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A key element for the prevention and management of COVID-19 is the development of effective therapeutics. Drug combination strategies of repurposed drugs offer several advantages over monotherapies, including the potential to achieve greater efficacy, the potential to increase the therapeutic index of drugs and the potential to reduce the emergence of drug resistance. Here, we report on the in vitro synergistic interaction between two FDA approved drugs, remdesivir and ivermectin resulting in enhanced antiviral activity against SARS-CoV-2. These findings warrant further investigations into the clinical potential of this combination, together with studies to define the underlying mechanism. Competing Interest Statement A.O. is a Director of Tandem Nano Ltd. A.O. has received research funding from ViiV, Merck, Janssen and consultancy from Gilead. These associations had no influence over the content of the current manuscript. P.O.N. is currently engaged in a collaboration with Romark LLC but this interaction had no influence over the content of the current manuscript. No other conflicts are declared by the authors. Footnotes * Figure 2 updated, author list updated.

Current liver-stage Plasmodium falciparum models are complex, expensive, and largely inaccessible, hindering research progress. Here, we show that a 3D liver spheroid model grown from immortalized HepG2/C3A cells supports the complete intrahepatocytic lifecycle of P. falciparum. Our results demonstrate sporozoite infection, development of exoerythrocytic forms, and breakthrough infection into erythrocytes. The 3D-grown spheroid hepatocytes are structurally and functionally polarised, displaying enhanced albumin and urea production and increased expression of key metabolic enzymes, mimicking in vivo conditions, relative to 2D cultures. This accessible, reproducible model lowers barriers to malaria research, promoting advancements in fundamental biology and translational research.Competing Interest StatementThe authors have declared no competing interest.

The ribonuclease (RNase) H class of enzymes degrades the RNA component of RNA:DNA hybrids and is important in nucleic acid metabolism. RNase H2 is specialized to remove single ribonucleotides [ribonucleoside monophosphates (rNMPs)] from duplex DNA, and its absence in budding yeast has been associated with the accumulation of deletions within short tandem repeats. Here, we demonstrate that rNMP-associated deletion formation requires the activity of Top1, a topoisomerase that relaxes supercoils by reversibly nicking duplex DNA. The reported studies extend the role of Top1 to include the processing of rNMPs in genomic DNA into irreversible single-strand breaks, an activity that can have distinct mutagenic consequences and may be relevant to human disease.

Background Taste loss may contribute to the loss of appetite in children with chronic kidney disease (CKD) and other serious medical conditions that result in malnutrition. Traditional methods for measurement of taste loss commonly use aqueous tastant solutions that can induce nausea, vomiting, or even pain in the mouth. An alternative is to measure fungiform papillae density on the anterior tongue since this correlates with taste sensitivity. Here we aimed to develop a non-invasive method for assessing papillae density on the anterior tongue and to use the method to determine if CKD patients [estimated glomerular filtrate (eGFR < 60 ml/min/1.73 m 2 )] have a lower density than clinical controls (CC)(eGFR > 89 ml/min/1.73 m 2 ). Methods Thirty-five healthy adults participated in the development of a method, which was assessed by 24 children, 12 of whom were CKD patients and 12 were clinical controls. Results Similar papillae densities were found using invasive and non-invasive methods (F (1,34)  = 0.647, p  = 0.427). The CKD group had a significantly lower papillae density (X 2  = 7.17, p  = 0.007) and poorer taste sensitivity than the CC group ( p  = 0.0272), and the density correlated significantly with eGFR ( r  = 0.56, p  < 0.01). Conclusions Loss of taste in children with CKD is due to the reduced number of papillae and their taste-sensing receptor cells.

The RNase H class of enzymes degrades the RNA component of RNA:DNA hybrids and is important in nucleic acid metabolism. RNase H2 is specialized to remove single ribonucleotides (rNMPs) from duplex DNA, and its absence in budding yeast has been associated with the accumulation of deletions within short tandem repeats. Here, we demonstrate that rNMP-associated deletion formation requires the activity of Top1, a topoisomerase that relaxes supercoils by reversibly nicking duplex DNA. The reported studies extend the role of Top1 to include the processing of rNMPs in genomic DNA into irreversible single-strand breaks, an activity that can have distinct mutagenic consequences and may be relevant to human disease.