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Clinical and Translational Medicine Jun 2024Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal... (Review)
Review
Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal roles in driving the progression of haematological malignancies. Among RNA modifications, N-methyladenosine (mA) RNA modification, the most abundant internal mRNA modification, stands out as the most extensively studied modification. This prominence underscores the crucial role of the layer of epitranscriptomic regulation in controlling haematopoietic cell fate and therefore the development of haematological malignancies. Additionally, other RNA modifications (non-mA RNA modifications) have gained increasing attention for their essential roles in haematological malignancies. Although the roles of the mA modification machinery in haematopoietic malignancies have been well reviewed thus far, such reviews are lacking for non-mA RNA modifications. In this review, we mainly focus on the roles and implications of non-mA RNA modifications, including N-acetylcytidine, pseudouridylation, 5-methylcytosine, adenosine to inosine editing, 2'-O-methylation, N-methyladenosine and N-methylguanosine in haematopoietic malignancies. We summarise the regulatory enzymes and cellular functions of non-mA RNA modifications, followed by the discussions of the recent studies on the biological roles and underlying mechanisms of non-mA RNA modifications in haematological malignancies. We also highlight the potential of therapeutically targeting dysregulated non-mA modifiers in blood cancer.
Topics: Humans; Hematologic Neoplasms; RNA Processing, Post-Transcriptional; RNA; Adenosine
PubMed: 38880983
DOI: 10.1002/ctm2.1666 -
Journal of Microorganism Control 2024Although recent propagation of carbapenemase-producing Enterobacterales (CPE) has become a problem worldwide, the picture of CPE infection in Japan has not fully been...
Although recent propagation of carbapenemase-producing Enterobacterales (CPE) has become a problem worldwide, the picture of CPE infection in Japan has not fully been elucidated. In this study, we examined clinical and microbiological characteristics of invasive CPE infection occurring at 8 hospitals in Minami Ibaraki Area between July 2001 to June 2017. Of 7294 Enterobacterales strains isolated from independent cases of bacteremia and/or meningitis, 10 (0.14%) were CPE (8 Enterobacter cloacae-complex, 1 Escherichia coli, and 1 Edwardsiella tarda), all of which had the bla gene and susceptible to gentamicin and trimethoprim/sulfamethoxazole. These strains were isolated from 7 adult and 2 infant bacteremia (1 infant patient developed CPE bacteremia twice) after 2007. The most common portal of entry was intravenous catheters. All of the adult patients were recovered, while the infant patients eventually died. Genomic analyses showed that the 8 E. cloacae-complex strains were classified into 5 groups, each of which was exclusively detected in specific facilities at intervals of up to 3 years, suggesting persistent colonization in the facilities. This study showed that invasive CPE infection in the area was rare, caused by IMP-1-type CPE having susceptibility to various antibiotics, and nonfatal among adult patients.
Topics: Humans; Japan; Bacteremia; Enterobacteriaceae Infections; beta-Lactamases; Male; Female; Anti-Bacterial Agents; Bacterial Proteins; Infant; Microbial Sensitivity Tests; Middle Aged; Adult; Aged; Enterobacter cloacae; Gentamicins; Trimethoprim, Sulfamethoxazole Drug Combination; Aged, 80 and over; Carbapenem-Resistant Enterobacteriaceae
PubMed: 38880620
DOI: 10.4265/jmc.29.2_81 -
BMC Ophthalmology Jun 2024Echinococcosis, commonly known as hydatid disease, is a zoonotic infection resulting from the tapeworm Echinococcus granulosus. The occurrence of hydatid cysts in the... (Review)
Review
BACKGROUND
Echinococcosis, commonly known as hydatid disease, is a zoonotic infection resulting from the tapeworm Echinococcus granulosus. The occurrence of hydatid cysts in the orbital region is uncommon, representing less than 1% of all reported hydatid cases. This report details a unique case of an intramuscular hydatid cyst in the orbital region that led to compressive optic neuropathy.
CASE PRESENTATION
A 22-year-old male from Kabul, Afghanistan presented with a five-month history of progressive proptosis in his left eye, associated with a gradual decrease in vision over the past three weeks. The left eye exhibited upward globe dystopia, ocular motility limitation, mild conjunctival injection, and chemosis. Diagnosis was achieved through imaging and histopathological examination. Treatment involves surgical removal of the cyst and prolonged albendazole therapy. The postoperative course showed significant improvement in the patient's condition and restoration of his vision.
