bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug Repurposing against KRAS Mutant G12C: A Machine Learning, Molecular Docking, and Molecular Dynamics Study
Authors: Srisongkram Tarapong , Weerapreeyakul Natthida
Published: January 2023

The Kirsten rat sarcoma viral G12C (KRASG12C) protein is one of the most common mutations in non-small-cell lung cancer (NSCLC). KRASG12C inhibitors are promising for NSCLC treatment, but their weaker activity in resistant tumors is their drawback. This study aims to identify new KRASG12C inhibitors from among the FDA-approved covalent drugs by taking advantage of artificial intelligence. The machine learning models were constructed using an extreme gradient boosting (XGBoost) algorithm. The models can predict KRASG12C inhibitors well, with an accuracy score of validation = 0.85 and Q2Ext = 0.76. From 67 FDA-covalent drugs, afatinib, dacomitinib, acalabrutinib, neratinib, zanubrutinib, dutasteride, and finasteride were predicted to be active inhibitors. Afatinib obtained the highest predictive log-inhibitory concentration at 50% (pIC50) value against KRASG12C protein close to the KRASG12C inhibitors. Only afatinib, neratinib, and zanubrutinib covalently bond at the active site like the KRASG12C inhibitors in the KRASG12C protein (PDB ID: 6OIM). Moreover, afatinib, neratinib, and zanubrutinib exhibited a distance deviation between the KRASG2C protein-ligand complex similar to the KRASG12C inhibitors. Therefore, afatinib, neratinib, and zanubrutinib could be used as drug candidates against the KRASG12C protein. This finding unfolds the benefit of artificial intelligence in drug repurposing against KRASG12C protein.
Ring-Opening Metathesis Polymerization and Related Olefin Metathesis Reactions in Benzotrifluoride as an Environmentally Advantageous Medium
Authors: Kovács Ervin , Balterer Bence , Anh Duc Nguyen , Szarka Györgyi , Owen Michael C. , Domján Attila , Iván Béla
Published: January 2023

A tremendous number of solvents, either as liquids or vapors, contaminate the environment on a daily basis worldwide. Olefin metathesis, which has been widely used as high-yielding protocols for ring-opening metathesis polymerization (ROMP), ring-closing metathesis (RCM), and isomerization reactions, is typically performed in toxic and volatile solvents such as dichloromethane. In this study, the results of our systematic experiments with the Grubbs G1, G2, and Hoveyda-Grubbs HG2 catalysts proved that benzotrifluoride (BTF) can replace dichloromethane (DCM) in these reactions, providing high yields and similar or even higher reaction rates in certain cases. The ROMP of norbornene resulted not only in high yields but also in polynorbornenes with a high molecular weight at low catalyst loadings. Ring-closing metathesis (RCM) experiments proved that, with the exception of the G1 catalyst, RCM occurs with similar high efficiencies in BTF as in DCM. It was found that isomerization of (Z)-but-2-ene-1,4-diyl diacetate with the G2 and HG2 catalysts proceeds at significantly higher initial rates in BTF than in DCM, leading to rapid isomerization with high yields in a short time. Overall, BTF is a suitable solvent for olefin metathesis, such as polymer syntheses by ROMP and the ring-closing and isomerization reactions.
Bacillus licheniformis FA6 Affects Zebrafish Lipid Metabolism through Promoting Acetyl-CoA Synthesis and Inhibiting β-Oxidation
Authors: Chen Sijia , Ye Weidong , Clements Kendall D. , Zan Ziye , Zhao Weishan , Zou Hong , Wang Guitang , Wu Shangong
Published: January 2023

The intestinal microbiota contributes to energy metabolism, but the molecular mechanisms involved remain less clear. Bacteria of the genus Bacillus regulate lipid metabolism in the host and are thus commonly used as beneficial probiotic supplements. In the present study, Bacillus licheniformis FA6 was selected to assess its role in modulating lipid metabolism of zebrafish (Danio rerio). Combining 16S rRNA high-throughput sequencing, micro-CT scan, metabolic parameters measurement, and gene expression analysis, we demonstrated that B. licheniformis FA6 changed the gut microbiota composition of zebrafish and increased both the Firmicutes/Bacteroidetes ratio and lipid accumulation. In terms of metabolites, B. licheniformis FA6 appeared to promote acetate production, which increased acetyl-CoA levels and promoted lipid synthesis in the liver. In contrast, addition of B. licheniformis lowered carnitine levels, which in turn reduced fatty acid oxidation in the liver. At a molecular level, B. licheniformis FA6 upregulated key genes regulating de novo fatty acid synthesis and downregulated genes encoding key rate-limiting enzymes of fatty acid β-oxidation, thereby promoting lipid synthesis and reducing fatty acid oxidation. Generally, our results reveal that B. licheniformis FA6 promotes lipid accumulation in zebrafish through improving lipid synthesis and reducing β-oxidation.
Transcriptome Profile in the Mouse Brain of Hepatic Encephalopathy and Alzheimer’s Disease
Authors: Kim Young-Kook , Jung Yoon Seok , Song Juhyun
Published: January 2023

