bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of Lightweight Renewable Microwave-Absorbing Bio-Polyurethane/Fe3O4 Composite Foam: Structure Analysis and Absorption Mechanism
Authors: Xu Xiaoling , Tian Xiaoke , Bo Guangxu , Su Xingjian , Yan Jinyong , Yan Yunjun
Published: October 2022

Sustainable renewable polymer foam used as a lightweight porous skeleton for microwave absorption is a novel strategy that can effectively solve the problems of the large surface density, high additive amount, and narrow absorbing band of absorbing materials. In this article, novel renewable microwave-absorbing foams were prepared using Sapiumse biferum kernel oil-based polyurethane foam (BPUF) as porous matrix and Fe3O4-nanoparticles as magnetic absorbents. The microstructure and the microwave absorption performance, the structural effects on the properties, and electromagnetic mechanism of the magnetic BPUF (mBPUF) were systematically characterized and analyzed. The results show that the mBPUF displayed a porous hierarchical structure and was multi-interfacial, which provided a skeleton and matching layer for the Fe3O4 nanoparticles. The effective reflection loss (RL ≤ −10 dB) frequency of the mBPUF was from 4.16 GHz to 18 GHz with only 9 wt% content of Fe3O4 nanoparticles at a thickness of 1.5~5 mm. The surface density of the mBPUF coatings was less than 0.5 kg/cm2 at a thickness of 1.8 mm. The lightweight characteristics and broadband absorption were attributed to the porous hierarchical structures and the dielectric combined with the magnetic loss effect. It indicates that the mBPUF is a prospective broadband-absorbing material in the field of lightweight stealth materials.
The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy
Authors: Zavileyskiy Lev G. , Aleshin Vasily A. , Kaehne Thilo , Karlina Irina S. , Artiukhov Artem V. , Maslova Maria V. , Graf Anastasia V. , Bunik Victoria I.
Published: October 2022

Abnormal energy expenditure during seizures and metabolic regulation through post-translational protein acylation suggest acylation as a therapeutic target in epilepsy. Our goal is to characterize an interplay between the brain acylation system components and their changes after seizures. In a rat model of pentylenetetrazole (PTZ)-induced epilepsy, we quantify 43 acylations in 29 cerebral cortex proteins; levels of NAD+; expression of NAD+-dependent deacylases (SIRT2, SIRT3, SIRT5); activities of the acyl-CoA-producing/NAD+-utilizing complexes of 2-oxoacid dehydrogenases. Compared to the control group, acylations of 14 sites in 11 proteins are found to differ significantly after seizures, with six of the proteins involved in glycolysis and energy metabolism. Comparing the single and chronic seizures does not reveal significant differences in the acylations, pyruvate dehydrogenase activity, SIRT2 expression or NAD+. On the contrary, expression of SIRT3, SIRT5 and activity of 2-oxoglutarate dehydrogenase (OGDH) decrease in chronic seizures vs. a single seizure. Negative correlations between the protein succinylation/glutarylation and SIRT5 expression, and positive correlations between the protein acetylation and SIRT2 expression are shown. Our findings unravel involvement of SIRT5 and OGDH in metabolic adaptation to seizures through protein acylation, consistent with the known neuroprotective role of SIRT5 and contribution of OGDH to the Glu/GABA balance perturbed in epilepsy.
Chronic Arsenic Exposure Upregulates the Expression of Basal Transcriptional Factors and Increases Invasiveness of the Non-Muscle Invasive Papillary Bladder Cancer Line RT4
Authors: Mehus Aaron A. , Bergum Nicholas , Knutson Peter , Shrestha Swojani , Kalonick Matthew , Zhou Xudong , Garrett Scott H. , Sens Donald A. , Sens Mary Ann , Somji Seema
Published: October 2022

The bladder is a target organ for inorganic arsenic, a carcinogen and common environmental contaminant found in soil and water. Urothelial carcinoma (UC) is the most common type of bladder cancer (BC) that develops into papillary or non-papillary tumors. Papillary tumors are mostly non-muscle invasive (NMIUC), easier treated, and have a better prognosis. Urothelial carcinoma can be molecularly sub-typed as luminal or basal, with papillary tumors generally falling into the luminal category and basal tumors exclusively forming muscle invasive urothelial carcinomas (MIUC). It is unclear why some UCs develop more aggressive basal phenotypes. We hypothesized that chronic arsenic exposure of a papillary luminal bladder cancer would lead to the development of basal characteristics and increase in invasiveness. We treated the human papillary bladder cancer cell line RT4 with 1 µM arsenite (As3+) for twenty passages. Throughout the study, key luminal and basal gene/protein markers in the exposed cells were evaluated and at passage twenty, the cells were injected into athymic mice to evaluate tumor histology and measure protein markers using immunohistochemistry. Our data indicates that chronic As3+- treatment altered cellular morphology and decreased several luminal markers in cell culture. The histology of the tumors generated from the As3+-exposed cells was similar to the parent (non-treated) however, they appeared to be more invasive in the liver and displayed elevated levels of some basal markers. Our study demonstrates that chronic As3+ exposure is able to convert a non-invasive papillary bladder cancer to an invasive form that acquires some basal characteristics.
Cathepsin S Inhibition Suppresses Experimental Systemic Lupus Erythematosus-Associated Pulmonary Arterial Remodeling
Authors: Yen Tzung-Hai , Ho Wan-Jing , Yeh Yung-Hsin , Lai Ying-Ju
Published: October 2022

