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Al Fayez, Nojoud, Majed S. Nassar, Abdullah A. Alshehri, Meshal K. Alnefaie, Fahad A. Almughem, Bayan Y. Alshehri, Abdullah O. Alawad i Essam A. Tawfik. "Recent Advancement in mRNA Vaccine Development and Applications". Pharmaceutics 15, nr 7 (18.07.2023): 1972. http://dx.doi.org/10.3390/pharmaceutics15071972.
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Messenger RNA (mRNA) vaccine development for preventive and therapeutic applications has evolved rapidly over the last decade. The mRVNA vaccine has proven therapeutic efficacy in various applications, including infectious disease, immunotherapy, genetic disorders, regenerative medicine, and cancer. Many mRNA vaccines have made it to clinical trials, and a couple have obtained FDA approval. This emerging therapeutic approach has several advantages over conventional methods: safety; efficacy; adaptability; bulk production; and cost-effectiveness. However, it is worth mentioning that the delivery to the target site and in vivo degradation and thermal stability are boundaries that can alter their efficacy and outcomes. In this review, we shed light on different types of mRNA vaccines, their mode of action, and the process to optimize their development and overcome their limitations. We also have explored various delivery systems focusing on the nanoparticle-mediated delivery of the mRNA vaccine. Generally, the delivery system plays a vital role in enhancing mRNA vaccine stability, biocompatibility, and homing to the desired cells and tissues. In addition to their function as a delivery vehicle, they serve as a compartment that shields and protects the mRNA molecules against physical, chemical, and biological activities that can alter their efficiency. Finally, we focused on the future considerations that should be attained for safer and more efficient mRNA application underlining the advantages and disadvantages of the current mRNA vaccines.
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Oohayyed, N. A., M. M. Mohammed, A. M. Al-Rahim, R. N. Al Chalabi, S. A. Shaban i A. A. J. Suleiman. "Identification of key miRNAs as regulatory biomarkers of gonadotropins leading to infertility in males". Obstetrics, Gynecology and Reproduction 17, nr 5 (12.11.2023): 607–24. http://dx.doi.org/10.17749/2313-7347/ob.gyn.rep.2023.398.
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Introduction. Infertility is a highly fatal reproductive system disorder that affects the ability of a couple to reproduce. Over the past decades, a drastic uplift has been recorded in infertility cases among males ranging from 20 to 70 % indicating spermatogenesis impairment.Aim: to identify key microRNAs (miRNAs) as regulatory biomarkers of gonadotropins involved in dysregulation of fertility-related genes to propose potential therapeutic strategies that would combat the action of oncogenic miRNAs (oncomiRs).Materials and Methods. Interaction analysis was performed between miRNAs and fertility-related genes namely luteinizing hormone choriogonadotropin receptor (LHCGR), gonadotropin-releasing hormone receptor (GnRHR), follicle-stimulating hormone receptor (FSHR) and cystic fibrosis transmembrane conductance regulator (CFTR) to identify key miRNAs as regulatory biomarkers of gonadotropins leading to infertility in males.Results. A total of 10, 13, 31 and 18 strong and potential binding sites were predicted for miRNAs-LHCGR, miRNAs-GnRHR, miRNAs-FSHR, and miRNAs-CFTR respectively employing miRWalk (comprehensive genetic database including miRNA targets) followed by identification of 6, 18, 55 and 17 significant interactions through RNA22. Subsequently shortlisted miRNAs and messenger RNA (mRNA) regions were subjected to Vfold-Pipeline and RNAComposer individually for 3D structure prediction. Additionally molecular docking was carried out between miRNAs and mRNAs models that discovered potential and stable interactions elucidating miR-6880-FSHR(R2) as a highly stable complex with least binding affinity (-566.3) and high confidence score (0.999).Conclusion. Hence this study proposes key oncomiRs as a diagnostic biomarker and therapeutic target to bring about a promising treatment strategy against male factor infertility. However wet lab investigations are required for further validations of proposed study.
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Gong, Congcong, Yang Hu, Mao Zhou, Maojin Yao, Zhengxiang Ning, Zhi Wang i Jiaoyan Ren. "Identification of specific modules and hub genes associated with the progression of gastric cancer". Carcinogenesis 40, nr 10 (26.02.2019): 1269–77. http://dx.doi.org/10.1093/carcin/bgz040.
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Abstract Gastric cancer (GC) has high morbidity and mortality rates worldwide. Abundant literature has reported several individual genes and their related pathways intimately involved in tumor progression. However, little is known about GC progression at the gene network level. Therefore, understanding the underlying mechanisms of pathological transition from early stage to late stage is urgently needed. This study aims to identify potential vital genes and modules involved in the progression of GC. To understand the gene regulatory network of GC progression, we analyzed micro RNAs and messenger RNA s expression profiles by using a couple of bioinformatics tools. miR-205 was identified by differentially expressed analysis and was further confirmed through using multiple kernel learning-based Kronecker regularized least squares. Using weighted gene co-expression network analysis, the gastric cancer progression-related module, which has the highest correlation value with cancer progression, was obtained. Kyoto Encyclopedia of Genes and Genomes pathways and biological processes of the GCPR module genes were related to cell adhesion. Meanwhile, large-scale genes of GCPR module were found to be targeted by miR-205, including two hub genes SORBS1 and LPAR1. In brief, through multiple analytical methods, we found that miR-205 and the GCPR module play critical roles in GC progression. In addition, miR-205 might maintain cell adhesion by regulating SORBS1 and LPAR1. To screen the potential drug candidates, the gene expression profile of the GCPR module was mapped connectivity map (Cmap), and the mTOR inhibitor (Sirolimus) was found to be the most promising candidate. We further confirmed that Sirolimus can suppress cell proliferation of GC cell in vitro.
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Weber, Ramona, Min-Yi Chung, Csilla Keskeny, Ulrike Zinnall, Markus Landthaler, Eugene Valkov, Elisa Izaurralde i Cátia Igreja. "4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay". Cell Reports 33, nr 2 (październik 2020): 108262. http://dx.doi.org/10.1016/j.celrep.2020.108262.
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Hanjin, Cui, Liu Tao, Li Pengfei, Yang Ali, Zhou Huajun, Luo Jiekun, Wang Yang i Tang Tao. "Altered Long Noncoding RNA and Messenger RNA Expression in Experimental Intracerebral Hemorrhage - a Preliminary Study". Cellular Physiology and Biochemistry 45, nr 3 (2018): 1284–301. http://dx.doi.org/10.1159/000487464.
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Background/Aims: Functional recovery in the chronic phase is a difficult problem in intracerebral hemorrhage (ICH) treatment. Long noncoding RNAs (lncRNAs) are demonstrated to be involved in central nervous system (CNS) disorders. However, the roles of lncRNAs in post-ICH injury and repair are poorly understood, especially those that may be attributed to long-term neurological deficit. The present study depicted the lncRNA and messenger RNA (mRNA) profile by microarray at late stage after an experimental ICH. Methods: LncRNA and mRNA microarray was used to first identify differentially expressed genes. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to determine bio-functions and signaling pathways, with which differentially expressed genes are most closely related. Quantitative real-time polymerase chain reaction (PCR) was used to validate the results of microarray. Finally, the lncRNA-mRNA co-expression network was constructed to find the interaction of genes. Results: A total of 625 differentially expressed lncRNAs and 826 expressed mRNAs were identified. Altered genes were enriched in mitochon-drial matrix, G-protein coupled receptor signaling pathway, and olfactory transduction, which may be associated with ICH-induced pathophysiologic changes in the long term. A co-expression network profile based on 5 validated differentially expressed lncRNAs and 205 interacted mRNAs was composed of 210 nodes and 298 connections. Conclusion: Mitochondrial matrix, reduced G-protein coupled receptor activity, and impaired olfactory transduction may be involved in the sequelae following ICH. Further, these dysregulated lncRNAs and mRNAs may be the promising therapeutic targets to overcome obstacles in functional recovery following ICH.
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Estevez, Mariana, Rui Li, Biplab Paul, Kaveh Daneshvar, Alan C. Mullen, Fabio Romerio i Balasubrahmanyam Addepalli. "Identification and mapping of post-transcriptional modifications on the HIV-1 antisense transcript Ast in human cells". RNA 28, nr 5 (15.02.2022): 697–710. http://dx.doi.org/10.1261/rna.079043.121.
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The human immunodeficiency virus type 1 (HIV-1) encodes multiple RNA molecules. Transcripts that originate from the proviral 5′ long terminal repeat (LTR) function as messenger RNAs for the expression of 16 different mature viral proteins. In addition, HIV-1 expresses an antisense transcript (Ast) from the 3′LTR, which has both protein-coding and noncoding properties. While the mechanisms that regulate the coding and noncoding activities of Ast remain unknown, post-transcriptional modifications are known to influence RNA stability, interaction with protein partners, and translation capacity. Here, we report the nucleoside modification profile of Ast obtained through liquid chromatography coupled with mass spectrometry (LC-MS) analysis. The epitranscriptome includes a limited set of modified nucleosides but predominantly ribose methylations. A number of these modifications were mapped to specific positions of the sequence through RNA modification mapping procedures. The presence of modifications on Ast is consistent with the RNA-modifying enzymes interacting with Ast. The identification and mapping of Ast post-transcriptional modifications is expected to elucidate the mechanisms through which this versatile molecule can carry out diverse activities in different cell compartments. Manipulation of post-transcriptional modifications on the Ast RNA may have therapeutic implications.
