bluuebunny/crossref_metadata_2025 huggingface dataset:
Histaminergic System and Inflammation-Related Genes in Normal Large Intestine and Adenocarcinoma Tissues: Transcriptional Profiles and Relations
Authors: Janikowska Grażyna , Janikowski Tomasz , Plato Marta , Mazurek Urszula , Orchel Joanna , Opiłka Mieszko , Lorenc Zbigniew
Published: March 2023

Transcriptional analyses such as microarray data have contributed to the progress in the diagnostics and therapy of colorectal cancer (CRC). The need for such research is still present because of the disease being common in both men and women with a high second position in cancer rankings. Little is known about the relations between the histaminergic system and inflammation in the large intestine and CRC. Therefore, the aim of this study was to evaluate the expression of genes related to the histaminergic system and inflammation in the CRC tissues at three cancer development designs: all tested CRC samples, low (LCS) and high (HCS) clinical stage, and four clinical stages (CSI–CSIV), to the control. The research was carried out at the transcriptomic level, analysing hundreds of mRNAs from microarrays, as well as carrying out RT-PCR analysis of histaminergic receptors. The following histaminergic mRNAs: GNA15, MAOA, WASF2A, and inflammation-related: AEBP1, CXCL1, CXCL2, CXCL3, CXCL8, SPHK1, TNFAIP6, were distinguished. Among all analysed transcripts, AEBP1 can be considered the most promising diagnostic marker in the early stage of CRC. The results showed 59 correlations between differentiating genes of the histaminergic system and inflammation in the control, control and CRC, and CRC. The tests confirmed the presence of all histamine receptor transcripts in both the control and colorectal adenocarcinoma. Significant differences in expression were stated for HRH2 and HRH3 in the advanced stages of CRC adenocarcinoma. The relations between the histaminergic system and inflammation-linked genes in both the control and the CRC have been observed.
The Potential Role of MiRs-139-5p and -454-3p in Endoglin-Knockdown-Induced Angiogenic Dysfunction in HUVECs
Authors: Cannavicci Anthony , Zhang Qiuwang , Kutryk Michael J. B.
Published: March 2023

Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by aberrant angiogenesis and vascular malformations. Mutations in the transforming growth factor beta co-receptor, endoglin (ENG), account for approximately half of known HHT cases and cause abnormal angiogenic activity in endothelial cells (ECs). To date, how ENG deficiency contributes to EC dysfunction remains to be fully understood. MicroRNAs (miRNAs) regulate virtually every cellular process. We hypothesized that ENG depletion results in miRNA dysregulation that plays an important role in mediating EC dysfunction. Our goal was to test the hypothesis by identifying dysregulated miRNAs in ENG-knockdown human umbilical vein endothelial cells (HUVECs) and characterizing their potential role in EC function. We identified 32 potentially downregulated miRNAs in ENG-knockdown HUVECs with a TaqMan miRNA microarray. MiRs-139-5p and -454-3p were found to be significantly downregulated after RT-qPCR validation. While the inhibition of miR-139-5p or miR-454-3p had no effect on HUVEC viability, proliferation or apoptosis, angiogenic capacity was significantly compromised as determined by a tube formation assay. Most notably, the overexpression of miRs-139-5p and -454-3p rescued impaired tube formation in HUVECs with ENG knockdown. To our knowledge, we are the first to demonstrate miRNA alterations after the knockdown of ENG in HUVECs. Our results indicate a potential role of miRs-139-5p and -454-3p in ENG-deficiency-induced angiogenic dysfunction in ECs. Further study to examine the involvement of miRs-139-5p and -454-3p in HHT pathogenesis is warranted.
Unravelling the Mechanism and Governing Factors in Lewis Acid and Non-Covalent Diels–Alder Catalysis: Different Perspectives
Authors: Vermeersch Lise , De Proft Frank , Faulkner Vicky , De Vleeschouwer Freija
Published: March 2023

In the current literature, many non-covalent interaction (NCI) donors have been proposed that can potentially catalyze Diels-Alder (DA) reactions. In this study, a detailed analysis of the governing factors in Lewis acid and non-covalent catalysis of three types of DA reactions was carried out, for which we selected a set of hydrogen-, halogen-, chalcogen-, and pnictogen-bond donors. We found that the more stable the NCI donor–dienophile complex, the larger the reduction in DA activation energy. We also showed that for active catalysts, a significant part of the stabilization was caused by orbital interactions, though electrostatic interactions dominated. Traditionally, DA catalysis was attributed to improved orbital interactions between the diene and dienophile. Recently, Vermeeren and co-workers applied the activation strain model (ASM) of reactivity, combined with the Ziegler-Rauk-type energy decomposition analysis (EDA), to catalyzed DA reactions in which energy contributions for the uncatalyzed and catalyzed reaction were compared at a consistent geometry. They concluded that reduced Pauli repulsion energy, and not enhanced orbital interaction energy, was responsible for the catalysis. However, when the degree of asynchronicity of the reaction is altered to a large extent, as is the case for our studied hetero-DA reactions, the ASM should be employed with caution. We therefore proposed an alternative and complementary approach, in which EDA values for the catalyzed transition-state geometry, with the catalyst present or deleted, can be compared one to one, directly measuring the effect of the catalyst on the physical factors governing the DA catalysis. We discovered that enhanced orbital interactions are often the main driver for catalysis and that Pauli repulsion plays a varying role.
Toxicity Study and Binding Analysis of Newly Synthesized Antifungal N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide Derivative with Bovine Serum Albumin
Authors: Wani Tanveer A. , Bakheit Ahmed H. , Zargar Seema , Altwaijry Nojood , Bhat Mashooq Ahmad , Alkahtani Hamad M. , Al-Rasheed Lamees S.
Published: March 2023

