IL-6), IL-12p70, and tumor necrosis factor-α in bronchoalveolar lavage fluid. Moreover, the number of conventional DCs (cDCs) was increased in the mLNs by the upregulation of C-C motif chemokine receptor 7 expression, and subsets of cDCs were also activated following the intranasal administration of CFP. In addition, the intranasal administration of CFPs promoted the activation of natural killer (NK) and T cells in the mLNs, which produce pro-inflammatory cytokines and cytotoxic mediators. Finally, daily administration of CFPs inhibited the infiltration of Lewis lung carcinoma cells into the lungs, and the preventive effect of CFPs on tumor growth required NK and CD8 T cells. Furthermore, CFPs combined with anti-programmed cell death-ligand 1 (PD-L1) antibody (Ab) improved the therapeutic effect of anti-PD-L1 Ab against lung cancer. Therefore, these data demonstrated that the intranasal administration of CFP induced mucosal immunity against lung cancer.
The Small Molecule Fractions of Floccularia luteovirens Induce Apoptosis of NSCLC Cells through Activating Caspase-3 Activity
Authors: Li Shuying , Gao Jie , Hou Lizhen , Gao Yaxin , Sun Jing , Zhang Nana , Fan Bei , Wang Fengzhong
Published: September 2021

Floccularia luteovirens is a rare wild edible and medicinal fungus endemic to the Qinghai-Tibet Plateau. In this study, the hollow fiber membranes with molecular weights of 50 kDa, 6 kDa and 3 kDa were used to extract different fractions of F. luteovirens, which were named as #1, #2 and #3. Then the antitumor activity of these fractions on NSCLC cell lines, PC9 and NCI-H460, were investigated by using MTT assay, flow cytometry analysis and Western blot assay. The results indicated that the #2 and #3 fractions showed obviously inhibitory activities on PC9 and NCI-H460 tumor cells and proved that these small molecule fractions induced apoptosis of NSCLC cells by activating caspase-3. Finally, a total of 15 components, including six amino acids, two nucleosides, two glycosides, two terpenoids, one phenylpropanoid, one ester and one alkaloid, were identified in #2 and #3 fractions. This is the first evidence that the small molecule components of F. luteovirens were able to inhibit lung cancer by inducing apoptosis in a caspase-3 manner. The present study indicated the benefits of F. luteovirens in lung cancer treatment, which might be a potential resource of functional food and drugs.
Behaviour of Titanium Dioxide Particles in Artificial Body Fluids and Human Blood Plasma
Authors: Korábková Eva , Kašpárková Věra , Jasenská Daniela , Moricová Dita , Daďová Eliška , Truong Thanh Huong , Capáková Zdenka , Vícha Jan , Pelková Jana , Humpolíček Petr
Published: September 2021

The growing application of materials containing TiO2 particles has led to an increased risk of human exposure, while a gap in knowledge about the possible adverse effects of TiO2 still exists. In this work, TiO2 particles of rutile, anatase, and their commercial mixture were exposed to various environments, including simulated gastric fluids and human blood plasma (both representing in vivo conditions), and media used in in vitro experiments. Simulated body fluids of different compositions, ionic strengths, and pH were used, and the impact of the absence or presence of chosen enzymes was investigated. The physicochemical properties and agglomeration of TiO2 in these media were determined. The time dependent agglomeration of TiO2 related to the type of TiO2, and mainly to the type and composition of the environment that was observed. The presence of enzymes either prevented or promoted TiO2 agglomeration. TiO2 was also observed to exhibit concentration-dependent cytotoxicity. This knowledge about TiO2 behavior in all the abovementioned environments is critical when TiO2 safety is considered, especially with respect to the significant impact of the presence of proteins and size-related cytotoxicity.
Monocarboxylate Transporter-2 Expression Restricts Tumor Growth in a Murine Model of Lung Cancer: A Multi-Omic Analysis
Authors: Khalyfa Abdelnaby , Qiao Zhuanhong , Raju Murugesan , Shyu Chi-Ren , Coghill Lyndon , Ericsson Aaron , Gozal David
Published: September 2021

