Synthesis and Resolution of 4'-Substituted Nucleosides with Potential Antiviral and Antisense Strategies.

Nucleoside derivatives having a 4-substituent show promise as potential antiviral agents as well as nucleoside units for constructing nucleic acid medicines. To develop new nucleosides, it is crucial to achieve feasible access to the intended derivatives, encompassing both enantiomers. Toward this end, we started synthesizing an achiral 4-hydroxymethyldihydrofuran as a sugar precursor, which we subjected to the oxidative glycosylation reaction using hypervalent iodine.

Subchondral insufficiency fractures of the medial tibial condyle are associated with medial meniscus extrusion: A retrospective observational study.

Background: To the best of our knowledge, no prior studies have identified any risk factors for subchondral insufficiency fractures of the medial tibial condyle. This study aimed to explain relationships between subchondral insufficiency fractures of the medial tibial condyle and the meniscus status, lower extremity alignment, or osteoporosis.

Methods: This retrospective study included 325 consecutive patients whose chief complaint is knee joint pain and who had visited one institution between April 2016 and March 2021, of which 70 patients (8 men and 62 women) who had suspected subchondral insufficiency fractures of the medial tibial condyle had undergone magnetic resonance imaging and radiographic examination.

Sofosbuvir Suppresses the Genome Replication of DENV1 in Human Hepatic Huh7 Cells.

Dengue virus (DENV) causes dengue fever and dengue hemorrhagic fever, and DENV infection kills 20,000 people annually worldwide. Therefore, the development of anti-DENV drugs is urgently needed. Sofosbuvir (SOF) is an effective drug for HCV-related diseases, and its triphosphorylated metabolite inhibits viral RNA synthesis by the RNA-dependent RNA polymerase (RdRp) of HCV.

Geographic expansion of the introduced Aedes albopictus and other native Aedes species in the Democratic Republic of the Congo.

Background: Aedes albopictus has been reported in several Central African countries, including the Democratic Republic of the Congo (DRC). The establishment of this mosquito species poses a serious threat as a vector of various infectious diseases. Although Ae.

Utilizing a novel high-resolution malaria dataset for climate-informed predictions with a deep learning transformer model.

Climatic factors influence malaria transmission via the effect on the Anopheles vector and Plasmodium parasite. Modelling and understanding the complex effects that climate has on malaria incidence can enable important early warning capabilities. Deep learning applications across fields are proving valuable, however the field of epidemiological forecasting is still in its infancy with a lack of applied deep learning studies for malaria in southern Africa which leverage quality datasets.

Synthesis of 4'-Thiomodified c-di-AMP Analogs.

Cyclic diadenosine monophosphate (c-di-AMP) is a bacterial cyclic dinucleotide (CDN) comprising two adenosine monophosphates covalently linked by two 3',5'-phosphodiester bonds. c-di-AMP works as a second messenger, regulating many biological processes in bacteria such as cell wall homeostasis, DNA integrity, and sporulation via specific protein and/or RNA receptors. Moreover, c-di-AMP can function as an immunomodulatory agent in eukaryote cells via the stimulator of interferon genes (STING) signaling pathway.

Exploring the Association between Ambient Temperature and Daily Hospital Admissions for Diarrhea in Mopani District, Limpopo Province, South Africa.

Diarrhea contributes significantly to global morbidity and mortality. There is evidence that diarrhea prevalence is associated with ambient temperature. This study aimed to determine if there was an association between ambient temperature and diarrhea at a rural site in South Africa.

Synthesis and Behavior of DNA Oligomers Containing the Ambiguous Z-Nucleobase 5-Aminoimidazole-4-carboxamide.