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Yang, Jing, Ying Cao i Ligeng Ma. "Co-Transcriptional RNA Processing in Plants: Exploring from the Perspective of Polyadenylation". International Journal of Molecular Sciences 22, nr 7 (24.03.2021): 3300. http://dx.doi.org/10.3390/ijms22073300.
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Most protein-coding genes in eukaryotes possess at least two poly(A) sites, and alternative polyadenylation is considered a contributing factor to transcriptomic and proteomic diversity. Following transcription, a nascent RNA usually undergoes capping, splicing, cleavage, and polyadenylation, resulting in a mature messenger RNA (mRNA); however, increasing evidence suggests that transcription and RNA processing are coupled. Plants, which must produce rapid responses to environmental changes because of their limited mobility, exhibit such coupling. In this review, we summarize recent advances in our understanding of the coupling of transcription with RNA processing in plants, and we describe the possible spatial environment and important proteins involved. Moreover, we describe how liquid–liquid phase separation, mediated by the C-terminal domain of RNA polymerase II and RNA processing factors with intrinsically disordered regions, enables efficient co-transcriptional mRNA processing in plants.
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Liu, Yaojuan, Yesenia Rodriguez, Robert L. Ross, Ruoxia Zhao, Jason A. Watts, Christopher Grunseich, Alan Bruzel i in. "RNA abasic sites in yeast and human cells". Proceedings of the National Academy of Sciences 117, nr 34 (11.08.2020): 20689–95. http://dx.doi.org/10.1073/pnas.2011511117.
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RNA abasic sites and the mechanisms involved in their regulation are mostly unknown; in contrast, DNA abasic sites are well-studied. We found surprisingly that, in yeast and human cells, RNA abasic sites are prevalent. When a base is lost from RNA, the remaining ribose is found as a closed-ring or an open-ring sugar with a reactive C1′ aldehyde group. Using primary amine-based reagents that react with the aldehyde group, we uncovered evidence for abasic sites in nascent RNA, messenger RNA, and ribosomal RNA from yeast and human cells. Mass spectroscopic analysis confirmed the presence of RNA abasic sites. The RNA abasic sites were found to be coupled to R-loops. We show that human methylpurine DNA glycosylase cleaves N-glycosidic bonds on RNA and that human apurinic/apyrimidinic endonuclease 1 incises RNA abasic sites in RNA–DNA hybrids. Our results reveal that, in yeast and human cells, there are RNA abasic sites, and we identify a glycosylase that generates these sites and an AP endonuclease that processes them.
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Grüschow, Sabine, Catherine S. Adamson i Malcolm F. White. "Specificity and sensitivity of an RNA targeting type III CRISPR complex coupled with a NucC endonuclease effector". Nucleic Acids Research 49, nr 22 (6.12.2021): 13122–34. http://dx.doi.org/10.1093/nar/gkab1190.
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Abstract Type III CRISPR systems detect invading RNA, resulting in the activation of the enzymatic Cas10 subunit. The Cas10 cyclase domain generates cyclic oligoadenylate (cOA) second messenger molecules, activating a variety of effector nucleases that degrade nucleic acids to provide immunity. The prophage-encoded Vibrio metoecus type III-B (VmeCmr) locus is uncharacterised, lacks the HD nuclease domain in Cas10 and encodes a NucC DNA nuclease effector that is also found associated with Cyclic-oligonucleotide-based anti-phage signalling systems (CBASS). Here we demonstrate that VmeCmr is activated by target RNA binding, generating cyclic-triadenylate (cA3) to stimulate a robust NucC-mediated DNase activity. The specificity of VmeCmr is probed, revealing the importance of specific nucleotide positions in segment 1 of the RNA duplex and the protospacer flanking sequence (PFS). We harness this programmable system to demonstrate the potential for a highly specific and sensitive assay for detection of the SARS-CoV-2 virus RNA with a limit of detection (LoD) of 2 fM using a commercial plate reader without any extrinsic amplification step. The sensitivity is highly dependent on the guide RNA used, suggesting that target RNA secondary structure plays an important role that may also be relevant in vivo.
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Stephan, W., i D. A. Kirby. "RNA folding in Drosophila shows a distance effect for compensatory fitness interactions." Genetics 135, nr 1 (1.09.1993): 97–103. http://dx.doi.org/10.1093/genetics/135.1.97.
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Abstract Phylogenetic-comparative analysis was used to construct a secondary structure of Adh precursor messenger RNA (pre-mRNA) in Drosophila. The analysis revealed that the rate of coevolution of base-pairing residues decreases with their physical distance. This result is in qualitative agreement with a model of compensatory fitness interactions which assumes that mutations are individually deleterious but become harmless (neutral) in appropriate combinations. This model predicts that coupled mutations can become fixed in a population under mutation pressure and random genetic drift, when the mutations are closely linked. However, the rate of joint fixation drops as distance between sites increases and recombination breaks up favorable combinations. RNA secondary structure was also used to interpret patterns of linkage disequilibrium at Adh.
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Hurt, Jessica A., Robert A. Obar, Bo Zhai, Natalie G. Farny, Steven P. Gygi i Pamela A. Silver. "A conserved CCCH-type zinc finger protein regulates mRNA nuclear adenylation and export". Journal of Cell Biology 185, nr 2 (13.04.2009): 265–77. http://dx.doi.org/10.1083/jcb.200811072.
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Coupling of messenger RNA (mRNA) nuclear export with prior processing steps aids in the fidelity and efficiency of mRNA transport to the cytoplasm. In this study, we show that the processes of export and polyadenylation are coupled via the Drosophila melanogaster CCCH-type zinc finger protein CG6694/dZC3H3 through both physical and functional interactions. We show that depletion of dZC3H3 from S2R+ cells results in transcript hyperadenylation. Using targeted coimmunoprecipitation and liquid chromatography mass spectrometry (MS)/MS techniques, we characterize interactions of known components of the mRNA nuclear export and polyadenylation machineries with dZC3H3. Furthermore, we demonstrate the functional conservation of this factor, as depletion of its human homologue ZC3H3 by small interfering RNA results in an mRNA export defect in human cells as well. Nuclear polyadenylated (poly(A)) RNA in ZC3H3-depleted cells is sequestered in foci removed from SC35-containing speckles, indicating a shift from the normal subnuclear distribution of poly(A) RNA. Our data suggest a model wherein ZC3H3 interfaces between the polyadenylation machinery, newly poly(A) mRNAs, and factors for transcript export.
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Ryabova, L., E. Volianik, O. Kurnasov, A. Spirin, Y. Wu i F. R. Kramer. "Coupled replication-translation of amplifiable messenger RNA. A cell-free protein synthesis system that mimics viral infection." Journal of Biological Chemistry 269, nr 2 (styczeń 1994): 1501–5. http://dx.doi.org/10.1016/s0021-9258(17)42284-8.
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Faza, Marius Boulos, Stefan Kemmler, Sonia Jimeno, Cristina González-Aguilera, Andrés Aguilera, Ed Hurt i Vikram Govind Panse. "Sem1 is a functional component of the nuclear pore complex–associated messenger RNA export machinery". Journal of Cell Biology 184, nr 6 (16.03.2009): 833–46. http://dx.doi.org/10.1083/jcb.200810059.
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The evolutionarily conserved protein Sem1/Dss1 is a subunit of the regulatory particle (RP) of the proteasome, and, in mammalian cells, binds the tumor suppressor protein BRCA2. Here, we describe a new function for yeast Sem1. We show that sem1 mutants are impaired in messenger RNA (mRNA) export and transcription elongation, and induce strong transcription-associated hyper-recombination phenotypes. Importantly, Sem1, independent of the RP, is functionally linked to the mRNA export pathway. Biochemical analyses revealed that, in addition to the RP, Sem1 coenriches with components of two other multisubunit complexes: the nuclear pore complex (NPC)-associated TREX-2 complex that is required for transcription-coupled mRNA export, and the COP9 signalosome, which is involved in deneddylation. Notably, targeting of Thp1, a TREX-2 component, to the NPC is perturbed in a sem1 mutant. These findings reveal an unexpected nonproteasomal function of Sem1 in mRNA export and in prevention of transcription-associated genome instability. Thus, Sem1 is a versatile protein that might stabilize multiple protein complexes involved in diverse pathways.
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Wang, Chengyuan, Vadim Molodtsov, Emre Firlar, Jason T. Kaelber, Gregor Blaha, Min Su i Richard H. Ebright. "Structural basis of transcription-translation coupling". Science 369, nr 6509 (20.08.2020): 1359–65. http://dx.doi.org/10.1126/science.abb5317.
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In bacteria, transcription and translation are coupled processes in which the movement of RNA polymerase (RNAP)–synthesizing messenger RNA (mRNA) is coordinated with the movement of the first ribosome-translating mRNA. Coupling is modulated by the transcription factors NusG (which is thought to bridge RNAP and the ribosome) and NusA. Here, we report cryo–electron microscopy structures of Escherichia coli transcription-translation complexes (TTCs) containing different-length mRNA spacers between RNAP and the ribosome active-center P site. Structures of TTCs containing short spacers show a state incompatible with NusG bridging and NusA binding (TTC-A, previously termed “expressome”). Structures of TTCs containing longer spacers reveal a new state compatible with NusG bridging and NusA binding (TTC-B) and reveal how NusG bridges and NusA binds. We propose that TTC-B mediates NusG- and NusA-dependent transcription-translation coupling.
