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Nature Oct 2020
Topics: Bacteria; Dinucleoside Phosphates
PubMed: 32989308
DOI: 10.1038/d41586-020-02712-8 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Nov 2022Cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP) is a newly-discovered second messenger in bacteria and archaea. By directly binding to or affecting the... (Review)
Review
Cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP) is a newly-discovered second messenger in bacteria and archaea. By directly binding to or affecting the expression of target proteins, c-di-AMP regulates the physiological functions of bacteria, including maintaining osmotic pressure, balancing central metabolism, monitoring DNA damage, and controlling biofilm and spore formation. As a new pathogen-associated molecular pattern (PAMP), it binds to the host pattern recognition receptor (PRR), induces cyclic GMP-AMP synthase (cGAS)-STING signal axis to produce type Ⅰ interferon by activating the stimulator of interferon genes (STING), and promotes the secretion of inflammatory factors through nuclear factor κB (NF-κB) signaling pathway, thereby playing an important role in host immunity to bacterial infection and tumorigenesis. Due to its immunogenicity, c-di-AMP could be used as an immune adjuvant to provide new targets for the development of vaccines. However, the specific mechanism of action of c-di-AMP in host immunity awaits further exploration. Herein, we presented the structure and biological characteristics of c-di-AMP, and summarized the possible mechanism of c-di-AMP's regulation of host immune response. In addition, we also reported the latest findings on using c-di-AMP as an immune adjuvant in clinical treatment. Research on the function of c-di-AMP and its mechanism of action on host immune response provides new ideas for finding clinical solutions to bacterial resistance, infection control, tumor prevention, and vaccine development in the future.
Topics: Dinucleoside Phosphates; Bacteria; Biofilms; Signal Transduction
PubMed: 36443059
DOI: 10.12182/20220860102 -
Infection and Immunity Oct 2021Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial...
Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial fitness, including but not limited to osmoregulation, envelope homeostasis, central metabolism, and biofilm formation. In this study, we uncovered the biological significance of c-di-AMP in the opportunistic pathogen Enterococcus faecalis by isolating and characterizing strains lacking genes responsible for c-di-AMP synthesis () and degradation ( and ). Using complementary approaches, we demonstrated that either complete loss of c-di-AMP (Δ strain) or c-di-AMP accumulation (Δ, Δ, and Δ Δ strains) drastically impaired general cell fitness and virulence of E. faecalis. In particular, the Δ strain was highly sensitive to envelope-targeting antibiotics, was unable to multiply and quickly lost viability in human serum or urine , and was virtually avirulent in an invertebrate (Galleria mellonella) and in two catheter-associated mouse infection models that recapitulate key aspects of enterococcal infections in humans. In addition to evidence linking these phenotypes to altered activity of metabolite and peptide transporters and inability to maintain osmobalance, we found that the attenuated virulence of the Δ strain also could be attributed to a defect in Ebp pilus production and activity that severely impaired biofilm formation under both and conditions. Collectively, these results demonstrate that c-di-AMP signaling is essential for E. faecalis pathogenesis and a desirable target for drug development.
Topics: Animals; Biofilms; Dinucleoside Phosphates; Enterococcus faecalis; Fimbriae, Bacterial; Gene Expression Regulation, Bacterial; Gram-Positive Bacterial Infections; Humans; Virulence
PubMed: 34424750
DOI: 10.1128/IAI.00365-21 -
MBio Jan 2021The development of safe and effective vaccines against viruses is central to disease control. With advancements in DNA synthesis technology, the production of synthetic... (Review)
Review
The development of safe and effective vaccines against viruses is central to disease control. With advancements in DNA synthesis technology, the production of synthetic viral genomes has fueled many research efforts that aim to generate attenuated viruses by introducing synonymous mutations. Elucidation of the mechanisms underlying virus attenuation through synonymous mutagenesis is revealing interesting new biology that can be exploited for vaccine development. Here, we review recent advancements in this field of synthetic virology and focus on the molecular mechanisms of attenuation by genetic recoding of viruses. We highlight the action of the zinc finger antiviral protein (ZAP) and RNase L, two proteins involved in the inhibition of viruses enriched for CpG and UpA dinucleotides, that are often the products of virus recoding algorithms. Additionally, we discuss current challenges in the field as well as studies that may illuminate how other host functions, such as translation, are potentially involved in the attenuation of recoded viruses.