Monocarboxylate transporter 2 (MCT2) is a major high-affinity pyruvate transporter encoded by the SLC16A7 gene, and is associated with glucose metabolism and cancer. Changes in the gut microbiota and host immune system are associated with many diseases, including cancer. Using conditionally expressed MCT2 in mice and the TC1 lung carcinoma model, we examined the effects of MCT2 on lung cancer tumor growth and local invasion, while also evaluating potential effects on fecal microbiome, plasma metabolome, and bulk RNA-sequencing of tumor macrophages. Conditional MCT2 mice were generated in our laboratory using MCT2loxP mouse intercrossed with mCre-Tg mouse to generate MCT2loxP/loxP; Cre+ mouse (MCT2 KO). Male MCT2 KO mice (8 weeks old) were treated with tamoxifen (0.18 mg/g BW) KO or vehicle (CO), and then injected with mouse lung carcinoma TC1 cells (10 × 105/mouse) in the left flank. Body weight, tumor size and weight, and local tumor invasion were assessed. Fecal DNA samples were extracted using PowerFecal kits and bacterial 16S rRNA amplicons were also performed. Fecal and plasma samples were used for GC−MS Polar, as well as non-targeted UHPLC-MS/MS, and tumor-associated macrophages (TAMs) were subjected to bulk RNAseq. Tamoxifen-treated MCT2 KO mice showed significantly higher tumor weight and size, as well as evidence of local invasion beyond the capsule compared with the controls. PCoA and hierarchical clustering analyses of the fecal and plasma metabolomics, as well as microbiota, revealed a distinct separation between the two groups. KO TAMs showed distinct metabolic pathways including the Acetyl-coA metabolic process, activation of immune response, b-cell activation and differentiation, cAMP-mediated signaling, glucose and glutamate processes, and T-cell differentiation and response to oxidative stress. Multi-Omic approaches reveal a substantial role for MCT2 in the host response to TC1 lung carcinoma that may involve alterations in the gut and systemic metabolome, along with TAM-related metabolic pathway. These findings provide initial opportunities for potential delineation of oncometabolic immunomodulatory therapeutic approaches.
The Embryonic Key Pluripotent Factor NANOG Mediates Glioblastoma Cell Migration via the SDF1/CXCR4 Pathway
Authors: Sánchez-Sánchez Ana Virginia , García-España Antonio , Sánchez-Gómez Pilar , Font-de-Mora Jaime , Merino Marián , Mullor José Luis
Published: September 2021

NANOG is a key transcription factor required for maintaining pluripotency of embryonic stem cells. Elevated NANOG expression levels have been reported in many types of human cancers, including lung, oral, prostate, stomach, breast, and brain. Several studies reported the correlation between NANOG expression and tumor metastasis, revealing itself as a powerful biomarker of poor prognosis. However, how NANOG regulates tumor progression is still not known. We previously showed in medaka fish that Nanog regulates primordial germ cell migration through Cxcr4b, a chemokine receptor known for its ability to promote migration and metastasis in human cancers. Therefore, we investigated the role of human NANOG in CXCR4-mediated cancer cell migration. Of note, we found that NANOG regulatory elements in the CXCR4 promoter are functionally conserved in medaka fish and humans, suggesting an evolutionary conserved regulatory axis. Moreover, CXCR4 expression requires NANOG in human glioblastoma cells. In addition, transwell assays demonstrated that NANOG regulates cancer cell migration through the SDF1/CXCR4 pathway. Altogether, our results uncover NANOG-CXCR4 as a novel pathway controlling cellular migration and support Nanog as a potential therapeutic target in the treatment of Nanog-dependent tumor progression.
Post-Embryonic Lateral Organ Development and Adaxial—Abaxial Polarity Are Regulated by the Combined Effect of ENHANCER OF SHOOT REGENERATION 1 and WUSCHEL in Arabidopsis Shoots
Authors: Ikeda Yoshihisa , Králová Michaela , Zalabák David , Kubalová Ivona , Aida Mitsuhiro
Published: September 2021