The presence of the p-aryl/cyclohexyl ring in the N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazine carbothioamide derivative (2C) is reported to enhance the antifungal properties when compared to those of itraconazole. Serum albumins present in plasma bind and transport ligands, including pharmaceuticals. This study explored 2C interactions with BSA using spectroscopic methods such as fluorescence and UV-visible spectroscopy. In order to acquire a deeper comprehension of how BSA interacts with binding pockets, a molecular docking study was carried out. The fluorescence of BSA was quenched by 2C via a static quenching mechanism since a decrease in quenching constants was observed from 1.27 × 105 to 1.14 × 105. Thermodynamic parameters indicated hydrogen and van der Waals forces responsible for the BSA–2C complex formation with binding constants ranging between 2.91 × 105 and 1.29 × 105, which suggest a strong binding interaction. Site marker studies displayed that 2C binds to BSA’s subdomains IIA and IIIA. Molecular docking studies were conducted to further comprehend the molecular mechanism of the BSA–2C interaction. The toxicity of 2C was predicted by Derek Nexus software. Human and mammalian carcinogenicity and skin sensitivity predictions were associated with a reasoning level of equivocal, inferring 2C to be a potential drug candidate.
Rapid Generation of Barley Homozygous Transgenic Lines Based on Microspore Culture: HvPR1 Overexpression as an Example
Authors: Chen Zhiwei , Jiang Qi , Guo Guimei , Shen Qiufang , Yang Jun , Wang Ertao , Zhang Guoping , Lu Ruiju , Liu Chenghong
Published: March 2023

Obtaining homozygous lines from transgenic plants is an important step for phenotypic evaluations, but the selection of homozygous plants is time-consuming and laborious. The process would be significantly shortened if anther or microspore culture could be completed in one generation. In this study, we obtained 24 homozygous doubled haploid (DH) transgenic plants entirely by microspore culture from one T0 transgenic plant overexpressing the gene HvPR1 (pathogenesis-related-1). Nine of the doubled haploids grew to maturity and produced seeds. qRCR (quantitative real-time PCR) validation showed that the HvPR1 gene was expressed differentially even among different DH1 plants (T2) from the same DH0 line (T1). Phenotyping analysis suggested that the overexpression of HvPR1 inhibited nitrogen use efficiency (NUE) only under low nitrogen treatment. The established method of producing homozygous transgenic lines will enable the rapid evaluation of transgenic lines for gene function studies and trait evaluation. As an example, the HvPR1 overexpression of DH lines also could be used for further analysis of NUE-related research in barley.
BMPER Improves Vascular Remodeling and the Contractile Vascular SMC Phenotype
Authors: Pankratz Franziska , Maksudova Aziza , Goesele Roman , Meier Lena , Proelss Kora , Marenne Katia , Thut Ann-Kathrin , Sengle Gerhard , Correns Annkatrin , Begelspacher Jeanina , Alkis Deniz , Siegel Patrick M. , Smolka Christian , Grundmann Sebastian , Moser Martin , Zhou Qian , Esser Jennifer S.
Published: March 2023

Dedifferentiated vascular smooth muscle cells (vSMCs) play an essential role in neointima formation, and we now aim to investigate the role of the bone morphogenetic protein (BMP) modulator BMPER (BMP endothelial cell precursor-derived regulator) in neointima formation. To assess BMPER expression in arterial restenosis, we used a mouse carotid ligation model with perivascular cuff placement. Overall BMPER expression after vessel injury was increased; however, expression in the tunica media was decreased compared to untreated control. Consistently, BMPER expression was decreased in proliferative, dedifferentiated vSMC in vitro. C57BL/6_Bmper+/− mice displayed increased neointima formation 21 days after carotid ligation and enhanced expression of Col3A1, MMP2, and MMP9. Silencing of BMPER increased the proliferation and migration capacity of primary vSMCs, as well as reduced contractibility and expression of contractile markers, whereas stimulation with recombinant BMPER protein had the opposite effect. Mechanistically, we showed that BMPER binds insulin-like growth factor-binding protein 4 (IGFBP4), resulting in the modulation of IGF signaling. Furthermore, perivascular application of recombinant BMPER protein prevented neointima formation and ECM deposition in C57BL/6N mice after carotid ligation. Our data demonstrate that BMPER stimulation causes a contractile vSMC phenotype and suggest that BMPER has the potential for a future therapeutic agent in occlusive cardiovascular diseases.
Towards Controlling the Local Bone Tissue Remodeling—Multifunctional Injectable Composites for Osteoporosis Treatment
Authors: Klara Joanna , Onak Sylwia , Kowalczyk Andrzej , Horak Wojciech , Wójcik Kinga , Lewandowska-Łańcucka Joanna
Published: March 2023

