bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut Serpinome: Emerging Evidence in IBD
Authors: Mkaouar Héla , Mariaule Vincent , Rhimi Soufien , Hernandez Juan , Kriaa Aicha , Jablaoui Amin , Akermi Nizar , Maguin Emmanuelle , Lesner Adam , Korkmaz Brice , Rhimi Moez
Published: June 2021

Inflammatory bowel diseases (IBD) are incurable disorders whose prevalence and global socioeconomic impact are increasing. While the role of host genetics and immunity is well documented, that of gut microbiota dysbiosis is increasingly being studied. However, the molecular basis of the dialogue between the gut microbiota and the host remains poorly understood. Increased activity of serine proteases is demonstrated in IBD patients and may contribute to the onset and the maintenance of the disease. The intestinal proteolytic balance is the result of an equilibrium between the proteases and their corresponding inhibitors. Interestingly, the serine protease inhibitors (serpins) encoded by the host are well reported; in contrast, those from the gut microbiota remain poorly studied. In this review, we provide a concise analysis of the roles of serine protease in IBD physiopathology and we focus on the serpins from the gut microbiota (gut serpinome) and their relevance as a promising therapeutic approach.
Regulatory Potential of Competing Endogenous RNAs in Myotonic Dystrophies
Authors: Koscianska Edyta , Kozlowska Emilia , Fiszer Agnieszka
Published: June 2021

Non-coding RNAs (ncRNAs) have been reported to be implicated in cell fate determination and various human diseases. All ncRNA molecules are emerging as key regulators of diverse cellular processes; however, little is known about the regulatory interaction among these various classes of RNAs. It has been proposed that the large-scale regulatory network across the whole transcriptome is mediated by competing endogenous RNA (ceRNA) activity attributed to both protein-coding and ncRNAs. ceRNAs are considered to be natural sponges of miRNAs that can influence the expression and availability of multiple miRNAs and, consequently, the global mRNA and protein levels. In this review, we summarize the current understanding of the role of ncRNAs in two neuromuscular diseases, myotonic dystrophy type 1 and 2 (DM1 and DM2), and the involvement of expanded CUG and CCUG repeat-containing transcripts in miRNA-mediated RNA crosstalk. More specifically, we discuss the possibility that long repeat tracts present in mutant transcripts can be potent miRNA sponges and may affect ceRNA crosstalk in these diseases. Moreover, we highlight practical information related to innovative disease modelling and studying RNA regulatory networks in cells. Extending knowledge of gene regulation by ncRNAs, and of complex regulatory ceRNA networks in DM1 and DM2, will help to address many questions pertinent to pathogenesis and treatment of these disorders; it may also help to better understand general rules of gene expression and to discover new rules of gene control.
Photo-Polymerization Damage Protection by Hydrogen Sulfide Donors for 3D-Cell Culture Systems Optimization
Authors: Buonvino Silvia , Ciocci Matteo , Seliktar Dror , Melino Sonia
Published: June 2021

Photo-polymerized hydrogels are ideally suited for stem-cell based tissue regeneration and three dimensional (3D) bioprinting because they can be highly biocompatible, injectable, easy to use, and their mechanical and physical properties can be controlled. However, photo-polymerization involves the use of potentially toxic photo-initiators, exposure to ultraviolet light radiation, formation of free radicals that trigger the cross-linking reaction, and other events whose effects on cells are not yet fully understood. The purpose of this study was to examine the effects of hydrogen sulfide (H2S) in mitigating cellular toxicity of photo-polymerization caused to resident cells during the process of hydrogel formation. H2S, which is the latest discovered member of the gasotransmitter family of gaseous signalling molecules, has a number of established beneficial properties, including cell protection from oxidative damage both directly (by acting as a scavenger molecule) and indirectly (by inducing the expression of anti-oxidant proteins in the cell). Cells were exposed to slow release H2S treatment using pre-conditioning with glutathione-conjugated-garlic extract in order to mitigate toxicity during the photo-polymerization process of hydrogel formation. The protective effects of the H2S treatment were evaluated in both an enzymatic model and a 3D cell culture system using cell viability as a quantitative indicator. The protective effect of H2S treatment of cells is a promising approach to enhance cell survival in tissue engineering applications requiring photo-polymerized hydrogel scaffolds.
Molecular Characterization of a Rare Case of Bilateral Vitreoretinal T Cell Lymphoma through Vitreous Liquid Biopsy
Authors: Cani Andi K. , Toral Marcus A. , Balikov Daniel A. , Betz Bryan L. , Hu Kevin , Liu Chia-Jen , Prifti Matthew V. , Chinnaiyan Arul M. , Tomlins Scott A. , Mahajan Vinit B. , Rao Rajesh C.
Published: June 2021