Patients with systemic lupus erythematosus (SLE) associated with pulmonary arterial hypnertension (PAH) receive targeted therapy for PAH to decrease pulmonary arterial systolic pressure and significantly prolong their survival. Cysteine cathepsin proteases play critical roles in the progression of cardiovascular disease. Inhibition of cathepsin S (Cat S) has been shown to improve SLE and lupus nephritis. However, the effect of Cat S inhibitors on SLE-associated PAH (SLE-PAH) remains unclear, and there is no animal model for translational research on SLE-PAH. We hypothesized that the inhibition of Cat S may affect PAH development and arterial remodeling associated with SLE. A female animal model of SLE-PAH, female MRL/lpr (Lupus), was used to evaluate the role of pulmonary arterial remodeling in SLE. The key finding of the research work is the establishment of an animal model of SLE associated with PAH in female MRL/lpr mice that is able to evaluate pulmonary arterial remodeling starting from the age of 11 weeks to 15 weeks. Cat S protein level was identified as a marker of experimental SLE. Pulmonary hypertension in female MRL/lpr (Lupus) mice was treated by administering the selective Cat S inhibitor Millipore-219393, which stimulated peroxisome proliferator-activated receptor-gamma (PPARγ) in the lungs to inhibit Cat S expression and pulmonary arterial remodeling. Studies provide an animal model of female MRL/lpr (Lupus) associated with PAH and a deeper understanding of the pathogenesis of SLE-PAH. The results may define the role of cathepsin S in preventing progressive and fatal SLE-PAH and provide approaches for therapeutic interventions in SLE-PAH.
Identification and Characterization of Piwi-Interacting RNAs for Early Testicular Development in Yak
Authors: La Yongfu , Ma Xiaoming , Bao Pengjia , Chu Min , Yan Ping , Guo Xian , Liang Chunnian
Published: October 2022

Normal testicular development plays a crucial role in male reproduction and is the precondition for spermatogenesis. PIWI-interacting RNAs (piRNAs) are novel noncoding RNAs expressed in animal germ cells that form complexes with PIWI family proteins and are involved in germ cell development, differentiation, and spermatogenesis. However, changes in piRNA expression profiles during early testicular development in yak have not been investigated. In this study, we used small RNA sequencing to evaluate the differences and potential functions of piRNA expression profiles in 6-, 18-, and 30-month-old yak testis tissues. Differential expression analysis found 109, 293, and 336 differentially expressed piRNAs in M30 vs. M18, M18 vs. M6, and M30 vs. M6, respectively, and found 30 common differentially expressed piRNAs in the three groups of M6, M18, and M30. In addition, the functional enrichment analysis of differentially expressed piRNAs target genes indicated that they were related to testicular development and spermatogenesis. Finally, we detected the expression of the PIWI protein family in the yak testis at different developmental stages and found that PIWIL1, PIWIL2, PIWIL3, and PIWIL4 were highly expressed in 18- and 30-month-old yak testis and almost not expressed in 6-month-old yak testis. In conclusion, this study summarizes the changes of piRNA expression patterns during the early development of yak testis and provides new clues for the regulatory role of piRNA in yak testis.
Time-Series Transcriptomic Analysis Reveals the Molecular Profiles of Diapause Termination Induced by Long Photoperiods and High Temperature in Chilo suppressalis
Authors: Bao Haibo , Zhu Hui , Yu Peihan , Luo Guanghua , Zhang Ru , Yue Qian , Fang Jichao
Published: October 2022

Survival and adaptation to seasonal changes are challenging for insects. Many temperate insects such as the rice stem borer (Chilo suppressalis) overcome the adverse situation by entering diapause, wherein development changes dynamically occur and metabolic activity is suppressed. The photoperiod and temperature act as major environmental stimuli of diapause. However, the physiological and molecular mechanisms that interpret the ecologically relevant environmental cues in ontogenetic development during diapause termination are poorly understood. Here, we used genome-wide high-throughput RNA-sequencing to examine the patterns of gene expression during diapause termination in C. suppressalis. Major shifts in biological processes and pathways including metabolism, environmental information transmission, and endocrine signalling were observed across diapause termination based on over-representation analysis, short time-series expression miner, and gene set enrichment analysis. Many new pathways were identified in diapause termination including circadian rhythm, MAPK signalling, Wnt signalling, and Ras signalling, together with previously reported pathways including ecdysteroid, juvenile hormone, and insulin/insulin-like signalling. Our results show that convergent biological processes and molecular pathways of diapause termination were shared across different insect species and provided a comprehensive roadmap to better understand diapause termination in C. suppressalis.
Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation
Authors: Fang Xiaona , Yan Qian , Liu Shan , Guan Xin-Yuan
Published: October 2022