Alendronate (ALN) is the most commonly prescribed oral nitrogen-containing bisphosphonate for osteoporosis therapy. However, its administration is associated with serious side effects. Therefore, the drug delivery systems (DDS) enabling local administration and localized action of that drug are still of great importance. Herein, a novel multifunctional DDS system based on the hydroxyapatite-decorated mesoporous silica particles (MSP-NH2-HAp-ALN) embedded into collagen/chitosan/chondroitin sulfate hydrogel for simultaneous osteoporosis treatment and bone regeneration is proposed. In such a system, the hydrogel serves as a carrier for the controlled delivery of ALN at the site of implantation, thus limiting potential adverse effects. The involvement of MSP-NH2-HAp-ALN in the crosslinking process was established, as well as the ability of hybrids to be used as injectable systems. We have shown that the attachment of MSP-NH2-HAp-ALN to the polymeric matrix provides a prolonged ALN release (up to 20 days) and minimizes the initial burst effect. It was revealed that obtained composites are effective osteoconductive materials capable of supporting the osteoblast-like cell (MG-63) functions and inhibiting osteoclast-like cell (J7741.A) proliferation in vitro. The purposely selected biomimetic composition of these materials (biopolymer hydrogel enriched with the mineral phase) allows their biointegration (in vitro study in the simulated body fluid) and delivers the desired physicochemical features (mechanical, wettability, swellability). Furthermore, the antibacterial activity of the composites in in vitro experiments was also demonstrated.
Antiviral Effect of Ginsenosides rk1 against Influenza a Virus Infection by Targeting the Hemagglutinin 1-Mediated Virus Attachment
Authors: Yang Xia , Sun Hailiang , Zhang Zhening , Ou Weixin , Xu Fengxiang , Luo Ling , Liu Yahong , Chen Weisan , Chen Jianxin
Published: March 2023

Influenza A virus (IAV) infections have been a serious hazard to public health everywhere. With the growing concern of drug-resistant IAV strains, there is an urgent need for novel anti-IAV medications, especially those with alternative mechanisms of action. Hemagglutinin (HA), an IAV glycoprotein, plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a good target for developing anti-IAV drugs. Panax ginseng is a widely used herb in traditional medicine with extensive biological effects in various disease models, and its extract was reported to show protection in IAV-infected mice. However, the main effective anti-IAV constituents in panax ginseng remain unclear. Here, we report that ginsenoside rk1 (G-rk1) and G-rg5, out of the 23 screened ginsenosides, exhibit significant antiviral effects against 3 different IAV subtypes (H1N1, H5N1, and H3N2) in vitro. Mechanistically, G-rk1 blocked IAV binding to sialic acid in a hemagglutination inhibition (HAI) assay and an indirect ELISA assay; more importantly, we showed that G-rk1 interacted with HA1 in a dose-dependent manner in a surface plasmon resonance (SPR) analysis. Furthermore, G-rk1 treatment by intranasal inoculation effectively reduced the weight loss and mortality of mice challenged with a lethal dose of influenza virus A/Puerto Rico/8/34 (PR8). In conclusion, our findings reveal for the first time that G-rk1 possesses potent anti-IAV effects in vitro and in vivo. We have also identified and characterized with a direct binding assay a novel ginseng-derived IAV HA1 inhibitor for the first time, which could present potential approaches to prevent and treat IAV infections.
Titanium Oxyfluoride as a Material for Negative Electrodes of Lithium-Ion Batteries
Authors: Astrova Ekaterina V. , Ulin Vladimir P. , Parfeneva Alesya V. , Li Galina V. , Yagovkina Maria A. , Lozhkina Darina A. , Krasilin Andrei A. , Tomkovich Maria V. , Rumyantsev Aleksander M.
Published: March 2023

A study of the electrochemical characteristics of titanium oxyfluoride obtained with the direct interaction of titanium with hydrofluoric acid is reported. Two materials T1 and T2 synthesized under different conditions in which some TiF3 is formed in T1 are compared. Both materials exhibit conversion-type anode properties. Based on the analysis of the charge–discharge curves of the half-cell, a model is proposed according to which the first electrochemical introduction of lithium occurs in two stages: the first stage is the irreversible reaction resulting in a reduction in Ti4+/3+, and the second stage is the reversible reaction with a change in the charge state Ti3+/1.5+. The difference in material behavior is quantitative: T1 has a higher reversible capacity but lower cycling stability and a slightly higher operating voltage. The Li diffusion coefficient determined from the CVA data for both materials averages 1.2–3.0 × 10−14 cm2/s. A distinctive feature of titanium oxyfluoride anodes is the asymmetry in kinetic characteristics that revealed themselves during lithium embedding and extraction. In the long cycling regime, the excess of Coulomb efficiency over 100% was found in the present study.
Recent Advances in Tick Antigen Discovery and Anti-Tick Vaccine Development
Authors: Abbas Muhammad Nadeem , Jmel Mohamed Amine , Mekki Imen , Dijkgraaf Ingrid , Kotsyfakis Michail
Published: March 2023

Ticks can seriously affect human and animal health around the globe, causing significant economic losses each year. Chemical acaricides are widely used to control ticks, which negatively impact the environment and result in the emergence of acaricide-resistant tick populations. A vaccine is considered as one of the best alternative approaches to control ticks and tick-borne diseases, as it is less expensive and more effective than chemical controls. Many antigen-based vaccines have been developed as a result of current advances in transcriptomics, genomics, and proteomic techniques. A few of these (e.g., Gavac® and TickGARD®) are commercially available and are commonly used in different countries. Furthermore, a significant number of novel antigens are being investigated with the perspective of developing new anti-tick vaccines. However, more research is required to develop new and more efficient antigen-based vaccines, including on assessing the efficiency of various epitopes against different tick species to confirm their cross-reactivity and their high immunogenicity. In this review, we discuss the recent advancements in the development of antigen-based vaccines (traditional and RNA-based) and provide a brief overview of recent discoveries of novel antigens, along with their sources, characteristics, and the methods used to test their efficiency.
Treatment with the Olive Secoiridoid Oleacein Protects against the Intestinal Alterations Associated with EAE
Authors: Gutiérrez-Miranda Beatriz , Gallardo Isabel , Melliou Eleni , Cabero Isabel , Álvarez Yolanda , Hernández Marta , Magiatis Prokopios , Hernández Marita , Nieto María Luisa
Published: March 2023