Topics: Animals; DNA Viruses; Dinucleoside Phosphates; Endoribonucleases; Genome, Viral; Humans; Silent Mutation; Vaccines, Attenuated; Viral Vaccines; Virus Replication; Viruses
PubMed: 33402534
DOI: 10.1128/mBio.02238-20 -
Viruses Sep 2021An evolutionary arms race occurs between viruses and hosts. Hosts have developed an array of antiviral mechanisms aimed at inhibiting replication and spread of viruses,... (Review)
Review
An evolutionary arms race occurs between viruses and hosts. Hosts have developed an array of antiviral mechanisms aimed at inhibiting replication and spread of viruses, reducing their fitness, and ultimately minimising pathogenic effects. In turn, viruses have evolved sophisticated counter-measures that mediate evasion of host defence mechanisms. A key aspect of host defences is the ability to differentiate between self and non-self. Previous studies have demonstrated significant suppression of CpG and UpA dinucleotide frequencies in the coding regions of RNA and small DNA viruses. Artificially increasing these dinucleotide frequencies results in a substantial attenuation of virus replication, suggesting dinucleotide bias could facilitate recognition of non-self RNA. The interferon-inducible gene, zinc finger antiviral protein (ZAP) is the host factor responsible for sensing CpG dinucleotides in viral RNA and restricting RNA viruses through direct binding and degradation of the target RNA. Herpesviruses are large DNA viruses that comprise three subfamilies, alpha, beta and gamma, which display divergent CpG dinucleotide patterns within their genomes. ZAP has recently been shown to act as a host restriction factor against human cytomegalovirus (HCMV), a beta-herpesvirus, which in turn evades ZAP detection by suppressing CpG levels in the major immediate-early transcript IE1, one of the first genes expressed by the virus. While suppression of CpG dinucleotides allows evasion of ZAP targeting, synonymous changes in nucleotide composition that cause genome biases, such as low GC content, can cause inefficient gene expression, especially in unspliced transcripts. To maintain compact genomes, the majority of herpesvirus transcripts are unspliced. Here we discuss how the conflicting pressures of ZAP evasion, the need to maintain compact genomes through the use of unspliced transcripts and maintaining efficient gene expression may have shaped the evolution of herpesvirus genomes, leading to characteristic CpG dinucleotide patterns.
Topics: Alphaherpesvirinae; Animals; Betaherpesvirinae; Dinucleoside Phosphates; Evolution, Molecular; Gammaherpesvirinae; Gene Expression; Genome, Viral; Herpesviridae; Host-Pathogen Interactions; Humans; Interferons; RNA Splicing; RNA, Viral; RNA-Binding Proteins; Signal Transduction; Viral Proteins
PubMed: 34578438
DOI: 10.3390/v13091857 -
Cyclic di-AMP, a second messenger of primary importance: tertiary structures and binding mechanisms.Nucleic Acids Research Apr 2020Cyclic diadenylate (c-di-AMP) is a widespread second messenger in bacteria and archaea that is involved in the maintenance of osmotic pressure, response to DNA damage,... (Review)
Review
Cyclic diadenylate (c-di-AMP) is a widespread second messenger in bacteria and archaea that is involved in the maintenance of osmotic pressure, response to DNA damage, and control of central metabolism, biofilm formation, acid stress resistance, and other functions. The primary importance of c-di AMP stems from its essentiality for many bacteria under standard growth conditions and the ability of several eukaryotic proteins to sense its presence in the cell cytoplasm and trigger an immune response by the host cells. We review here the tertiary structures of the domains that regulate c-di-AMP synthesis and signaling, and the mechanisms of c-di-AMP binding, including the principal conformations of c-di-AMP, observed in various crystal structures. We discuss how these c-di-AMP molecules are bound to the protein and riboswitch receptors and what kinds of interactions account for the specific high-affinity binding of the c-di-AMP ligand. We describe seven kinds of non-covalent-π interactions between c-di-AMP and its receptor proteins, including π-π, C-H-π, cation-π, polar-π, hydrophobic-π, anion-π and the lone pair-π interactions. We also compare the mechanisms of c-di-AMP and c-di-GMP binding by the respective receptors that allow these two cyclic dinucleotides to control very different biological functions.
Topics: Animals; Dinucleoside Phosphates; Molecular Conformation; Riboswitch; Second Messenger Systems; Signal Transduction
PubMed: 32095817
DOI: 10.1093/nar/gkaa112 -
The Journal of Physical Chemistry. B Dec 2022Autofluorescence imaging has been widely applied as advanced noninvasive diagnostics for in vivo and ex vivo tissues. The optical redox ratio (ORR), which is defined as...
Autofluorescence imaging has been widely applied as advanced noninvasive diagnostics for in vivo and ex vivo tissues. The optical redox ratio (ORR), which is defined as the fluorescence intensity ratio between reduced nicotine adenine dinucleotide (NADH) and oxidized flavin adenine dinucleotide (FAD), has been used as a diagnostic parameter strongly, because NADH and FAD play an important role in energetic and respiratory metabolism as coenzymes. The ORR method has provided successful assessment in cancer diagnosis including breast, cervical, and oral cancer; few studies have been reported about optical and chemical interference between two molecules resulting in a change in ORR values. In this study, we investigated the variations in ORR values of NADH/FAD mixtures dissolved in tris(hydroxymethyl)aminomethane, phosphate buffer, and deionized water environments. In vitro solutions were prepared in various concentration ratios and the experimental and theoretical ORR values were obtained from fluorescence and absorption spectra in time series. Based on the spectroscopic analysis, we concluded that the inner filter effect causes an instant decrease in FAD fluorescence just after dissolution and that the oxidation-reduction coupled with oxygenation reaction results in time-varying decreases in NADH fluorescence and FAD emission.
