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Veterinary Medicine and Science Jul 2024Canine parvovirus type 2 (CPV-2) is the most common enteric virus that infects canids. CPV is the causative agent of a contagious disease defined mostly by clinical...
BACKGROUND
Canine parvovirus type 2 (CPV-2) is the most common enteric virus that infects canids. CPV is the causative agent of a contagious disease defined mostly by clinical gastrointestinal signs in dogs. During the late 1970s, CPV-2 emerged as a new virus capable of infecting domestic dogs and growing across the world. The VP2 gene stands out as a key determinant in the pathogenicity, antigenicity, and host interactions of CPV-2.
AIMS
The molecular characterization of the VP2 gene is crucial for understanding CPV evolution and epidemiology.
MATERIALS & METHODS
Genes encoding the VP2 protein were sequenced and compared to reference strains worldwide. The maximum likelihood method was used to build a phylogenetic tree using CPV VP2 gene nucleotide sequences.
RESULTS
Our phylogenetic analysis of the VP2 gene revealed that five strains were very similar and clustered together, and three strains were in the 2b clade, whereas the other two were in the 2a/2b clade.
DISCUSSION
This paper reports the molecular characterization of two novel CPV-2a/2b subtypes in dogs with gastrointestinal symptoms. Genetic analysis was conducted on a CPV genomic region encompassing one of the open reading frames (ORFs) encoding the structural protein VP2. Sequence analysis indicates new and unreported sequence changes, mainly affecting the VP2 gene, which includes the mutations Ser297Ala and Leu87Met. This study represents the first evidence of a new CPV-2a/2b subtype in Türkiye. Due to VP2's crucial role in encoding the capsid protein of CPV-2 and its significant involvement in the host-virus interaction, it is critical to closely monitor its evolutionary changes and be cautious while searching for novel or pre-existing subtypes.
CONCLUSION
This study highlights the significance of continuous molecular research for acquiring more insights on the circulation of novel CPV mutants.
Topics: Animals; Dogs; Parvovirus, Canine; Dog Diseases; Parvoviridae Infections; Phylogeny; Gastrointestinal Diseases
PubMed: 38958584
DOI: 10.1002/vms3.1523 -
Pediatric Critical Care Medicine : a... Jul 2024
Topics: Humans; Anti-Bacterial Agents; Critical Illness; Respiratory Tract Infections; Child; Intensive Care Units, Pediatric; Child, Preschool
PubMed: 38958550
DOI: 10.1097/PCC.0000000000003517 -
Advanced Science (Weinheim,... Jul 2024α-halo alkylboronic esters, acting as ambiphilic synthons, play a pivotal role as versatile intermediates in fields like pharmaceutical science and organic chemistry....
α-halo alkylboronic esters, acting as ambiphilic synthons, play a pivotal role as versatile intermediates in fields like pharmaceutical science and organic chemistry. The sequential transformation of carbon-boron and carbon-halogen bonds into a broad range of carbon-X bonds allows for programmable bond formation, facilitating the incorporation of multiple substituents at a single position and streamlining the synthesis of complex molecules. Nevertheless, the synthetic potential of these compounds is constrained by limited reaction patterns. Additionally, the conventional methods often necessitate the use of bulk toxic solvents, exhibit sensitivity to air/moisture, rely on expensive metal catalysts, and involve extended reaction times. In this report, a ball milling technique is introduced that overcomes these limitations, enabling the external catalyst-free multicomponent coupling of aryl diazonium salts, alkenes, and simple metal halides. This approach offers a general and straightforward method for obtaining a diverse array of α-halo alkylboronic esters, thereby paving the way for the extensive utilization of these synthons in the synthesis of fine chemicals.