Multiple sclerosis (MS) is a CNS inflammatory demyelinating disease. Recent investigations highlight the gut-brain axis as a communication network with crucial implications in neurological diseases. Thus, disrupted intestinal integrity allows the translocation of luminal molecules into systemic circulation, promoting systemic/brain immune-inflammatory responses. In both, MS and its preclinical model, the experimental autoimmune encephalomyelitis (EAE) gastrointestinal symptoms including “leaky gut” have been reported. Oleacein (OLE), a phenolic compound from extra virgin olive oil or olive leaves, harbors a wide range of therapeutic properties. Previously, we showed OLE effectiveness preventing motor defects and inflammatory damage of CNS tissues on EAE mice. The current studies examine its potential protective effects on intestinal barrier dysfunction using MOG35-55-induced EAE in C57BL/6 mice. OLE decreased EAE-induced inflammation and oxidative stress in the intestine, preventing tissue injury and permeability alterations. OLE protected from EAE-induced superoxide anion and accumulation of protein and lipid oxidation products in colon, also enhancing its antioxidant capacity. These effects were accompanied by reduced colonic IL-1β and TNFα levels in OLE-treated EAE mice, whereas the immunoregulatory cytokines IL-25 and IL-33 remained unchanged. Moreover, OLE protected the mucin-containing goblet cells in colon and the serum levels of iFABP and sCD14, markers that reflect loss of intestinal epithelial barrier integrity and low-grade systemic inflammation, were significantly reduced. These effects on intestinal permeability did not draw significant differences on the abundance and diversity of gut microbiota. However, OLE induced an EAE-independent raise in the abundance of Akkermansiaceae family. Consistently, using Caco-2 cells as an in vitro model, we confirmed that OLE protected against intestinal barrier dysfunction induced by harmful mediators present in both EAE and MS. This study proves that the protective effect of OLE in EAE also involves normalizing the gut alterations associated to the disease.
The Dual Role of Oxidants in Male (In)fertility: Every ROSe Has a Thorn
Authors: Mancini Antonio , Oliva Alessandro , Vergani Edoardo , Festa Roberto , Silvestrini Andrea
Published: March 2023

The role of oxidative stress (OS) in male infertility as a primary etiology and/or concomitant cause in other situations, such as inflammation, varicocele and gonadotoxin effects, is well documented. While reactive oxygen species (ROS) are implicated in many important roles, from spermatogenesis to fertilization, epigenetic mechanisms which are transmissible to offspring have also recently been described. The present review is focused on the dual aspects of ROS, which are regulated by a delicate equilibrium with antioxidants due to the special frailty of spermatozoa, in continuum from physiological condition to OS. When the ROS production is excessive, OS ensues and is amplified by a chain of events leading to damage of lipids, proteins and DNA, ultimately causing infertility and/or precocious pregnancy termination. After a description of positive ROS actions and of vulnerability of spermatozoa due to specific maturative and structural characteristics, we linger on the total antioxidant capacity (TAC) of seminal plasma, which is a measure of non-enzymatic non-proteic antioxidants, due to its importance as a biomarker of the redox status of semen; the therapeutic implications of these mechanism play a key role in the personalized approach to male infertility.
Brain-Derived Neurotrophic Factor Is Indispensable to Continence Recovery after a Dual Nerve and Muscle Childbirth Injury Model
Authors: Balog Brian M. , Deng Kangli , Askew Tessa , Hanzlicek Brett , Kuang Mei , Damaser Margot S.
Published: March 2023

In women, stress urinary incontinence (SUI), leakage of urine from increased abdominal pressure, is correlated with pudendal nerve (PN) injury during childbirth. Expression of brain-derived neurotrophic factor (BDNF) is dysregulated in a dual nerve and muscle injury model of childbirth. We aimed to use tyrosine kinase B (TrkB), the receptor of BDNF, to bind free BDNF and inhibit spontaneous regeneration in a rat model of SUI. We hypothesized that BDNF is essential for functional recovery from the dual nerve and muscle injuries that can lead to SUI. Female Sprague–Dawley rats underwent PN crush (PNC) and vaginal distension (VD) and were implanted with osmotic pumps containing saline (Injury) or TrkB (Injury + TrkB). Sham Injury rats received sham PNC + VD. Six weeks after injury, animals underwent leak-point-pressure (LPP) testing with simultaneous external urethral sphincter (EUS) electromyography recording. The urethra was dissected for histology and immunofluorescence. LPP after injury and TrkB was significantly decreased compared to Injury rats. TrkB treatment inhibited reinnervation of neuromuscular junctions in the EUS and promoted atrophy of the EUS. These results demonstrate that BDNF is essential to neuroregeneration and reinnervation of the EUS. Treatments aimed at increasing BDNF periurethrally could promote neuroregeneration to treat SUI.
Role of Ganetespib, an HSP90 Inhibitor, in Cancer Therapy: From Molecular Mechanisms to Clinical Practice
Authors: Youssef Mahmoud E. , Cavalu Simona , Hasan Alexandru Madalin , Yahya Galal , Abd-Eldayem Marwa A. , Saber Sameh
Published: March 2023