Vitreoretinal lymphoma (VRL) is an uncommon eye malignancy, and VRLs of T cell origin are rare. They are difficult to treat, and their molecular underpinnings, including actionable genomic alterations, remain to be elucidated. At present, vitreous fluid liquid biopsies represent a valuable VRL sample for molecular analysis to study VRLs. In this study, we report the molecular diagnostic workup of a rare case of bilateral T cell VRL and characterize its genomic landscape, including identification of potentially targetable alterations. Using next-generation sequencing of vitreous-derived DNA with a pan-cancer 126-gene panel, we found a copy number gain of BRAF and copy number loss of tumor suppressor DNMT3A. To the best of our knowledge, this represents the first exploration of the T cell VRL cancer genome and supports vitreous liquid biopsy as a suitable approach for precision oncology treatments.
Loss of Nnt Increases Expression of Oxidative Phosphorylation Complexes in C57BL/6J Hearts
Authors: Williams Jack L. , Hall Charlotte L. , Meimaridou Eirini , Metherell Lou A.
Published: June 2021

Nicotinamide nucleotide transhydrogenase (NNT) is a proton pump in the inner mitochondrial membrane that generates reducing equivalents in the form of NAPDH, which can be used for anabolic pathways or to remove reactive oxygen species (ROS). A number of studies have linked NNT dysfunction to cardiomyopathies and increased risk of atherosclerosis; however, biallelic mutations in humans commonly cause a phenotype of adrenal insufficiency, with rare occurrences of cardiac dysfunction and testicular tumours. Here, we compare the transcriptomes of the hearts, adrenals and testes from three mouse models: the C57BL/6N, which expresses NNT; the C57BL/6J, which lacks NNT; and a third mouse, expressing the wild-type NNT sequence on the C57BL/6J background. We saw enrichment of oxidative phosphorylation genes in the C57BL/B6J in the heart and adrenal, possibly indicative of an evolved response in this substrain to loss of Nnt. However, differential gene expression was mainly driven by mouse background with some changes seen in all three tissues, perhaps reflecting underlying genetic differences between the C57BL/B6J and -6N substrains.
A cis-Acting Mutation in the PxABCG1 Promoter Is Associated with Cry1Ac Resistance in Plutella xylostella (L.)
Authors: Qin Jianying , Ye Fan , Xu Linzheng , Zhou Xuguo , Crickmore Neil , Zhou Xiaomao , Zhang Youjun , Guo Zhaojiang
Published: June 2021

The molecular mechanisms of insect resistance to Cry toxins generated from the bacterium Bacillus thuringiensis (Bt) urgently need to be elucidated to enable the improvement and sustainability of Bt-based products. Although downregulation of the expression of midgut receptor genes is a pivotal mechanism of insect resistance to Bt Cry toxins, the underlying transcriptional regulation of these genes remains elusive. Herein, we unraveled the regulatory mechanism of the downregulation of the ABC transporter gene PxABCG1 (also called Pxwhite), a functional midgut receptor of the Bt Cry1Ac toxin in Plutella xylostella. The PxABCG1 promoters of Cry1Ac-susceptible and Cry1Ac-resistant strains were cloned and analyzed, and they showed clear differences in activity. Subsequently, a dual-luciferase reporter assay, a yeast one-hybrid (Y1H) assay, and RNA interference (RNAi) experiments demonstrated that a cis-mutation in a binding site of the Hox transcription factor Antennapedia (Antp) decreased the promoter activity of the resistant strain and eliminated the binding and regulation of Antp, thereby enhancing the resistance of P. xylostella to the Cry1Ac toxin. These results advance our knowledge of the roles of cis- and trans-regulatory variations in the regulation of midgut Cry receptor genes and the evolution of Bt resistance, contributing to a more complete understanding of the Bt resistance mechanism.
The Impact of the Circadian Clock on Skin Physiology and Cancer Development
Authors: Lubov Janet , Cvammen William , Kemp Michael
Published: June 2021

Skin cancers are growing in incidence worldwide and are primarily caused by exposures to ultraviolet (UV) wavelengths of sunlight. UV radiation induces the formation of photoproducts and other lesions in DNA that if not removed by DNA repair may lead to mutagenesis and carcinogenesis. Though the factors that cause skin carcinogenesis are reasonably well understood, studies over the past 10–15 years have linked the timing of UV exposure to DNA repair and skin carcinogenesis and implicate a role for the body’s circadian clock in UV response and disease risk. Here we review what is known about the skin circadian clock, how it affects various aspects of skin physiology, and the factors that affect circadian rhythms in the skin. Furthermore, the molecular understanding of the circadian clock has led to the development of small molecules that target clock proteins; thus, we discuss the potential use of such compounds for manipulating circadian clock-controlled processes in the skin to modulate responses to UV radiation and mitigate cancer risk.
Activation of the Integrated Stress Response and ER Stress Protect from Fluorizoline-Induced Apoptosis in HEK293T and U2OS Cell Lines
Authors: Saura-Esteller José , Sánchez-Vera Ismael , Núñez-Vázquez Sonia , Cosialls Ana M. , Gama-Pérez Pau , Bhosale Gauri , Mendive-Tapia Lorena , Lavilla Rodolfo , Pons Gabriel , Garcia-Roves Pablo M. , Duchen Michael R. , Iglesias-Serret Daniel , Gil Joan
Published: June 2021