Hepatocellular carcinoma (HCC) remains the most predominant type of liver cancer with an extremely poor prognosis due to its late diagnosis and high recurrence rate. One of the culprits for HCC recurrence and metastasis is the existence of cancer stem cells (CSCs), which are a small subset of cancer cells possessing robust stem cell properties within tumors. CSCs play crucial roles in tumor heterogeneity constitution, tumorigenesis, tumor relapse, metastasis, and resistance to anti-cancer therapies. Elucidation of how these CSCs maintain their stemness features is essential for the development of CSCs-based therapy. In this review, we summarize the present knowledge of intrinsic molecules and signaling pathways involved in hepatic CSCs, especially the CSC surface markers and associated signaling in regulating the stemness characteristics and the heterogeneous subpopulations within the CSC pool. In addition, we recapitulate the effects of crucial extrinsic cellular components in the tumor microenvironment, including stromal cells and immune cells, on the modulation of hepatic CSCs. Finally, we synopsize the currently valuable CSCs-targeted therapy strategies based on intervention in these intrinsic and extrinsic molecular mechanisms, in the hope of shedding light on better clinical management of HCC patients.
Ubiquitin Proteasome Gene Signatures in Ependymoma Molecular Subtypes
Authors: Vriend Jerry , Thanasupawat Thatchawan , Sinha Namita , Klonisch Thomas
Published: October 2022

The ubiquitin proteasome system (UPS) is critically important for cellular homeostasis and affects virtually all key functions in normal and neoplastic cells. Currently, a comprehensive review of the role of the UPS in ependymoma (EPN) brain tumors is lacking but may provide valuable new information on cellular networks specific to different EPN subtypes and reveal future therapeutic targets. We have reviewed publicly available EPN gene transcription datasets encoding components of the UPS pathway. Reactome analysis of these data revealed genes and pathways that were able to distinguish different EPN subtypes with high significance. We identified differential transcription of several genes encoding ubiquitin E2 conjugases associated with EPN subtypes. The expression of the E2 conjugase genes UBE2C, UBE2S, and UBE2I was elevated in the ST_EPN_RELA subtype. The UBE2C and UBE2S enzymes are associated with the ubiquitin ligase anaphase promoting complex (APC/c), which regulates the degradation of substrates associated with cell cycle progression, whereas UBE2I is a Sumo-conjugating enzyme. Additionally, elevated in ST_EPN_RELA were genes for the E3 ligase and histone deacetylase HDAC4 and the F-box cullin ring ligase adaptor FBX031. Cluster analysis demonstrated several genes encoding E3 ligases and their substrate adaptors as EPN subtype specific genetic markers. The most significant Reactome Pathways associated with differentially expressed genes for E3 ligases and their adaptors included antigen presentation, neddylation, sumoylation, and the APC/c complex. Our analysis provides several UPS associated factors that may be attractive markers and future therapeutic targets for the subtype-specific treatment of EPN patients.
Punicalagin Protects against the Development of Methotrexate-Induced Hepatotoxicity in Mice via Activating Nrf2 Signaling and Decreasing Oxidative Stress, Inflammation, and Cell Death
Authors: Al-khawalde Alayn’ Al-marddyah A. , Abukhalil Mohammad H. , Jghef Muthana M. , Alfwuaires Manal A. , Alaryani Fatima S. , Aladaileh Saleem H. , Algefare Abdulmohsen I. , Karimulla Shaik , Alasmari Fawaz , Aldal’in Hammad Khalifeh , Alanezi Abdulkareem A. , Althunibat Osama Y.
Published: October 2022

Despite its effectiveness in treating inflammatory diseases and various malignancies, methotrexate (MTX) is well known to cause hepatotoxicity, which involves increased oxidative stress and inflammation, limiting its clinical use. Herein, we looked into the effect of punicalagin (PU), a polyphenolic molecule having a variety of health-promoting attributes, on MTX-induced hepatotoxicity in mice. PU (25 and 50 mg/kg/day) was given orally to the mice for 10 days, while a single dose of MTX (20 mg/kg) was injected intraperitoneally (i.p.) at day 7. The MTX-induced liver damage was demonstrated by remarkably higher transaminases (ALT and AST), ALP, and LDH, as well as significant histological alterations in hepatic tissues. MTX-injected mice also demonstrated increases in hepatic oxidative stress markers, including malondialdehyde (MDA) and nitric oxide (NO), with a concordant drop in glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities. PU significantly attenuated the MTX-induced serum transaminases, ALP and LDH elevations, and hepatic oxidative stress measures and boosted antioxidant defenses in the liver. Moreover, the liver of MTX-treated mice showed increases in NF-κB p65 expression, pro-inflammatory cytokine (IL-6 and TNF-α) levels, and pro-apoptotic protein (caspase-3 and Bax) expression, whereas Bcl-2 and Nrf2 expressions were reduced, which were all attenuated by PU treatment. Collectively, PU inhibits oxidative damage, inflammation, and apoptosis and upregulates Nrf2 in the liver of MTX-induced mice. Thus, these findings suggest that PU may have great therapeutic potential for the prevention of MTX-induced hepatotoxicity, pending further exploration in upcoming studies.
The Binding of CSL Proteins to Either Co-Activators or Co-Repressors Protects from Proteasomal Degradation Induced by MAPK-Dependent Phosphorylation
Authors: Fechner Johannes , Ketelhut Manuela , Maier Dieter , Preiss Anette , Nagel Anja C.
Published: October 2022