Heat-shock proteins are upregulated in cancer and protect several client proteins from degradation. Therefore, they contribute to tumorigenesis and cancer metastasis by reducing apoptosis and enhancing cell survival and proliferation. These client proteins include the estrogen receptor (ER), epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), human epidermal growth factor receptor 2 (HER-2), and cytokine receptors. The diminution of the degradation of these client proteins activates different signaling pathways, such as the PI3K/Akt/NF-κB, Raf/MEK/ERK, and JAK/STAT3 pathways. These pathways contribute to hallmarks of cancer, such as self-sufficiency in growth signaling, an insensitivity to anti-growth signals, the evasion of apoptosis, persistent angiogenesis, tissue invasion and metastasis, and an unbounded capacity for replication. However, the inhibition of HSP90 activity by ganetespib is believed to be a promising strategy in the treatment of cancer because of its low adverse effects compared to other HSP90 inhibitors. Ganetespib is a potential cancer therapy that has shown promise in preclinical tests against various cancers, including lung cancer, prostate cancer, and leukemia. It has also shown strong activity toward breast cancer, non-small cell lung cancer, gastric cancer, and acute myeloid leukemia. Ganetespib has been found to cause apoptosis and growth arrest in these cancer cells, and it is being tested in phase II clinical trials as a first-line therapy for metastatic breast cancer. In this review, we will highlight the mechanism of action of ganetespib and its role in treating cancer based on recent studies.
Treatment Strategy of Uncontrolled Chronic Rhinosinusitis with Nasal Polyps: A Review of Recent Evidence
Authors: Kim Sung-Dong , Cho Kyu-Sup
Published: March 2023

Chronic rhinosinusitis (CRS) is recognized as a heterogeneous disease with a wide range of clinical features, resulting in significant morbidity and cost to the healthcare system. While the phenotypic classification is determined by the presence or absence of nasal polyps and comorbidities, the endotype classification has been established based on molecular biomarkers or specific mechanisms. Research on CRS has now developed based on information based on three major endotypes: types 1, 2, and 3. Recently, biological therapies targeting type 2 inflammation have been clinically expanded and may be applied to other inflammatory endotypes in the future. The purpose of this review is to discuss the treatment options according to the type of CRS and summarize recent studies on new therapeutic approaches for patients with uncontrolled CRS with nasal polyps.
Understanding the Continuum between High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia
Authors: Zavras Phaedon D. , Sinanidis Ilias , Tsakiroglou Panagiotis , Karantanos Theodoros
Published: March 2023

Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm characterized by bone marrow dysplasia, failure of hematopoiesis and variable risk of progression to acute myeloid leukemia (AML). Recent large-scale studies have demonstrated that distinct molecular abnormalities detected at earlier stages of MDS alter disease biology and predict progression to AML. Consistently, various studies analyzing these diseases at the single-cell level have identified specific patterns of progression strongly associated with genomic alterations. These pre-clinical results have solidified the conclusion that high-risk MDS and AML arising from MDS or AML with MDS-related changes (AML-MRC) represent a continuum of the same disease. AML-MRC is distinguished from de novo AML by the presence of certain chromosomal abnormalities, such as deletion of 5q, 7/7q, 20q and complex karyotype and somatic mutations, which are also present in MDS and carry crucial prognostic implications. Recent changes in the classification and prognostication of MDS and AML by the International Consensus Classification (ICC) and the World Health Organization (WHO) reflect these advances. Finally, a better understanding of the biology of high-risk MDS and the mechanisms of disease progression have led to the introduction of novel therapeutic approaches, such as the addition of venetoclax to hypomethylating agents and, more recently, triplet therapies and agents targeting specific mutations, including FLT3 and IDH1/2. In this review, we analyze the pre-clinical data supporting that high-risk MDS and AML-MRC share the same genetic abnormalities and represent a continuum, describe the recent changes in the classification of these neoplasms and summarize the advances in the management of patients with these neoplasms.
Understanding Passive Membrane Permeation of Peptides: Physical Models and Sampling Methods Compared
Authors: Mazzanti Liuba , Ha-Duong Tâp
Published: March 2023

The early characterization of drug membrane permeability is an important step in pharmaceutical developments to limit possible late failures in preclinical studies. This is particularly crucial for therapeutic peptides whose size generally prevents them from passively entering cells. However, a sequence-structure-dynamics-permeability relationship for peptides still needs further insight to help efficient therapeutic peptide design. In this perspective, we conducted here a computational study for estimating the permeability coefficient of a benchmark peptide by considering and comparing two different physical models: on the one hand, the inhomogeneous solubility–diffusion model, which requires umbrella–sampling simulations, and on the other hand, a chemical kinetics model which necessitates multiple unconstrained simulations. Notably, we assessed the accuracy of the two approaches in relation to their computational cost.
Usefulness and Limitations of Multiple Ligation-Dependent Probe Amplification in Antithrombin Deficiency
Authors: Cifuentes Rosa , Padilla José , de la Morena-Barrio María Eugenia , de la Morena-Barrio Belén , Bravo-Pérez Carlos , Garrido-Rodríguez Pedro , Llamas María , Miñano Antonia , Vicente Vicente , Lozano María Luisa , Corral Javier
Published: March 2023