5-Amino-1-β-D-ribofuranosylimidazole-4-carboxamide 5'-monophosphate (ZMP) is a central intermediate in de novo purine nucleotide biosynthesis. Its nucleobase moiety, 5-aminoimidazole-4-carboxamide (Z-base), is considered an ambiguous base that can pair with any canonical base owing to the rotatable nature of its 5-carboxamide group. This idea of ambiguous base pairing due to free rotation of the carboxamide has been applied to designing mutagenic antiviral nucleosides, such as ribavirin and T-705.

Synthesis of oligonucleotides containing 5'-homo-4'-selenouridine derivative and its increased resistance against nuclease.

As technologies using RNA or DNA have been developed, various chemical modifications of nucleosides have been attempted to increase the stability of oligonucleotides. Since it is known that 2'-OMe-modification greatly contributes to increasing the stability of oligonucleotides, we added 2'-OMe to our previously developed 4'-selenonucleoside and 5'-homo-4'-selenonucleoside as the modified monomers for oligonucleotide: 2'-methoxy-4'-selenouridine (2'-OMe-4'-Se-U) and 5'-homo-2'-methoxy-4'-selenouridine (5'-homo-2'-OMe-4'-Se-U). We synthesized oligonucleotides containing the chemically modified 4'-selenouridine and evaluated their thermal stability and nuclease resistance.

The Golgi-resident protein ACBD3 concentrates STING at ER-Golgi contact sites to drive export from the ER.

STING, an endoplasmic reticulum (ER)-resident receptor for cyclic di-nucleotides (CDNs), is essential for innate immune responses. Upon CDN binding, STING moves from the ER to the Golgi, where it activates downstream type-I interferon (IFN) signaling. General cargo proteins exit from the ER via concentration at ER exit sites.

Discovery of super-insecticide-resistant dengue mosquitoes in Asia: Threats of concomitant knockdown resistance mutations.

(Linnaeus, 1762) is the main mosquito vector for dengue and other arboviral infectious diseases. Control of this important vector highly relies on the use of insecticides, especially pyrethroids. The high frequency (>78%) of the L982W substitution was detected at the target site of the pyrethroid insecticide, the voltage-gated sodium channel (Vgsc) of collected from Vietnam and Cambodia.

Synthesis and properties of fully-modified 4'-selenoRNA, an endonuclease-resistant RNA analog.

A large number of chemically modified oligonucleotides (ONs) have been developed for RNA-based technologies. In most modified RNAs, the characteristic 2'-hydroxyl (2'-OH) groups are removed to enhance both nuclease resistance and hybridization ability. However, the importance of the 2'-OH group in RNA structure and function is well known.

Novel Antiviral Efficacy of and Extracts against Dengue Virus, Japanese Encephalitis Virus, and Zika Virus Infection and Immunoregulatory Cytokine Signatures.

Currently, there are no specific therapeutics for flavivirus infections, including dengue virus (DENV) and Zika virus (ZIKV). In this study, we evaluated extracts from the plants (HD) and (AC) to determine the antiviral activity against DENV, ZIKV, and Japanese encephalitis virus (JEV). HD and AC demonstrated inhibitory activity against JEV, ZIKV, and DENV replication and reduced viral RNA levels in a dose-responsive manner, with non-cytotoxic concentration ranging from 0.

Cas9-mediated DNA cleavage guided by enzymatically prepared 4'-thio-modified RNA.

CRISPR-Cas9-mediated DNA editing relies on guide RNAs (gRNAs) that direct site-specific DNA cleavage by the Cas endonuclease. Because natural gRNA is susceptible to intracellular degradation, it is desirable to chemically protect it for efficient editing. Using 4'-thioribonucleoside 5'-triphosphates and T7 transcription, we have prepared 4'-thio-modified gRNAs that guide Cas9-mediated DNA cleavage.

Rewriting the Central Dogma with Synthetic Genetic Polymers.