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B. Malas, Tareq, i Timothy Ravasi. "Computational Tools for Genome-Wide miRNA Prediction and Study". Open Biology Journal 5, nr 1 (2.11.2012): 23–30. http://dx.doi.org/10.2174/1874196701205010023.
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MicroRNAs (miRNAs) are single-stranded non-coding RNA susually of 22 nucleotidesin length that play an important post-transcriptional regulation role in many organisms. MicroRNAs bind a seed sequence to the 3'-untranslated region (UTR) region of the target messenger RNA (mRNA), inducing degradation or inhibition of translation and resulting in a reduction in the protein level. This regulatory mechanism is central to many biological processes and perturbation could lead to diseases such as cancer. Given the biological importance, of miRNAs, there is a great need to identify and study their targets and functions. However, miRNAs are very difficult to clone in the lab and this has hindered the identification of novel miRNAs. Next-generation sequencing coupled with new computational tools has recently evolved to help researchers efficiently identify large numbers of novel miRNAs. In this review, we describe recent miRNA prediction tools and discuss their priorities, advantages and disadvantages.
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Aitken, Stuart, Ross D. Alexander i Jean D. Beggs. "A rule-based kinetic model of RNA polymerase II C-terminal domain phosphorylation". Journal of The Royal Society Interface 10, nr 86 (6.09.2013): 20130438. http://dx.doi.org/10.1098/rsif.2013.0438.
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The complexity of many RNA processing pathways is such that a conventional systems modelling approach is inadequate to represent all the molecular species involved. We demonstrate that rule-based modelling permits a detailed model of a complex RNA signalling pathway to be defined. Phosphorylation of the RNA polymerase II (RNAPII) C-terminal domain (CTD; a flexible tail-like extension of the largest subunit) couples pre-messenger RNA capping, splicing and 3′ end maturation to transcriptional elongation and termination, and plays a central role in integrating these processes. The phosphorylation states of the serine residues of many heptapeptide repeats of the CTD alter along the coding region of genes as a function of distance from the promoter. From a mechanistic perspective, both the changes in phosphorylation and the location at which they take place on the genes are a function of the time spent by RNAPII in elongation as this interval provides the opportunity for the kinases and phosphatases to interact with the CTD. On this basis, we synthesize the available data to create a kinetic model of the action of the known kinases and phosphatases to resolve the phosphorylation pathways and their kinetics.
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Adams, Grace. "A beginner’s guide to RT-PCR, qPCR and RT-qPCR". Biochemist 42, nr 3 (15.06.2020): 48–53. http://dx.doi.org/10.1042/bio20200034.
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The development of the polymerase chain reaction (PCR), for which Kary Mullis received the 1992 Novel Prize in Chemistry, revolutionized molecular biology. At around the time that prize was awarded, research was being carried out by Russel Higuchi which led to the discovery that PCR can be monitored using fluorescent probes, facilitating quantitative real-time PCR (qPCR). In addition, the earlier discovery of reverse transcriptase (in 1970) laid the groundwork for the development of RT-PCR (used in molecular cloning). The latter can be coupled to qPCR, termed RT-qPCR, allowing analysis of gene expression through messenger RNA (mRNA) quantitation. These techniques and their applications have transformed life science research and clinical diagnosis.
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Schuwirth, Barbara S., Maria A. Borovinskaya, Cathy W. Hau, Wen Zhang, Antón Vila-Sanjurjo, James M. Holton i Jamie H. Doudna Cate. "Structures of the Bacterial Ribosome at 3.5 Å Resolution". Science 310, nr 5749 (3.11.2005): 827–34. http://dx.doi.org/10.1126/science.1117230.
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We describe two structures of the intact bacterial ribosome from Escherichia coli determined to a resolution of 3.5 angstroms by x-ray crystallography. These structures provide a detailed view of the interface between the small and large ribosomal subunits and the conformation of the peptidyl transferase center in the context of the intact ribosome. Differences between the two ribosomes reveal a high degree of flexibility between the head and the rest of the small subunit. Swiveling of the head of the small subunit observed in the present structures, coupled to the ratchet-like motion of the two subunits observed previously, suggests a mechanism for the final movements of messenger RNA (mRNA) and transfer RNAs (tRNAs) during translocation.
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Chatterjee, Surajit, Adrien Chauvier, Shiba S. Dandpat, Irina Artsimovitch i Nils G. Walter. "A translational riboswitch coordinates nascent transcription–translation coupling". Proceedings of the National Academy of Sciences 118, nr 16 (13.04.2021): e2023426118. http://dx.doi.org/10.1073/pnas.2023426118.
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Bacterial messenger RNA (mRNA) synthesis by RNA polymerase (RNAP) and first-round translation by the ribosome are often coupled to regulate gene expression, yet how coupling is established and maintained is ill understood. Here, we develop biochemical and single-molecule fluorescence approaches to probe the dynamics of RNAP–ribosome interactions on an mRNA with a translational preQ1-sensing riboswitch in its 5′ untranslated region. Binding of preQ1 leads to the occlusion of the ribosome binding site (RBS), inhibiting translation initiation. We demonstrate that RNAP poised within the mRNA leader region promotes ribosomal 30S subunit binding, antagonizing preQ1-induced RBS occlusion, and that the RNAP–30S bridging transcription factors NusG and RfaH distinctly enhance 30S recruitment and retention, respectively. We further find that, while 30S–mRNA interaction significantly impedes RNAP in the absence of translation, an actively translating ribosome promotes productive transcription. A model emerges wherein mRNA structure and transcription factors coordinate to dynamically modulate the efficiency of transcription–translation coupling.
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Carter, T. D., X. Y. Chen, G. Carlile, E. Kalapothakis, D. Ogden i W. H. Evans. "Porcine aortic endothelial gap junctions: identification and permeation by caged InsP3". Journal of Cell Science 109, nr 7 (1.07.1996): 1765–73. http://dx.doi.org/10.1242/jcs.109.7.1765.
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Gap junction channels permit the direct intercellular transfer of ions and small molecules and allow electrotonic coupling within tissues. Porcine aortic endothelial cells were extensively coupled, as assessed by gap junctional transfer of Lucifer yellow and the fluorescent calcium indicators fluo-3 and furaptra, but were not permeable to rhodamine B isothiocyanate-dextran 10S. The subunit composition of gap junction channels of porcine aortic endothelial cells was characterised using both northern blot analysis and RT-PCR techniques. Messenger RNA encoding connexins 37 and 43, but not 26, 32 or 40, were found in freshly isolated and cultured porcine aortic endothelial cells. Western blots using antipeptide antibodies raised to unique sequences of connexins 37, 40 and 43 showed the presence of connexins 37 and 43, but no connexin 40 was detected. Immunostaining with anticonnexin 43 antibodies showed extensive punctate fluorescent decoration of contacting membranes, whilst antibodies to connexin 37 showed predominantly intracellular staining. Caged InsP3 was found to readily permeate endothelial gap junctions. These results show that primary cultures of porcine aortic endothelial cells express connexin 37 and 43, and provide strong evidence that the second messenger molecule InsP3 can permeate porcine endothelial gap junctions.
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Li, Zhouhua, Liwei Wang, Thomas S. Hays i Yu Cai. "Dynein-mediated apical localization of crumbs transcripts is required for Crumbs activity in epithelial polarity". Journal of Cell Biology 180, nr 1 (14.01.2008): 31–38. http://dx.doi.org/10.1083/jcb.200707007.
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Asymmetrical localization of transcripts coupled with localized translation constitutes an important mechanism widely deployed to regulate gene activity in a spatial manner. The conserved transmembrane protein Crumbs (Crb) is an important regulator of epithelial polarity. However, it remains unclear how Crb is targeted to the apical domain. Here, we show that the cytoplasmic dynein complex transports both Crb protein and transcripts to the apical domain of Drosophila melanogaster follicular cells (FCs). The crb 3′ untranslated region (UTR) is necessary and sufficient for the apical localization of its transcript and this apical transcript localization is crucial for crb function. In crb mutant FCs, Crb protein derived from transgenes lacking the 3′ UTR does not effectively localize to the apical domain and does not effectively restore normal epithelial polarity. We propose that dynein-mediated messenger RNA transport coupled with a localized translation mechanism is involved in localizing Crb to the apical domain to mediate epithelial apicobasal polarity and that this mechanism might be widely used to regulate cellular polarity.
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Divorty, Nina, Graeme Milligan, Delyth Graham i Stuart A. Nicklin. "The Orphan Receptor GPR35 Contributes to Angiotensin II–Induced Hypertension and Cardiac Dysfunction in Mice". American Journal of Hypertension 31, nr 9 (31.05.2018): 1049–58. http://dx.doi.org/10.1093/ajh/hpy073.
