Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda, from 2016 to 2019. Median ICs were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of for 218 of these isolates demonstrated many nonsynonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%), and D1116G/N/Y (16%). The G223S mutation was associated with decreased susceptibility to SJ733, PA92, and KAE609. The D1116G/N/Y mutations were associated with decreased susceptibility to SJ733, and the presence of mutations at both codons 223 and 1116 was associated with decreased susceptibility to PA92 and SJ733. In all of these cases, absolute differences in susceptibilities of wild-type (WT) and mutant parasites were modest. Analysis of clones separated from mixed field isolates consistently identified mutant clones as less susceptible than WT. Analysis of isolates from other sites demonstrated the presence of the G223S and D1116G/N/Y mutations across Uganda. Our results indicate that malaria parasites circulating in Uganda have a number of polymorphisms in PfATP4 and that modestly decreased susceptibility to PfATP4 inhibitors is associated with some mutations now present in Ugandan parasites.
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http://dx.doi.org/10.1128/AAC.00771-21 | DOI Listing |
Arthroplast Today
December 2024
Department of Orthopedic Surgery, Vanderbilt University, Nashville, TN, USA.
Background: Aseptic loosening is the most common aseptic failure modality following total knee arthroplasty. Recent literature suggests that the implant-cement interface is the "weak-link" in fixation and lipid contamination may drive this debonding pattern. Therefore, the purpose of this study was to determine if the "double-butter" technique would significantly decrease lipid contamination of the tibial tray.
View Article and Find Full Text PDFFront Physiol
December 2024
Institute of Biochemistry and Cell Biology, National Research Council (CNR), Monterotondo (RM), Italy.
Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, a subsarcolemmal protein whose absence results in increased susceptibility of the muscle fiber membrane to contraction-induced injury. This results in increased calcium influx, oxidative stress, and mitochondrial dysfunction, leading to chronic inflammation, myofiber degeneration, and reduced muscle regenerative capacity. Fast glycolytic muscle fibers have been shown to be more vulnerable to mechanical stress than slow oxidative fibers in both DMD patients and DMD mouse models.
View Article and Find Full Text PDFJHEP Rep
January 2025
Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Background & Aims: EGF-containing fibulin extracellular matrix protein 1 (EFEMP1, also called fibulin-3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibrotic disease of the neonatal extrahepatic bile duct. Fibulin-3 is deposited in most tissues and null mice have decreased elastic fibers in visceral fascia; however, fibulin-3 does not have a role in the development of large elastic fibers and its overall function in the extrahepatic bile ducts remains unclear.
Methods: We used staining and histology to define the amount and organization of key extracellular matrix components in the extrahepatic bile ducts.
Front Endocrinol (Lausanne)
December 2024
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China.
Background: Observational studies suggest the risk of primary ovarian insufficiency (POI) is increased in autoimmune disorders (AIDs), but it is unclear whether there is a causal relationship. Therefore, we aimed to investigate the bidirectional causality between 20 AIDs and POI using Mendelian randomization (MR) analysis.
Methods: A bidirectional two-sample MR investigation was designed by using publicly accessible summary-level data from genome-wide association studies (GWAS).
Infect Drug Resist
December 2024
Department of Bacteriology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
Background: Patients with tuberculosis (TB) often harbor diverse bacteria in their sputum, including both commensal and opportunistic pathogens. This study aimed to characterize the sputum microbiota of TB patients before and after the intensive phase of anti-TB treatment and assess changes in bacterial diversity and antibiotic resistance profiles.
Methods: A total of 162 patients with TB (128 males, 34 females; age range 18-82 years) provided sputum samples at baseline, of which 72 provided follow-up sputum after two months of intensive phase treatment.
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