bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Transcriptome Analysis Provides Insights into the Resistance in Pueraria [Pueraria lobata (Willd.) Ohwi] in Response to Pseudo-Rust Disease
Authors: Huang Xinlu , Huang Xiaoxi , Guo Lijun , He Longfei , Xiao Dong , Zhan Jie , Wang Aiqin , Liang Renfan
Published: May 2022

Pueraria lobata is an important medicinal and edible homologous plant that is widely cultivated in Asian countries. However, its production and quality are seriously threatened by its susceptibility to pseudo-rust disease. The underlying molecular mechanisms are poorly known, particularly from a transcriptional perspective. Pseudo-rust disease is a major disease in pueraria, primarily caused by Synchytrium puerariae Miy (SpM). In this study, transcriptomic profiles were analyzed and compared between two pueraria varieties: the disease-resistant variety (GUIGE18) and the susceptible variety (GUIGE8). The results suggest that the number of DEGs in GUIGE18 is always more than in GUIGE8 at each of the three time points after SpM infection, indicating that their responses to SpM infection may be different, and that the active response of GUIGE18 to SpM infection may occur earlier than that of GUIGE8. A total of 7044 differentially expressed genes (DEGs) were identified, and 406 co-expressed DEGs were screened out. Transcription factor analysis among the DEGs revealed that the bHLH, WRKY, ERF, and MYB families may play an important role in the interaction between pueraria and pathogens. A GO and KEGG enrichment analysis of these DEGs showed that they were mainly involved in the following pathways: metabolic, defense response, plant hormone signal transduction, MAPK signaling pathway-plant, plant pathogen interaction, flavonoid biosynthesis, phenylpropanoid biosynthesis, and secondary metabolite biosynthesis. The CPK, CESA, PME, and CYP gene families may play important roles in the early stages after SpM infection. The DEGs that encode antioxidase (CAT, XDH, and SOD) were much more up-regulated. Defense enzyme activity, endogenous hormones, and flavonoid content changed significantly in the two varieties at the three infection stages. Finally, we speculated on the regulatory pathways of pueraria pseudo-rust and found that an oxidation-reduction process, flavonoid biosynthesis, and ABA signaling genes may be associated with the response to SpM infection in pueraria. These results expand the understanding of pueraria resistance and physiological regulations by multiple pathways.
Deacclimation-Induced Changes of Photosynthetic Efficiency, Brassinosteroid Homeostasis and BRI1 Expression in Winter Oilseed Rape (Brassica napus L.)—Relation to Frost Tolerance
Authors: Stachurska Julia , Rys Magdalena , Pociecha Ewa , Kalaji Hazem M. , Dąbrowski Piotr , Oklestkova Jana , Jurczyk Barbara , Janeczko Anna
Published: May 2022

The objective of this study was to answer the question of how the deacclimation process affects frost tolerance, photosynthetic efficiency, brassinosteroid (BR) homeostasis and BRI1 expression of winter oilseed rape. A comparative study was conducted on cultivars with different agronomic and physiological traits. The deacclimation process can occur when there are periods of higher temperatures, particularly in the late autumn or winter. This interrupts the process of the acclimation (hardening) of winter crops to low temperatures, thus reducing their frost tolerance and becoming a serious problem for agriculture. The experimental model included plants that were non-acclimated, cold acclimated (at 4 °C) and deacclimated (at 16 °C/9 °C, one week). We found that deacclimation tolerance (maintaining a high frost tolerance despite warm deacclimating periods) was a cultivar-dependent trait. Some of the cultivars developed a high frost tolerance after cold acclimation and maintained it after deacclimation. However, there were also cultivars that had a high frost tolerance after cold acclimation but lost some of it after deacclimation (the cultivars that were more susceptible to deacclimation). Deacclimation reversed the changes in the photosystem efficiency that had been induced by cold acclimation, and therefore, measuring the different signals associated with photosynthetic efficiency (based on prompt and delayed chlorophyll fluorescence) of plants could be a sensitive tool for monitoring the deacclimation process (and possible changes in frost tolerance) in oilseed rape. Higher levels of BR were characteristic of the better frost-tolerant cultivars in both the cold-acclimated and deacclimated plants. The relative expression of the BRI1 transcript (encoding the BR-receptor protein) was lower after cold acclimation and remained low in the more frost-tolerant cultivars after deacclimation. The role of brassinosteroids in oilseed rape acclimation/deacclimation is briefly discussed.
Transcription Factor Lmx1b Negatively Regulates Osteoblast Differentiation and Bone Formation
Authors: Kim Kabsun , Kim Jung Ha , Kim Inyoung , Seong Semun , Han Jeong Eun , Lee Keun-Bae , Koh Jeong-Tae , Kim Nacksung
Published: May 2022