Hepatic encephalopathy (HE) is a chronic metabolic disease accompanied by neuropathological and neuropsychiatric features, including memory deficits, psychomotor dysfunction, depression, and anxiety. Alzheimer’s disease (AD), the most common neurodegenerative disease, is characterized by tau hyperphosphorylation, excessive amyloid beta (Aβ) accumulation, the formation of fibrillary tangles, hippocampus atrophy, and neuroinflammation. Recent studies have suggested a positive correlation between HE and AD. Some studies reported that an impaired cholesterol pathway, abnormal bile acid secretion, excessive ammonia level, impaired Aβ clearance, astrocytic dysfunction, and abnormal γ-aminobutyric acid GABAergic neuronal signaling in HE may also be involved in AD pathology. However, the mechanisms and related genes involved in AD-like pathology in the HE brain are unclear. Thus, we compared the cortical transcriptome profile between an HE mouse model, bile duct ligation (BDL), and an AD mouse model, the 5×FAD. Our study showed that the expression of many genes implicated in HE is associated with neuronal dysfunction in AD mice. We found changes in various protein-coding RNAs, implicated in synapses, neurogenesis, neuron projection, neuron differentiation, and neurite outgrowth, and non-coding RNAs possibly associated with neuropathology. Our data provide an important resource for further studies to elucidate AD-like pathophysiology in HE patients.
Near-Infrared Imaging of Steroid Hormone Activities Using Bright BRET Templates
Authors: Kim Sung-Bae , Nishihara Ryo , Paulmurugan Ramasamy
Published: January 2023

Bioluminescence (BL) is an excellent optical readout for bioassays and molecular imaging. Herein, we accomplished new near infrared bioluminescence resonance energy transfer (NIR-BRET) templates for monitoring molecular events in cells with higher sensitivity. We first identified the best resonance energy donor for the NIR-BRET templates through the characterization of many coelenterazine (CTZ)–marine luciferase combinations. As a result, we found that NLuc–DBlueC and ALuc47–nCTZ combinations showed luminescence in the blue emission wavelength with excellent BL intensity and stability, for example, the NLuc–DBlueC and ALuc47–nCTZ combinations were 17-fold and 22-fold brighter than their second highest combinations, respectively, and were stably bright in living mammalian cells for at least 10 min. To harness the excellent BL properties to the NIR-BRET systems, NLuc and ALuc47 were genetically fused to fluorescent proteins (FPs), allowing large “blue-to-red” shifts, such as LSSmChe, LSSmKate2, and LSSmNep (where LSS means Large Stokes Shift). The excellent LSSmNep–NLuc combination showed approximately 170 nm large resonance energy shift from blue to red. The established templates were further utilized in the development of new NIR-BRET systems for imaging steroid hormone activities by sandwiching the ligand-binding domain of a nuclear receptor (NR-LBD) between the luciferase and the FP of the template. The NIR-BRET systems showed a specific luminescence signal upon exposure to steroid hormones, such as androgen, estrogen, and cortisol. The present NIR-BRET templates are important additions for utilizing their advantageous imaging of various molecular events with high efficiency and brightness in physiological samples.
Genetic Mapping of Behavioral Traits Using the Collaborative Cross Resource
Authors: Xuan Wei , Zhang Ling , Zhang Yu , Sun Xiuping , Wang Jue , Li Xianglei , Zhang Lingyan , Wang Xinpei , Morahan Grant , Qin Chuan
Published: January 2023

The complicated interactions between genetic background, environment and lifestyle factors make it difficult to study the genetic basis of complex phenotypes, such as cognition and anxiety levels, in humans. However, environmental and other factors can be tightly controlled in mouse studies. The Collaborative Cross (CC) is a mouse genetic reference population whose common genetic and phenotypic diversity is on par with that of humans. Therefore, we leveraged the power of the CC to assess 52 behavioral measures associated with locomotor activity, anxiety level, learning and memory. This is the first application of the CC in novel object recognition tests, Morris water maze tasks, and fear conditioning tests. We found substantial continuous behavioral variations across the CC strains tested, and mapped six quantitative trait loci (QTLs) which influenced these traits, defining candidate genetic variants underlying these QTLs. Overall, our findings highlight the potential of the CC population in behavioral genetic research, while the identified genomic loci and genes driving the variation of relevant behavioral traits provide a foundation for further studies.
Active Targeting of Versatile Nanocomplex Using the Novel Biomarker of Breast Cancer Stem Cells
Authors: Koh Eun-Young , Kim Keun-Sik , Park Hee-Bin , Kim Jong-Seok , Kim Pyung-Hwan
Published: January 2023

Breast cancer in women is one of the most common life-threatening malignancies. Despite of the development for the improved treatment, there are still many limitations to overcome. Among them, cancer stem cells (CSCs) are well known for tumor formation, development, cellular heterogeneity, and cancer recurrence. Therefore, to completely cure breast cancer, treatment of both cancer and CSC is required. To selectively target CSCs, we generated a liposome-based smart nano complex using CEACAM 6 (CD66c) antibody (Ab), a novel cell-surface biomarker of breast-derived CSCs (BCSCs) discovered in our previous research. Selective and increased cellular uptake was observed in BCSCs treated with CD66c Ab-conjugated rhodamine-labeled liposomes (CDRHOL) depending on the expression level of CD66c. CD66c Ab-conjugated doxorubicin (DOX)-loaded liposomes (CDDOXL) selectively showed increased cell killing effects in BCSCs with high CD66c expression levels. In an in vivo animal study, CDRHOL showed enhanced accumulation in xenografted BCSC tumors with low delivery into non-target organs. Moreover, mice treated with CDDOXL have assessed the decreased induction ability of immune response by low expression levels of pro-inflammatory cytokines and reduced liver toxicity by histopathological analysis. Finally, the improved antitumor effect of CDDOXL was evaluated in a metastatic BCSC mouse model via systemic administration. Collectively, our study is the first to demonstrate that a multi-functional nano complex using a novel surface biomarker of BCSC may be a more effective therapeutic agent for the treatment of cancer and CSCs.
Effects of Physiological and Pathological Urea Concentrations on Human Microvascular Endothelial Cells
Authors: Colombo Graziano , Altomare Alessandra , Astori Emanuela , Landoni Lucia , Garavaglia Maria Lisa , Rossi Ranieri , Giustarini Daniela , Lionetti Maria Chiara , Gagliano Nicoletta , Milzani Aldo , Dalle-Donne Isabella
Published: January 2023