Multiplex ligation-dependent probe amplification (MLPA) identifies genetic structural variants in SERPINC1 in 5% of cases with antithrombin deficiency (ATD), the most severe congenital thrombophilia. Our aim was to unravel the utility and limitations of MLPA in a large cohort of unrelated patients with ATD (N = 341). MLPA identified 22 structural variants (SVs) causing ATD (6.5%). MLPA did not detect SVs affecting introns (four cases), and the diagnosis was inaccurate in two cases according to long-range PCR or nanopore sequencing. MLPA was used to detect possible hidden SVs in 61 cases with type I deficiency with single nucleotide variations (SNVs) or small insertion/deletion (INDEL). One case had a false deletion of exon 7, as the 29-bp deletion affected an MLPA probe. We evaluated 32 variants affecting MLPA probes: 27 SNVs and 5 small INDELs. In three cases, MLPA gave false-positive results, all diagnosed as deletions of the affected exon: a small INDEL complex, and two SNVs affecting MLPA probes. Our study confirms the utility of MLPA to detect SVs in ATD, but also shows some limitations in detecting intronic SVs. MLPA renders imprecise and false-positive results for genetic defects which affect MLPA probes. Our results encourage the validation of MLPA results.
Polyoxometalates Impact as Anticancer Agents
Authors: Carvalho Fátima , Aureliano Manuel
Published: March 2023

Polyoxometalates (POMs) are oxoanions of transition metal ions, such as V, Mo, W, Nb, and Pd, forming a variety of structures with a wide range of applications. Herein, we analyzed recent studies on the effects of polyoxometalates as anticancer agents, particularly their effects on the cell cycle. To this end, a literature search was carried out between March and June 2022, using the keywords “polyoxometalates” and “cell cycle”. The effects of POMs on selected cell lines can be diverse, such as their effects in the cell cycle, protein expression, mitochondrial effects, reactive oxygen species (ROS) production, cell death and cell viability. The present study focused on cell viability and cell cycle arrest. Cell viability was analyzed by dividing the POMs into sections according to the constituent compound, namely polyoxovanadates (POVs), polyoxomolybdates (POMos), polyoxopaladates (POPds) and polyoxotungstates (POTs). When comparing and sorting the IC50 values in ascending order, we obtained first POVs, then POTs, POPds and, finally, POMos. When comparing clinically approved drugs and POMs, better results of POMs in relation to drugs were observed in many cases, since the dose required to have an inhibitory concentration of 50% is 2 to 200 times less, depending on the POMs, highlighting that these compounds could become in the future an alternative to existing drugs in cancer therapy.
Learning Science through Cloud Gamification: A Framework for Remote Gamified Science Learning Activities Integrating Cloud Tool Sets and Three-Dimensional Scaffolding
Authors: Hou Huei-Tse
Published: March 2023

In today’s world where virtual interaction is becoming more and more important, remote collaborative problem solving has become a promising teaching strategy. The motivation to promote collaborative science learning and the depth of group discussions are key research issues. The use of gamification strategies has the potential to facilitate remote synchronous science instruction. In order to promote learners’ collaborative science problem-solving skills, it is critical to design appropriate scaffolds and provide a guiding framework for teachers to integrate cloud-based interactive tools to design remote synchronous gamification activities. Based on years of research on scaffold-based gamified teaching, this study proposes a framework for gamified teaching activities that integrates a cloud-based toolset and a three-dimensional scaffolding (cognitive scaffolding, peer scaffolding, and metacognitive scaffolding). The framework can be used as a reference for science teachers to combine cloud tools for remote gamified teaching and for researchers in this field.
An Automated Path-Focused Test Case Generation with Dynamic Parameterization Using Adaptive Genetic Algorithm (AGA) for Structural Program Testing
Authors: Rajagopal Manikandan , Sivasakthivel Ramkumar , Loganathan Karuppusamy , Sarris Loannis E.
Published: March 2023

Various software engineering paradigms and real-time projects have proved that software testing is the most critical and highly important phase in the SDLC. In general, software testing takes approximately 40–60% of the total effort and time involved in project development. Generating test cases is the most important process in software testing. There are many techniques involved in the automatic generation of these test cases which aim to find a smaller group of cases that could allow for an adequacy level to be achieved which will hence reduce the effort and cost involved in software testing. In the structural testing of a product, the auto-generation of test cases that are path focused in an efficient manner is a challenging process. These are often considered optimization problems and hence search-based methods such as genetic algorithm (GA) and swarm optimizations have been proposed to handle this issue. The significance of the study is to address the optimization problem of automatic test case generation in search-based software engineering. The proposed methodology aims to close the gap of genetic algorithms acquiring local minimum due to poor diversity. Here, dynamic adjustment of cross-over and mutation rate is achieved by calculating the individual measure of similarity and fitness and searching for the more global optimum. The proposed method is applied and experimented on a benchmark of five industrial projects. The results of the experiments have confirmed the efficiency of generating test cases that have optimum path coverage.
Modeling the Influence of Fake Accounts on User Behavior and Information Diffusion in Online Social Networks
Authors: Fahmy Sara G. , Abdelgaber Khaled M. , Karam Omar H. , Elzanfaly Doaa S.
Published: March 2023