The LIM-homeodomain transcription factor Lmx1b plays a key role in body pattern formation during development. Although Lmx1b is essential for the normal development of multiple tissues, its regulatory mechanism in bone cells remains unclear. Here, we demonstrated that Lmx1b negatively regulates bone morphogenic protein 2 (BMP2)-induced osteoblast differentiation. Overexpressed Lmx1b in the osteoblast precursor cells inhibited alkaline phosphatase (ALP) activity and nodule formation, as well as the expression of osteoblast maker genes, including runt-related transcription factor 2 (Runx2), alkaline phosphatase (Alpl), bone sialoprotein (Ibsp), and osteocalcin (Bglap). Conversely, the knockdown of Lmx1b in the osteoblast precursors enhanced the osteoblast differentiation and function. Lmx1b physically interacted with and repressed the transcriptional activity of Runx2 by reducing the recruitment of Runx2 to the promoter region of its target genes. In vivo analysis of BMP2-induced ectopic bone formation revealed that the knockdown of Lmx1b promoted osteogenic differentiation and bone regeneration. Our data demonstrate that Lmx1b negatively regulates osteoblast differentiation and function through regulation of Runx2 and provides a molecular basis for therapeutic targets for bone diseases.
The Protective Role of pVHL in Imiquimod-Induced Psoriasis-like Skin Inflammation
Authors: Martínez-Torres Isaí , Tepale-Segura Araceli , Castro-Escamilla Octavio , Cancino-Diaz Juan Carlos , Rodríguez-Martínez Sandra , Perez-Tapia Sonia Mayra , Bonifaz Laura C. , Cancino-Diaz Mario Eugenio
Published: May 2022

Psoriasis is a chronic inflammatory disease distinguished by an excessive proliferation and abnormal differentiation of keratinocytes. Immune cells, such as T lymphocytes and neutrophils, and inflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and interleukin 17 (IL-17), are essential for maintaining psoriatic lesions. Additionally, a hypoxic milieu present in the skin promotes the expression of transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1α). This protein regulates the expression of angiogenic and glycolytic factors, such as vascular endothelial grown factor and lactate dehydrogenase (LDH), both relevant in chronic inflammation. The von Hippel–Lindau protein (pVHL) is a negative regulator of HIF-1α. Previously, we found that pVHL was almost absent in the lesions of psoriasis patients; therefore, we investigated the impact of rescue pVHL expression in lesional skin. We used the imiquimod-induced psoriasis-like mouse model as an adenoviral vector that allowed us to express pVHL in the skin. Our data show that, in lesional skin, pVHL expression was reduced, whereas HIF-1α was increased. Remarkably, the retrieval of pVHL prevented psoriatic lesions, diminishing erythema, scale, and epidermal and vascular thickness. Furthermore, pVHL expression was capable of reducing HIF-1α, LDH, TNF-α and immune cell infiltration (mainly IL-17+ neutrophils). In conclusion, our results demonstrate that pVHL has a protective role to play in the pathophysiology of psoriasis.
The Interaction of Anti-DNA Antibodies with DNA: Evidence for Unconventional Binding Mechanisms
Authors: Pisetsky David S. , Garza Reyna Angel , Belina Morgan E. , Spencer Diane M.
Published: May 2022

Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus, a prototypic autoimmune disease. These antibodies bind to conserved sites on single-stranded and double-stranded DNA and display variable region somatic mutations consistent with antigen selection. Nevertheless, the interaction of anti-DNA with DNA has unconventional features. Anti-DNA antibodies bind by a mechanism called monogamous bivalency, in which stable interaction requires contact of both Fab sites with determinants on the same extended DNA molecule; the size of this DNA can be hundreds to thousands of bases, especially in solid phase assays. This binding also requires the presence of the Fc portion of IgG, a binding mechanism known as Fc-dependent monogamous bivalency. As shown by the effects of ionic strength in association and dissociation assays, anti-DNA binding is primarily electrostatic. Like anti-DNA autoantibodies, anti-DNA antibodies that bind specifically to non-conserved sites on bacterial DNA, a type of anti-DNA found in otherwise healthy individuals, also interact by monogamous bivalency. The unconventional features of anti-DNA antibodies may reflect the highly charged and polymeric nature of DNA and the need for molecular rearrangements to facilitate monogamous bivalency; the Fc portion contributes to binding in an as yet unknown way.
Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin
Authors: Ahmadvand Parvaneh , Avillan Johannetsy J. , Lewis Jacob A. , Call Douglas R. , Kang ChulHee
Published: May 2022

Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several beta-lactamase inhibitors, such as clavulanate, are used to inhibit the activity of these enzymes. To understand the mechanism of CTX-M-15 activity, we have determined the crystal structures of CTX-M-15 in complex with two specific classes of beta-lactam compounds, desfuroylceftiofur (DFC) and ampicillin, and an inhibitor, clavulanic acid. The crystal structures revealed that Ser70 and five other residues (Lys73, Tyr105, Glu166, Ser130, and Ser237) participate in catalysis and binding of those compounds. Based on analysis of steady-state kinetics, thermodynamic data, and molecular docking to both wild-type and S70A mutant structures, we determined that CTX-M-15 has a similar affinity for all beta-lactam compounds (ceftiofur, nitrocefin, DFC, and ampicillin), but with lower affinity for clavulanic acid. A catalytic mechanism for tested β-lactams and two-step inhibition mechanism of clavulanic acid were proposed. CTX-M-15 showed a higher activity toward DFC and nitrocefin, but significantly lower activity toward ampicillin and ceftiofur. The interaction between CTX-M-15 and both ampicillin and ceftiofur displayed a higher entropic but lower enthalpic effect, compared with DFC and nitrocefin. DFC, a metabolite of ceftiofur, displayed lower entropy and higher enthalpy than ceftiofur. This finding suggests that compounds containing amine moiety (e.g., ampicillin) and the furfural moiety (e.g., ceftiofur) could hinder the hydrolytic activity of CTX-M-15.
Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis
Authors: Inomata Yosuke , Oh Jae-Won , Taniguchi Kohei , Sugito Nobuhiko , Kawaguchi Nao , Hirokawa Fumitoshi , Lee Sang-Woong , Akao Yukihiro , Takai Shinji , Kim Kwang-Pyo , Uchiyama Kazuhisa
Published: May 2022