Urea is the uremic toxin accumulating with the highest concentration in the plasma of chronic kidney disease (CKD) patients, not being completely cleared by dialysis. Urea accumulation is reported to exert direct and indirect side effects on the gastrointestinal tract, kidneys, adipocytes, and cardiovascular system (CVS), although its pathogenicity is still questioned since studies evaluating its side effects lack homogeneity. Here, we investigated the effects of physiological and pathological urea concentrations on a human endothelial cell line from the microcirculation (Human Microvascular Endothelial Cells-1, HMEC-1). Urea (5 g/L) caused a reduction in the proliferation rate after 72 h of exposure and appeared to be a potential endothelial-to-mesenchymal transition (EndMT) stimulus. Moreover, urea induced actin filament rearrangement, a significant increase in matrix metalloproteinases 2 (MMP-2) expression in the medium, and a significant up- or down-regulation of other EndMT biomarkers (keratin, fibrillin-2, and collagen IV), as highlighted by differential proteomic analysis. Among proteins whose expression was found to be significantly dysregulated following exposure of HMEC-1 to urea, dimethylarginine dimethylaminohydrolase (DDAH) and vasorin turned out to be down-regulated. Both proteins have been directly linked to cardiovascular diseases (CVD) by in vitro and in vivo studies. Future experiments will be needed to deepen their role and investigate the signaling pathways in which they are involved to clarify the possible link between CKD and CVD.
Kinetics of Immunolatex Deposition at Abiotic Surfaces under Flow Conditions: Towards Quantitative Agglutination Assays
Authors: Żeliszewska Paulina , Szych Jolanta , Wasilewska Monika , Adamczyk Zbigniew
Published: January 2023

Physicochemical properties of immunolatex, prepared by incubation of negatively charged polystyrene microparticles with polyclonal rabbit IgGs, were determined by a variety of experimental techniques. These comprised dynamic light scattering (DLS), laser Doppler velocimetry (LDV) and atomic force microscopy (AFM). The particle diffusion coefficient, the hydrodynamic diameter, the electrophoretic mobility, the zeta potential and the suspension stability were determined as a function of pH for different ionic strengths. The deposition of the immunolatex on bare and polyallylamine (PAH) functionalized mica was investigated using the microfluidic oblique impinging-jet cell, with an in situ, real-time image analysis module. The particle deposition kinetics was acquired by a direct particle enumeration procedure. The measurements enabled us to determine the range of pH where the specific deposition of the immunolatex on these substrates was absent. We argue that the obtained results have practical significance for conducting efficient flow immunoassays governed by specific antigen/antibody interactions.
Stable and Unstable Concentration Oscillations Induced by Temperature Oscillations on Reversible Nonequilibrium Chemical Reactions of Helicene Oligomers
Authors: Zhang Sheng , Bao Ming , Arisawa Mieko , Yamaguchi Masahiko
Published: January 2023

Temperature oscillations can affect behaviors of living things. In this article, we describe the effect of triangle temperature oscillations on reversible nonequilibrium chemical reactions detected as concentration oscillations. When amplification through self-catalytic reactions is involved in the chemical reactions, concentration oscillations exhibit diverse nonequilibrium phenomena, which include equilibrium intersecting, equilibrium noncontact, and equilibrium sliding. Both stable and unstable concentration oscillations occur, during which repeated cycles provide the same and different concentration oscillations, respectively. Concentration oscillations are classified according to their waveforms in concentration/time profiles, the shapes of hysteresis curves in concentration/temperature profiles, the nature of self-catalytic reactions, and their relationships with equilibrium. An unstable concentration oscillation may be transformed into a stable concentration oscillation, which is described on the basis of the classifications. Experimental examples are shown using reversible association and dissociation reactions of helicene oligomers.
Disabled-2 (DAB2): A Key Regulator of Anti- and Pro-Tumorigenic Pathways
Authors: Price Zoe K. , Lokman Noor A. , Yoshihara Masato , Kajiyama Hiroaki , Oehler Martin K. , Ricciardelli Carmela
Published: January 2023

Disabled-2 (DAB2), a key adaptor protein in clathrin mediated endocytosis, is implicated in the regulation of key signalling pathways involved in homeostasis, cell positioning and epithelial to mesenchymal transition (EMT). It was initially identified as a tumour suppressor implicated in the initiation of ovarian cancer, but was subsequently linked to many other cancer types. DAB2 contains key functional domains which allow it to negatively regulate key signalling pathways including the mitogen activated protein kinase (MAPK), wingless/integrated (Wnt) and transforming growth factor beta (TGFβ) pathways. Loss of DAB2 is primarily associated with activation of these pathways and tumour progression, however this review also explores studies which demonstrate the complex nature of DAB2 function with pro-tumorigenic effects. A recent strong interest in microRNAs (miRNA) in cancer has identified DAB2 as a common target. This has reignited an interest in DAB2 research in cancer. Transcriptomics of tumour associated macrophages (TAMs) has also identified a pro-metastatic role of DAB2 in the tumour microenvironment. This review will cover the broad depth literature on the tumour suppressor role of DAB2, highlighting its complex relationships with different pathways. Furthermore, it will explore recent findings which suggest DAB2 has a more complex role in cancer than initially thought.
Phosphodiesterase 5a Signalling in Skeletal Muscle Pathophysiology
Authors: De Arcangelis Valeria , De Angelis Luciana , Barbagallo Federica , Campolo Federica , de Oliveira do Rego Ana Gabriela , Pellegrini Manuela , Naro Fabio , Giorgi Mauro , Monaco Lucia
Published: January 2023