The primary role of Notch is to specify cellular identities, whereby the cells respond to amazingly small changes in Notch signalling activity. Hence, dosage of Notch components is crucial to regulation. Central to Notch signal transduction are CSL proteins: together with respective cofactors, they mediate the activation or the silencing of Notch target genes. CSL proteins are extremely similar amongst species regarding sequence and structure. We noticed that the fly homologue suppressor of hairless (Su(H)) is stabilised in transcription complexes. Using specific transgenic fly lines and HeLa RBPJKO cells we provide evidence that Su(H) is subjected to proteasomal degradation with a half-life of about two hours if not protected by binding to co-repressor hairless or co-activator Notch. Moreover, Su(H) stability is controlled by MAPK-dependent phosphorylation, matching earlier data for RBPJ in human cells. The homologous murine and human RBPJ proteins, however, are largely resistant to degradation in our system. Mutating presumptive protein contact sites, however, sensitised RBPJ for proteolysis. Overall, our data highlight the similarities in the regulation of CSL protein stability across species and imply that turnover of CSL proteins may be a conserved means of regulating Notch signalling output directly at the level of transcription.
Identification of miRNAs Mediating Seed Storability of Maize during Germination Stage by High-Throughput Sequencing, Transcriptome and Degradome Sequencing
Authors: Song Yongfeng , Lv Zhichao , Wang Yue , Li Chunxiang , Jia Yue , Zhu Yong , Cao Mengna , Zhou Yu , Zeng Xing , Wang Zhenhua , Zhang Lin , Di Hong
Published: October 2022

Seed storability is an important trait for improving grain quality and germplasm conservation, but little is known about the regulatory mechanisms and gene networks involved. MicroRNAs (miRNAs) are small non-coding RNAs regulating the translation and accumulation of their target mRNAs by means of sequence complementarity and have recently emerged as critical regulators of seed germination. Here, we used the germinating embryos of two maize inbred lines with significant differences in seed storability to identify the miRNAs and target genes involved. We identified a total of 218 previously known and 448 novel miRNAs by miRNA sequencing and degradome analysis, of which 27 known and 11 newly predicted miRNAs are differentially expressed in two maize inbred lines, as measured by Gene Ontology (GO) enrichment analysis. We then combined transcriptome sequencing and real-time quantitative polymerase chain reaction (RT-PCR) to screen and confirm six pairs of differentially expressed miRNAs associated with seed storability, along with their negative regulatory target genes. The enrichment analysis suggested that the miRNAs/target gene mediation of seed storability occurs via the ethylene activation signaling pathway, hormone synthesis and signal transduction, as well as plant organ morphogenesis. Our results should help elucidate the mechanisms through which miRNAs are involved in seed storability in maize.
Identification of Novel Nucleocapsid Chimeric Proteins Inhibiting HIV-1 Replication
Authors: Kim Hae-In , Kim Ga-Na , Yu Kyung-Lee , Park Seong-Hyun , You Ji Chang
Published: October 2022

The positive transcription elongation factor b (P-TEFb) is an essential factor that induces transcription elongation and is also negatively regulated by the cellular factor HEXIM1. Previously, the chimeric protein HEXIM1-Tat (HT) was demonstrated to inhibit human immunodeficiency virus-1 (HIV)-1 transcription. In this study, we attempted to develop an improved antiviral protein that specifically binds viral RNA (vRNA) by fusing HT to HIV-1 nucleocapsid (NC). Thus, we synthesized NC-HEXIM1-Tat (NHT) and HEXIM1-Tat-NC (HTN). NHT and HTN inhibited virus proliferation more effectively than HT, and they did not attenuate the function of HT. Notably, NHT and HTN inhibited the infectivity of the progeny virus, whereas HT had no such effect. NHT and HTN selectively and effectively interacted with vRNA and inhibited the proper packaging of the HIV-1 genome. Taken together, our results illustrated that the novel NC-fused chimeric proteins NHT and HTN display novel mechanisms of anti-HIV effects by inhibiting both HIV-1 transcription and packaging.
Complex Relationships between HIV-1 Integrase and Its Cellular Partners
Authors: Rozina Anna , Anisenko Andrey , Kikhai Tatiana , Silkina Maria , Gottikh Marina
Published: October 2022

RNA viruses, in pursuit of genome miniaturization, tend to employ cellular proteins to facilitate their replication. HIV-1, one of the most well-studied retroviruses, is not an exception. There is numerous evidence that the exploitation of cellular machinery relies on nucleic acid-protein and protein-protein interactions. Apart from Vpr, Vif, and Nef proteins that are known to regulate cellular functioning via interaction with cell components, another viral protein, integrase, appears to be crucial for proper virus-cell dialog at different stages of the viral life cycle. The goal of this review is to summarize and systematize existing data on known cellular partners of HIV-1 integrase and their role in the HIV-1 life cycle.
Bioactive Lipodepsipeptides Produced by Bacteria and Fungi
Authors: Evidente Antonio
Published: October 2022