CONCLUSIONS
Despite its rarity, this case underscores the importance of awareness and knowledge of hydatid disease among physicians, especially those working in endemic areas. It emphasizes the importance of including hydatid disease in the differential diagnosis of orbital masses, particularly in endemic regions.
Topics: Humans; Male; Echinococcosis; Young Adult; Optic Nerve Diseases; Eye Infections, Parasitic; Orbital Diseases; Magnetic Resonance Imaging; Albendazole; Tomography, X-Ray Computed
PubMed: 38877497
DOI: 10.1186/s12886-024-03502-w -
BMC Microbiology Jun 2024Long-term treatment with trimethoprim-sulfamethoxazole (SXT) can lead to the formation of small-colony variants (SCVs) of Staphylococcus aureus. However, the mechanism...
BACKGROUND
Long-term treatment with trimethoprim-sulfamethoxazole (SXT) can lead to the formation of small-colony variants (SCVs) of Staphylococcus aureus. However, the mechanism behind SCVs formation remains poorly understood. In this study, we explored the phenotype and omics-based characterization of S. aureus SCVs induced by SXT and shed light on the potential causes of SCV formation.
METHODS
Stable SCVs were obtained by continuously treating S. aureus isolates using 12/238 µg/ml of SXT, characterized by growth kinetics, antibiotic susceptibility testing, and auxotrophism test. Subsequently, a pair of representative strains (SCV and its parental strain) were selected for genomic, transcriptomic and metabolomic analysis.
RESULTS
Three stable S. aureus SCVs were successfully screened and proven to be homologous to their corresponding parental strains. Phenotypic tests showed that all SCVs were non-classical mechanisms associated with impaired utilization of menadione, heme and thymine, and exhibited slower growth and higher antibiotic minimum inhibitory concentrations (MICs), compared to their corresponding parental strains. Genomic data revealed 15 missense mutations in 13 genes in the representative SCV, which were involved in adhesion, intramolecular phosphate transfer on ribose, transport pathways, and phage-encoded proteins. The combination analysis of transcriptome and metabolome identified 35 overlapping pathways possible associated with the phenotype switching of S. aureus. These pathways mainly included changes in metabolism, such as purine metabolism, pyruvate metabolism, amino acid metabolism, and ABC transporters, which could play a crucial role in promoting SCVs development by affecting nucleic acid synthesis and energy metabolism in bacteria.
CONCLUSION
This study provides profound insights into the causes of S. aureus SCV formation induced by SXT. The findings may offer valuable clues for developing new strategies to combat S. aureus SCV infections.
Topics: Staphylococcus aureus; Trimethoprim, Sulfamethoxazole Drug Combination; Microbial Sensitivity Tests; Anti-Bacterial Agents; Metabolomics; Humans; Genomics; Phenotype; Staphylococcal Infections; Bacterial Proteins; Transcriptome; Gene Expression Profiling; Multiomics
PubMed: 38877418
DOI: 10.1186/s12866-024-03364-8 -
Proceedings of the National Academy of... Jun 2024Human bocavirus 1 (HBoV1) is a human parvovirus that causes lower respiratory tract infections in young children. It contains a single-stranded (ss) DNA genome of ~5.5...
Human bocavirus 1 (HBoV1) is a human parvovirus that causes lower respiratory tract infections in young children. It contains a single-stranded (ss) DNA genome of ~5.5 kb that encodes a small noncoding RNA of 140 nucleotides known as bocavirus-encoded small RNA (BocaSR), in addition to viral proteins. Here, we determined the secondary structure of BocaSR in vivo by using DMS-MaPseq. Our findings reveal that BocaSR undergoes N6-methyladenosine (m6A) modification at multiple sites, which is critical for viral DNA replication in both dividing HEK293 cells and nondividing cells of the human airway epithelium. Mechanistically, we found that m6A-modified BocaSR serves as a mediator for recruiting Y-family DNA repair DNA polymerase (Pol) η and Pol κ likely through a direct interaction between BocaSR and the viral DNA replication origin at the right terminus of the viral genome. Thus, this report represents direct involvement of a viral small noncoding RNA in viral DNA replication through m6A modification.
Topics: Humans; Adenosine; Virus Replication; DNA-Directed DNA Polymerase; DNA Replication; DNA, Viral; HEK293 Cells; RNA, Viral; Human bocavirus; Genome, Viral; Parvoviridae Infections
PubMed: 38875150
DOI: 10.1073/pnas.2320782121 -
Antiviral Therapy Jun 2024Angiotensin-converting enzyme 2 (ACE2) is the receptor that enables SARS-CoV-2 to invade host cells. Previous studies have reported that reducing ACE2 expression may...