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Abstract BACKGROUND The orphan receptor G protein–coupled receptor 35 (GPR35) has been associated with a range of diseases, including cancer, inflammatory bowel disease, diabetes, hypertension, and heart failure. To assess the potential for GPR35 as a therapeutic target in cardiovascular disease, this study investigated the cardiovascular phenotype of a GPR35 knockout mouse under both basal conditions and following pathophysiological stimulation. METHODS Blood pressure was monitored in male wild-type and GPR35 knockout mice over 7–14 days using implantable telemetry. Cardiac function and dimensions were assessed using echocardiography, and cardiomyocyte morphology evaluated histologically. Two weeks of angiotensin II (Ang II) infusion was used to investigate the effects of GPR35 deficiency under pathophysiological conditions. Gpr35 messenger RNA expression in cardiovascular tissues was assessed using quantitative polymerase chain reaction. RESULTS There were no significant differences in blood pressure, cardiac function, or cardiomyocyte morphology in GPR35 knockout mice compared with wild-type mice. Following Ang II infusion, GPR35 knockout mice were protected from significant increases in systolic, diastolic, and mean arterial blood pressure or impaired left ventricular systolic function, in contrast to wild-type mice. There were no significant differences in Gpr35 messenger RNA expression in heart, kidney, and aorta following Ang II infusion in wild-type mice. CONCLUSIONS Although GPR35 does not appear to influence basal cardiovascular regulation, these findings demonstrate that it plays an important pathological role in the development of Ang II–induced hypertension and impaired cardiac function. This suggests that GPR35 is a potential novel drug target for therapeutic intervention in hypertension.
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Stoll, S., G. Müller, M. Kurimoto, J. Saloga, T. Tanimoto, H. Yamauchi, H. Okamura, J. Knop i A. H. Enk. "Production of IL-18 (IFN-gamma-inducing factor) messenger RNA and functional protein by murine keratinocytes." Journal of Immunology 159, nr 1 (1.07.1997): 298–302. http://dx.doi.org/10.4049/jimmunol.159.1.298.
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Abstract Recently, the novel cytokine IL-18 (IFN-gamma-inducing factor) has been described as a growth and differentiation factor for Th1 cells. Epidermal keratinocytes (KC) are known to direct T cell education by production of cytokines. Therefore, expression of IL-18 was sought in KC. Epidermal RNA was analyzed following stimulation with contact sensitizers or controls for IL-18 mRNA expression by semiquantitative reverse transcription-PCR. Constitutive expression of IL-18 mRNA was low in untreated epidermal cells (EC), but early up-regulation of IL-18 mRNA signals was detected following application of a contact allergen in vivo. The peak strength of IL-18 signals was observed within 4 to 6 h following stimulation with an allergen. Application of an irritant (benzalconiumchloride) or solvents did not result in increased signal strength. To determine the cellular origin of IL-18 mRNA in EC, depletion experiments were performed. IL-18 signals were not affected by depletion with anti-CD3 (T cells) or anti-MHC class II mAb-coupled beads identifying KC as a major source of IL-18. These results were confirmed by analysis of mRNA derived from the KC cell line PAM 212. Strong IL-18 signals could be detected by reverse transcription-PCR. To delineate whether IL-18 protein was produced by EC/KC, a sandwich ELISA was used to assay for IL-18 production. Supernatants from allergen-stimulated EC and KC showed production of IL-18 protein. To confirm that IL-18 protein was functional, EC or KC supernatants were tested for their ability to induce IFN-gamma production. Significant amounts of IFN-gamma were detected in supernatants of allergen-treated cells. In aggregate, our data indicate that murine KC are a source of both IL-18 mRNA and functional protein.
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Webster, Michael William, Maria Takacs, Chengjin Zhu, Vita Vidmar, Ayesha Eduljee, Mo’men Abdelkareem i Albert Weixlbaumer. "Structural basis of transcription-translation coupling and collision in bacteria". Science 369, nr 6509 (20.08.2020): 1355–59. http://dx.doi.org/10.1126/science.abb5036.
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Prokaryotic messenger RNAs (mRNAs) are translated as they are transcribed. The lead ribosome potentially contacts RNA polymerase (RNAP) and forms a supramolecular complex known as the expressome. The basis of expressome assembly and its consequences for transcription and translation are poorly understood. Here, we present a series of structures representing uncoupled, coupled, and collided expressome states determined by cryo–electron microscopy. A bridge between the ribosome and RNAP can be formed by the transcription factor NusG, which stabilizes an otherwise-variable interaction interface. Shortening of the intervening mRNA causes a substantial rearrangement that aligns the ribosome entrance channel to the RNAP exit channel. In this collided complex, NusG linkage is no longer possible. These structures reveal mechanisms of coordination between transcription and translation and provide a framework for future study.
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Feng, Mengdie, Xueqin Xie, Guoqiang Han, Tiantian Zhang, Yashu Li, Yicun Li, Rong Yin i in. "YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner". Blood 138, nr 1 (24.03.2021): 71–85. http://dx.doi.org/10.1182/blood.2020009676.
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Abstract RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.
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Schultz, P., P. Stannek, M. Voigt, K. H. Jakobs i P. Gierschik. "Complementation of formyl peptide receptor-mediated signal transduction in Xenopus laevis oocytes". Biochemical Journal 284, nr 1 (15.05.1992): 207–12. http://dx.doi.org/10.1042/bj2840207.
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Formyl-methionine-containing peptides (e.g. fMet-Leu-Phe) stimulate a variety of neutrophil functions by interacting with specific cell surface receptors which are coupled via G-proteins to stimulation of phospholipase C. Two markedly distinct cDNAs coding for formyl peptide receptors have recently been isolated from a rabbit and a human cDNA library respectively. To examine the hitherto unknown signal transduction properties of the formyl peptide receptor encoded by the human cDNA, we have used the PCR to clone this cDNA from poly(A)+ RNA of myeloid differentiated human leukaemia (HL-60) cells, and have injected the cDNA-derived receptor cRNA into Xenopus laevis oocytes. Receptor activity was determined electrophysiologically by measuring the agonist-dependent opening of intracellular Ca2+ concentration ([Ca2+]i)-independent Cl- channels. Injection of pure formyl peptide receptor cRNA did not lead to peptide-dependent changes in membrane current. In contrast, marked alterations of membrane current were observed in response to formyl peptides when the receptor cRNA was supplemented with poly(A)+ RNA isolated from undifferentiated HL-60 cells. Injection of the latter RNA did not lead to formyl-peptide-dependent alterations of membrane current. Binding studies using a radioiodinated formyl peptide revealed that injection of formyl peptide receptor cRNA alone led to expression of the formyl peptide receptor on the oocyte surface, and that co-injection of poly(A)+ RNA from undifferentiated HL-60 cells did not alter the level of receptor expression. Size fractionation of poly(A)+ RNA from undifferentiated HL-60 cells showed that the mRNA required to complement formyl-peptide-dependent signal transduction in oocytes had a size of approx. 3-3.5 kb. These results strongly suggest that the human formyl peptide receptor requires a specific cofactor(s), which is lacking in Xenopus oocytes but is present in undifferentiated HL-60 cells, to activate the second messenger pathway in oocytes. Identification of this factor will provide important information about the molecular mechanisms by which G-protein-coupled granulocyte-activating receptors stimulate phospholipase C.
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Tikhonov, M. V., P. G. Georgiev i O. G. Maksimenko. "Competition within Introns: Splicing Wins over Polyadenylation via a General Mechanism". Acta Naturae 5, nr 4 (15.12.2013): 52–61. http://dx.doi.org/10.32607/20758251-2013-5-4-52-61.
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Most eukaryotic messenger RNAs are capped, spliced, and polyadenylated via co-transcriptional processes that are coupled to each other and to the transcription machinery. Coordination of these processes ensures correct RNA maturation and provides for the diversity of the transcribed isoforms. Thus, RNA processing is a chain of events in which the completion of one event is coupled to the initiation of the next one. In this context, the relationship between splicing and polyadenylation is an important aspect of gene regulation. We have found that cryptic polyadenylation signals are widely distributed over the intron sequences of Drosophila melanogaster. As shown by analyzing the distribution of genes arranged in a nested pattern, where one gene is fully located within an intron of another gene, overlapping of putative polyadenylation signals is a fairly common event affecting about 17% of all genes. Here we show that polyadenylation signals are silenced within introns: the poly(A) signal is utilized in the exonic but not in the intronic regions of the transcript. The transcription does not end within the introns, either in a transient reporter system or in the genomic context, while deletion of the 5'-splice site restores their functionality. According to a full Drosophila transcriptome analysis, utilization of intronic polyadenylation signals occurs very rarely and such events are likely to be inducible. These results confirm that the transcription apparatus ignores premature polyadenylation signals for as long as they are intronic.
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Kashida, Shunnichi, Dan Ohtan Wang, Hirohide Saito i Zoher Gueroui. "Nanoparticle-based local translation reveals mRNA as a translation-coupled scaffold with anchoring function". Proceedings of the National Academy of Sciences 116, nr 27 (19.06.2019): 13346–51. http://dx.doi.org/10.1073/pnas.1900310116.