Natural products are a vital source for agriculture, medicine, cosmetics and other fields. Lipodepsipeptides (LPDs) are a wide group of natural products distributed among living organisms such as bacteria, fungi, yeasts, virus, insects, plants and marine organisms. They are a group of compounds consisting of a lipid connected to a peptide, which are able to self-assemble into several different structures. They have shown different biological activities such as phytotoxic, antibiotic, antiviral, antiparasitic, antifungal, antibacterial, immunosuppressive, herbicidal, cytotoxic and hemolytic activities. Their biological activities seem to be due to their interactions with the plasma membrane (MP) because they are able to mimic the architecture of the native membranes interacting with their hydrophobic segment. LPDs also have surfactant properties. The review has been focused on the lipodepsipeptides isolated from fungal and bacterial sources, on their biological activity, on the structure–activity relationships of some selected LPD subgroups and on their potential application in agriculture and medicine. The chemical and biological characterization of lipodepsipeptides isolated in the last three decades and findings that resulted from SCI-FINDER research are reported. A critical evaluation of the most recent reviews dealing with the same argument has also been described.
Analyses of circRNA Expression throughout the Light-Dark Cycle Reveal a Strong Regulation of Cdr1as, Associated with Light Entrainment in the SCN
Authors: Ivanov Andranik , Mattei Daniele , Radscheit Kathrin , Compagnion Anne-Claire , Pett Jan Patrick , Herzel Hanspeter , Paolicelli Rosa Chiara , Piwecka Monika , Meyer Urs , Beule Dieter
Published: October 2022

Circular RNAs (circRNAs) are a large class of relatively stable RNA molecules that are highly expressed in animal brains. Many circRNAs have been associated with CNS disorders accompanied by an aberrant wake-sleep cycle. However, the regulation of circRNAs in brain homeostasis over daily light-dark (LD) cycles has not been characterized. Here, we aim to quantify the daily expression changes of circRNAs in physiological conditions in healthy adult animals. Using newly generated and public RNA-Seq data, we monitored circRNA expression throughout the 12:12 h LD cycle in various mouse brain regions. We identified that Cdr1as, a conserved circRNA that regulates synaptic transmission, is highly expressed in the suprachiasmatic nucleus (SCN), the master circadian pacemaker. Despite its high stability, Cdr1as has a very dynamic expression in the SCN throughout the LD cycle, as well as a significant regulation in the hippocampus following the entry into the dark phase. Computational integration of different public datasets predicted that Cdr1as is important for regulating light entrainment in the SCN. We hypothesize that the expression changes of Cdr1as in the SCN, particularly during the dark phase, are associated with light-induced phase shifts. Importantly, our work revises the current beliefs about natural circRNA stability and suggests that the time component must be considered when studying circRNA regulation.
Blood-Brain Barrier Disintegration in Growth-Restricted Fetuses with Brain Sparing Effect
Authors: Misan Natalia , Michalak Sławomir , Kapska Katarzyna , Osztynowicz Krystyna , Ropacka-Lesiak Mariola
Published: October 2022

The endothelial cells of the blood-brain barrier adhere closely, which is provided by tight junctions (TJs). The aim of the study was to assess the damage to the endothelial TJs in pregnancy, complicated by fetal growth restriction (FGR) and circulatory centralization (brain-sparing effect, BS). The serum concentrations of NR1 subunit of the N-methyl-D-aspartate receptor (NR1), nucleoside diphosphate kinase A (NME1), S100 calcium-binding protein B (S100B), occludin (OCLN), claudin-5 (CLN5), and zonula occludens protein – 1 (zo-1), and the placental expressions of OCLN, claudin-4 (CLN4), CLN5, and zo-1 were assessed with ELISA. The significantly higher serum NME1 concentrations and the serum CLN5/zo-1 index were observed in FGR pregnancy with BS, as compared to the FGR group without BS. The FGR newborns with BS were about 20 times more likely to develop an intraventricular hemorrhage (IVH) than the FGR infants without BS. The cerebroplacental ratio (CPR) allowed to predict the IVH in growth-restricted fetuses. The significantly lower placental CLN4 expression was observed in the FGR group with BS and who postnatally developed an IVH, as compared to the growth-restricted infants with BS without IVH signs. Pregnancy complicated by FGR and BS is associated with the destabilization of the fetal blood-brain barrier. The IVH in newborns is reflected in the inhibition of the placental CLN4 expression, which may be a useful marker in the prediction of an IVH among growth-restricted fetuses.
Complementary Dual Approach for In Silico Target Identification of Potential Pharmaceutical Compounds in Cystic Fibrosis
Authors: Vinhoven Liza , Stanke Frauke , Hafkemeyer Sylvia , Nietert Manuel Manfred
Published: October 2022

Cystic fibrosis is a genetic disease caused by mutation of the CFTR gene, which encodes a chloride and bicarbonate transporter in epithelial cells. Due to the vast range of geno- and phenotypes, it is difficult to find causative treatments; however, small-molecule therapeutics have been clinically approved in the last decade. Still, the search for novel therapeutics is ongoing, and thousands of compounds are being tested in different assays, often leaving their mechanism of action unknown. Here, we bring together a CFTR-specific compound database (CandActCFTR) and systems biology model (CFTR Lifecycle Map) to identify the targets of the most promising compounds. We use a dual inverse screening approach, where we employ target- and ligand-based methods to suggest targets of 309 active compounds in the database amongst 90 protein targets from the systems biology model. Overall, we identified 1038 potential target–compound pairings and were able to suggest targets for all 309 active compounds in the database.
The Influence of Prenatal Exposure to Quetiapine Fumarate on the Development of Dopaminergic Neurons in the Ventral Midbrain of Mouse Embryos
Authors: Alsanie Walaa F. , Abdelrahman Sherin , Alhomrani Majid , Gaber Ahmed , Alosimi Ebtisam Abdulah , Habeeballah Hamza , Alkhatabi Heba A. , Felimban Raed I. , Hauser Charlotte A. E. , Tayeb Hossam H. , Alamri Abdulhakeem S. , Alamri Abdulwahab , Raafat Bassem M. , Alswat Khaled A. , Althobaiti Yusuf S. , Asiri Yousif A.
Published: October 2022