PubMed: 38958542
DOI: 10.1002/advs.202404071 -
Journal of Cellular Physiology Jul 2024Autophagy is a lysosome-mediated self-degradation process of central importance for cellular quality control. It also provides macromolecule building blocks and... (Review)
Review
Autophagy is a lysosome-mediated self-degradation process of central importance for cellular quality control. It also provides macromolecule building blocks and substrates for energy metabolism during nutrient or energy deficiency, which are the main stimuli for autophagy induction. However, like most biological processes, autophagy itself requires ATP, and there is an energy threshold for its initiation and execution. We here present the first comprehensive review of this often-overlooked aspect of autophagy research. The studies in which ATP deficiency suppressed autophagy in vitro and in vivo were classified according to the energy pathway involved (oxidative phosphorylation or glycolysis). A mechanistic insight was provided by pinpointing the critical ATP-consuming autophagic events, including transcription/translation/interaction of autophagy-related molecules, autophagosome formation/elongation, autophagosome fusion with the lysosome, and lysosome acidification. The significance of energy-dependent fine-tuning of autophagic response for preserving the cell homeostasis, and potential implications for the therapy of cancer, autoimmunity, metabolic disorders, and neurodegeneration are discussed.
PubMed: 38958520
DOI: 10.1002/jcp.31366 -
Proteins Jul 2024The ongoing global pandemic of the coronavirus 2019 (COVID-19) disease is caused by the virus SARS-CoV-2, with very few highly effective antiviral treatments currently...
The ongoing global pandemic of the coronavirus 2019 (COVID-19) disease is caused by the virus SARS-CoV-2, with very few highly effective antiviral treatments currently available. The machinery responsible for the replication and transcription of viral RNA during infection is made up of several important proteins. Two of these are nsp12, the catalytic subunit of the viral polymerase, and nsp9, a cofactor of nsp12 involved in the capping and priming of viral RNA. While several recent studies have determined the structural details of the interaction of nsp9 with nsp12 in the context of RNA capping, very few biochemical or biophysical details are currently available. In this study, we have used a combination of surface plasmon resonance (SPR) experiments, size exclusion chromatography (SEC) experiments, and biochemical assays to identify specific nsp9 residues that are critical for nsp12 binding as well as RNAylation, both of which are essential for the RNA capping process. Our data indicate that nsp9 dimerization is unlikely to play a significant functional role in the virus. We confirm that a set of recently discovered antiviral peptides inhibit nsp9-nsp12 interaction by specifically binding to nsp9; however, we find that these peptides do not impact RNAylation. In summary, our results have important implications for future drug discovery efforts to combat SARS-CoV-2 and any newly emerging coronaviruses.
PubMed: 38958516
DOI: 10.1002/prot.26725 -
MSystems Jul 2024
PubMed: 38958483
DOI: 10.1128/msystems.00714-24 -
The Biochemical Journal Jul 2024The application of dyes to understanding the aetiology of infection inspired antimicrobial chemotherapy and the first wave of antibacterial drugs. The second wave of... (Review)
Review
The application of dyes to understanding the aetiology of infection inspired antimicrobial chemotherapy and the first wave of antibacterial drugs. The second wave of antibacterial drug discovery was driven by rapid discovery of natural products, now making up 69% of current antibacterial drugs. But now with the most prevalent natural products already discovered, ∼107 new soil-dwelling bacterial species must be screened to discover one new class of natural product. Therefore, instead of a third wave of antibacterial drug discovery, there is now a discovery bottleneck. Unlike natural products which are curated by billions of years of microbial antagonism, the vast synthetic chemical space still requires artificial curation through the therapeutics science of antibacterial drugs - a systematic understanding of how small molecules interact with bacterial physiology, effect desired phenotypes, and benefit the host. Bacterial molecular genetics can elucidate pathogen biology relevant to therapeutics development, but it can also be applied directly to understanding mechanisms and liabilities of new chemical agents with new mechanisms of action. Therefore, the next phase of antibacterial drug discovery could be enabled by integrating chemical expertise with systematic dissection of bacterial infection biology. Facing the ambitious endeavour to find new molecules from nature or new-to-nature which cure bacterial infections, the capabilities furnished by modern chemical biology and molecular genetics can be applied to prospecting for chemical modulators of new targets which circumvent prevalent resistance mechanisms.