The development of above-ground lateral organs is initiated at the peripheral zone of the shoot apical meristem (SAM). The coordination of cell fate determination and the maintenance of stem cells are achieved through a complex regulatory network comprised of transcription factors. Two AP2/ERF transcription factor family genes, ESR1/DRN and ESR2/DRNL/SOB/BOL, regulate cotyledon and flower formation and de novo organogenesis in tissue culture. However, their roles in post-embryonic lateral organ development remain elusive. In this study, we analyzed the genetic interactions among SAM-related genes, WUS and STM, two ESR genes, and one of the HD-ZIP III members, REV, whose protein product interacts with ESR1 in planta. We found that esr1 mutations substantially enhanced the wus and stm phenotypes, which bear a striking resemblance to those of the wus rev and stm rev double mutants, respectively. Aberrant adaxial–abaxial polarity is observed in wus esr1 at relatively low penetrance. On the contrary, the esr2 mutation partially suppressed stm phenotypes in the later vegetative phase. Such complex genetic interactions appear to be attributed to the distinct expression pattern of two ESR genes because the ESR1 promoter-driving ESR2 is capable of rescuing phenotypes caused by the esr1 mutation. Our results pose the unique genetic relevance of ESR1 and the SAM-related gene interactions in the development of rosette leaves.
Acetaminophen-Induced Liver Injury Exposes Murine IL-22 as Sex-Related Gene Product
Authors: Stülb Hendrik , Bachmann Malte , Gonther Sina , Mühl Heiko
Published: September 2021

Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.
DNA Binding Mode Analysis of a Core-Extended Naphthalene Diimide as a Conformation-Sensitive Fluorescent Probe of G-Quadruplex Structures
Authors: Platella Chiara , Gaglione Rosa , Napolitano Ettore , Arciello Angela , Pirota Valentina , Doria Filippo , Musumeci Domenica , Montesarchio Daniela
Published: September 2021

G-quadruplex existence was proved in cells by using both antibodies and small molecule fluorescent probes. However, the G-quadruplex probes designed thus far are structure- but not conformation-specific. Recently, a core-extended naphthalene diimide (cex-NDI) was designed and found to provide fluorescent signals of markedly different intensities when bound to G-quadruplexes of different conformations or duplexes. Aiming at evaluating how the fluorescence behaviour of this compound is associated with specific binding modes to the different DNA targets, cex-NDI was here studied in its interaction with hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex models by biophysical techniques, molecular docking, and biological assays. cex-NDI showed different binding modes associated with different amounts of stacking interactions with the three DNA targets. The preferential binding sites were the groove, outer quartet, or intercalative site of the hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex, respectively. Interestingly, our data show that the fluorescence intensity of DNA-bound cex-NDI correlates with the amount of stacking interactions formed by the ligand with each DNA target, thus providing the rationale behind the conformation-sensitive properties of cex-NDI and supporting its use as a fluorescent probe of G-quadruplex structures. Notably, biological assays proved that cex-NDI mainly localizes in the G-quadruplex-rich nuclei of cancer cells.
Development of A Surgical Treatment Algorithm for Breast Reconstruction in Poland Syndrome Patients Considering Severity, Sex, and BMI
Authors: Mahrhofer Maximilian , Schoeller Thomas , Casari Maria , Bachleitner Kathrin , Weitgasser Laurenz
Published: September 2021

Introduction: Poland syndrome is a rare, challenging combination of chest wall and breast deformities for reconstructive surgeons and selecting the treatment can prove difficult. This study aims to help surgeons in choosing the best viable option for treatment by sharing our institutional experience and proposing a guiding algorithm. Methods: A retrospective analysis of all patients with Poland syndrome undergoing treatment for breast and chest wall deformities at a single institution between December 2011 and May 2020 was performed. Medical charts were reviewed to allow for a description of patient demographics, treatment modalities and complications. A treatment algorithm to aid in selecting the adequate reconstructive option based on our institutional experience was formulated. Results: A total of 22 patients (six male, 16 female) were identified who received treatment for Poland Syndrome related deformities. Nine received microsurgical free flap reconstruction (three Deep Inferior Epigastric Perforator flaps, six Transverse Myocutaneous Gracilis flaps), two received reconstruction with a local flap (two Latissimus dorsi flaps), nine received implant based reconstruction, and two were treated with autologous free fat transfer only (17 in combination with other surgical methods). Conclusion: Free flap reconstruction with the TMG flap is a valid option for patients with low Body Mass Index (BMI), while Deep Inferior Epigastric Perforator flaps should be considered for patients with a higher BMI. Autologous free fat transfer proves to be a safe and efficient treatment option in mild cases of Poland syndrome for male and female patients, in combination with or without implant based reconstructive surgery. Multicentre studies should be conducted to achieve higher case numbers of this rare disease and support clinical decisions with more data.
Cyber Crime Investigation: Landscape, Challenges, and Future Research Directions
Authors: Horan Cecelia , Saiedian Hossein
Published: September 2021