Phosphodiesterase 5A (PDE5A) is involved in cGMP hydrolysis, regulating many physiological processes. Increased activity of PDE5A has been found in several pathological conditions, and the pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications. We have identified the presence of three different Pde5a isoforms in cardiomyocytes, and we have found that the expression of specific Pde5a isoforms may have a causal role in the onset of pathological responses in these cells. In our previous study, we demonstrated that PDE5A inhibition could ameliorate muscular dystrophy by acting at different levels, as assessed by the altered genomic response of muscular cells following treatment with the PDE5A inhibitor tadalafil. Thus, considering the importance of PDE5A in various pathophysiological conditions, we further investigated the regulation of this enzyme. Here, we analysed the expression of Pde5a isoforms in the pathophysiology of skeletal muscle. We found that skeletal muscle tissues and myogenic cells express Pde5a1 and Pde5a2 isoforms, and we observed an increased expression of Pde5a1 in damaged skeletal muscles, while Pde5a2 levels remained unchanged. We also cloned and characterized the promoters that control the transcription of Pde5a isoforms, investigating which of the transcription factors predicted by bioinformatics analysis could be involved in their modulation. In conclusion, we found an overexpression of Pde5a1 in compromised muscle and identified an involvement of MyoD and Runx1 in Pde5a1 transcriptional activity.
How Are Synapses Born? A Functional and Molecular View of the Role of the Wnt Signaling Pathway
Authors: Bonansco Christian , Cerpa Waldo , Inestrosa Nibaldo C.
Published: January 2023

Synaptic transmission is a dynamic process that requires precise regulation. Early in life, we must be able to forge appropriate connections (add and remove) to control our behavior. Neurons must recognize appropriate targets, and external soluble factors that activate specific signaling cascades provide the regulation needed to achieve this goal. Wnt signaling has been implicated in several forms of synaptic plasticity, including functional and structural changes associated with brain development. The analysis of synapses from an electrophysiological perspective allows us to characterize the functional role of cellular signaling pathways involved in brain development. The application of quantal theory to principles of developmental plasticity offers the possibility of dissecting the function of structural changes associated with the birth of new synapses as well as the maturation of immature silent synapses. Here, we focus on electrophysiological and molecular evidence that the Wnt signaling pathway regulates glutamatergic synaptic transmission, specifically N-methyl-d-aspartate receptors (NMDARs), to control the birth of new synapses. We also focus on the role of Wnts in the conversion of silent synapses into functional synapses.
Splice-Site Variants in the Gene Encoding GABA-A Receptor Delta Subunit Are Associated with Amphetamine Use in Patients under Methadone Maintenance Treatment
Authors: Lin Yen-Feng , Chou Wen-Hai , Liu Tung-Hsia , Fang Chiu-Ping , Kuo Hsiang-Wei , Kuo Po-Hsiu , Tsai Shih-Jen , Wang Sheng-Chang , Chung Ren-Hua , Tsou Hsiao-Hui , Chen Andrew C. H. , Liu Yu-Li
Published: January 2023

Chronic opioid use disorder patients often also use other substances such as amphetamines. The gene-based analysis method was applied in the genomic database obtained from our previous study with 343 methadone maintenance treatment (MMT) patients. We found that the gene encoding gamma-aminobutyric acid type A receptors (GABA-A receptor) delta subunit isoforms (GABRD) was associated with amphetamine use in heroin dependent patients under MMT in Taiwan. A total of 15% of the 343 MMT patients tested positive for amphetamine in the urine toxicology test. Two genetic variants in the GABRD, rs2889475 and rs2376805, were found to be associated with the positive urine amphetamine test. They are located in the exon 1 of the splice variant and altered amino acid compositions (T126I, C/T, for rs2889475, and R252Q, G/A, for rs2376805). The CC genotype carriers of rs2889475 showed a four times higher risk of amphetamine use than those with TT genotype. The GG genotype carriers of rs2376805 showed a three times higher risk of amphetamine use than the AA genotype carriers. To our knowledge, this is the first report that demonstrated an association of the delta splice variant isoform in the GABA-A receptor with an increased risk of amphetamine use in MMT patients. Our results suggest that rs2889475 and rs2376805 may be indicators for the functional role and risk of amphetamine use in MMT patients.
Application of Antimicrobial Photodynamic Therapy for Inactivation of Acinetobacter baumannii Biofilms
Authors: Buchovec Irina , Vyčaitė Enrika , Badokas Kazimieras , Sužiedelienė Edita , Bagdonas Saulius
Published: January 2023