Non-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression.
The Role of NLRP3 Inflammasome Activation and Oxidative Stress in Varicocele-Mediated Male Hypofertility
Authors: Poli Giulia , Fabi Consuelo , Sugoni Chiara , Bellet Marina Maria , Costantini Claudio , Luca Giovanni , Brancorsini Stefano
Published: May 2022

Varicocele (VC) is the most common abnormality identified in men evaluated for hypofertility. Increased levels of reactive oxygen species (ROS) and reduced antioxidants concentrations are key contributors in varicocele-mediated hypofertility. Moreover, inflammation and alterations in testicular immunity negatively impact male fertility. In particular, NLRP3 inflammasome activation was hypothesized to lead to seminal inflammation, in which the levels of specific cytokines, such as IL-1β and IL-18, are overexpressed. In this review, we described the role played by oxidative stress (OS), inflammation, and NLRP3 inflammasome activation in VC disease. The consequences of ROS overproduction in testis, including inflammation, lipid peroxidation, mitochondrial dysfunction, chromatin damage, and sperm DNA fragmentation, leading to abnormal testicular function and failed spermatogenesis, were highlighted. Finally, we described some therapeutic antioxidant strategies, with recognized beneficial effects in counteracting OS and inflammation in testes, as possible therapeutic drugs against varicocele-mediated hypofertility.
Current Status of Experimental Animal Skin Flap Models: Ischemic Preconditioning and Molecular Factors
Authors: Lee Ju-Hee , You Hi-Jin , Lee Tae-Yul , Kang Hyo Jin
Published: May 2022

Skin flaps are necessary in plastic and reconstructive surgery for the removal of skin cancer, wounds, and ulcers. A skin flap is a portion of skin with its own blood supply that is partially separated from its original position and moved from one place to another. The use of skin flaps is often accompanied by cell necrosis or apoptosis due to ischemia–reperfusion (I/R) injury. Proinflammatory cytokines, such as nuclear factor kappa B (NF-κB), inhibitor of kappa B (IκB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and oxygen free radicals are known causative agents of cell necrosis and apoptosis. To prevent I/R injury, many investigators have suggested the inhibition of proinflammatory cytokines, stem-cell therapies, and drug-based therapies. Ischemic preconditioning (IPC) is a strategy used to prevent I/R injury. IPC is an experimental technique that uses short-term repetition of occlusion and reperfusion to adapt the area to the loss of blood supply. IPC can prevent I/R injury by inhibiting proinflammatory cytokine activity. Various stem cell applications have been studied to facilitate flap survival and promote angiogenesis and vascularization in animal models. The possibility of constructing tissue engineered flaps has also been investigated. Although numerous animal studies have been published, clinical data with regard to IPC in flap reconstruction have never been reported. In this study, we present various experimental skin flap methods, IPC methods, and methods utilizing molecular factors associated with IPC.
Overexpression of VEGF in the MOPC 315 Plasmacytoma Induces Tumor Immunity in Mice
Authors: Kim Byung-Gyu , Choi Sung Hee , Letterio John J. , Song Jie-Young , Huang Alex Y.
Published: May 2022

Vascular endothelial growth factor (VEGF) has important effects on hematopoietic and immune cells. A link between VEGF expression, tumor progression, and metastasis has been established in various solid tumors; however, the impact of VEGF expression by hematopoietic neoplasias remains unclear. Here, we investigated the role of VEGF in plasma cell neoplasia. Overexpression of VEGF in MOPC 315 tumor cells (MOPCSVm) had no effect on their growth in vitro. However, constitutive ectopic expression of VEGF dramatically reduced tumorigenicity of MOPC 315 when implanted subcutaneously into BALB/c mice. Mice implanted with MOPCSVm effectively rejected tumor grafts and showed strong cytotoxic T lymphocyte (CTL) activity against parental MOPC 315 cells. MOPCSVm implants were not rejected in nude mice, suggesting the process is T-cell-dependent. Adoptive transfer of splenocytes from recipients inoculated with MOPCSVm cells conferred immunity to naïve BALB/c mice, and mice surviving inoculation with MOPCSVm rejected the parental MOPC 315 tumor cells following a second inoculation. Immunohistochemical analysis showed that MOPCSVm induced a massive infiltration of CD3+ cells and MHC class II+ cells in vivo. In addition, exogenous VEGF induced the expression of CCR3 in T cells in vitro. Together, these data are the first to demonstrate that overexpression of VEGF in plasmacytoma inhibits tumor growth and enhances T-cell-mediated antitumor immune response.
Artificial Intelligence Predictor for Alzheimer’s Disease Trained on Blood Transcriptome: The Role of Oxidative Stress
Authors: Chiricosta Luigi , D’Angiolini Simone , Gugliandolo Agnese , Mazzon Emanuela
Published: May 2022