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The spatial regulation of messenger RNA (mRNA) translation is central to cellular functions and relies on numerous complex processes. Biomimetic approaches could bypass these endogenous complex processes, improve our comprehension of the regulation, and allow for controlling local translation regulations and functions. However, the causality between local translation and nascent protein function remains elusive. Here, we developed a nanoparticle (NP)-based strategy to magnetically control mRNA spatial patterns in mammalian cell extracts and investigate how local translation impacts nascent protein localization and function. By monitoring the translation of the magnetically localized mRNAs, we show that mRNA–NP complexes operate as a source for the continuous production of proteins from defined positions. By applying this approach to actin-binding proteins, we triggered the local formation of actin cytoskeletons and identified the minimal requirements for spatial control of the actin filament network. In addition, our bottom-up approach identified a role for mRNA as a translation-coupled scaffold for the function of nascent N-terminal protein domains. Our approach will serve as a platform for regulating mRNA localization and investigating the function of nascent protein domains during translation.
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Guo, Caixia, Lisa Savage, Kevin D. Sarge i Ok-Kyong Park-Sarge. "Gonadotropins Decrease Estrogen Receptor-β Messenger Ribonucleic Acid Stability in Rat Granulosa Cells*". Endocrinology 142, nr 6 (1.06.2001): 2230–37. http://dx.doi.org/10.1210/endo.142.6.8102.
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Abstract We have previously shown that the preovulatory LH surge down-regulates estrogen receptor-β (ERβ) messenger RNA (mRNA) levels selectively in the granulosa cells of preovulatory follicles. To gain insight into the underlying mechanisms, we examined whether the LH-induced loss of ERβ mRNA expression in rat granulosa cells is attributable to the hormone-induced changes at the level of transcription and/or mRNA degradation. When the rate of ERβ gene transcription was assessed in cultured granulosa cells, by nuclear run-off assays, we observed only a marginal effect of hCG on ERβ gene transcription. In contrast, when ERβ mRNA levels were estimated in granulosa cells that were cultured in the presence of 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB), an RNA synthesis inhibitor, we observed a significant inhibitory effect of human CG (hCG) on ERβ mRNA expression at a magnitude similar to that observed in the absence of DRB. Forskolin (FSK) and 2-O-tetradecanol-phorbol-13-acetate (TPA), pharmacological agents that mimic LH actions in granulosa cells, also showed similar effects. Thus, these results suggest that LH decreases ERβ mRNA expression in the granulosa cells of preovulatory follicles, primarily by destabilizing the preexisting ERβ mRNA. We next determined the decay rate of the ERβ mRNA in granulosa cells that were cultured in the presence of DRB and additional hCG, FSK, or TPA for various time periods, by estimating ERβ mRNA levels, using semiquantitative RT-PCR assays and subsequent linear regression analyses. The half-life of the ERβ mRNA in the presence of vehicle was 17.87 ± 1.2 h (n = 4). hCG dramatically decreased the half-life of the ERβ mRNA (4.85 ± 0.49 h, n = 4). Similarly, both FSK and TPA decreased the half-life of the ERβ mRNA to 3.57 ± 0.31 h and 4.02± 0.13 h, respectively. We extended these findings by examining whether the LH-induced down-regulation of the ERβ mRNA is cycloheximide-sensitive. When granulosa cells were cultured in the presence of cycloheximide, a protein synthesis inhibitor, the inhibitory effects of hCG, FSK, and TPA on ERβ mRNA levels were abolished. Similar results were obtained in the presence or absence of DRB, indicating that the hormone-induced destabilization of the ERβ mRNA is coupled with translation processes. Taken together, our results demonstrate that LH decreases ERβ mRNA expression, predominantly at the posttranscriptional level, in a cycloheximide-sensitive manner.
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Albarqi, Mennatallah M. Y., i Sean P. Ryder. "The endogenous mex-3 3´UTR is required for germline repression and contributes to optimal fecundity in C. elegans". PLOS Genetics 17, nr 8 (23.08.2021): e1009775. http://dx.doi.org/10.1371/journal.pgen.1009775.
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RNA regulation is essential to successful reproduction. Messenger RNAs delivered from parent to progeny govern early embryonic development. RNA-binding proteins (RBPs) are the key effectors of this process, regulating the translation and stability of parental transcripts to control cell fate specification events prior to zygotic gene activation. The KH-domain RBP MEX-3 is conserved from nematode to human. It was first discovered in Caenorhabditis elegans, where it is essential for anterior cell fate and embryo viability. Here, we show that loss of the endogenous mex-3 3´UTR disrupts its germline expression pattern. An allelic series of 3´UTR deletion variants identify repressing regions of the UTR and demonstrate that repression is not precisely coupled to reproductive success. We also show that several RBPs regulate mex-3 mRNA through its 3´UTR to define its unique germline spatiotemporal expression pattern. Additionally, we find that both poly(A) tail length control and the translation initiation factor IFE-3 contribute to its expression pattern. Together, our results establish the importance of the mex-3 3´UTR to reproductive health and its expression in the germline. Our results suggest that additional mechanisms control MEX-3 function when 3´UTR regulation is compromised.
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Fang, Liying, Lina Guo, Min Zhang, Xianchun Li i Zhongyuan Deng. "Analysis of Polyadenylation Signal Usage with Full-Length Transcriptome in Spodoptera frugiperda (Lepidoptera: Noctuidae)". Insects 13, nr 9 (2.09.2022): 803. http://dx.doi.org/10.3390/insects13090803.
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During the messenger RNA (mRNA) maturation process, RNA polyadenylation is a key step, and is coupled to the termination of transcription. Various cis-acting elements near the cleavage site and their binding factors would affect the process of polyadenylation, and AAUAAA, a highly conserved hexamer, was the most important polyadenylation signal (PAS). PAS usage is one of the critical modification determinants targeted at mRNA post-transcription. The full-length transcriptome has recently generated a massive amount of sequencing data, revealing poly(A) variation and alternative polyadenylation (APA) in Spodoptera frugiperda. We identified 50,616 polyadenylation signals in Spodoptera frugiperda via analysis of full-length transcriptome combined with expression Sequence Tags Technology (EST). The polyadenylation signal usage in Spodoptera frugiperda is conserved, and it is similar to that of flies and other animals. AAUAAA and AUUAAA are the most highly conserved polyadenylation signals of all polyadenylation signals we identified. Additionally, we found the U/GU-rich downstream sequence element (DSE) in the cleavage site. These results demonstrate that APA in Spodoptera frugiperda plays a significant role in root growth and development. This is the first polyadenylation signal usage analysis in agricultural pests, which can deepen our understanding of Spodoptera frugiperda and provide a theoretical basis for pest control.
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Li, Shanshan, Huoqing Luo, Ronghui Lou, Cuiping Tian, Chen Miao, Lisha Xia, Chen Pan i in. "Multiregional profiling of the brain transmembrane proteome uncovers novel regulators of depression". Science Advances 7, nr 30 (lipiec 2021): eabf0634. http://dx.doi.org/10.1126/sciadv.abf0634.
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Transmembrane proteins play vital roles in mediating synaptic transmission, plasticity, and homeostasis in the brain. However, these proteins, especially the G protein–coupled receptors (GPCRs), are underrepresented in most large-scale proteomic surveys. Here, we present a new proteomic approach aided by deep learning models for comprehensive profiling of transmembrane protein families in multiple mouse brain regions. Our multiregional proteome profiling highlights the considerable discrepancy between messenger RNA and protein distribution, especially for region-enriched GPCRs, and predicts an endogenous GPCR interaction network in the brain. Furthermore, our new approach reveals the transmembrane proteome remodeling landscape in the brain of a mouse depression model, which led to the identification of two previously unknown GPCR regulators of depressive-like behaviors. Our study provides an enabling technology and rich data resource to expand the understanding of transmembrane proteome organization and dynamics in the brain and accelerate the discovery of potential therapeutic targets for depression treatment.
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Oikonomou, Panos, Roberto Salatino i Saeed Tavazoie. "In vivo mRNA display enables large-scale proteomics by next generation sequencing". Proceedings of the National Academy of Sciences 117, nr 43 (9.10.2020): 26710–18. http://dx.doi.org/10.1073/pnas.2002650117.
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Large-scale proteomic methods are essential for the functional characterization of proteins in their native cellular context. However, proteomics has lagged far behind genomic approaches in scalability, standardization, and cost. Here, we introduce in vivo mRNA display, a technology that converts a variety of proteomics applications into a DNA sequencing problem. In vivo-expressed proteins are coupled with their encoding messenger RNAs (mRNAs) via a high-affinity stem-loop RNA binding domain interaction, enabling high-throughput identification of proteins with high sensitivity and specificity by next generation DNA sequencing. We have generated a high-coverage in vivo mRNA display library of the Saccharomyces cerevisiae proteome and demonstrated its potential for characterizing subcellular localization and interactions of proteins expressed in their native cellular context. In vivo mRNA display libraries promise to circumvent the limitations of mass spectrometry-based proteomics and leverage the exponentially improving cost and throughput of DNA sequencing to systematically characterize native functional proteomes.
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Carling, Tobias, Jonas Rastad, Eva Szabó, Gunnar Westin i Göran Åkerström. "Reduced Parathyroid Vitamin D Receptor Messenger Ribonucleic Acid Levels in Primary and Secondary Hyperparathyroidism*". Journal of Clinical Endocrinology & Metabolism 85, nr 5 (1.05.2000): 2000–2003. http://dx.doi.org/10.1210/jcem.85.5.6607.