As technology has become pivotal a part of life, it has also become a part of criminal life. Criminals use new technology developments to commit crimes, and investigators must adapt to these changes. Many people have, and will become, victims of cybercrime, making it even more important for investigators to understand current methods used in cyber investigations. The two general categories of cyber investigations are digital forensics and open-source intelligence. Cyber investigations are affecting more than just the investigators. They must determine what tools they need to use based on the information that the tools provide and how effectively the tools and methods work. Tools are any application or device used by investigators, while methods are the process or technique of using a tool. This survey compares the most common methods available to investigators to determine what kind of evidence the methods provide, and which of them are the most effective. To accomplish this, the survey establishes criteria for comparison and conducts an analysis of the tools in both mobile digital forensic and open-source intelligence investigations. We found that there is no single tool or method that can gather all the evidence that investigators require. Many of the tools must be combined to be most effective. However, there are some tools that are more useful than others. Out of all the methods used in mobile digital forensics, logical extraction and hex dumps are the most effective and least likely to cause damage to the data. Among those tools used in open-source intelligence, natural language processing has more applications and uses than any of the other options.
Thermal Conductivity of Sand-Lime Products Modified with Foam Glass Granulate
Authors: Jasińska Iga , Dachowski Ryszard , Jaworska-Wędzińska Monika
Published: September 2021

Waste glass constitutes a significant part of general waste worldwide. Unfortunately, only a small percentage is recycled. It is, therefore, quite important that it can be applied in the production of construction materials. The main aim of this article is to determine the thermal conductivity of the products modified with granulated foam glass (GFG) (recycled product) of the 0.25–0.5 mm fraction, as well as to indicate dependence of the change in volume density of samples caused by the use of GFG and the change of the thermal conductivity coefficient compared to reference samples. For the purpose of this research, various parameters were examined i.a. volume density, water absorption, determination of the pore size distribution by mercury porosimetry and determination of the heat conduction coefficient with the use of a plate apparatus. The test results were developed on the basis of a mathematical model that determined the influence of the filler on the functional properties of the product. The research has shown that the use of GFG in the sand-lime products will contribute to lowering their thermal conductivity by more than 50% compared to traditional products.
A Study on the Heat Transfer Characteristics of Steel Plate in the Matrix Laminar Cooling Process
Authors: Xu Jing , Chen Guang , Bao Xiangjun , He Xin , Duan Qingyue
Published: September 2021

Accurate prediction and control of the steel plate temperature in the laminar cooling process are very challenging. In this research, an experimental platform was built to measure the heat transfer characteristics of the steel plate in the process of matrix laminar spray cooling when the steel plate is one millimeter away from the upper surface. The “buried couple method” was used, including the cooling temperature and cooling rate. Then, the temperature and the integrated heat transfer coefficient at the steel plate surface were calculated by the time-sequential function method (TSFM). The obtained results show that the fast cooling stage under the water cooling condition occurred in the first 1.5 s, and the measuring point temperature decreased by 8%. The “re-reddening” phenomenon of the steel plate appeared with time, and the measuring point temperature increased by 37%. Second, the maximum calculated difference between the surface temperature and the measuring point temperature was 0.75 °C, and the integrated heat transfer coefficient conformed to the periodic boundary features. The comprehensive convective heat transfer coefficient on the surface was in agreement with the periodic boundary characteristics, and its value exhibited oscillatory attenuation with the cooling process, and the oscillatory peak period was about 6 seconds. Two methods, sequential function method (SFM) and finite difference method (FDM), were used to verify the correctness of TSFM.