Alzheimer’s disease (AD) is an incurable neurodegenerative disease diagnosed by clinicians through healthcare records and neuroimaging techniques. These methods lack sensitivity and specificity, so new antemortem non-invasive strategies to diagnose AD are needed. Herein, we designed a machine learning predictor based on transcriptomic data obtained from the blood of AD patients and individuals without dementia (non-AD) through an 8 × 60 K microarray. The dataset was used to train different models with different hyperparameters. The support vector machines method allowed us to reach a Receiver Operating Characteristic score of 93% and an accuracy of 89%. High score levels were also achieved by the neural network and logistic regression methods. Furthermore, the Gene Ontology enrichment analysis of the features selected to train the model along with the genes differentially expressed between the non-AD and AD transcriptomic profiles shows the “mitochondrial translation” biological process to be the most interesting. In addition, inspection of the KEGG pathways suggests that the accumulation of β-amyloid triggers electron transport chain impairment, enhancement of reactive oxygen species and endoplasmic reticulum stress. Taken together, all these elements suggest that the oxidative stress induced by β-amyloid is a key feature trained by the model for the prediction of AD with high accuracy.
Salt-Templated Nanoarchitectonics of CoSe2-NC Nanosheets as an Efficient Bifunctional Oxygen Electrocatalyst for Water Splitting
Authors: Cao Hong , Li Hailong , Liu Linhao , Xue Kangning , Niu Xinkai , Hou Juan , Chen Long
Published: May 2022

Recently, the extensive research of efficient bifunctional electrocatalysts (oxygen evolution reaction (OER) and hydrogen evolution reaction (HER)) on water splitting has drawn increasing attention. Herein, a salt-template strategy is prepared to synthesize nitrogen-doped carbon nanosheets encapsulated with dispersed CoSe2 nanoparticles (CoSe2-NC NSs), while the thickness of CoSe2-NC NSs is only about 3.6 nm. Profiting from the ultrathin morphology, large surface area, and promising electrical conductivity, the CoSe2-NC NSs exhibited excellent electrocatalytic of 10 mA·cm−2 current density at small overpotentials of 247 mV for OER and 75 mV for HER. Not only does the nitrogen-doped carbon matrix effectively avoid self-aggregation of CoSe2 nanoparticles, but it also prevents the corrosion of CoSe2 from electrolytes and shows favorable durability after long-term stability tests. Furthermore, an overall water-splitting system delivers a current density of 10 mA·cm−2 at a voltage of 1.54 V with resultants being both the cathode and anode catalyst in alkaline solutions. This work provides a new way to synthesize efficient and nonprecious bifunctional electrocatalysts for water splitting.
Interplay between A-to-I Editing and Splicing of RNA: A Potential Point of Application for Cancer Therapy
Authors: Goncharov Anton O. , Shender Victoria O. , Kuznetsova Ksenia G. , Kliuchnikova Anna A. , Moshkovskii Sergei A.
Published: May 2022

Adenosine-to-inosine RNA editing is a system of post-transcriptional modification widely distributed in metazoans which is catalyzed by ADAR enzymes and occurs mostly in double-stranded RNA (dsRNA) before splicing. This type of RNA editing changes the genetic code, as inosine generally pairs with cytosine in contrast to adenosine, and this expectably modulates RNA splicing. We review the interconnections between RNA editing and splicing in the context of human cancer. The editing of transcripts may have various effects on splicing, and resultant alternatively spliced isoforms may be either tumor-suppressive or oncogenic. Dysregulated RNA splicing in cancer often causes the release of excess amounts of dsRNA into cytosol, where specific dsRNA sensors provoke antiviral-like responses, including type I interferon signaling. These responses may arrest cell division, causing apoptosis and, externally, stimulate antitumor immunity. Thus, small-molecule spliceosome inhibitors have been shown to facilitate the antiviral-like signaling and are considered to be potential cancer therapies. In turn, a cytoplasmic isoform of ADAR can deaminate dsRNA in cytosol, thereby decreasing its levels and diminishing antitumor innate immunity. We propose that complete or partial inhibition of ADAR may enhance the proapoptotic and cytotoxic effects of splicing inhibitors and that it may be considered a promising addition to cancer therapies targeting RNA splicing.
One AP2/ERF Transcription Factor Positively Regulates Pi Uptake and Drought Tolerance in Poplar
Authors: Chen Ningning , Qin Jiajia , Tong Shaofei , Wang Weiwei , Jiang Yuanzhong
Published: May 2022

Drought decreases the inorganic phosphate (Pi) supply of soil, resulting in Pi starvation of plants, but the molecular mechanism of how plants, especially the perennial trees, are tolerant to drought stress and Pi starvation, is still elusive. In this study, we identified an AP2/ERF transcription factor gene, PalERF2, from Populus alba var. pyramidalis, and it was induced by both mannitol treatment and Pi starvation. Overexpressing and knocking-down of PalERF2 both enhanced and attenuated tolerance to drought stress and Pi deficiency compared to WT, respectively. Moreover, the overexpression of PalERF2 up-regulated the expression levels of Pi starvation-induced (PSI) genes and increased Pi uptake under drought conditions; however, its RNAi poplar showed the opposite phenotypes. Subsequent analysis indicated that PalERF2 directly modulated expressions of drought-responsive genes PalRD20 and PalSAG113, as well as PSI genes PalPHL2 and PalPHT1;4, through binding to the DRE motifs on their promoters. These results clearly indicate that poplars can recruit PalERF2 to increase the tolerance to drought and also elevate Pi uptake under drought stress.
The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches
Authors: Lagreca Ivana , Riva Giovanni , Nasillo Vincenzo , Barozzi Patrizia , Castelli Ilaria , Basso Sabrina , Bettelli Francesca , Giusti Davide , Cuoghi Angela , Bresciani Paola , Messerotti Andrea , Gilioli Andrea , Pioli Valeria , Colasante Corrado , Vallerini Daniela , Paolini Ambra , Maccaferri Monica , Donatelli Francesca , Forghieri Fabio , Morselli Monica , Colaci Elisabetta , Leonardi Giovanna , Marasca Roberto , Potenza Leonardo , Manfredini Rossella , Tagliafico Enrico , Trenti Tommaso , Comoli Patrizia , Luppi Mario
Published: May 2022