The mechanisms of information diffusion in Online Social Networks (OSNs) have been studied extensively from various perspectives with some focus on identifying and modeling the role of heterogeneous nodes. However, none of these studies have considered the influence of fake accounts on human accounts and how this will affect the rumor diffusion process. This paper aims to present a new information diffusion model that characterizes the role of bots in the rumor diffusion process in OSNs. The proposed SIhIbR model extends the classical SIR model by introducing two types of infected users with different infection rates: the users who are infected by human (Ih) accounts with a normal infection rate and the users who are infected by bot accounts (Ib) with a different diffusion rate that reflects the intent and steadiness of this type of account to spread the rumors. The influence of fake accounts on human accounts diffusion rate has been measured using the social impact theory, as it better reflects the deliberate behavior of bot accounts to spread a rumor to a large portion of the network by considering both the strength and the bias of the source node. The experiment results show that the accuracy of the SIhIbR model outperforms the SIR model when simulating the rumor diffusion process in the existence of fake accounts. It has been concluded that fake accounts accelerate the rumor diffusion process as they impact many people in a short time.
RETRACTED: Simplicial Complex-Enhanced Manifold Embedding of Spatiotemporal Data for Structural Health Monitoring
Authors: Xu Nan , Zhang Zhiming , Liu Yongming
Published: March 2023

Structural Health Monitoring requires the continuous assessment of a structure’s operational conditions, which involves the collection and analysis of a large amount of data in both spatial and temporal domains. Conventionally, both data-driven and physics-based models for structural damage detection have relied on handcrafted features, which are susceptible to the practitioner’s expertise and experience in feature selection. The limitations of handcrafted features stem from the potential for information loss during the extraction of high-dimensional spatiotemporal data collected from the sensing system. To address this challenge, this paper proposes a novel, automated structural damage detection technique called Simplicial Complex Enhanced Manifold Embedding (SCEME). The key innovation of SCEME is the reduction of dimensions in both the temporal and spatial domains for efficient and information-preserving feature extraction. This is achieved by constructing a simplicial complex for each signal and using the resulting topological invariants as key features in the temporal domain. Subsequently, curvature-enhanced topological manifold embedding is performed for spatial dimension reduction. The proposed methodology effectively represents both intra-series and inter-series correlations in the low-dimensional embeddings, making it useful for classification and visualization. Numerical simulations and two benchmark experimental datasets validate the high accuracy of the proposed method in classifying different damage scenarios and preserving useful information for structural identification. It is especially beneficial for structural damage detection using complex data with high spatial and temporal dimensions and large uncertainties in reality.
Nutritional Value of Silkworm Pupae (Bombyx mori) with Emphases on Fatty Acids Profile and Their Potential Applications for Humans and Animals
Authors: Hăbeanu Mihaela , Gheorghe Anca , Mihalcea Teodor
Published: March 2023

Bombyx mori is an ideal lepidopteran species representative of many scientific studies, a model of studies for medicine and a significant insect from an ecological standpoint. This review was performed to summarize the fatty acids (FA) composition of silkworm pupae (SP) that are associated with other important compounds that could add value to SP, diversifying the ways of valorization. The proposal to complete plant-based feeds with insect-based feeds represents a viable option to beneficially impact human and animal health and the environment. The quality and quantity of fats consumed significantly impact the aetiology of certain diseases. The key compounds of fat named essential FA (EFA) substantially influence the prevention and treatment of several diseases through their nutraceutical functions. Due to its excellent profile in nutrients such as protein and fat, amino acids and fatty acids composition, SP has become an important alternative feed ingredient and source of EFA. SP is a by-product that was discarded in large quantities. Following the need to act to improve human health and reduce climate change impact, many researchers focused on studying SP applications in the medical and agricultural industries. Several authors noticed an improvement in the health markers by using SP. The feed cost for the animal was reduced with economic implications. Minimization of environmental impact was recorded. Few precautions were recommended regarding SP use, although they should not be ignored. The composition of SP and its potential for use in various industries provides us with persuasive arguments for continuing to develop the sericulture industry.
Upgrade of Thomson Scattering Diagnostic on HL-2A
Authors: Guo Wenping , Huang Yuan , Liu Chunhua , Feng Zhen , Hou Zhipei , Zhai Wenyan , Funaba Hisamichi , Yamada Ichihiro , Li Yonggao , Shi Zhongbin
Published: March 2023

The Thomson scattering diagnostic of the HL-2A tokamak device was upgraded to improve its multi-point diagnostic capability, including new collection optics, fibers bundles, and data analysis code. The small old collection lens was replaced by a six-piece lens with a Cooke optical design. The aperture of its first standard sphere face is 310.125 mm, which successfully increases the amount of collected scattering light by about three times. The new collection optic module allows for up to twenty-six spatial points. A kind of Y-type fiber bundle has also been used to ensure that the fiber end-face matches the image of the laser beam exactly. Additionally, the new data analysis code can provide preview results in seconds. Finally, the multi-point Te diagnostic ability has been significantly improved.
The Potential Roles of Exosomes Carrying APP and Tau Cleavage Products in Alzheimer’s Disease
Authors: Zhao Yanfang , Gu Yujin , Zhang Qili , Liu Hongliang , Liu Yingying
Published: March 2023