Angiotensin-converting enzyme 2 (ACE2) is the receptor that enables SARS-CoV-2 to invade host cells. Previous studies have reported that reducing ACE2 expression may have an anti-SARS-CoV-2 effect. In this study, we constructed a pGL4.10-F2-ACE2 vector with double luciferase genes (firefly and Renilla luciferase) under the control of the ACE2 promoter and used it to screen compounds from Chinese traditional medicinal herbs (CTMHs) that can inhibit ACE2 transcription in human cells. We transfected HEK293T cells with pGL4.10-F2-ACE2 and treated them with CTMH compounds and then measured fluorescence to evaluate the indirect inhibition of ACE2 transcription. Out of 37 compounds tested, andrographolide demonstrated a dose-dependent inhibition of ACE2 transcription. We further confirmed by RT-qPCR and Western blot assays that andrographolide also reduced ACE2 expression in BEAS-2B cells in a dose-dependent manner. Moreover, pseudovirus infection assays in BEAS-2B cells demonstrated that andrographolide can inhibit SARS-CoV-2 infection in a dose-dependent manner. These results suggest that andrographolide has potential anti-SARS-CoV-2 activity and could be a candidate drug for COVID-19 prevention and treatment.
Topics: Humans; Diterpenes; Angiotensin-Converting Enzyme 2; SARS-CoV-2; HEK293 Cells; Down-Regulation; COVID-19 Drug Treatment; COVID-19; Antiviral Agents; Drugs, Chinese Herbal
PubMed: 38873947
DOI: 10.1177/13596535241259952 -
Scientific Reports Jun 2024Transplantation of stem cell-derived β-cells is a promising therapeutic advancement in the treatment of type 1 diabetes mellitus. A current limitation of this approach...
Transplantation of stem cell-derived β-cells is a promising therapeutic advancement in the treatment of type 1 diabetes mellitus. A current limitation of this approach is the long differentiation timeline that generates a heterogeneous population of pancreatic endocrine cells. To address this limitation, an inducible lentiviral overexpression system of mature β-cell markers was introduced into human induced-pluripotent stem cells (hiPSCs). Following the selection of the successfully transduced hiPSCs, the cells were treated with doxycycline in the pancreatic progenitor induction medium to support their transition toward the pancreatic lineage. Cells cultured with doxycycline presented the markers of interest, NGN3, PDX1, and MAFA, after five days of culture, and glucose-stimulated insulin secretion assays demonstrated that the cells were glucose-responsive in a monolayer culture. When cultured as a spheroid, the markers of interest and insulin secretion in a static glucose-stimulated insulin secretion assay were maintained; however, insulin secretion upon consecutive glucose challenges was limited. Comparison to human fetal and adult donor tissues identified that although the hiPSC-derived spheroids present similar markers to adult insulin-producing cells, they are functionally representative of fetal development. Together, these results suggest that with optimization of the temporal expression of these markers, forward programming of hiPSCs towards insulin-producing cells could be a possible alternative for islet transplantation.
Topics: Humans; Insulin-Secreting Cells; Homeodomain Proteins; Trans-Activators; Induced Pluripotent Stem Cells; Basic Helix-Loop-Helix Transcription Factors; Nerve Tissue Proteins; Cell Differentiation; Maf Transcription Factors, Large; Insulin; Glucose; Insulin Secretion; Cells, Cultured; Doxycycline
PubMed: 38871849
DOI: 10.1038/s41598-024-64346-4 -
Scientific Reports Jun 2024Natural products play a significant role in providing the current demand as antiparasitic agents, which offer an attractive approach for the discovery of novel drugs....