Multiple Myeloma (MM) is a malignant growth of clonal plasma cells, typically arising from asymptomatic precursor conditions, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Profound immunological dysfunctions and cytokine deregulation are known to characterize the evolution of the disease, allowing immune escape and proliferation of neoplastic plasma cells. In the past decades, several studies have shown that the immune system can recognize MGUS and MM clonal cells, suggesting that anti-myeloma T cell immunity could be harnessed for therapeutic purposes. In line with this notion, chimeric antigen receptor T cell (CAR-T) therapy is emerging as a novel treatment in MM, especially in the relapsed/refractory disease setting. In this review, we focus on the pivotal contribution of T cell impairment in the immunopathogenesis of plasma cell dyscrasias and, in particular, in the disease progression from MGUS to SMM and MM, highlighting the potentials of T cell-based immunotherapeutic approaches in these settings.
Soy-Derived Equol Induces Antioxidant Activity in Zebrafish in an Nrf2-Independent Manner
Authors: Watanabe Asami , Muraki Kyoji , Tamaoki Junya , Kobayashi Makoto
Published: May 2022

Antioxidant effects of soy-derived isoflavones are predicted to be mediated by the Keap1-Nrf2 pathway. Recently, we constructed an assay system to evaluate the antioxidant effects of dietary phytochemicals in zebrafish and revealed a relationship between these effects and the Keap1-Nrf2 pathway. In this study, we used this system to examine the antioxidant effects of seven isoflavones. Among those seven, equol showed strong antioxidant effects when arsenite was used as an oxidative stressor. The antioxidant effect of equol was also shown in Nrf2-mutant zebrafish nfe2l2afh318, suggesting that this effect was not mediated by the Keap1-Nrf2 pathway. To elucidate this unidentified mechanism, the gene expression profiles of equol-treated larvae were analyzed using RNA-seq and qRT-PCR, while no noticeable changes were detected in the expression of genes related to antioxidant effects, except weak induction of Nrf2 target genes. Because nfe2l2afh318 is an amino acid-substitution mutant (Arg485Lue), we considered that the antioxidant effect of equol in this mutant might be due to residual Nrf2 activity. To examine this possibility, we generated an Nrf2-knockout zebrafish nfe2l2ait321 using CRISPR-Cas9 and analyzed the antioxidant effect of equol. As a result, equol showed strong antioxidant effects even in Nrf2-knockout larvae, suggesting that equol indeed upregulates antioxidant activity in zebrafish in an Nrf2-independent manner.
Multiomic Profiling Identified EGF Receptor Signaling as a Potential Inhibitor of Type I Interferon Response in Models of Oncolytic Therapy by Vesicular Stomatitis Virus
Authors: Nikitina Anastasia S. , Lipatova Anastasia V. , Goncharov Anton O. , Kliuchnikova Anna A. , Pyatnitskiy Mikhail A. , Kuznetsova Ksenia G. , Hamad Azzam , Vorobyev Pavel O. , Alekseeva Olga N. , Mahmoud Marah , Shakiba Yasmin , Anufrieva Ksenia S. , Arapidi Georgy P. , Ivanov Mark V. , Tarasova Irina A. , Gorshkov Mikhail V. , Chumakov Peter M. , Moshkovskii Sergei A.
Published: May 2022

Cancer cell lines responded differentially to type I interferon treatment in models of oncolytic therapy using vesicular stomatitis virus (VSV). Two opposite cases were considered in this study, glioblastoma DBTRG-05MG and osteosarcoma HOS cell lines exhibiting resistance and sensitivity to VSV after the treatment, respectively. Type I interferon responses were compared for these cell lines by integrative analysis of the transcriptome, proteome, and RNA editome to identify molecular factors determining differential effects observed. Adenosine-to-inosine RNA editing was equally induced in both cell lines. However, transcriptome analysis showed that the number of differentially expressed genes was much higher in DBTRG-05MG with a specific enrichment in inflammatory proteins. Further, it was found that two genes, EGFR and HER2, were overexpressed in HOS cells compared with DBTRG-05MG, supporting recent reports that EGF receptor signaling attenuates interferon responses via HER2 co-receptor activity. Accordingly, combined treatment of cells with EGF receptor inhibitors such as gefitinib and type I interferon increases the resistance of sensitive cell lines to VSV. Moreover, sensitive cell lines had increased levels of HER2 protein compared with non-sensitive DBTRG-05MG. Presumably, the level of this protein expression in tumor cells might be a predictive biomarker of their resistance to oncolytic viral therapy.
PLATO: A Predictive Drug Discovery Web Platform for Efficient Target Fishing and Bioactivity Profiling of Small Molecules
Authors: Ciriaco Fulvio , Gambacorta Nicola , Trisciuzzi Daniela , Nicolotti Orazio
Published: May 2022