The prohibitin (PHB)-binding compound fluorizoline as well as PHB-downregulation activate the integrated stress response (ISR) in HEK293T and U2OS human cell lines. This activation is denoted by phosphorylation of eIF2α and increases in ATF4, ATF3, and CHOP protein levels. The blockage of the activation of the ISR by overexpression of GRP78, as well as an increase in IRE1 activity, indicate the presence of ER stress after fluorizoline treatment. The inhibition of the ER stress response in HEK293T and U2OS led to increased sensitivity to fluorizoline-induced apoptosis, indicating a pro-survival role of this pathway after fluorizoline treatment in these cell lines. Fluorizoline induced an increase in calcium concentration in the cytosol and the mitochondria. Finally, two different calcium chelators reduced fluorizoline-induced apoptosis in U2OS cells. Thus, we have found that fluorizoline causes increased ER stress and activation of the integrated stress response, which in HEK293T and U2OS cells are protective against fluorizoline-induced apoptosis.
Elucidating the Response of Crop Plants towards Individual, Combined and Sequentially Occurring Abiotic Stresses
Authors: Anwar Khalid , Joshi Rohit , Dhankher Om Parkash , Singla-Pareek Sneh L. , Pareek Ashwani
Published: June 2021

In nature, plants are exposed to an ever-changing environment with increasing frequencies of multiple abiotic stresses. These abiotic stresses act either in combination or sequentially, thereby driving vegetation dynamics and limiting plant growth and productivity worldwide. Plants’ responses against these combined and sequential stresses clearly differ from that triggered by an individual stress. Until now, experimental studies were mainly focused on plant responses to individual stress, but have overlooked the complex stress response generated in plants against combined or sequential abiotic stresses, as well as their interaction with each other. However, recent studies have demonstrated that the combined and sequential abiotic stresses overlap with respect to the central nodes of their interacting signaling pathways, and their impact cannot be modelled by swimming in an individual extreme event. Taken together, deciphering the regulatory networks operative between various abiotic stresses in agronomically important crops will contribute towards designing strategies for the development of plants with tolerance to multiple stress combinations. This review provides a brief overview of the recent developments in the interactive effects of combined and sequentially occurring stresses on crop plants. We believe that this study may improve our understanding of the molecular and physiological mechanisms in untangling the combined stress tolerance in plants, and may also provide a promising venue for agronomists, physiologists, as well as molecular biologists.
A Signature of Four Circulating microRNAs as Potential Biomarkers for Diagnosing Early-Stage Breast Cancer
Authors: Itani Maha M. , Nassar Farah J. , Tfayli Arafat H. , Talhouk Rabih S. , Chamandi Ghada K. , Itani Abdul Rahman S. , Makoukji Joelle , Boustany Rose-Mary N. , Hou Lifang , Zgheib Nathalie K. , Nasr Rihab R.
Published: June 2021

Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation. In this study, we investigated the expression of 12 microRNA (miR-21/miR-155/miR-23a/miR-130a/miR-145/miR-425-5p/miR-139-5p/miR-451/miR-195/miR-125b/miR-100, and miR-182) in the plasma of 41 newly diagnosed Lebanese BC patients with early invasive ductal carcinoma as compared with 32 healthy controls. Total RNA was extracted from plasma, and expression levels of miRNA of interest were measured using RT-qPCR followed by statistical analysis; miR-21, miR-155, miR-23a, miR-130a, miR-145, miR-425-5p, and miR-139-5p were significantly upregulated and miR-451 was significantly downregulated, in the plasma of BC patients as compared with healthy controls. The positively correlated miR-23a, miR-21, and miR-130a had a high diagnostic accuracy (86%). Importantly, the combination of miR-145/miR-425-5p/miR-139-5p/miR-130a scored the highest diagnostic accuracy of 95% with AUC = 0.97 (sensitivity 97% and specificity 91%). MicroRNAs are promising non-invasive diagnostic biomarkers for early-stage BC with the panel of miR-145/miR-425-5p/miR-139-5p/miR-130a having the highest diagnostic accuracy.
Cerebral Pericytes and Endothelial Cells Communicate through Inflammasome-Dependent Signals
Authors: Kozma Mihály , Mészáros Ádám , Nyúl-Tóth Ádám , Molnár Kinga , Costea Laura , Hernádi Zsófia , Fazakas Csilla , Farkas Attila E. , Wilhelm Imola , Krizbai István A.
Published: June 2021