Acinetobacter baumannii is a dangerous hospital pathogen primarily due to its ability to form biofilms on different abiotic and biotic surfaces. The present study investigated the effect of riboflavin- and chlorophyllin-based antimicrobial photodynamic therapy, performed with near-ultraviolet or blue light on the viability of bacterial cells in biofilms and their structural stability, also determining the extent of photoinduced generation of intracellular reactive oxygen species as well as the ability of A. baumannii to form biofilms after the treatment. The efficacy of antimicrobial photodynamic therapy was compared with that of light alone and the role of the photosensitizer type on the photosensitization mechanism was demonstrated. We found that the antibacterial effect of riboflavin-based antimicrobial photodynamic therapy depends on the ability of photoactivated riboflavin to generate intracellular reactive oxygen species but does not depend on the concentration of riboflavin and pre-incubation time before irradiation. Moreover, our results suggest a clear interconnection between the inactivation efficiency of chlorophyllin-based antimicrobial photodynamic therapy and the sensitivity of A. baumannii biofilms to used light. In summary, all the analyzed results suggest that riboflavin-based antimicrobial photodynamic therapy and chlorophyllin-based antimicrobial photodynamic therapy have the potential to be applied as an antibacterial treatment against A. baumannii biofilms or as a preventive measure against biofilm formation.
In Silico Identification and In Vitro Evaluation of New ABCG2 Transporter Inhibitors as Potential Anticancer Agents
Authors: Di Micco Simone , Di Sarno Veronica , Rossi Martina , Vestuto Vincenzo , Konno Takumi , Novi Sara , Tecce Mario Felice , Napolitano Valeria , Ciaglia Tania , Vitale Andrea , Gomez-Monterrey Isabel Maria , Bifulco Giuseppe , Bertamino Alessia , Ostacolo Carmine , Blasi Paolo , Fasano Alessio , Campiglia Pietro , Musella Simona
Published: January 2023

Different molecular mechanisms contribute to the development of multidrug resistance in cancer, including increased drug efflux, enhanced cellular repair mechanisms and alterations of drug metabolism or drug targets. ABCG2 is a member of the ATP-binding cassette superfamily transporters that promotes drug efflux, inducing chemotherapeutic resistance in malignant cells. In this context, the development of selective ABCG2 inhibitors might be a suitable strategy to improve chemotherapy efficacy. Thus, through a multidisciplinary approach, we identified a new ABCG2 selective inhibitor (8), highlighting its ability to increase mitoxantrone cytotoxicity in both hepatocellular carcinoma (EC50from 8.67 ± 2.65 to 1.25 ± 0.80 μM) and transfected breast cancer cell lines (EC50from 9.92 ± 2.32 to 2.45 ± 1.40 μM). Moreover, mitoxantrone co-administration in both transfected and non-transfected HEK293 revealed that compound 8 notably lowered the mitoxantrone EC50, demonstrating its efficacy along with the importance of the ABCG2 extrusion pump overexpression in MDR reversion. These results were corroborated by evaluating the effect of inhibitor 8 on mitoxantrone cell uptake in multicellular tumor spheroids and via proteomic experiments.
Why Is Longevity Still a Scientific Mystery? Sirtuins—Past, Present and Future
Authors: Ziętara Patrycja , Dziewięcka Marta , Augustyniak Maria
Published: January 2023

The sirtuin system consists of seven highly conserved regulatory enzymes responsible for metabolism, antioxidant protection, and cell cycle regulation. The great interest in sirtuins is associated with the potential impact on life extension. This article summarizes the latest research on the activity of sirtuins and their role in the aging process. The effects of compounds that modulate the activity of sirtuins were discussed, and in numerous studies, their effectiveness was demonstrated. Attention was paid to the role of a caloric restriction and the risks associated with the influence of careless sirtuin modulation on the organism. It has been shown that low modulators’ bioavailability/retention time is a crucial problem for optimal regulation of the studied pathways. Therefore, a detailed understanding of the modulator structure and potential reactivity with sirtuins in silico studies should precede in vitro and in vivo experiments. The latest achievements in nanobiotechnology make it possible to create promising molecules, but many of them remain in the sphere of plans and concepts. It seems that solving the mystery of longevity will have to wait for new scientific discoveries.
The Association between the Bisphenols Residues in Amniotic Fluid and Fetal Abnormalities in Polish Pregnant Women—Its Potential Clinical Application
Authors: Tuzimski Tomasz , Szubartowski Szymon , Stupak Aleksandra , Kwaśniewski Wojciech , Szultka-Młyńska Małgorzata , Kwaśniewska Anna , Buszewski Bogusław
Published: January 2023

The present study aimed to investigate the relationship between the concentrations of bisphenols residues in the amniotic fluid (AF) samples collected during amniocentesis and fetal chromosomal abnormalities in pregnant women. A total of 33 pregnant Polish women aged between 24 and 44 years, and screened to detect high risk for chromosomal defects in the first trimester, were included in this study. Samples were collected from these patients during routine diagnostic and treatment procedures at mid-gestation. The concentrations of various bisphenols residues in the samples were determined by liquid chromatography coupled with triple quadrupole tandem mass spectrometry (LC-ESI-QqQ-MS/MS). Residues of eight analytes (BPS, BPF, BPA, BPAF, BADGE, BADGE•2H2O, BADGE•H2O•HCl and BADGE•2HCl) were detected in amniotic fluid samples in the range 0.69 ng/mL to 3.38 ng/mL. Fetuses with chromosomal abnormalities showed a slightly higher frequency of occurrence of selected bisphenols residues in the AF samples collected between 15–26 weeks of pregnancies. Finally, the proposed method was applied in the simultaneous determination of several endocrine-disrupting chemicals from bisphenol group in 33 human AF samples. BADGE•H2O•HCl has been identified in the AF samples taken from women older than average in the examined group. The number of detected compounds has been significant for the following analytes: BPS, BPAF, BADGE•H2O•HCl and BADGE. The proposed method may be an attractive alternative for application in large-scale human biomonitoring studies.
Cytokinin Modulates Responses to Phytomelatonin in Arabidopsis thaliana under High Light Stress
Authors: Bychkov Ivan A. , Andreeva Aleksandra A. , Kudryakova Natalia V. , Kusnetsov Victor V.
Published: January 2023