The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase(Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations.
Functional Characterization of Heat Shock Factor (CrHsf) Families Provide Comprehensive Insight into the Adaptive Mechanisms of Canavalia rosea (Sw.) DC. to Tropical Coral Islands
Authors: Zhang Mei , Wang Zhengfeng , Jian Shuguang
Published: October 2022

Heat shock transcription factors (Hsfs) are key regulators in plant heat stress response, and therefore, they play vital roles in signal transduction pathways in response to environmental stresses, as well as in plant growth and development. Canavalia rosea (Sw.) DC. is an extremophile halophyte with good adaptability to high temperature and salt-drought tolerance, and it can be used as a pioneer species for ecological reconstruction on tropical coral islands. To date, very little is known regarding the functions of Hsfs in the adaptation mechanisms of plant species with specialized habitats, especially in tropical leguminous halophytes. In this study, a genome-wide analysis was performed to identify all the Hsfs in C. rosea based on whole-genome sequencing information. The chromosomal location, protein domain or motif organization, and phylogenetic relationships of 28 CrHsfs were analyzed. Promoter analyses indicated that the expression levels of different CrHsfs were precisely regulated. The expression patterns also revealed clear transcriptional changes among different C. rosea tissues, indicating that the regulation of CrHsf expression varied among organs in a developmental or tissue-specific manner. Furthermore, the expression levels of most CrHsfs in response to environmental conditions or abiotic stresses also implied a possible positive regulatory role of this gene family under abiotic stresses, and suggested roles in adaptation to specialized habitats such as tropical coral islands. In addition, some CrHsfAs were cloned and their possible roles in abiotic stress tolerance were functionally characterized using a yeast expression system. The CrHsfAs significantly enhanced yeast survival under thermal and oxidative stress challenges. Our results contribute to a better understanding of the plant Hsf gene family and provide a basis for further study of CrHsf functions in environmental thermotolerance. Our results also provide valuable information on the evolutionary relationships among CrHsf genes and the functional characteristics of the gene family. These findings are beneficial for further research on the natural ecological adaptability of C. rosea to tropical environments.
Differential Analysis of Gly211Val and Gly286Val Mutations Affecting Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) in Congenital Pseudomyotonia Romagnola Cattle
Authors: Akyürek Eylem Emek , Busato Francesca , Murgiano Leonardo , Bianchini Elisa , Carotti Marcello , Sandonà Dorianna , Drögemüller Cord , Gentile Arcangelo , Sacchetto Roberta
Published: October 2022

Congenital pseudomyotonia in cattle (PMT) is a rare skeletal muscle disorder, clinically characterized by stiffness and by delayed muscle relaxation after exercise. Muscle relaxation impairment is due to defective content of the Sarco(endo)plasmic Reticulum Ca2+ ATPase isoform 1 (SERCA1) protein, caused by missense mutations in the ATP2A1 gene. PMT represents the only mammalian model of human Brody myopathy. In the Romagnola breed, two missense variants occurring in the same allele were described, leading to Gly211Val and Gly286Val (G211V/G286V) substitutions. In this study, we analyzed the consequences of G211V and G286V mutations. Results support that the reduced amount of SERCA1 is a consequence of the G211V mutation, the G286V mutation almost being benign and the ubiquitin–proteasome system (UPS) being involved. After blocking the proteasome using a proteasome inhibitor, we found that the G211V mutant accumulates in cells at levels comparable to those of WT SERCA1. Our conclusion is that G211/286V mutations presumably originate in a folding-defective SERCA1 protein, recognized and diverted to degradation by UPS, although still catalytically functional, and that the main role is played by G211V mutation. Rescue of mutated SERCA1 to the sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca2+ concentration and prevent the appearance of pathological signs, paving the way for a possible therapeutic approach against Brody disease.
Clostridioides difficile Flagellin Activates the Intracellular NLRC4 Inflammasome
Authors: Chebly Hiba , Marvaud Jean-Christophe , Safa Layale , Elkak Assem Khalil , Kobeissy Philippe Hussein , Kansau Imad , Larrazet Cécile
Published: October 2022

Clostridioides difficile (C. difficile), is a major cause of nosocomial diarrhea and colitis. C. difficile flagellin FliC contributes toxins to gut inflammation by interacting with the immune Toll-like receptor 5 (TLR5) to activate nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways. Flagella of intracellular pathogens can activate the NLR family CARD domain-containing protein 4 (NLRC4) inflammasome pathway. In this study, we assessed whether flagellin of the extracellular bacterium C. difficile internalizes into epithelial cells and activates the NLRC4 inflammasome. Confocal microscopy showed internalization of recombinant green fluorescent protein (GFP)-FliC into intestinal Caco-2/TC7 cell line. Full-length GFP-FliC activates NLRC4 in Caco-2/TC7 cells in contrast to truncated GFP-FliC lacking the C-terminal region recognized by the inflammasome. FliC induced cleavage of pro-caspase-1 into two subunits, p20 and p10 as well as gasdermin D (GSDMD), suggesting the caspase-1 and NLRC4 inflammasome activation. In addition, colocalization of GFP-FliC and pro-caspase-1 was observed, indicating the FliC-dependent NLRC4 inflammasome activation. Overexpression of the inflammasome-related interleukin (interleukin (IL)-1β, IL-18, and IL-33) encoding genes as well as increasing of the IL-18 synthesis was detected after cell stimulation. Inhibition of I-kappa-B kinase alpha (IKK-α) decreased the FliC-dependent inflammasome interleukin gene expression suggesting a role of the NF-κB pathway in regulating inflammasome. Altogether, these results suggest that FliC internalizes into the Caco-2/TC7 cells and activates the intracellular NLRC4 inflammasome thus contributing to the inflammatory process of C. difficile infection.
Characterization of the Human Papillomavirus 16 Oncogenes in K14HPV16 Mice: Sublineage A1 Drives Multi-Organ Carcinogenesis
Authors: Cochicho Daniela , Nunes Alexandra , Gomes João Paulo , Martins Luís , Cunha Mário , Medeiros-Fonseca Beatriz , Oliveira Paula , Bastos Margarida M. S. M. , Medeiros Rui , Mendonça Joana , Vieira Luis , Gil da Costa Rui M. , Felix Ana
Published: October 2022