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Abstract Vitamin D, via its receptor (VDR), inhibits the hormone secretion and proliferation of parathyroid cells. Vitamin D deficiency and reduced parathyroid VDR expression has been associated with development of hyperparathyroidism (HPT) secondary to uremia. VDR polymorphisms may influence VDR messenger RNA (mRNA) levels and have been coupled to an increased risk of parathyroid adenoma of primary HPT. VDR mRNA relative to glyceraldehyde-3-phosphate dehydrogenase mRNA levels were determined by RNase protection assay in 42 single parathyroid adenomas of patients with primary HPT, 23 hyperplastic glands of eight patients with uremic HPT, and 15 normal human parathyroid glands. The adenomas and hyperplasias demonstrated similar VDR mRNA levels, which were reduced (42 ± 2.8% and 44 ± 4.0%) compared with the normal glands (P < 0.0001). Comparison of parathyroid adenoma with a normal-sized parathyroid gland of the same individual (n = 3 pairs) showed a 20–58% reduction in the tumor. Nodularly enlarged glands represent a more advanced form of secondary HPT and showed greater reduction in the VDR mRNA levels than the diffusely enlarged glands (P < 0.005). The reduced VDR expression is likely to impair the 1,25(OH)2D3-mediated control of parathyroid functions, and to be of importance for the pathogenesis of not only uremic but also primary HPT. Circulating factors like calcium, PTH, and 1,25(OH)2D3 seem to be less likely candidates mediating the decreased VDR gene expression in HPT.
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Ruan, B., I. Ahel, A. Ambrogelly, H. D. Becker, S. Bunjun, L. Feng, D. Tumbula-Hansen i in. "Genomics and the evolution of aminoacyl-tRNA synthesis." Acta Biochimica Polonica 48, nr 2 (30.06.2001): 313–21. http://dx.doi.org/10.18388/abp.2001_3917.
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Translation is the process by which ribosomes direct protein synthesis using the genetic information contained in messenger RNA (mRNA). Transfer RNAs (tRNAs) are charged with an amino acid and brought to the ribosome, where they are paired with the corresponding trinucleotide codon in mRNA. The amino acid is attached to the nascent polypeptide and the ribosome moves on to the next codon. Thus, the sequential pairing of codons in mRNA with tRNA anticodons determines the order of amino acids in a protein. It is therefore imperative for accurate translation that tRNAs are only coupled to amino acids corresponding to the RNA anticodon. This is mostly, but not exclusively, achieved by the direct attachment of the appropriate amino acid to the 3'-end of the corresponding tRNA by the aminoacyl-tRNA synthetases. To ensure the accurate translation of genetic information, the aminoacyl-tRNA synthetases must display an extremely high level of substrate specificity. Despite this highly conserved function, recent studies arising from the analysis of whole genomes have shown a significant degree of evolutionary diversity in aminoacyl-tRNA synthesis. For example, non-canonical routes have been identified for the synthesis of Asn-tRNA, Cys-tRNA, Gln-tRNA and Lys-tRNA. Characterization of non-canonical aminoacyl-tRNA synthesis has revealed an unexpected level of evolutionary divergence and has also provided new insights into the possible precursors of contemporary aminoacyl-tRNA synthetases.
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Li, Li, Xincang Li, Lu Li, Jinxing Wang i Wenrui Jin. "Ultra-sensitive DNA assay based on single-molecule detection coupled with fluorescent quantum dot-labeling and its application to determination of messenger RNA". Analytica Chimica Acta 685, nr 1 (styczeń 2011): 52–57. http://dx.doi.org/10.1016/j.aca.2010.11.012.
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Pei, Jingjing, Nicole D. Wagner, Angela J. Zou, Srirupa Chatterjee, Dominika Borek, Aidan R. Cole, Preston J. Kim i in. "Structural basis for IFN antagonism by human respiratory syncytial virus nonstructural protein 2". Proceedings of the National Academy of Sciences 118, nr 10 (1.03.2021): e2020587118. http://dx.doi.org/10.1073/pnas.2020587118.
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Human respiratory syncytial virus (RSV) nonstructural protein 2 (NS2) inhibits host interferon (IFN) responses stimulated by RSV infection by targeting early steps in the IFN-signaling pathway. But the molecular mechanisms related to how NS2 regulates these processes remain incompletely understood. To address this gap, here we solved the X-ray crystal structure of NS2. This structure revealed a unique fold that is distinct from other known viral IFN antagonists, including RSV NS1. We also show that NS2 directly interacts with an inactive conformation of the RIG-I–like receptors (RLRs) RIG-I and MDA5. NS2 binding prevents RLR ubiquitination, a process critical for prolonged activation of downstream signaling. Structural analysis, including by hydrogen-deuterium exchange coupled to mass spectrometry, revealed that the N terminus of NS2 is essential for binding to the RIG-I caspase activation and recruitment domains. N-terminal mutations significantly diminish RIG-I interactions and result in increased IFNβ messenger RNA levels. Collectively, our studies uncover a previously unappreciated regulatory mechanism by which NS2 further modulates host responses and define an approach for targeting host responses.
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Mick, David U., Milena Vukotic, Heike Piechura, Helmut E. Meyer, Bettina Warscheid, Markus Deckers i Peter Rehling. "Coa3 and Cox14 are essential for negative feedback regulation of COX1 translation in mitochondria". Journal of Cell Biology 191, nr 1 (27.09.2010): 141–54. http://dx.doi.org/10.1083/jcb.201007026.
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Regulation of eukaryotic cytochrome oxidase assembly occurs at the level of Cox1 translation, its central mitochondria-encoded subunit. Translation of COX1 messenger RNA is coupled to complex assembly in a negative feedback loop: the translational activator Mss51 is thought to be sequestered to assembly intermediates, rendering it incompetent to promote translation. In this study, we identify Coa3 (cytochrome oxidase assembly factor 3; Yjl062w-A), a novel regulator of mitochondrial COX1 translation and cytochrome oxidase assembly. We show that Coa3 and Cox14 form assembly intermediates with newly synthesized Cox1 and are required for Mss51 association with these complexes. Mss51 exists in equilibrium between a latent, translational resting, and a committed, translation-effective, state that are represented as distinct complexes. Coa3 and Cox14 promote formation of the latent state and thus down-regulate COX1 expression. Consequently, lack of Coa3 or Cox14 function traps Mss51 in the committed state and promotes Cox1 synthesis. Our data indicate that Coa1 binding to sequestered Mss51 in complex with Cox14, Coa3, and Cox1 is essential for full inactivation.
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Hu, S.-P., J.-J. Zhao, W.-X. Wang, Y. Liu, H.-F. Wu, C. Chen, L. Yu i J.-B. Gui. "Dexmedetomidine increases acetylation level of histone through ERK1/2 pathway in dopamine neuron". Human & Experimental Toxicology 36, nr 5 (22.06.2016): 474–82. http://dx.doi.org/10.1177/0960327116652458.
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Dexmedetomidine is a highly selective α2-adrenoceptor agonist with sedation, anesthetic sparing, analgesia, sympatholytic, and neuroprotective properties. This study evaluated neuroprotective effects of dexmedetomidine on dopamine neurons correlated to histone acetylation via extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) pathway. Animals were randomly assigned to four groups and treatments were given as onetime doses: dimethyl sulfoxide (DMSO; n = 6), dexmedetomidine 1 mg/kg ( n = 6), 10 mg/kg ( n = 6), and 100 mg/kg ( n = 6). Acetylation histone protein levels and ERK protein levels in rats dopamine neuron from striatum were determined by Western blotting after various doses of dexmedetomidine (1, 10, and 100 mg/kg) treatments. The messenger RNA expression related to signal transduction coupled to 5-hydroxytryptamine receptor (5-HTR) in striatum was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Dexmedetomidine administration increased expression of ERK1/2 phosphorylation and histones H3 acetylation. PD098059, an inhibitor of pERK1/2, almost completely blocked dexmedetomidine-induced histones H3 acetylation. In addition, bioinformatics analysis in combination with qRT-PCR demonstrated that dexmedetomidine could regulate the genes that are related to signal transduction coupled to 5-HTR via α2-adrenoceptor. Our results define dexmedetomidine as a modulator of histones H3 acetylation via ERK1/2 signaling pathway in dopamine neuron from striatum, which may provide clues for the mechanism underlying the neuroprotective effects of dexmedetomidine.
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Ren, Xianyun, Xueqiong Bian, Huixin Shao, Shaoting Jia, Zhenxing Yu, Ping Liu, Jian Li i Jitao Li. "Regulation Mechanism of Dopamine Receptor 1 in Low Temperature Response of Marsupenaeus japonicus". International Journal of Molecular Sciences 24, nr 20 (17.10.2023): 15278. http://dx.doi.org/10.3390/ijms242015278.