Topics: Anti-Bacterial Agents; Drug Discovery; Bacteria; Humans; Biological Products; Bacterial Infections
PubMed: 38958473
DOI: 10.1042/BCJ20220062 -
MSphere Jul 2024Five years ago, as I was starting my lab, I wrote about two functional genomic screens in fungi that had inspired me (mSphere 4:e00299-19,... (Review)
Review
Five years ago, as I was starting my lab, I wrote about two functional genomic screens in fungi that had inspired me (mSphere 4:e00299-19, https://doi.org/10.1128/mSphere.00299-19). Now, I want to discuss some of the principles and questions that I ask myself and my students as we embark on our own screens. A good screen, whether it is a genetic or chemical screen, can be the starting point for new discovery and an excellent basis for the beginning of a scientific research project. However, screens are often criticized for being "fishing expeditions." To stretch this metaphor to the extreme, this is because people are worried that we do not know how to fish, that we will come home without any fish, bring home the wrong fish, or not know what to do with a fish if we caught it. How you set up the screen and analyze the results determines whether the screen will be useful. In this mini-review, and in the spirit of teaching a scientist to fish, I will discuss recent excellent fungal genetic and chemical screens that illustrate some of the key aspects of a successful screen.
PubMed: 38958459
DOI: 10.1128/msphere.00638-23 -
MSphere Jul 2024McKenzie Lehman works in the field of bacterial pathogenesis and metabolism. In this mSphere of Influence article, she reflects on how three papers entitled "Glycolytic...
McKenzie Lehman works in the field of bacterial pathogenesis and metabolism. In this mSphere of Influence article, she reflects on how three papers entitled "Glycolytic dependency of high-level nitric oxide resistance and virulence in by N. P. Vitko, N. A. Spahich, and A. R. Richardson (mBio 6:e00045-15, 2015, https://doi.org/10.1128/mbio.00045-15), "The cystine transporters TcyABC and TcyP facilitate nutrient sulfur acquisition during infection" by J. M. Lensmire, J. P. Dodson, B. Y. Hsueh, M. R. Wischer, et al. (Infect Immun 88:e00690-19, 2020, https://doi.org/10.1128/iai.00690-19), and "The second messenger c-di-AMP inhibits the osmolyte uptake system OpuC in " by C. F. Schuster, L. E. Bellows, T. Tosi, I. Campeotto, et al. (Sci Signal 16:ra81, 2016, https://doi.org/10.1126/scisignal.aaf7279) impacted her work on bacterial metabolism and pathogenesis.
PubMed: 38958458
DOI: 10.1128/msphere.00239-24 -
Antimicrobial Agents and Chemotherapy Jul 2024As comparative pharmacokinetic/pharmacodynamic (PK/PD) studies of liposomal amphotericin B (L-AMB) against spp. are lacking, we explored L-AMB pharmacodynamics against...
As comparative pharmacokinetic/pharmacodynamic (PK/PD) studies of liposomal amphotericin B (L-AMB) against spp. are lacking, we explored L-AMB pharmacodynamics against different species in an PK/PD dilution model. Eight , , and isolates (EUCAST/CLSI AMB MIC 0.125-1 mg/L) were studied in the PK/PD model simulating L-AMB = 0.25-64 mg/L and = 9 h. The model was validated with one susceptible and one resistant isolate. The /MIC-logCFU/mL reduction from the initial inoculum was analyzed with the model, and Monte Carlo analysis was performed for the standard (3 mg/kg with = 21.87 ± 12.47 mg/L) and higher (5 mg/kg with = 83 ± 35.2 mg/L) L-AMB dose. A ≥1.5 logCFU/mL reduction was found at L-AMB = 8 mg/L against , , and isolates (MIC 0.25-0.5 mg/L) whereas L-AMB ≥ 32 mg/L was required for isolates. The PK/PD relationship followed a sigmoidal pattern ( ≥ 0.85) with a mean /MIC required for stasis of 2.1 for (close to the stasis), 24/17 (EUCAST/CLSI) for , 8 for , and 10 for . The probability of target attainment was ≥99% for wild-type (WT) isolates with 3 mg/kg and for wild-type isolates of the other species with 5 mg/kg. L-AMB was four- to eightfold less active against the included non-. species than . A standard 3-mg/kg dose is pharmacodynamically sufficient for whereas our data suggest that 5 mg/kg may be recommendable for the included non-. species.
PubMed: 38958455
DOI: 10.1128/aac.00225-24