Topics: Adenine; Nicotine; Flavin-Adenine Dinucleotide; NAD; Dinucleoside Phosphates; Oxidation-Reduction
PubMed: 36399328
DOI: 10.1021/acs.jpcb.2c05292 -
Communications Biology Jul 2022Predicting protein-protein interaction and non-interaction are two important different aspects of multi-body structure predictions, which provide vital information about...
Predicting protein-protein interaction and non-interaction are two important different aspects of multi-body structure predictions, which provide vital information about protein function. Some computational methods have recently been developed to complement experimental methods, but still cannot effectively detect real non-interacting protein pairs. We proposed a gene sequence-based method, named NVDT (Natural Vector combine with Dinucleotide and Triplet nucleotide), for the prediction of interaction and non-interaction. For protein-protein non-interactions (PPNIs), the proposed method obtained accuracies of 86.23% for Homo sapiens and 85.34% for Mus musculus, and it performed well on three types of non-interaction networks. For protein-protein interactions (PPIs), we obtained accuracies of 99.20, 94.94, 98.56, 95.41, and 94.83% for Saccharomyces cerevisiae, Drosophila melanogaster, Helicobacter pylori, Homo sapiens, and Mus musculus, respectively. Furthermore, NVDT outperformed established sequence-based methods and demonstrated high prediction results for cross-species interactions. NVDT is expected to be an effective approach for predicting PPIs and PPNIs.
Topics: Animals; Dinucleoside Phosphates; Drosophila melanogaster; Genetic Techniques; Genetic Vectors; Helicobacter pylori; Mice; Saccharomyces cerevisiae
PubMed: 35780196
DOI: 10.1038/s42003-022-03617-0 -
International Urogynecology Journal Oct 2021This systematic review evaluated the rigor of the development of clinical practice guidelines (CPG). (Review)
Review
INTRODUCTION AND HYPOTHESIS
This systematic review evaluated the rigor of the development of clinical practice guidelines (CPG).
METHODS
The searched sources were MEDLINE, EMBASE, Web of Science, Scopus, and specific databases of CPG. Reviewers, organized in triplicate and independently, selected the studies and assessed the quality of the guidelines using the Appraisal of Guidelines Research and Evaluation (AGREE II) instrument, which contains six domains for classification. The classification of the CPGs prioritized the domain 3 (developmental rigor) considering: high (score > 60%), moderate (score 30-60%), or low quality (score < 30%). The results were checked for discrepancies and decided by consensus. The interventions were described. Descriptive statistics presented the results.
RESULTS
Of the ten CPGs evaluated, five were of high methodological quality, three were of moderate quality, and two of low quality. Three documents were not recommended for use. The domains with the highest scores were scope and purpose (mean = 90.1%) and clarity of presentation (mean = 88.9%). The domains of editorial independence (mean = 41.4%) and applicability (mean = 29.3%) were those with the lowest score. The most cited interventions in CPGs were the nonpharmacological, such as lifestyle interventions, bladder training, or re-education and pelvic floor muscle training.
CONCLUSION
Most guidelines showed rigor in development and were recommended for use; however, editorial independence and applicability were domains that need to be improved in these documents. Our findings can guide the choice of CPG for the treatment of urinary incontinence.
Topics: Bibliometrics; Databases, Factual; Dinucleoside Phosphates; Humans; Life Style; Urinary Incontinence
PubMed: 33704538
DOI: 10.1007/s00192-021-04729-7 -
Chemistry (Weinheim An Der Bergstrasse,... May 2024Biomolecules containing adenosine di- or triphosphate (ADP or ATP) are crucial for diverse biological processes. Synthesis of these biomolecules and development of their...
Biomolecules containing adenosine di- or triphosphate (ADP or ATP) are crucial for diverse biological processes. Synthesis of these biomolecules and development of their chemical probes are important to elucidate their functions. Enabling reproducible and high-yielding access to these ADP- and ATP-containing molecules via conventional P(III)-P(V) and P(V)-P(V) coupling reactions is challenging owing to water content in highly polar phosphate-containing substrates. Herein, we report an efficient and reliable method for protecting-group-free P(V)-P(V) coupling reaction through in situ activation of phosphates using hydrolysis-stable 2-[N-(2-methylimidazoyl)]-1,3-dimethylimidazolinium chloride (2-MeImIm-Cl), providing the corresponding electrophilic P(V) intermediates for subsequent nucleophilic attack using their coupling partners. This P(V)-P(V) coupling reaction proceeded even in a wet reaction medium and showed a broad substrate scope, accommodating protecting-group-free synthesis of ADP-ribose and nicotinamide adenine diphosphate analogs, ATP-containing biomolecules, and ADP-ribosyl peptides.
PubMed: 38763895
DOI: 10.1002/chem.202401302