PLATO (Polypharmacology pLATform predictiOn) is an easy-to-use drug discovery web platform, which has been designed with a two-fold objective: to fish putative protein drug targets and to compute bioactivity values of small molecules. Predictions are based on the similarity principle, through a reverse ligand-based screening, based on a collection of 632,119 compounds known to be experimentally active on 6004 protein targets. An efficient backend implementation allows to speed-up the process that returns results for query in less than 20 s. The graphical user interface is intuitive to give practitioners easy input and transparent output, which is available as a standard report in portable document format. PLATO has been validated on thousands of external data, with performances better than those of other parallel approaches. PLATO is available free of charge (http://plato.uniba.it/ accessed on 13 April 2022).
Strigolactones Modulate Salicylic Acid-Mediated Disease Resistance in Arabidopsis thaliana
Authors: Kusajima Miyuki , Fujita Moeka , Soudthedlath Khamsalath , Nakamura Hidemitsu , Yoneyama Koichi , Nomura Takahito , Akiyama Kohki , Maruyama-Nakashita Akiko , Asami Tadao , Nakashita Hideo
Published: May 2022

Strigolactones are low-molecular-weight phytohormones that play several roles in plants, such as regulation of shoot branching and interactions with arbuscular mycorrhizal fungi and parasitic weeds. Recently, strigolactones have been shown to be involved in plant responses to abiotic and biotic stress conditions. Herein, we analyzed the effects of strigolactones on systemic acquired resistance induced through salicylic acid-mediated signaling. We observed that the systemic acquired resistance inducer enhanced disease resistance in strigolactone-signaling and biosynthesis-deficient mutants. However, the amount of endogenous salicylic acid and the expression levels of salicylic acid-responsive genes were lower in strigolactone signaling-deficient max2 mutants than in wildtype plants. In both the wildtype and strigolactone biosynthesis-deficient mutants, the strigolactone analog GR24 enhanced disease resistance, whereas treatment with a strigolactone biosynthesis inhibitor suppressed disease resistance in the wildtype. Before inoculation of wildtype plants with pathogenic bacteria, treatment with GR24 did not induce defense-related genes; however, salicylic acid-responsive defense genes were rapidly induced after pathogenic infection. These findings suggest that strigolactones have a priming effect on Arabidopsis thaliana by inducing salicylic acid-mediated disease resistance.
Consecutive Aromatic Residues Are Required for Improved Efficacy of β-Sheet Breakers
Authors: Jarmuła Adam , Zubalska Monika , Stępkowski Dariusz
Published: May 2022

Alzheimer’s disease is a fatal neurodegenerative malady which up to very recently did not have approved therapy modifying its course. After controversial approval of aducanumab (monoclonal antibody clearing β-amyloid plaques) by FDA for use in very early stages of disease, possibly new avenue opened for the treatment of patients. In line with this approach is search for compounds blocking aggregation into amyloid oligomers subsequently forming fibrils or compounds helping in getting rid of plaques formed by β-amyloid fibrils. Here we present in silico work on 627 sixtapeptide β-sheet breakers (BSBs) containing consecutive three aromatic residues. Three of these BSBs caused dissociation of one or two β-amyloid chains from U-shaped β-amyloid protofibril model 2BEG after docking and subsequent molecular dynamics simulations. Thorough analysis of our results let us postulate that the first steps of binding these successful BSBs involve π–π interactions with stacked chains of F19 and later also with F20 (F3 and F4 in 2BEG model of protofibril). The consecutive location of aromatic residues in BSBs makes them more attractive for chains of stacked F3 and F4 within the 2BEG model. Spotted by us, BSBs may be prospective lead compounds for an anti-Alzheimer’s therapy.
Ocular Ischemic Syndrome and Its Related Experimental Models
Authors: Lee Deokho , Tomita Yohei , Yang Lizhu , Negishi Kazuno , Kurihara Toshihide
Published: May 2022

Ocular ischemic syndrome (OIS) is one of the severe ocular disorders occurring from stenosis or occlusion of the carotid arteries. As the ophthalmic artery is derived from the branch of the carotid artery, stenosis or occlusion of the carotid arteries could induce chronic ocular hypoperfusion, finally leading to the development of OIS. To date, the pathophysiology of OIS is still not clearly unraveled. To better explore the pathophysiology of OIS, several experimental models have been developed in rats and mice. Surgical occlusion or stenosis of common carotid arteries or internal carotid arteries was conducted bilaterally or unilaterally for model development. In this regard, final ischemic outcomes in the eye varied depending on the surgical procedure, even though similar findings on ocular hypoperfusion could be observed. In the current review, we provide an overview of the pathophysiology of OIS from various experimental models, as well as several clinical cases. Moreover, we cover the status of current therapies for OIS along with promising preclinical treatments with recent advances. Our review will enable more comprehensive therapeutic approaches to prevent the development and/or progression of OIS.
Identification of Key Genes and Pathways Associated with PIEZO1 in Bone-Related Disease Based on Bioinformatics
Authors: Zhou Yuanyuan , Zhang Chen , Zhou Zhongguo , Zhang Chao , Wang Jiali
Published: May 2022