Natural products play a significant role in providing the current demand as antiparasitic agents, which offer an attractive approach for the discovery of novel drugs. The present study aimed to evaluate in vitro the potential impact of seaweed Padina pavonica (P. pavonica) extract in combating Acanthamoeba castellanii (A. castellanii). The phytochemical constituents of the extract were characterized by Gas chromatography-mass spectrometry. Six concentrations of the algal extract were used to evaluate its antiprotozoal activity at various incubation periods. Our results showed that the extract has significant inhibition against trophozoites and cysts viability, with complete inhibition at the high concentrations. The IC of P. pavonica extract was 4.56 and 4.89 µg/mL for trophozoites and cysts, respectively, at 24 h. Morphological alterations of A. castellanii trophozoites/cysts treated with the extract were assessed using inverted and scanning electron microscopes and showed severe damage features upon treatment with the extract at different concentrations. Molecular Docking of extracted compounds against Acanthamoeba cytochrome P450 monooxygenase (AcCYP51) was performed using Autodock vina1.5.6. A pharmacokinetic study using SwissADME was also conducted to investigate the potentiality of the identified bioactive compounds from Padina extract to be orally active drug candidates. In conclusion, this study highlights the in vitro amoebicidal activity of P. pavonica extract against A. castellanii adults and cysts and suggests potential AcCYP51 inhibition.
Topics: Acanthamoeba castellanii; Molecular Docking Simulation; Acanthamoeba Keratitis; Plant Extracts; Antiprotozoal Agents; Trophozoites; Animals; Humans
PubMed: 38871751
DOI: 10.1038/s41598-024-63691-8 -
Global Health, Science and Practice Jun 2024Nigeria accounts for substantial proportions of global malaria infections and deaths, with children aged younger than 5 years being the most affected group. This...
BACKGROUND
Nigeria accounts for substantial proportions of global malaria infections and deaths, with children aged younger than 5 years being the most affected group. This suggests that access to lifesaving malaria interventions could be suboptimal, especially at public health facilities where most rural dwellers seek health care. We conducted this study to ascertain if public health facilities have the commodities and the robust supply chain management (SCM) system required to deliver malaria interventions to children younger than 5 years.
METHOD
We conducted a cross-sectional survey in 1,858 health facilities across 7 states in Nigeria. Using structured questionnaires, we assessed the availability of selected malaria commodities required by children aged younger than 5 years. We also interviewed health workers to evaluate other core SCM activities.
RESULT
More than 50% of health facilities in 5 states were stocked out of malaria rapid diagnostic tests (mRDTs), and stock-out rates for artemisinin-based combination therapies (ACTs) were over 50% for almost all assessed ACTs across all states. The percentage of health facilities that received malaria commodities within the recommended lead time was below average across most states (71%). States with a higher percentage of health workers who were aware of and placed orders following the national reporting timeline and those that delivered commodities to the last mile predominantly through third-party logistics service providers tended to have higher availability of mRDTs and artemether/lumefantrine combinations. The top 2 logistics challenges were insecurity and inadequate funding.
CONCLUSION
The availability of lifesaving malaria commodities across the health facilities visited was suboptimal, possibly due to several SCM challenges. The results from this study underscore the urgent need to implement effective interventions to address the observed gaps. This will contribute to reducing malaria morbidity and mortality among children aged younger than 5 years in Nigeria.
Topics: Humans; Nigeria; Malaria; Cross-Sectional Studies; Antimalarials; Child, Preschool; Public Sector; Artemisinins; Infant; Health Services Accessibility; Health Facilities; Surveys and Questionnaires
PubMed: 38871381
DOI: 10.9745/GHSP-D-22-00547 -
Journal of Infection and Public Health Jul 2024The objective of this were conducted to elucidate spatiotemporal variations in malaria epidemiology in Gabon since 1980. For that, five databases, were used to collect... (Meta-Analysis)
Meta-Analysis Review
The objective of this were conducted to elucidate spatiotemporal variations in malaria epidemiology in Gabon since 1980. For that, five databases, were used to collect and identify all studies published between 1980 and 2023 on malaria prevalence, antimalarial drug resistance, markers of antimalarial drug resistance and insecticide resistance marker. The findings suggest that Gabon continues to face malaria as an urgent public health problem, with persistently high prevalence rates. Markers of resistance to CQ persist despite its withdrawal, and markers of resistance to SP have emerged with a high frequency, reaching 100 %, while ACTs remain effective. Also, recent studies have identified markers of resistance to the insecticides Kdr-w and Kdr-e at frequencies ranging from 25 % to 100 %. Ace1R mutation was reported with a frequency of 0.4 %. In conclusion, the efficacy of ACTs remains above the threshold recommended by the WHO. Organo-phosphates and carbamates could provide an alternative for vector control.
Topics: Gabon; Humans; Malaria; Prevalence; Antimalarials; Insecticide Resistance; Drug Resistance; Animals; Insecticides
PubMed: 38870682
DOI: 10.1016/j.jiph.2024.05.047