DNA and RNA are ubiquitous molecules responsible for storage and transmission of genetic information and together comprise the central dogma of molecular biology. However, the recent emergence of synthetic genetic polymers is providing an opportunity to challenge the fundamental principles of life. Herein, we describe the ongoing attempts to rewrite the central dogma with 4'-thioDNA and 4'-thioRNA, which feature a sulfur instead of an oxygen atom in the furanose ring moiety.

Effectiveness of screened ceilings over the current best practice in reducing malaria prevalence in western Kenya: a cluster randomised controlled trial.

Increases in bed net coverage and antimalarial treatment have reduced the risk of malaria in sub-Saharan Africa. However, the pace of reduction has slowed, and new tools are needed to reverse this trend. We evaluated houses screened with insecticide-treated ceiling nets using a cluster randomized-controlled trial in western Kenya.

A comparative study of dengue virus vectors in major parks and adjacent residential areas in Ho Chi Minh City, Vietnam.

The primary dengue virus vectors, Aedes aegypti and Aedes albopictus, are primarily daytime biting mosquitoes. The risk of infection is suspected to be considerable in urban parks due to visitor traffic. Despite the importance of vector control for reducing dengue transmission, little information is available on vector populations in urban parks.

Direct Viral RNA Detection of SARS-CoV-2 and DENV in Inactivated Samples by Real-Time RT-qPCR: Implications for Diagnosis in Resource Limited Settings with Flavivirus Co-Circulation.

The RT-qPCR method remains the gold standard and first-line diagnostic method for the detection of SARS-CoV-2 and flaviviruses, especially in the early stage of viral infection. Rapid and accurate viral detection is a starting point in the containment of the COVID-19 pandemic and flavivirus outbreaks. However, the shortage of diagnostic reagents and supplies, especially in resource-limited countries that experience co-circulation of SARS-CoV-2 and flaviviruses, are limitations that may result in lesser availability of RT-qPCR-based diagnostic tests.

Synthesis and Anti-dengue Virus Activity of 5-Ethynylimidazole-4-carboxamide (EICA) Nucleotide Prodrugs.

We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to some cell lines, while its 4-thio derivative, 5-ethynyl-(4-thio-1-β-D-ribofuranosyl)imidazole-4-carboxamide (2; 4'-thioEICAR), has less cytotoxicity but also less anti-DENV activity. Based on the hypothesis that the lower anti-DENV activity of 2 is due to reduced susceptibility to phosphorylation by cellular kinase(s), we investigated whether a monophosphate prodrug of 2 can improve its activity. Here, we first prepared two types of prodrug of 1, which revealed that the S-acyl-2-thioethyl (SATE) prodrug had stronger anti-DENV activity than the aryloxyphosphoramidate (so-called ProTide) prodrug.

Convenient Synthesis of 3-Deazapurine Nucleosides (3-Deazainosine, 3-Deazaadenosine and 3-Deazaguanosine) Using Inosine as a Starting Material.

A convenient synthetic method for preparing 3-deazapurine nucleosides (3-deazainosine, 3-deazaadenosine, and 3-deazaguanosine) from inosine via a 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR) derivative, which is a key intermediate, is described. A large-scale synthesis of an EICAR derivative starting from inosine was achieved in six steps via dinitrophenylation at the N position followed by ring opening, iodination of the resulting 5-amino group, and a palladium-catalyzed cross-coupling reaction. The resulting EICAR derivative was then converted into 3-deazainosine, 3-deazaadenosine, and 3-deazaguanosine.

Replacement of oxygen with sulfur on the furanose ring of cyclic dinucleotides enhances the immunostimulatory effect STING activation.

Cyclic dinucleotides (CDNs) are secondary messengers composed of two purine nucleotides linked two phosphodiester linkages: c-di-GMP, c-di-AMP, 3',3'-cGAMP, and 2',3'-cGAMP. CDNs activate the stimulator of interferon genes (STING) and trigger immune responses in mammalian species. CDNs are thus fascinating molecules as drug candidates, and chemically stable CDN analogues that act as STING agonists are highly desired at present.