By upregulation of cell adhesion molecules and secretion of proinflammatory cytokines, cells of the neurovascular unit, including pericytes and endothelial cells, actively participate in neuroinflammatory reactions. As previously shown, both cell types can activate inflammasomes, cerebral endothelial cells (CECs) through the canonical pathway, while pericytes only through the noncanonical pathway. Using complex in vitro models, we demonstrate here that the noncanonical inflammasome pathway can be induced in CECs as well, leading to a further increase in the secretion of active interleukin-1β over that observed in response to activation of the canonical pathway. In parallel, a more pronounced disruption of tight junctions takes place. We also show that CECs respond to inflammatory stimuli coming from both the apical/blood and the basolateral/brain directions. As a result, CECs can detect factors secreted by pericytes in which the noncanonical inflammasome pathway is activated and respond with inflammatory activation and impairment of the barrier properties. In addition, upon sensing inflammatory signals, CECs release inflammatory factors toward both the blood and the brain sides. Consequently, CECs activate pericytes by upregulating their expression of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome-forming pattern recognition receptor. In conclusion, cerebral pericytes and endothelial cells mutually activate each other in inflammation.
Accumulation Dynamics of Transcripts and Proteins of Cold-Responsive Genes in Fragaria vesca Genotypes of Differing Cold Tolerance
Authors: Fattash Isam , Deitch Zachary , Njah Relindis , Osuagwu Nelson , Mageney Vera , Wilson Robert C. , Davik Jahn , Alsheikh Muath , Randall Stephen
Published: June 2021

Identifying and characterizing cold responsive genes in Fragaria vesca associated with or responsible for low temperature tolerance is a vital part of strawberry cultivar development. In this study we have investigated the transcript levels of eight genes, two dehydrin genes, three putative ABA-regulated genes, two cold–inducible CBF genes and the alcohol dehydrogenase gene, extracted from leaf and crown tissues of three F. vesca genotypes that vary in cold tolerance. Transcript levels of the CBF/DREB1 transcription factor FvCBF1E exhibited stronger cold up-regulation in comparison to FvCBF1B.1 in all genotypes. Transcripts of FvADH were highly up-regulated in both crown and leaf tissues from all three genotypes. In the ‘ALTA’ genotype, FvADH transcripts were significantly higher in leaf than crown tissues and more than 10 to 20-fold greater than in the less cold-tolerant ‘NCGR1363’ and ‘FDP817’ genotypes. FvGEM, containing the conserved ABRE promoter element, transcript was found to be cold-regulated in crowns. Direct comparison of the kinetics of transcript and protein accumulation of dehydrins was scrutinized. In all genotypes and organs, the changes of XERO2 transcript levels generally preceded protein changes, while levels of COR47 protein accumulation preceded the increases in COR47 RNA in ‘ALTA’ crowns.
Effects of Aqueous Dispersions of C60, C70 and Gd@C82 Fullerenes on Genes Involved in Oxidative Stress and Anti-Inflammatory Pathways
Authors: Proskurnina Elena V. , Mikheev Ivan V. , Savinova Ekaterina A. , Ershova Elizaveta S. , Veiko Natalia N. , Kameneva Larisa V. , Dolgikh Olga A. , Rodionov Ivan V. , Proskurnin Mikhail A. , Kostyuk Svetlana V.
Published: June 2021

Background: Fullerenes and metallofullerenes can be considered promising nanopharmaceuticals themselves and as a basis for chemical modification. As reactive oxygen species homeostasis plays a vital role in cells, the study of their effect on genes involved in oxidative stress and anti-inflammatory responses are of particular importance. Methods: Human fetal lung fibroblasts were incubated with aqueous dispersions of C60, C70, and Gd@C82 in concentrations of 5 nM and 1.5 µM for 1, 3, 24, and 72 h. Cell viability, intracellular ROS, NOX4, NFκB, PRAR-γ, NRF2, heme oxygenase 1, and NAD(P)H quinone dehydrogenase 1 expression have been studied. Results & conclusion: The aqueous dispersions of C60, C70, and Gd@C82 fullerenes are active participants in reactive oxygen species (ROS) homeostasis. Low and high concentrations of aqueous fullerene dispersions (AFD) have similar effects. C70 was the most inert substance, C60 was the most active substance. All AFDs have both “prooxidant” and “antioxidant” effects but with a different balance. Gd@C82 was a substance with more pronounced antioxidant and anti-inflammatory properties, while C70 had more pronounced “prooxidant” properties.
PRMT5 Selective Inhibitor Enhances Therapeutic Efficacy of Cisplatin in Lung Cancer Cells
Authors: Bajbouj Khuloud , Ramakrishnan Rakhee K. , Saber-Ayad Maha , Omar Hany A. , Saheb Sharif-Askari Narjes , Shafarin Jasmin , Elmoselhi Adel B. , Ihmaid Ahmed , AlHaj Ali Suhib , Alalool Abdulla , Abdullah Reem , Hamid Qutayba
Published: June 2021