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Dopamine receptors (DARs) are important transmembrane receptors responsible for receiving extracellular signals in the DAR-mediated signaling pathway, and are involved in a variety of physiological functions. Herein, the D1 DAR gene from Marsupenaeus japonicus (MjDAD1) was identified and characterized. The protein encoded by MjDAD1 has the typical structure and functional domains of the G-protein coupled receptor family. MjDAD1 expression was significantly upregulated in the gills and hepatopancreas after low temperature stress. Moreover, double-stranded RNA-mediated silencing of MjDAD1 significantly changed the levels of protein kinases (PKA and PKC), second messengers (cyclic AMP (cAMP), cyclic cGMP, calmodulin, and diacyl glycerol), and G-protein effectors (adenylate cyclase and phospholipase C). Furthermore, MjDAD1 silencing increased the apoptosis rate of gill and hepatopancreas cells. Thus, following binding to their specific receptors, G-protein effectors are activated by MjDAD1, leading to DAD1-cAMP/PKA pathway-mediated regulation of caspase-dependent mitochondrial apoptosis. We suggest that MjDAD1 is indispensable for the environmental adaptation of M. japonicus.
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Crisanti, Patricia, Boubaker Omri, Eleanor J. Hughes, Geri Meduri, Christiane Hery, Eric Clauser, Claude Jacquemin i Bertrand Saunier. "The Expression of Thyrotropin Receptor in the Brain**This work was supported in part by a grant from the Faculté de Médecine de Bicêtre (Université Paris XI, Orsay, France) and Program Tournesol (Ministère des Affaires Etrangères, Paris, France)." Endocrinology 142, nr 2 (1.02.2001): 812–22. http://dx.doi.org/10.1210/endo.142.2.7943.
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Abstract The regulation of the thyroid gland by TSH is mediated by a heterotrimeric G protein-coupled receptor. Nonthyroid effects of TSH have been reported, and expression of its receptor has been described in adipocytes and lymphocytes. We have previously reported the existence of specific and saturable binding sites of TSH and specific TSH effects in primary cultured rat brain astroglial cells. We now report expression of the TSH receptor gene in these cells; the coding sequence of the corresponding complementary DNA is identical to that previously established in thyroid. Using specific antisense RNA probe, expression of this gene was detected in some isolated or clustered glial fibrillary acidic protein-positive primary cultured cells by in situ hybridization. With this technique, we further detected TSH receptor messenger RNA (mRNA) expression in rat brain cryoslices in both neuronal cells and astrocytes. Its presence predominated in neuron-rich areas (pyriform and postcingulate cortex, hippocampus, and hypothalamic nuclei) and was mostly colocalized with neuron-specific enolase. In astrocytes, this mRNA was detected in the ependymal cell layer and the subependymal zone, and several isolated cells were also found in the brain parenchyma. We also detected TSH receptor mRNA and protein in primary cultured human astrocytes. The protein was detected as well in both rat and human brain cryoslices. Together, these findings clearly demonstrate the expression of the TSH receptor gene in the brain in both neuronal cells and astrocytes.
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Kong, Ling-Shang, Ran Tao, Yi-Fan Li, Wen-Bin Wang i Xue Zhao. "METTL5 promotes cell proliferation, invasion, and migration by up-regulating Toll-like receptor 8 expression in colorectal cancer". World Journal of Gastrointestinal Oncology 16, nr 5 (15.05.2024): 2006–17. http://dx.doi.org/10.4251/wjgo.v16.i5.2006.
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BACKGROUND N6-methyladenosine (m6A) modification represents the predominant alteration found in eukaryotic messenger RNA and plays a crucial role in the progression of various tumors. However, despite its significance, the comprehensive investigation of METTL5, a key m6A methyltransferase, in colorectal cancer (CRC) remains limited. AIM To investigate the role of METTL5 in CRC. METHODS We assessed METTL5 expression levels in clinical samples obtained from CRC patients as well as in CRC cell lines. To elucidate the downstream targets of METTL5, we performed RNA-sequencing analysis coupled with correlation analysis, leading us to identify Toll-like receptor 8 (TLR8) as a potential downstream target. In vitro functional assessments of METTL5 and TLR8 were conducted using CCK-8 assays, scratch assays, as well as assays measuring cell migration and invasion. RESULTS Our findings reveal a pronounced upregulation of METTL5 expression in both CRC cells and tissues, which correlated significantly with an unfavorable prognosis. In vitro experiments unequivocally demonstrated the oncogenic role of METTL5, as evidenced by its promotion of CRC cell proliferation, invasion, and migration. Notably, we identified TLR8 as a downstream target of METTL5, and subsequent down-regulation of TLR8 led to a significant inhibition of CRC cell proliferation, invasion, and tumor growth. CONCLUSION The heightened expression of METTL5 in CRC is strongly associated with clinicopathological features and a poor prognosis, thereby underscoring its potential utility as a critical marker for facilitating early diagnosis and prognostication in CRC.
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Gobeil, Jr., Fernand, Alejandro Vazquez-Tello, Anne Marilise Marrache, Mosumi Bhattacharya, Daniella Checchin, Ghassan Bkaily, Pierre Lachapelle, Alfredo Ribeiro-Da-Silva i Sylvain Chemtob. "Nuclear prostaglandin signaling system: biogenesis and actions via heptahelical receptors". Canadian Journal of Physiology and Pharmacology 81, nr 2 (1.02.2003): 196–204. http://dx.doi.org/10.1139/y02-163.
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Prostaglandins are ubiquitous lipid mediators that play pivotal roles in cardiovascular homeostasis, reproduction, and inflammation, as well as in many important cellular processes including gene expression and cell proliferation. The mechanism of action of these lipid messengers is thought to be primarily dependent on their interaction with specific cell surface receptors that belong to the heptahelical transmembrane spanning G protein-coupled receptor superfamily. Accumulating evidence suggests that these receptors may co-localize at the cell nucleus where they can modulate gene expression through a series of biochemical events. In this context, we have recently demonstrated that prostaglandin E2-EP3 receptors display an atypical nuclear compartmentalization in cerebral microvascular endothelial cells. Stimulation of these nuclear EP3 receptors leads to an increase of eNOS RNA in a cell-free isolated nuclear system. This review will emphasize these findings and describe how nuclear prostaglandin receptors, notably EP3 receptors, may affect gene expression, specifically of eNOS, by identifying putative transducing elements located within this organelle. The potential sources of lipid ligand activators for these intracellular sites will also be addressed. The expressional control of G-protein-coupled receptors located at the perinuclear envelope constitutes a novel and distinctive mode of gene regulation.Key words: PGE2, EP receptors, cell nucleus, signal transduction, gene transcription.
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Sanchez-Pernaute, Rosario, i Anna-Liisa Brownell. "Therapeutic Exploration of Metabotropic Glutamate Receptor Antagonists in Parkinson’s Disease by Positron Emission Tomography". US Neurology 05, nr 02 (2010): 21. http://dx.doi.org/10.17925/usn.2010.05.02.21.
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Metabotropic glutamate receptors (mGluR)s are G-protein-coupled receptors that function as modulators of synaptic function and glutamate transmission. Post-synaptically localized subtype 5 mGlu5 receptors are co-localized with adenosine A2a, dopamine, and N-methyl-D-aspartate (NMDA) receptors and regulate local protein synthesis and messenger RNA (mRNA) translation at synapses, and are thus ideally positioned to control synaptic plasticity. Aberrant synaptic plasticity appears to be involved in a number of developmental and degenerative neuropsychiatric disorders, including Parkinsons disease. Pharmacological modulation of mGluR5 could potentially open new therapeutic avenues for the treatment of such disorders, for both symptomatic and neuroprotective purposes. In this review, we summarize a series ofin vivostudies we performed in order to delineate the anatomical basis and functional role of mGluR5 antagonists in Parkinsons disease models, taking advantage of high-resolution positron emission tomography (PET) and the recent development of novel specific radiopharmaceuticals. Our findings of a prevalent distribution of mGluR5 in the striatum and limbic structures and a significant binding enhancement following dopamine lesions support the role of mGlu5 receptors in modulating dopamine- and glutamate-dependent signaling and synaptic plasticity within the basal ganglia corticosubcortical loops.
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Erales, Jenny, Virginie Marchand, Baptiste Panthu, Sandra Gillot, Stéphane Belin, Sandra E. Ghayad, Maxime Garcia i in. "Evidence for rRNA 2′-O-methylation plasticity: Control of intrinsic translational capabilities of human ribosomes". Proceedings of the National Academy of Sciences 114, nr 49 (20.11.2017): 12934–39. http://dx.doi.org/10.1073/pnas.1707674114.
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Ribosomal RNAs (rRNAs) are main effectors of messenger RNA (mRNA) decoding, peptide-bond formation, and ribosome dynamics during translation. Ribose 2′-O-methylation (2′-O-Me) is the most abundant rRNA chemical modification, and displays a complex pattern in rRNA. 2′-O-Me was shown to be essential for accurate and efficient protein synthesis in eukaryotic cells. However, whether rRNA 2′-O-Me is an adjustable feature of the human ribosome and a means of regulating ribosome function remains to be determined. Here we challenged rRNA 2′-O-Me globally by inhibiting the rRNA methyl-transferase fibrillarin in human cells. Using RiboMethSeq, a nonbiased quantitative mapping of 2′-O-Me, we identified a repertoire of 2′-O-Me sites subjected to variation and demonstrate that functional domains of ribosomes are targets of 2′-O-Me plasticity. Using the cricket paralysis virus internal ribosome entry site element, coupled to in vitro translation, we show that the intrinsic capability of ribosomes to translate mRNAs is modulated through a 2′-O-Me pattern and not by nonribosomal actors of the translational machinery. Our data establish rRNA 2′-O-Me plasticity as a mechanism providing functional specificity to human ribosomes.