The study of human papillomavirus (HPV)-induced carcinogenesis uses multiple in vivo mouse models, one of which relies on the cytokeratin 14 gene promoter to drive the expression of all HPV early oncogenes. This study aimed to determine the HPV16 variant and sublineage present in the K14HPV16 mouse model. This information can be considered of great importance to further enhance this K14HPV16 model as an essential research tool and optimize its use for basic and translational studies. Our study evaluated HPV DNA from 17 samples isolated from 4 animals, both wild-type (n = 2) and HPV16-transgenic mice (n = 2). Total DNA was extracted from tissues and the detection of HPV16 was performed using a qPCR multiplex. HPV16-positive samples were subsequently whole-genome sequenced by next-generation sequencing techniques. The phylogenetic positioning clearly shows K14HPV16 samples clustering together in the sub-lineage A1 (NC001526.4). A comparative genome analysis of K14HPV16 samples revealed three mutations to the human papillomaviruses type 16 sublineage A1 representative strain. Knowledge of the HPV 16 variant is fundamental, and these findings will allow the rational use of this animal model to explore the role of the A1 sublineage in HPV-driven cancer.
Role of B Lymphocytes in the Pathogenesis of NAFLD: A 2022 Update
Authors: Deng Chu-Jun , Lo Tak-Ho , Chan Ka-Ying , Li Xiang , Wu Meng-Yao , Xiang Zou , Wong Chi-Ming
Published: October 2022

Non-alcoholic fatty liver disease and its related complications are becoming one of the most important health problems globally. The liver functions as both a metabolic and an immune organ. The crosstalk between hepatocytes and intrahepatic immune cells plays a key role in coordinating a dual function of the liver in terms of the protection of the host from antigenic overload as a result of receiving nutrients and gut microbiota antigenic stimulation via facilitating immunologic tolerance. B cells are the most abundant lymphocytes in the liver. The crucial role of intrahepatic B cells in energy metabolism under different immune conditions is now emerging in the literature. The accumulating evidence has demonstrated that the antibodies and cytokines produced by B cells in the microenvironment play key and distinct roles in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Herein, we have aimed to consolidate and update the current knowledge about the pathophysiological roles of B cells as well as the underlying mechanisms in energy metabolism. Understanding how B cells can exacerbate and suppress liver damage by exploiting the antibodies and cytokines they produce will be of great importance for designing B-cell targeting therapies to treat various liver diseases.
Unraveling the Potential Role of NEDD4-like E3 Ligases in Cancer
Authors: Jayaprakash Sujitha , Hegde Mangala , BharathwajChetty Bandari , Girisa Sosmitha , Alqahtani Mohammed S. , Abbas Mohamed , Sethi Gautam , Kunnumakkara Ajaikumar B.
Published: October 2022

Cancer is a deadly disease worldwide, with an anticipated 19.3 million new cases and 10.0 million deaths occurring in 2020 according to GLOBOCAN 2020. It is well established that carcinogenesis and cancer development are strongly linked to genetic changes and post-translational modifications (PTMs). An important PTM process, ubiquitination, regulates every aspect of cellular activity, and the crucial enzymes in the ubiquitination process are E3 ubiquitin ligases (E3s) that affect substrate specificity and must therefore be carefully regulated. A surfeit of studies suggests that, among the E3 ubiquitin ligases, neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4)/NEDD4-like E3 ligases show key functions in cellular processes by controlling subsequent protein degradation and substrate ubiquitination. In addition, it was demonstrated that NEDD4 mainly acts as an oncogene in various cancers, but also plays a tumor-suppressive role in some cancers. In this review, to comprehend the proper function of NEDD4 in cancer development, we summarize its function, both its tumor-suppressive and oncogenic role, in multiple types of malignancies. Moreover, we briefly explain the role of NEDD4 in carcinogenesis and progression, including cell survival, cell proliferation, autophagy, cell migration, invasion, metastasis, epithelial-mesenchymal transition (EMT), chemoresistance, and multiple signaling pathways. In addition, we briefly explain the significance of NEDD4 as a possible target for cancer treatment. Therefore, we conclude that targeting NEDD4 as a therapeutic method for treating human tumors could be a practical possibility.
Role of Vitronectin and Its Receptors in Neuronal Function and Neurodegenerative Diseases
Authors: Ruzha Yelizhati , Ni Junjun , Quan Zhenzhen , Li Hui , Qing Hong
Published: October 2022