As a therapeutic approach, epigenetic modifiers have the potential to enhance the efficacy of chemotherapeutic agents. Protein arginine methyltransferase 5 (PRMT5), highly expressed in lung adenocarcinoma, was identified to be involved in tumorigenesis. In the current study, we examined the potential antineoplastic activity of PRMT5 inhibitor, arginine methyltransferase inhibitor 1 (AMI-1), and cisplatin on lung adenocarcinoma. Bioinformatic analyses identified apoptosis, DNA damage, and cell cycle progression as the main PRMT5-associated functional pathways, and survival analysis linked the increased PRMT5 gene expression to worse overall survival in lung adenocarcinoma. Combined AMI-1 and cisplatin treatment significantly reduced cell viability and induced apoptosis. Cell cycle arrest in A549 and DMS 53 cells was evident after AMI-1, and was reinforced after combination treatment. Western blot analysis showed a reduction in demethylation histone 4, a PRMT5- downstream target, after treatment with AMI-1 alone or in combination with cisplatin. While the combination approach tackled lung cancer cell survival, it exhibited cytoprotective abilities on HBEpC (normal epithelial cells). The survival of normal bronchial epithelial cells was not affected by using AMI-1. This study highlights evidence of novel selective antitumor activity of AMI-1 in combination with cisplatin in lung adenocarcinoma cells.
Silver- and Zinc-Decorated Polyurethane Ionomers with Tunable Hard/Soft Phase Segregation
Authors: Rapone Irene , Taresco Vincenzo , Lisio Valerio Di , Piozzi Antonella , Francolini Iolanda
Published: June 2021

Segmented polyurethane ionomers find prominent applications in the biomedical field since they can combine the good mechanical and biostability properties of polyurethanes (PUs) with the strong hydrophilicity features of ionomers. In this work, PU ionomers were prepared from a carboxylated diol, poly(tetrahydrofuran) (soft phase) and a small library of diisocyanates (hard phase), either aliphatic or aromatic. The synthesized PUs were characterized to investigate the effect of ionic groups and the nature of diisocyanate upon the structure–property relationship. Results showed how the polymer hard/soft phase segregation was affected by both the concentration of ionic groups and the type of diisocyanate. Specifically, PUs obtained with aliphatic diisocyanates possessed a hard/soft phase segregation stronger than PUs with aromatic diisocyanates, as well as greater bulk and surface hydrophilicity. In contrast, a higher content of ionic groups per polymer repeat unit promoted phase mixing. The neutralization of polymer ionic groups with silver or zinc further increased the hard/soft phase segregation and provided polymers with antimicrobial properties. In particular, the Zinc/PU hybrid systems possessed activity only against the Gram-positive Staphylococcus epidermidis while Silver/PU systems were active also against the Gram-negative Pseudomonas aeruginosa. The herein-obtained polyurethanes could find promising applications as antimicrobial coatings for different kinds of surfaces including medical devices, fabric for wound dressings and other textiles.
Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview
Authors: Timis Teodora Larisa , Florian Ioan Alexandru , Susman Sergiu , Florian Ioan Stefan
Published: June 2021

Aneurysms and vascular malformations of the brain represent an important source of intracranial hemorrhage and subsequent mortality and morbidity. We are only beginning to discern the involvement of microglia, the resident immune cell of the central nervous system, in these pathologies and their outcomes. Recent evidence suggests that activated proinflammatory microglia are implicated in the expansion of brain injury following subarachnoid hemorrhage (SAH) in both the acute and chronic phases, being also a main actor in vasospasm, considerably the most severe complication of SAH. On the other hand, anti-inflammatory microglia may be involved in the resolution of cerebral injury and hemorrhage. These immune cells have also been observed in high numbers in brain arteriovenous malformations (bAVM) and cerebral cavernomas (CCM), although their roles in these lesions are currently incompletely ascertained. The following review aims to shed a light on the most significant findings related to microglia and their roles in intracranial aneurysms and vascular malformations, as well as possibly establish the course for future research.
Complete Plastid and Mitochondrial Genomes of Aeginetia indica Reveal Intracellular Gene Transfer (IGT), Horizontal Gene Transfer (HGT), and Cytoplasmic Male Sterility (CMS)
Authors: Choi Kyoung-Su , Park Seonjoo
Published: June 2021

Orobanchaceae have become a model group for studies on the evolution of parasitic flowering plants, and Aeginetia indica, a holoparasitic plant, is a member of this family. In this study, we assembled the complete chloroplast and mitochondrial genomes of A. indica. The chloroplast and mitochondrial genomes were 56,381 bp and 401,628 bp long, respectively. The chloroplast genome of A. indica shows massive plastid genes and the loss of one IR (inverted repeat). A comparison of the A. indica chloroplast genome sequence with that of a previous study demonstrated that the two chloroplast genomes encode a similar number of proteins (except atpH) but differ greatly in length. The A. indica mitochondrial genome has 53 genes, including 35 protein-coding genes (34 native mitochondrial genes and one chloroplast gene), 15 tRNA (11 native mitochondrial genes and four chloroplast genes) genes, and three rRNA genes. Evidence for intracellular gene transfer (IGT) and horizontal gene transfer (HGT) was obtained for plastid and mitochondrial genomes. ψndhB and ψcemA in the A. indica mitogenome were transferred from the plastid genome of A. indica. The atpH gene in the plastid of A. indica was transferred from another plastid angiosperm plastid and the atpI gene in mitogenome A. indica was transferred from a host plant like Miscanthus siensis. Cox2 (orf43) encodes proteins containing a membrane domain, making ORF (Open Reading Frame) the most likely candidate gene for CMS development in A. indica.
Mutagenic Consequences of Sublethal Cell Death Signaling
Authors: Hawkins Christine J. , Miles Mark A.
Published: June 2021

Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate apoptosis of cancer cells, may overcome classical blocks exploited by cancer cells to evade apoptotic cell death. However, there is increasing evidence that cells surviving sublethal exposure to classical apoptotic signaling may recover with newly acquired genomic changes which may have oncogenic potential, and so could theoretically spur the development of subsequent cancers in cured patients. Encouragingly, cells surviving sublethal necroptotic signaling did not acquire mutations, suggesting that necroptosis-inducing anti-cancer drugs may be less likely to trigger therapy-related cancers. We are yet to develop effective direct inducers of other cell death pathways, and as such, data regarding the consequences of cells surviving sublethal stimulation of those pathways are still emerging. This review details the currently known mutagenic consequences of cells surviving different cell death signaling pathways, with implications for potential oncogenic transformation. Understanding the mechanisms of mutagenesis associated (or not) with various cell death pathways will guide us in the development of future therapeutics to minimize therapy-related side effects associated with DNA damage.
Cancer-Associated Glycosphingolipids as Tumor Markers and Targets for Cancer Immunotherapy
Authors: Groux-Degroote Sophie , Delannoy Philippe
Published: June 2021

Aberrant expression of glycosphingolipids is a hallmark of cancer cells and is associated with their malignant properties. Disialylated gangliosides GD2 and GD3 are considered as markers of neuroectoderm origin in tumors, whereas fucosyl-GM1 is expressed in very few normal tissues but overexpressed in a variety of cancers, especially in small cell lung carcinoma. These gangliosides are absent in most normal adult tissues, making them targets of interest in immuno-oncology. Passive and active immunotherapy strategies have been developed, and have shown promising results in clinical trials. In this review, we summarized the current knowledge on GD2, GD3, and fucosyl-GM1 expression in health and cancer, their biosynthesis pathways in the Golgi apparatus, and their biological roles. We described how their overexpression can affect intracellular signaling pathways, increasing the malignant phenotypes of cancer cells, including their metastatic potential and invasiveness. Finally, the different strategies used to target these tumor-associated gangliosides for immunotherapy were discussed, including the use and development of monoclonal antibodies, vaccines, immune system modulators, and immune effector-cell therapy, with a special focus on adoptive cellular therapy with T cells engineered to express chimeric antigen receptors.
Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice
Authors: Leitz Dominik H. W. , Duerr Julia , Mulugeta Surafel , Seyhan Agircan Ayça , Zimmermann Stefan , Kawabe Hiroshi , Dalpke Alexander H. , Beers Michael F. , Mall Marcus A.
Published: June 2021

Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of Nedd4-2 in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na+ channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of Nedd4-2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4-2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4-2fl/fl/CCSP-rtTA2S-M2/LC1 mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of Nedd4-2 caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of Nedd4-2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4-2 may support studies of the pathogenesis and preclinical development of therapies for chILD.
Association of MALAT1 and PVT1 Variants, Expression Profiles and Target miRNA-101 and miRNA-186 with Colorectal Cancer: Correlation with Epithelial-Mesenchymal Transition
Authors: Radwan Abdullah F. , Shaker Olfat G. , El-Boghdady Noha A. , Senousy Mahmoud A.
Published: June 2021

The influence of PVT1 and MALAT1 variants on colorectal cancer (CRC) susceptibility and their impact on PVT1/miRNA-186/epithelial-mesenchymal transition (EMT) and MALAT1/miRNA-101/EMT axes in CRC are unknown. We investigated the influence of PVT1 rs13255292 and MALAT1 rs3200401 on the risk of CRC and adenomatous polyps (AP), their impact on the long noncoding RNAs PVT1 and MALAT1 expression and their target miRNA-186, miRNA-101/E-cadherin pathways, along with their potential as early CRC biomarkers. Overall, 280 individuals were recruited: 140 patients with CRC, 40 patients with AP, and 100 healthy volunteers. Genotyping and serum expression profiles were assessed using qPCR. The EMT biomarker, E-cadherin, was measured by ELISA. rs3200401 was associated with increased CRC risk, whereas rs13255292 was protective. Serum PVT1 and MALAT1 were upregulated in CRC and AP patients versus healthy controls, whereas, miRNA-186, miRNA-101 and E-cadherin were downregulated in CRC versus non-CRC groups. MALAT1 showed superior diagnostic potential for CRC and predicted CRC risk among non-CRC groups in the multivariate logistic analysis. PVT1, MALAT1, miRNA-186 and miRNA-101 levels were correlated with E-cadherin, tumor stage, lymph node and distant metastasis. E-cadherin was lost in metastatic vs. non-metastatic CRC. rs3200401CC genotype carriers showed higher E-cadherin levels than CC + CT carriers. rs3200401 was correlated with lymph node status. For the first time, rs13255292 and rs3200401 are potential genetic CRC predisposition markers, with rs3200401 possibly impacting the EMT process. Serum PVT1, MALAT1, miRNA-186 and miRNA-101 are novel non-invasive diagnostic biomarkers that could improve the clinical outcome of CRC.
Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors
Authors: Mongelli Alessia , Barbi Veronica , Gottardi Zamperla Michela , Atlante Sandra , Forleo Luana , Nesta Marialisa , Massetti Massimo , Pontecorvi Alfredo , Nanni Simona , Farsetti Antonella , Catalano Oronzo , Bussotti Maurizio , Dalla Vecchia Laura Adelaide , Bachetti Tiziana , Martelli Fabio , La Rovere Maria Teresa , Gaetano Carlo
Published: June 2021