Alzheimer’s disease (AD) is the leading cause of dementia throughout the world. It is characterized by major amyloid plaques and neurofibrillary tangles (NFTs), which are composed of amyloid-β (Aβ) peptide and hyperphosphorylated Tau (p-Tau), respectively. Exosomes, which are secreted by cells, are single-membrane lipid bilayer vesicles found in bodily fluids and they have a diameter of 30–150 nm. Recently, they have been considered as critical carriers and biomarkers in AD, as they facilitate communication between cells and tissues by delivering proteins, lipids, and nucleic acids. This review demonstrates that exosomes are natural nanocontainers that carry APP as well as Tau cleavage products secreted by neuronal cells and that their formation is associated with the endosomal–lysosomal pathway. Moreover, these exosomes can transfer AD pathological molecules and participate in the pathophysiological process of AD; therefore, they have potential diagnostic and therapeutic value for AD and might also provide novel insights for screening and prevention of the disease.
Combining HAIC and Sorafenib as a Salvage Treatment for Patients with Treatment-Failed or Advanced Hepatocellular Carcinoma: A Single-Center Experience
Authors: Chen Chia-Bang , Chen Chun-Min , Tzeng Ruo-Han , Chou Chen-Te , Su Pei-Yuan , Hsu You-Chuen , Yang Cheng-Da
Published: March 2023

Background: Hepatic arterial infusion chemotherapy (HAIC) has been proven to be an effective treatment for advanced HCC. In this study, we present our single-center experience of implementing combined sorafenib and HAIC treatment for these patients and compare the treatment benefit with that of sorafenib alone. Methods: This was a retrospective single-center study. Our study included 71 patients who started taking sorafenib between 2019 and 2020 at Changhua Christian Hospital in order to treat advanced HCC or as a salvage treatment after the failure of a previous treatment for HCC. Of these patients, 40 received combined HAIC and sorafenib treatment. The efficacy of sorafenib alone or in combination with HAIC was measured in regard to overall survival and progression-free survival. Multivariate regression analysis was performed to identify factors associated with overall survival and progression-free survival. Results: HAIC combined with sorafenib treatment and sorafenib alone resulted in different outcomes. The combination treatment resulted in a better image response and objective response rate. Moreover, among the patients aged under 65 years old and male patients, the combination therapy resulted in a better progression-free survival than sorafenib alone. A tumor size ≥ 3 cm, AFP > 400, and ascites were associated with a poor progression-free survival among young patients. However, the overall survival of these two groups showed no significant difference. Conclusions: Combined HAIC and sorafenib treatment showed a treatment effect equivalent to that of sorafenib alone as a salvage treatment modality used to treat patients with advanced HCC or with experience of a previously failed treatment.
Systematic Review and Meta-Analysis of Observational Studies on the Effectiveness and Safety of Ustekinumab among Patients with Inflammatory Bowel Disease in Eastern and Western Countries
Authors: Zhou He , Wang Fang , Wan Jian , Su Song , Shi Yanting , Li Xiaofei , Wu Tong , Liang Jie
Published: March 2023

Background: Ustekinumab (UST) is an IL12/23 inhibitor utilized for altering inflammatory responses in inflammatory bowel disease (IBD). Clinical trials and case reports suggested that the effectiveness and safety of UST may differ among IBD patients in Eastern and Western countries. However, related data have not been systematically reviewed and analyzed. Methods: This systematic review and meta-analysis of the safety and effectiveness of UST in IBD included relevant literature from the Medline and Embase databases. The main outcomes were clinical response, clinical remission, endoscopic response, endoscopic remission, and adverse events in IBD. Results: We analyzed 49 real-world studies, most of which included patients with biological failure (89.1% CD and 97.1% UC). In UC patients, clinical remission rates were 34% at 12 weeks, 40% at 24 weeks, and 37% at 1 year. In CD patients, clinical remission rates were 46% at 12 weeks, 51% at 24 weeks, and 47% at 1 year. Clinical remission rates of CD patients were 40% at 12 weeks and 44% at 24 weeks in Western countries, versus 63% and 72% in Eastern countries, respectively. Conclusion: UST is an effective drug for IBD with a promising safety profile. Although no RCTs have been performed in Eastern countries, the effectiveness of UST on CD patients is not inferior to that in Western countries based on the existing data.
Acute Kidney Injury in the ICU during Ganciclovir Treatment, an Observational Study
Authors: Al Fartousi Mina , Guda Kaylen , Geersing Tjerk H. , van der Voort Peter H. J. , Franssen Eric J. F.
Published: March 2023

The aim of this study is to investigate the relationship between ganciclovir exposure with TDM and the development of AKI in ICU patients. This retrospective single-center observational cohort study included adult ICU patients treated with ganciclovir who had a minimum of one ganciclovir trough serum level. Patients receiving less than two days of treatment and patients with fewer than two measurements of serum creatinine, RIFLE scores, and/or renal SOFA scores were excluded. Acute kidney injury incidence was assessed with the difference between the final and first values of the renal SOFA score, RIFLE score, and serum creatinine. Nonparametric statistical tests were performed. In addition, the clinical relevance of these results was evaluated. A total of 64 patients were included with a median cumulative dose of 3150 mg. The mean difference in serum creatinine during ganciclovir treatment was reduced by 7.3 μmol/L (p = 0.143). The RIFLE score decreased by 0.04 (p = 0.912), and the renal SOFA score was reduced by 0.07 (p = 0.551). This single-center observational cohort study showed that ICU patients using ganciclovir with TDM-guided dosing did not develop acute kidney injury as measured by serum creatinine, RIFLE score, and renal SOFA score.