Fine-tuned interactions between melatonin (MT) and hormones affected by environmental inputs are crucial for plant growth. Under high light (HL) conditions, melatonin reduced photodamage in Arabidopsis thaliana and contributed to the restoration of the expression of the cytokinin (CK) synthesis genes IPT3, IPT5 and LOG7 and genes for CK signal transduction AHK2,3 and ARR 1, 4, 5 and 12 which were downregulated by stress. However, CK signaling mutants displayed no significant changes in the expression of CK genes following HL + MT treatment, implying that a fully functional cytokinin signaling pathway is a prerequisite for MT–CK interactions. In turn, cytokinin treatment increased the expression of the key melatonin synthesis gene ASMT under both moderate and HL in wild-type plants. This upregulation was further accentuated in the ipt3,5,7 mutant which is highly sensitive to CK. In this mutant, in addition to ASMT, the melatonin synthesis genes SNAT and COMT, as well as the putative signaling genes CAND2 and GPA1, displayed elevated transcript levels. The results of the study suggest that melatonin acts synergistically with CK to cope with HL stress through melatonin-associated activation or repression of the respective hormonal genes.
Biochemical and Structural Analyses Shed Light on the Mechanisms of RadD DNA Binding and Its ATPase from Escherichia coli
Authors: Tian Li-Fei , Kuang Xiaolin , Ding Ke , Gao Hongwei , Tang Qun , Yan Xiao-Xue , Xu Wenqing
Published: January 2023

DNA double-strand breaks (DSBs) are the most perilous and harmful type of DNA damage and can cause tumorigenesis or cell death if left repaired with an error or unrepaired. RadD, a member of the SF2 family, is a recently discovered DNA repair protein involved in the repair of DSBs after radiation or chemical damage. However, the function of RadD in DNA repair remains unclear. Here, we determined the crystal structures of RadD/ATPγS and RadD/ATP complexes and revealed the novel mechanism of RadD binding to DNA and ATP hydrolysis with biochemical data. In the RadD catalytic center, the Gly34 and Gly36 on the P-loop are key residues for ATP binding besides the conserved amino acids Lys37 and Arg343 in the SF2 family. If any of them mutate, then RadD loses ATPase activity. Asp117 polarizes the attacking water molecule, which then starts a nucleophilic reaction toward γ-phosphate, forming the transition state. Lys68 acts as a pocket switch to regulate substrate entry and product release. We revealed that the C-terminal peptide of single-stranded DNA-binding protein (SSB) binds the RadD C-terminal domain (CTD) and promotes the RadD ATPase activity. Our mutagenesis studies confirmed that the residues Arg428 on the zinc finger domain (ZFD) and Lys488 on the CTD of RadD are the key sites for binding branched DNA. Using the Coot software combined with molecular docking, we propose a RadD-binding DNA model for the DNA damage repair process.
Formation and Properties of Thermistor Chips Based on Semiconductor 3D Metal Oxide Films Obtained by RF-Magnetron Sputtering
Authors: Novozhilov Valery , Belov Alexey
Published: January 2023

The formation of oxide semiconductor films of the (Mn,Co,Cu)3O4 type by radio frequency magnetron sputtering is presented. The conditions of deposition and subsequent heat treatment make it possible to obtain films with electrophysical characteristics close to those of the bulk ceramic materials used as a target for magnetron sputtering. Two variants of thermistor geometry were implemented. In the first case, the working layer of oxide semiconductor was deposited directly on the dielectric substrate (planar geometry), and in the second case on the layer with high electrical conductivity (Ni or Al) forming the inner electrode (layered geometry). The lower limit of the nominal resistance of the planar thermistor while maintaining high temperature nonlinearity is ~ 10 kΩ. The layered structure with the inner electrode makes it possible to reduce the lower limit of resistance up to ~ 50 Ω without losing the temperature nonlinearity of the thermistor. In addition, heat treatment above 450 °C or current self-heating with sufficient power output leads to the appearance of a pronounced voltage nonlinearity, which increases the thermal constant B of thermistors from 2400–3400 to 5000–5500 K. The fields of application of oxide-film structures for the correction of linear resistors and the implementation of integration approaches in the construction of linearized sensors are discussed.
Spectroscopic Characterization and Biological Activity of Hesperetin Schiff Bases and Their Cu(II) Complexes
Authors: Sykuła Anna , Nowak Adriana , Garribba Eugenio , Dzeikala Aliaksandr , Rowińska-Żyrek Magdalena , Czerwińska Justyna , Maniukiewicz Waldemar , Łodyga-Chruścińska Elżbieta
Published: January 2023