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Müller, Berndt, Jane Blackburn, Carmen Feijoo, Xiujie Zhao i Carl Smythe. "DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication". Journal of Cell Biology 179, nr 7 (24.12.2007): 1385–98. http://dx.doi.org/10.1083/jcb.200708106.
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DNA and histone synthesis are coupled and ongoing replication is required to maintain histone gene expression. Here, we expose S phase–arrested cells to the kinase inhibitors caffeine and LY294002. This uncouples DNA replication from histone messenger RNA (mRNA) abundance, altering the efficiency of replication stress–induced histone mRNA down-regulation. Interference with caffeine-sensitive checkpoint kinases ataxia telangiectasia and Rad3 related (ATR)/ataxia telangiectasia mutated (ATM) does not affect histone mRNA down- regulation, which indicates that ATR/ATM alone cannot account for such coupling. LY294002 potentiates caffeine's ability to uncouple histone mRNA stabilization from replication only in cells containing functional DNA-activated protein kinase (DNA-PK), which indicates that DNA-PK is the target of LY294002. DNA-PK is activated during replication stress and DNA-PK signaling is enhanced when ATR/ATM signaling is abrogated. Histone mRNA decay does not require Chk1/Chk2. Replication stress induces phosphorylation of UPF1 but not hairpin-binding protein/stem-loop binding protein at S/TQ sites, which are preferred substrate recognition motifs of phosphatidylinositol 3-kinase–like kinases, which indicates that histone mRNA stability may be directly controlled by ATR/ATM- and DNA-PK–mediated phosphorylation of UPF1.
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KAUNISTO, KARI M., i HANNU J. RAJANIEMI. "Expression and Localization of the Na+/H+ Exchanger Isoform NHE3 in the Rat Efferent Ducts". Journal of Andrology 23, nr 2 (4.03.2002): 237–41. http://dx.doi.org/10.1002/j.1939-4640.2002.tb02620.x.
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ABSTRACT: The efferent ducts reabsorb most of the fluid released with spermatozoa from the testis. This absorptive capacity results in a severalfold increase in sperm concentration in the proximal epididymis and is partly responsible for maintenance of the optimal microenvironment for the sperm maturation. The fluid absorption is coupled to active Na+ transport and is inhibitable by amiloride, both of which suggest a role for a Na+/H+ exchanger (NHE). NHE3 is an apical membrane NHE responsible for sodium absorption in renal proximal tubule and intestinal epithelium. In the present study, we examined the expression of NHE3 messenger RNA (mRNA) and protein in the rat efferent ducts by reverse transcription‐polymerase chain reaction (RT‐PCR) and Western blotting and the localization of NHE3 by indirect immunofluoresce. RT‐PCR indicated the expression of NHE3 mRNA, and Western blotting showed an NHE3 protein in the efferent duct membrane homogenate. By immunofluorescence, NHE3 was localized to the apical membrane of the nonciliated cells in the efferent duct epithelium, which also expressed aquaporin‐1 water channel protein. These results suggest that NHE3 potentially plays an important role in the fluid reabsorption in the efferent ducts.
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Roache, Tavia. "Consequences of Genomic DNA Mono-Ribonucleotides for Chromosomal Stability". Innovation in Aging 5, Supplement_1 (1.12.2021): 997. http://dx.doi.org/10.1093/geroni/igab046.3579.
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Abstract Mono-ribonucleotides are building blocks for polynucleotide RNA chains (e.g., messenger RNA), but if mis-incorporated into duplex DNA can cause mutagenesis and chromosomal instability. During DNA synthesis by Pol γ, remnants of unremoved RNA primers contribute to elevated mono-ribonucleotide triphosphates resulting in nucleotide pool imbalance, ultimately favoring mis-incorporated ribonucleotides during replication. Moreover, although polymerases generally replicate DNA with high fidelity, the steric gate occasionally allows a mis-incorporated ribonucleotide. Thus, a mono-ribonucleotide is one of the most abundant lesions in genomic DNA of eukaryotes. If unremoved from double-stranded DNA, the ribonucleotide exerts negative effects on replication, transcription, and genomic maintenance, with lasting effects on cellular homeostasis. Even a single ribonucleotide in telomeric DNA comprises shelterin binding and telomere capping causing vulnerability to spontaneous hydrolysis which potentiates telomere shortening. Consistent with this, a ribonucleotide positioned in double-helical DNA alters its structure by torsinally distorting the sugar-phosphate backbone. Fortunately, cellular response and repair pathways exist to help cells cope with mis-incorporated mono-ribonucleotides. The Ribonucleotide Excision Repair (RER) or a Topoisomerase 1 (Top1)-mediated pathway remove embedded ribonucleotides. For RER, RNase H2 incises 5’ of a mono-ribonucleotide, creating an access point for its removal. If cells are deficient in RNase H2, Top1 initiates removal of the ribonucleotide. However, Top1 is less accurate than RNase H2, which can lead to mutagenesis. Studying the mechanisms in which ribonucleotides are incorporated into DNA or further metabolized should provide insight to their negative consequences for chromosomal integrity, cancer, and auto-immune disease attributed to a genetic deficiency of RNase H2.
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Wu, Fengxi, Zhongyuan Xiang, Zhenghao He, Ping Yi, Ming Yang, Haijing Wu i Min Hu. "Abnormally high expression of D1-like dopamine receptors on lupus CD4+T cells promotes Tfh cell differentiation". Lupus Science & Medicine 10, nr 2 (sierpień 2023): e000943. http://dx.doi.org/10.1136/lupus-2023-000943.
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ObjectiveSLE is a chronic autoimmune disease that places a great burden on human society. T follicular helper (Tfh) cells play a critical role in the pathological process of SLE. Therefore, elucidating the mechanism of Tfh cell differentiation will contribute to SLE treatment. Dopamine receptors (DRDs) are members of the family of G protein-coupled receptors and are primarily divided into D1-like and D2-like receptors. Previous studies have found that DRDs can regulate differentiation of immune cells. However, there is currently a lack of research on DRDs and Tfh cells. We here explore the relationship between DRDs and Tfh cells, and analyse the relationship between DRD expression on Tfh cells and the course of SLE.MethodsWe first detected plasma catecholamine concentrations in patients with SLE and healthy controls by mass spectrometry, followed by reverse transcription-quantitative PCR (RT-qPCR) to detect DRD messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) and CD4+T cells, and flow cytometry to detect DRD expression in Tfh cells. Finally, in vitro experiments and RNA sequencing (RNA-seq) were used to explore the possible pathway by which DRDs regulate Tfh cell differentiation.ResultsThe plasma dopamine concentration in patients with SLE was significantly increased, and abnormal mRNA expression of DRDs was observed in both PBMCs and CD4+T cells. The results of flow cytometry showed that D1-like receptors were highly expressed in Tfh cells of patients with SLE and associated with disease activity. In vitro induction experiments showed that differentiation of naïve T cells into Tfh cells was accompanied by an increase in D1-like receptor expression. RNA-seq and RT-qPCR results indicate that D1-like receptors might promote Tfh cell differentiation through the Phosphatidylinositol3-kinase (PI3K)/protein kinase B (AKT)/Forkhead box protein O1 (FOXO1)/Kruppel-like factor 2 (Klf2) pathway.ConclusionTfh cells in patients with SLE highly express D1-like receptors, which correlate with disease activity. D1-like receptors may promote Tfh cell differentiation through the PI3K/AKT/FOXO1/Klf2 pathway.
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Gerdes, Kenn. "Hypothesis: type I toxin–antitoxin genes enter the persistence field—a feedback mechanism explaining membrane homoeostasis". Philosophical Transactions of the Royal Society B: Biological Sciences 371, nr 1707 (5.11.2016): 20160189. http://dx.doi.org/10.1098/rstb.2016.0189.
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Bacteria form persisters, cells that are tolerant to multiple antibiotics and other types of environmental stress. Persister formation can be induced either stochastically in single cells of a growing bacterial ensemble, or by environmental stresses, such as nutrient starvation, in a subpopulation of cells. In many cases, the molecular mechanisms underlying persistence are still unknown. However, there is growing evidence that, in enterobacteria, both stochastically and environmentally induced persistence are controlled by the second messenger (p)ppGpp. For example, the ‘alarmone’ (p)ppGpp activates Lon, which, in turn, activates type II toxin–antitoxin (TA) modules to thereby induce persistence. Recently, it has been shown that a type I TA module, hokB / sokB , also can induce persistence. In this case, the underlying mechanism depends on the universally conserved GTPase Obg and, surprisingly, also (p)ppGpp. In the presence of (p)ppGpp, Obg stimulates hokB transcription and induces persistence. HokB toxin expression is under both negative and positive control: SokB antisense RNA inhibits hokB mRNA translation, while (p)ppGpp and Obg together stimulate hokB transcription. HokB is a small toxic membrane protein that, when produced in modest amounts, leads to membrane depolarization, cell stasis and persistence. By contrast, overexpression of HokB disrupts the membrane potential and kills the cell. These observations raise the question of how expression of HokB is regulated. Here, I propose a homoeostatic control mechanism that couples HokB expression to the membrane-bound RNase E that degrades and inactivates SokB antisense RNA. This article is part of the themed issue ‘The new bacteriology’.