PIEZO1 is a mechano-sensitive ion channel that can sense various forms of mechanical stimuli and convert them into biological signals, affecting bone-related diseases. The present study aimed to identify key genes and signaling pathways in Piezo1-regulated bone-related diseases and to explain the potential mechanisms using bioinformatic analysis. The differentially expressed genes (DEGs) in tendon, femur, and humerus bone tissue; cortical bone; and bone-marrow-derived macrophages were identified with the criteria of |log2FC| > 1 and adjusted p-value < 0.05 analysis based on a dataset from GSE169261, GSE139121, GSE135282, and GSE133069, respectively, and visualized in a volcano plot. Venn diagram analyses were performed to identify the overlapping DEGs expressed in the above-mentioned tissues. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, protein–protein interaction (PPI) analysis, and module analysis were also conducted. Furthermore, qRT-PCR was performed to validate the above results using primary chondrocytes. As a result, a total of 222 overlapping DEGs and 12 mostly overlapping DEGs were identified. Key Piezo1-related genes, such as Lcn2, Dkk3, Obscn, and Tnnt1, were identified, and pathways, such as Wnt/β-catenin and PI3k-Akt, were also identified. The present informatic study provides insight, for the first time, into the potential therapeutic targets of Piezo1-regulated bone-related diseases
Genome-Wide Identification of the Eucalyptus urophylla GATA Gene Family and Its Diverse Roles in Chlorophyll Biosynthesis
Authors: Du Kang , Xia Yufei , Zhan Dingju , Xu Tingting , Lu Te , Yang Jun , Kang Xiangyang
Published: May 2022

GATA transcription factors have been demonstrated to play key regulatory roles in plant growth, development, and hormonal response. However, the knowledge concerning the evolution of GATA genes in Eucalyptus urophylla and their trans-regulatory interaction is indistinct. Phylogenetic analysis and study of conserved motifs, exon structures, and expression patterns resolved the evolutionary relationships of these GATA proteins. Phylogenetic analysis showed that EgrGATAs are broadly distributed in four subfamilies. Cis-element analysis of promoters revealed that EgrGATA genes respond to light and are influenced by multiple hormones and abiotic stresses. Transcriptome analysis revealed distinct temporal and spatial expression patterns of EgrGATA genes in various tissues of E. urophylla S.T.Blake, which was confirmed by real-time quantitative PCR (RT-qPCR). Further research revealed that EurGNC and EurCGA1 were localized in the nucleus, and EurGNC directly binds to the cis-element of the EurGUN5 promoter, implying its potential roles in the regulation of chlorophyll synthesis. This comprehensive study provides new insights into the evolution of GATAs and could help to improve the photosynthetic assimilation and vegetative growth of E. urophylla at the genetic level.
Novel Tumor-Targeting Nanoparticles for Cancer Treatment—A Review
Authors: Niculescu Adelina-Gabriela , Grumezescu Alexandru Mihai
Published: May 2022

Being one of the leading causes of death and disability worldwide, cancer represents an ongoing interdisciplinary challenge for the scientific community. As currently used treatments may face limitations in terms of both efficiency and adverse effects, continuous research has been directed towards overcoming existing challenges and finding safer specific alternatives. In particular, increasing interest has been gathered around integrating nanotechnology in cancer management and subsequentially developing various tumor-targeting nanoparticles for cancer applications. In this respect, the present paper briefly describes the most used cancer treatments in clinical practice to set a reference framework for recent research findings, further focusing on the novel developments in the field. More specifically, this review elaborates on the top recent studies concerning various nanomaterials (i.e., carbon-based, metal-based, liposomes, cubosomes, lipid-based, polymer-based, micelles, virus-based, exosomes, and cell membrane-coated nanomaterials) that show promising potential in different cancer applications.
MicroRNAs (miRNAs) in Cardiovascular Complications of Rheumatoid Arthritis (RA): What Is New?
Authors: Tanase Daniela Maria , Gosav Evelina Maria , Petrov Daniela , Teodorescu Dan-Stefan , Buliga-Finis Oana Nicoleta , Ouatu Anca , Tudorancea Ionut , Rezus Elena , Rezus Ciprian
Published: May 2022

Rheumatoid Arthritis (RA) is among the most prevalent and impactful rheumatologic chronic autoimmune diseases (AIDs) worldwide. Within a framework that recognizes both immunological activation and inflammatory pathways, the exact cause of RA remains unclear. It seems however, that RA is initiated by a combination between genetic susceptibility, and environmental triggers, which result in an auto-perpetuating process. The subsequently, systemic inflammation associated with RA is linked with a variety of extra-articular comorbidities, including cardiovascular disease (CVD), resulting in increased mortality and morbidity. Hitherto, vast evidence demonstrated the key role of non-coding RNAs such as microRNAs (miRNAs) in RA, and in RA-CVD related complications. In this descriptive review, we aim to highlight the specific role of miRNAs in autoimmune processes, explicitly on their regulatory roles in the pathogenesis of RA, and its CV consequences, their main role as novel biomarkers, and their possible role as therapeutic targets.
Clostridium perfringens-Induced Necrotic Diseases: An Overview
Authors: Fu Ying , Alenezi Tahrir , Sun Xiaolun
Published: May 2022