The three Schiff base ligands, derivatives of hesperetin, HHSB (N-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]isonicotinohydrazide), HIN (N-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]benzhydrazide) and HTSC (N-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]thiosemicarbazide) and their copper complexes, CuHHSB, CuHIN, and CuHTSC were designed, synthesized and analyzed in terms of their spectral characterization and the genotoxic activity. Their structures were established using several methods: elemental analysis, FT-IR, UV-Vis, EPR, and ESI-MS. Spectral data showed that in the acetate complexes the tested Schiff bases act as neutral tridentate ligand coordinating to the copper ion through two oxygen (or oxygen and sulphur) donor atoms and a nitrogen donor atom. EPR measurements indicate that in solution the complexes keep their structures with the ligands remaining bound to copper(II) in a tridentate fashion with (O–, N, Oket) or (O–, N, S) donor set. The genotoxic activity of the compounds was tested against model tumour (HeLa and Caco-2) and normal (LLC-PK1) cell lines. In HeLa cells the genotoxicity for all tested compounds was noticed, for HHSB and CuHHSB was the highest, for HTSC and CuHTSC–the lowest. Generally, Cu complexes displayed lower genotoxicity to HeLa cells than ligands. In the case of Caco-2 cell line HHSB and HTSC induced the strongest breaks to DNA. On the other side, CuHHSB and CuHTSC induced the highest DNA damage against LLC-PK1.
Non-Noble-Metal Mono and Bimetallic Composites for Efficient Electrocatalysis of Phosphine Oxide and Acetylene C-H/P-H Coupling under Mild Conditions
Authors: Tarasov Maxim V. , Bochkova Olga D. , Gryaznova Tatyana V. , Mustafina Asiya R. , Budnikova Yulia H.
Published: January 2023

The present work describes an efficient reaction of electrochemical phosphorylation of phenylacetylene controlled by the composition of catalytic nanoparticles based on non-noble-metals. The sought-after products are produced via the simple synthetic protocol based on room temperature, atom-economical reactions, and silica nanoparticles (SNs) loaded by one or two d-metal ions as nanocatalysts. The redox and catalytic properties of SNs can be tuned with a range of parameters, such as compositions of the bimetallic systems, their preparation method, and morphology. Monometallic SNs give phosphorylated acetylene with retention of the triple bond, and bimetallic SNs give a bis-phosphorylation product. This is the first example of acetylene and phosphine oxide C-H/P-H coupling with a regenerable and recyclable catalyst.
High Acetate Concentration Protects Intestinal Barrier and Exerts Anti-Inflammatory Effects in Organoid-Derived Epithelial Monolayer Cultures from Patients with Ulcerative Colitis
Authors: Deleu Sara , Arnauts Kaline , Deprez Lowie , Machiels Kathleen , Ferrante Marc , Huys Geert R. B. , Thevelein Johan M. , Raes Jeroen , Vermeire Séverine
Published: January 2023

Short-chain fatty acids as well as their bacterial producers are of increasing interest in inflammatory bowel diseases. Although less studied compared to butyrate, acetate might also be of interest as it may be less toxic to epithelial cells, stimulate butyrate-producing bacteria by cross-feeding, and have anti-inflammatory and barrier-protective properties. Moreover, one of the causative factors of the probiotic potency of Saccharomyces cerevisae var. boulardii is thought to be its high acetate production. Therefore, the objective was to preclinically assess the effects of high acetate concentrations on inflammation and barrier integrity in organoid-based monolayer cultures from ulcerative colitis patients. Confluent organoid-derived colonic epithelial monolayers (n = 10) were exposed to basolateral inflammatory stimulation or control medium. After 24 h, high acetate or control medium was administered apically for an additional 48 h. Changes in TEER were measured after 48 h. Expression levels of barrier genes and inflammatory markers were determined by qPCR. Pro-inflammatory proteins in the supernatant were quantified using the MSD platform. Increased epithelial resistance was observed with high acetate administration in both inflamed and non-inflamed conditions, together with decreased expression levels of IL8 and TNFα and CLDN1. Upon high acetate administration to inflamed monolayers, upregulation of HIF1α, MUC2, and MKI67, and a decrease of the majority of pro-inflammatory cytokines was observed. In our patient-derived human epithelial cell culture model, a protective effect of high acetate administration on epithelial resistance, barrier gene expression, and inflammatory protein production was observed. These findings open up new possibilities for acetate-mediated management of barrier defects and inflammation in IBD.
G-Protein-Coupled Receptors Mediate Modulations of Cell Viability and Drug Sensitivity by Aberrantly Expressed Recoverin 3 within A549 Cells
Authors: Ichioka Hanae , Hirohashi Yoshihiko , Sato Tatsuya , Furuhashi Masato , Watanabe Megumi , Ida Yosuke , Hikage Fumihito , Torigoe Toshihiko , Ohguro Hiroshi
Published: January 2023

To elucidate the currently unknown molecular mechanisms responsible for the aberrant expression of recoverin (Rec) within cancerous cells, we examined two-dimensional (2D) and three-dimensional (3D) cultures of Rec-negative lung adenocarcinoma A549 cells which had been transfected with a plasmid containing human recoverin cDNA (A549 Rec) or an empty plasmid as a mock control (A549 MOCK). Using these cells, we measured cytotoxicity by several anti-tumor agents (2D), cellular metabolism including mitochondrial and glycolytic functions by a Seahorse bio-analyzer (2D), the physical properties, size and stiffness of the 3D spheroids, trypsin sensitivities (2D and 3D), and RNA sequencing analysis (2D). Compared with the A549 MOCK, the A549 Rec cells showed (1) more sensitivity toward anti-tumor agents (2D) and a 0.25% solution of trypsin (3D); (2) a metabolic shift from glycolysis to oxidative phosphorylation; and (3) the formation of larger and stiffer 3D spheroids. RNA sequencing analysis and bioinformatic analyses of the differentially expressed genes (DEGs) using Gene Ontology (GO) enrichment analysis suggested that aberrantly expressed Rec is most likely associated with several canonical pathways including G-protein-coupled receptor (GPCR)-mediated signaling and signaling by the cAMP response element binding protein (CREB). The findings reported here indicate that the aberrantly expressed Rec-induced modulation of the cell viability and drug sensitivity may be GPCR mediated.
Non-Fungible Tokens (NFT): A Systematic Review
Authors: Taherdoost Hamed
Published: January 2023