Vitronectin (VTN), a multifunctional glycoprotein with various physiological functions, exists in plasma and the extracellular matrix. It is known to be involved in the cell attachment, spreading and migration through binding to the integrin receptor, mainly via the RGD sequence. VTN is also widely used in the maintenance and expansion of pluripotent stem cells, but its effects go beyond that. Recent evidence shows more functions of VTN in the nervous system as it participates in neural differentiation, neuronutrition and neurogenesis, as well as in regulating axon size, supporting and guiding neurite extension. Furthermore, VTN was proved to play a key role in protecting the brain as it can reduce the permeability of the blood–brain barrier by interacting with integrin receptors in vascular endothelial cells. Moreover, evidence suggests that VTN is associated with neurodegenerative diseases, such as Alzheimer’s disease, but its function has not been fully understood. This review summarizes the functions of VTN and its receptors in neurons and describes the role of VTN in the blood–brain barrier and neurodegenerative diseases.
The Yin/Yang Balance of Communication between Sensory Neurons and Macrophages in Traumatic Peripheral Neuropathic Pain
Authors: Gheorghe Roxana-Olimpia , Grosu Andreea Violeta , Bica-Popi Melania , Ristoiu Violeta
Published: October 2022

Traumatic peripheral neuropathic pain is a complex syndrome caused by a primary lesion or dysfunction of the peripheral nervous system. Secondary to the lesion, resident or infiltrating macrophages proliferate and initiate a cross-talk with the sensory neurons, at the level of peripheral nerves and sensory ganglia. The neuron–macrophage interaction, which starts very early after the lesion, is very important for promoting pain development and for initiating changes that will facilitate the chronicization of pain, but it also has the potential to facilitate the resolution of injury-induced changes and, consequently, promote the reduction of pain. This review is an overview of the unique characteristics of nerve-associated macrophages in the peripheral nerves and sensory ganglia and of the molecules and signaling pathways involved in the neuro-immune cross-talk after a traumatic lesion, with the final aim of better understanding how the balance between pro- and anti-nociceptive dialogue between neurons and macrophages may be modulated for new therapeutic approaches.
Transport in the Brain Extracellular Space: Diffusion, but Which Kind?
Authors: Postnikov Eugene B. , Lavrova Anastasia I. , Postnov Dmitry E.
Published: October 2022

The mechanisms of transport of substances in the brain parenchyma have been a hot topic in scientific discussion in the past decade. This discussion was triggered by the proposed glymphatic hypothesis, which assumes a directed flow of cerebral fluid within the parenchyma, in contrast to the previous notion that diffusion is the main mechanism. However, when discussing the issue of “diffusion or non-diffusion”, much less attention was given to the question that diffusion itself can have a different character. In our opinion, some of the recently published results do not fit into the traditional understanding of diffusion. In this regard, we outline the relevant new theoretical approaches on transport processes in complex random media such as concepts of diffusive diffusivity and time-dependent homogenization, which expands the understanding of the forms of transport of substances based on diffusion.
Interoperable Test Cases to Mediate between Supply Chain’s Test Processes
Authors: Franke Marco , Thoben Klaus-Dieter
Published: October 2022

Heterogeneous test processes with respect to test script languages are an integral part of the development process of mechatronic systems that are carried out in supply chains. Up to now, test cases are not exchangeable between test processes because interoperability is not given. The developed approach enables the source-to-source compiling of test cases between test script languages. With this, the interoperability of test cases is achieved, and seamless integration within the supply chain is possible. The developed approach uses transcompilers as a baseline. In doing so, an interoperability model for test cases is presented. Based on the interoperability model, a source-to-source compiling for test cases is shown. The outcome is a prototype that handles test script languages, which are different with respect to type safety and applied programming paradigms. The approach ensures that test cases are still understandable and usable for test reports. The evaluation confirms the translation capabilities as well as the readability of the generated test case for the high-lift scenario from aviation. The interoperability of test cases within the supply chain enables the formalisation of procedural test knowledge to be used in a broad range of future scenarios, such as test automation, digital twins and predictive maintenance.
Natural Enemies and Biological Control of Stink Bugs (Hemiptera: Heteroptera) in North America
Authors: Ademokoya Blessing , Athey Kacie , Ruberson John
Published: October 2022

Stink bugs comprise a significant and costly pest complex for numerous crops in the US, including row crops, vegetables, and tree fruits and nuts. Most management relies on the use of broad-spectrum and disruptive insecticides with high human and environmental risks associated with them. Growing concerns about pesticide resistance in stink bugs are forcing pest managers to explore safer and more sustainable options. Here, we review the diverse suite of natural enemies of stink bugs in the US, noting that the egg and the late nymphal and adult stages of stink bugs are the most commonly attacked by parasitoids, whereas eggs and young nymphs are the stages most commonly attacked by predators. The effectiveness of stink bugs’ natural enemies varies widely with stink bug species and habitats, influencing the biological control of stink bugs across crops. Historically, biological control of stink bugs has focused on introduction of exotic natural enemies against exotic stink bugs. Conservation and augmentation methods of biological control have received less attention in the US, although there may be good opportunities to utilize these approaches. We identify some considerations for the current and future use of biological control for stink bugs, including the potential for area-wide management approaches.