Clostridium perfringens, a prevalent Gram-positive bacterium, causes necrotic diseases associated with abundant life loss and economic burdens of billions of USD. The mechanism of C. perfringens-induced necrotic diseases remains largely unknown, in part, because of the lack of effective animal models and the presence of a large array of exotoxins and diverse disease manifestations from the skin and deep tissues to the gastrointestinal tract. In the light of the advancement of medical and veterinary research, a large body of knowledge is accumulating on the factors influencing C. perfringens-induced necrotic disease onset, development, and outcomes. Here, we present an overview of the key virulence factors of C. perfringens exotoxins. Subsequently, we focus on comprehensively reviewing C. perfringens-induced necrotic diseases such as myonecrosis, acute watery diarrhea, enteritis necroticans, preterm infant necrotizing enterocolitis, and chicken necrotic enteritis. We then review the current understanding on the mechanisms of myonecrosis and enteritis in relation to the immune system and intestinal microbiome. Based on these discussions, we then review current preventions and treatments of the necrotic diseases and propose potential new intervention options. The purpose of this review is to provide an updated and comprehensive knowledge on the role of the host–microbe interaction to develop new interventions against C. perfringens-induced necrotic diseases.
Value of Time and Elasticity of Portuguese Freeway Users: Insights from Analysis of Survey Data
Authors: Lombardi Claudio , Picado-Santos Luís , Annaswamy Anuradha M.
Published: May 2022

Value of time (VOT) is a crucial aspect of travel demand modeling. VOT impacts most mobility projects and the evaluations therein. It has been noted to be influenced by multiple factors, mainly related to individuals’ demographics and trips’ characteristics. This paper presents the results of a survey conducted among users of the Portuguese national freeway network, aiming to derive insights about their travel choice mechanism for testing mobility projects, in particular dynamic pricing strategies. Particular attention is dedicated to the value they attribute to travel time by analyzing willingness-to-pay for avoiding congestion and saving travel time. An elaborate questionnaire survey was distributed through online survey campaigns between March and June of 2021, eliciting 163 valid responses. Even after a stratification process, results revealed that VOT is generally lower than our original expectations; various statistical distributions were tested to fit the empirical data, the best performing ones were selected and the results were compared with a previous survey-based VOT study. We finally measured the elasticity of the freeway demand and of the whole demand for transportation, which confirmed the generally low willingness to pay for less congested travels.
Using Autumnal Trap Crops to Manage Tarnished Plant Bugs (Lygus lineolaris)
Authors: Dumont François , Provost Caroline
Published: May 2022

For insects, surviving winter depends on their capacity to store enough energy and find proper hibernation sites. A common strategy is to minimize movement and hibernate near autumn food sources. We investigated the efficiency of autumnal hosts to act as trap crops where insects could be exposed to targeted repressive treatments. This approach could reduce the local populations of insect pests in the next production season, reducing the need for insecticides. First, we tested the mullein plant’s attractiveness as an autumn trap crop for Lygus lineolaris (Hemiptera: Miridae) in strawberry fields by comparing peak population density among mullein (Verbascum thapsus), strawberry plants (Fragaria × ananassa), buckwheat (Fagopyrum esculentum), and mustard (Sinapis alba). Second, we tested four treatments applied to the autumn trap crops to reduce L. lineolaris winter survivorship: (1) hot water, (2) a pathogen (Beauveria bassiana), (3) insecticide (cypermethrin), and (4) a control. The density of the L. lineolaris population on mullein in autumn and on buckwheat in summer was higher than on strawberry and mustard. Of the overwintering L. lineolaris, 0% survived the winter when treated with the insecticide cypermethrin, while 38.3% survived in the control treatment (without repressive treatment). The B. bassiana and hot water treatments did not differ from the control. The mullein autumn trap crops combined with insecticide treatments could contribute to reducing the overwintering population, hence potentially reducing population during the following growing season.
Safety Evaluation of Chemical Insecticides to Tetrastichus howardi (Hymenoptera: Eulophidae), a Pupal Parasitoid of Spodoptera frugiperda (Lepidoptera: Noctuidae) Using Three Exposure Routes
Authors: Liu Zhuo , Su Hao , Lyu Baoqian , Yan Sanqiang , Lu Hui , Tang Jihong
Published: May 2022

Spodoptera frugiperda has become a major pest in many crops worldwide. The main control strategies are biological and chemical controls. However, pesticides have varying degrees of toxicity to parasitic wasps in the field. To integrate chemical and biological controls, we evaluated the safety of insecticides to Tetrastichus howardi, an important pupal parasitoid of S. frugiperda. This study assessed the toxicity of six major control insecticides (emamectin benzoate, chlorfenapyr, indoxacarb, chlorantraniliprole, bisultap, and lufenuron) to T. howardi based on risk quotient. The results showed that indoxacarb had the lowest risk quotient (RQ = 7.43). Then the side effects of three sublethal concentrations (LC20, LC30, LC40) of indoxacarb were tested using three methods (1. Adult exposure to pesticide residues on the glass tube; 2. Adult exposure to pesticide residues on the host; 3. Larval exposure to pesticides through host exposure). Overall, T. howardi had a lower parasitism rate and emergence rate with the higher pesticide concentrations. Furthermore, among three methods, the adult exposure to pesticide residues on the glass tube was the most efficient in inhibiting the parasitism rate, and impairing the emergence rate and the offspring female/male ratio. This study guides a more scientific and comprehensive application of pesticides and releases natural enemies in the field.