Non-fungible tokens (NFTs) are gaining in popularity and are already extensively implemented. New use cases for NFTs are constantly developing. NFTs may prevent counterfeiting since each token carries the owner’s digital signature and is thus unique. For the usage of NFTs to progress in an institutional environment, the potential for using NFTs must be investigated in detail. This discovery prompted a comprehensive examination of NFTs developed between 2012 and 2022. The scope is confined to the journal and the keywords “Blockchain”, “Block-chain”, “Non-fungible Token”, and “NFT” are used. Also excluded are studies based on interviews, articles in the press, non-English articles, reviews, conferences, book chapters, dissertations, and monographs. This evaluation includes 34 papers from the last decade. This research examines the current state and development trends of NFT. In addition, the gaps and difficulties in the related literature have been explored, with an emphasis on the limits. These results highlight many unsolved research questions and potential future research avenues that would likely be beneficial to academics and professionals.
Extracting Narrative Patterns in Different Textual Genres: A Multilevel Feature Discourse Analysis
Authors: Maestre María Miró , Vicente Marta , Lloret Elena , Cueto Armando Suárez
Published: January 2023

We present a data-driven approach to discover and extract patterns in textual genres with the aim of identifying whether there is an interesting variation of linguistic features among different narrative genres depending on their respective communicative purposes. We want to achieve this goal by performing a multilevel discourse analysis according to (1) the type of feature studied (shallow, syntactic, semantic, and discourse-related); (2) the texts at a document level; and (3) the textual genres of news, reviews, and children’s tales. To accomplish this, several corpora from the three textual genres were gathered from different sources to ensure a heterogeneous representation, paying attention to the presence and frequency of a series of features extracted with computational tools. This deep analysis aims at obtaining more detailed knowledge of the different linguistic phenomena that directly shape each of the genres included in the study, therefore showing the particularities that make them be considered as individual genres but also comprise them inside the narrative typology. The findings suggest that this type of multilevel linguistic analysis could be of great help for areas of research within natural language processing such as computational narratology, as they allow a better understanding of the fundamental features that define each genre and its communicative purpose. Likewise, this approach could also boost the creation of more consistent automatic story generation tools in areas of language generation.
Shrinkage of Micro-Synthetic Fiber-Reinforced Mortar
Authors: Safitri Endah , Kusworo Ridan Adi , Kristiawan Stefanus Adi
Published: January 2023

Repair materials have been developed in this research by adding micro-synthetic fibers in cement-based mortar. In addition, accelerator is incorporated in the mortar to obtain high early strength of the repair materials. Their shrinkage behavior is of interest. This study aims to determine the shrinkage of the micro-synthetic fiber-reinforced mortar and propose models to reflect their shrinkage behavior. The results show that rapid developments of shrinkage are observed at an early age where the 3-day shrinkage already attains about 40–50% of the 84-day shrinkage value. Moreover, after 14 days of age the shrinkage curves tend to approach the asymptotic value. The ACI 209.2R-08 and CEB-MC 90-99 models do not reflect the shape of the shrinkage curves of the micro-synthetic fiber-reinforced mortar. Therefore, this research proposes a modified ACI 209.2R-08 and CEB-MC 90-99 that can describe the shrinkage behavior of the micro-synthetic fiber-reinforced mortar. The accuracy of the modified models has been confirmed quantitatively using the method of best fit line, residual analysis, and coefficient of error.
Hemolymph Metabolism Analysis of Honey Bee (Apis mellifera L.) Response to Different Bee Pollens
Authors: Chang Hongcai , Ding Guiling , Jia Guangqun , Feng Mao , Huang Jiaxing
Published: January 2023

Pollen is essential to the development of honey bees. The nutrients in bee pollen vary greatly among plant species. Here, we analyzed the differences in the amino acid compositions of pear (Pyrus bretschneideri), rape (Brassica napus), and apricot (Armeniaca sibirica) pollens and investigated the variation in hemolymph metabolites and metabolic pathways through untargeted metabolomics in caged adult bees at days 7 and 14. The results showed that the levels of five essential amino acids (isoleucine, phenylalanine, lysine, methionine, and histidine) were the highest in pear pollen, and the levels of four amino acids (isoleucine: 50.75 ± 1.93 mg/kg, phenylalanine: 87.25 ± 2.66 mg/kg, methionine: 16.00 ± 0.71 mg/kg and histidine: 647.50 ± 24.80 mg/kg) were significantly higher in pear pollen than in the other two kinds of bee pollen (p < 0.05). The number of metabolites in bee hemolymph on day 14 (615) was significantly lower than that on day 7 (1466). The key metabolic pathways of bees, namely, “sphingolipid metabolism (p = 0.0091)”, “tryptophan metabolism (p = 0.0245)”, and “cysteine and methionine metabolism (p = 0.0277)”, were significantly affected on day 7. There was no meaningful pathway enrichment on day 14. In conclusion, pear pollen had higher nutritional value among the three bee pollens in terms of amino acid level, followed by rape and apricot pollen, and the difference in amino acid composition among bee pollens was reflected in the lipid and amino acid metabolism pathways of early adult honey bee hemolymph. This study provides new insights into the physiological and metabolic functions of different bee pollens in bees.