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).
Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders
Authors: Ashayeri Ahmadabad Rezan , Mirzaasgari Zahra , Gorji Ali , Khaleghi Ghadiri Maryam
Published: June 2021

Toll-like receptors (TLRs), a class of pattern recognition proteins, play an integral role in the modulation of systemic inflammatory responses. Cerebrovascular diseases (CVDs) are a group of pathological conditions that temporarily or permanently affect the brain tissue mostly via the decrease of oxygen and glucose supply. TLRs have a critical role in the activation of inflammatory cascades following hypoxic-ischemic events and subsequently contribute to neuroprotective or detrimental effects of CVD-induced neuroinflammation. The TLR signaling pathway and downstream cascades trigger immune responses via the production and release of various inflammatory mediators. The present review describes the modulatory role of the TLR signaling pathway in the inflammatory responses developed following various CVDs and discusses the potential benefits of the modulation of different TLRs in the improvement of functional outcomes after brain ischemia.
Aldosterone Negatively Regulates Nrf2 Activity: An Additional Mechanism Contributing to Oxidative Stress and Vascular Dysfunction by Aldosterone
Authors: Rodrigues Daniel , Costa Tiago J. , Silva Josiane F. , Neto José Teles de Oliveira , Alves Juliano V. , Fedoce Aline G. , Costa Rafael Menezes , Tostes Rita C.
Published: June 2021

High levels of aldosterone (Aldo) trigger oxidative stress and vascular dysfunction independent of effects on blood pressure. We sought to determine whether Aldo disrupts Nrf2 signaling, the main transcriptional factor involved in antioxidant responses that aggravate cell injury. Thoracic aorta from male C57Bl/6J mice and cultured human endothelial cells (EA.hy926) were stimulated with Aldo (100 nM) in the presence of tiron [reactive oxygen species (ROS) scavenger, eplerenone [mineralocorticoid receptor (MR) antagonist], and L-sulforaphane (SFN; Nrf2 activator). Thoracic aortas were also isolated from mice infused with Aldo (600 μg/kg per day) for 14 days. Aldo decreased endothelium-dependent vasorelaxation and increased ROS generation, effects prevented by tiron and MR blockade. Pharmacological activation of Nrf2 with SFN abrogated Aldo-induced vascular dysfunction and ROS generation. In EA.hy926 cells, Aldo increased ROS generation, which was prevented by eplerenone, tiron, and SFN. At short times, Aldo-induced ROS generation was linked to increased Nrf2 activation. However, after three hours, Aldo decreased the nuclear accumulation of Nrf2. Increased Keap1 protein expression, but not activation of p38 MAPK, was linked to Aldo-induced reduced Nrf2 activity. Arteries from Aldo-infused mice also exhibited decreased nuclear Nrf2 and increased Keap1 expression. Our findings suggest that Aldo reduces vascular Nrf2 transcriptional activity by Keap1-dependent mechanisms, contributing to mineralocorticoid-induced vascular dysfunction.
Cryopreservation of Agronomic Plant Germplasm Using Vitrification-Based Methods: An Overview of Selected Case Studies
Authors: Roque-Borda Cesar Augusto , Kulus Dariusz , Vacaro de Souza Angela , Kaviani Behzad , Vicente Eduardo Festozo
Published: June 2021

Numerous environmental and endogenous factors affect the level of genetic diversity in natural populations. Genetic variability is the cornerstone of evolution and adaptation of species. However, currently, more and more plant species and local varieties (landraces) are on the brink of extinction due to anthropopression and climate change. Their preservation is imperative for the sake of future breeding programs. Gene banks have been created worldwide to conserve different plant species of cultural and economic importance. Many of them apply cryopreservation, a conservation method in which ultra-low temperatures (−135 °C to −196 °C) are used for long-term storage of tissue samples, with little risk of variation occurrence. Cells can be successfully cryopreserved in liquid nitrogen (LN) when the adverse effect of ice crystal formation and growth is mitigated by the removal of water and the formation of the so-called biological glass (vitrification). This state can be achieved in several ways. The involvement of key cold-regulated genes and proteins in the acquisition of cold tolerance in plant tissues may additionally improve the survival of LN-stored explants. The present review explains the importance of cryostorage in agronomy and presents an overview of the recent works accomplished with this strategy. The most widely used cryopreservation techniques, classic and modern cryoprotective agents, and some protocols applied in crops are considered to understand which parameters provide the establishment of high quality and broadly applicable cryopreservation. Attention is also focused on the issues of genetic integrity and functional genomics in plant cryobiology.
Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation
Authors: Sharifi-Sanjani Maryam , Berman Mariah , Goncharov Dmitry , Alhamaydeh Mohammad , Avolio Theodore Guy , Baust Jeffrey , Chang Baojun , Kobir Ahasanul , Ross Mark , St. Croix Claudette , Nouraie Seyed Mehdi , McTiernan Charles F. , Moravec Christine S. , Goncharova Elena , Al Ghouleh Imad
Published: June 2021

Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFβ and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFβ/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFβ/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFβ/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF.
Honey Bee Health in Maine Wild Blueberry Production
Authors: Drummond Francis A. , Lund Jennifer , Eitzer Brian
Published: June 2021

A two-year study was conducted in Maine wild blueberry fields (Vaccinium angustifolium Aiton) on the health of migratory honey bee colonies in 2014 and 2015. In each year, three or five colonies were monitored at each of nine wild blueberry field locations during bloom (mid-May until mid-June). Colony health was measured by assessing colony strength during wild blueberry bloom. Potential factors that might affect colony health were queen failure or supersedure; pesticide residues on trapped pollen, wax comb, and bee bread; and parasites and pathogens. We found that Varroa mite and pesticide residues on trapped pollen were significant predictors of colony health measured as the rate of change in the amount of sealed brood during bloom. These two factors explained 71% of the variance in colony health over the two years. Pesticide exposure was different in each year as were pathogen prevalence and incidence. We detected high prevalence and abundance of two recently discovered pathogens and one recently discovered parasite, the trypanosome Lotmaria passim Schwartz, the Sinai virus, and the phorid fly, Apocephalus borealis Brues.
Impact of Nosema Disease and American Foulbrood on Gut Bacterial Communities of Honeybees Apis mellifera
Authors: Panjad Poonnawat , Yongsawas Rujipas , Sinpoo Chainarong , Pakwan Chonthicha , Subta Phakamas , Krongdang Sasiprapa , In-on Ammarin , Chomdej Siriwadee , Chantawannakul Panuwan , Disayathanoowat Terd
Published: June 2021

Honeybees, Apis mellifera, are important pollinators of many economically important crops. However, one of the reasons for their decline is pathogenic infection. Nosema disease and American foulbrood (AFB) disease are the most common bee pathogens that propagate in the gut of honeybees. This study investigated the impact of gut-propagating pathogens, including Nosema ceranae and Paenibacillus larvae, on bacterial communities in the gut of A. mellifera using 454-pyrosequencing. Pyrosequencing results showed that N. ceranae was implicated in the elimination of Serratia and the dramatic increase in Snodgrassella and Bartonella in adult bees’ guts, while bacterial communities of P. larvae-infected larvae were not affected by the infection. The results indicated that only N. ceranae had an impact on some core bacteria in the gut of A. mellifera through increasing core gut bacteria, therefore leading to the induction of dysbiosis in the bees’ gut.
Compass Cue Integration and Its Relation to the Visual Ecology of Three Tribes of Ball-Rolling Dung Beetles
Authors: Khaldy Lana , Tocco Claudia , Byrne Marcus , Dacke Marie
Published: June 2021

To guide their characteristic straight-line orientation away from the dung pile, ball-rolling dung beetles steer according to directional information provided by celestial cues, which, among the most relevant are the sun and polarised skylight. Most studies regarding the use of celestial cues and their influence on the orientation system of the diurnal ball-rolling beetle have been performed on beetles of the tribe Scarabaeini living in open habitats. These beetles steer primarily according to the directional information provided by the sun. In contrast, Sisyphus fasciculatus, a species from a different dung-beetle tribe (the Sisyphini) that lives in habitats with closely spaced trees and tall grass, relies predominantly on directional information from the celestial pattern of polarised light. To investigate the influence of visual ecology on the relative weight of these cues, we studied the orientation strategy of three different tribes of dung beetles (Scarabaeini, Sisyphini and Gymnopleurini) living within the same biome, but in different habitat types. We found that species within a tribe share the same orientation strategy, but that this strategy differs across the tribes; Scarabaeini, living in open habitats, attribute the greatest relative weight to the directional information from the sun; Sisyphini, living in closed habitats, mainly relies on directional information from polarised skylight; and Gymnopleurini, also living in open habitats, appear to weight both cues equally. We conclude that, despite exhibiting different body size, eye size and morphology, dung beetles nevertheless manage to solve the challenge of straight-line orientation by weighting visual cues that are particular to the habitat in which they are found. This system is however dynamic, allowing them to operate equally well even in the absence of the cue given the greatest relative weight by the particular species.