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Background: Cerebellar ataxia affects the coordination and balance of patients. The impact of this disease increases burden in patients, caregivers and society. Costs and the burden of this disease have not been investigated in Hong Kong.Objectives: (1) To estimate the socioeconomic cost of cerebellar ataxia in Hong Kong for the base year 2019, (2) to assess the health-related quality of life (HRQoL) and severity of ataxia, and (3) to establish the correlation between the severity and cost of cerebellar ataxia and to examine the correlation between the severity of cerebellar ataxia and HRQoL.Methods: A retrospective cross-sectional study was conducted amongst 31 patients with cerebellar ataxia. Cost-related data were obtained through self-reported questionnaires. The severity of ataxia was assessed using the Scale for Assessment and Rating of Ataxia, and HRQoL was assessed using the Short Form (36) Health Survey (SF-36). Pearson correlation was used for normally distributed data, whereas Spearman correlation was used otherwise.Results: The mean severity of ataxia was 21 out of 40. The average direct and indirect costs of a patient with ataxia in 6 months were HKD 51,371 and HKD 93,855, respectively. The mean difference between the independent to minimally dependent in activities of daily living (ADL) group and the moderate to maximally dependent in ADL group for direct and indirect costs was HKD 33,829 and HKD 51,444, respectively. Significant expenditure was related to production lost (42%), caregiver salary (17%), and in-patient care (16%). The physical functioning (r = −0.58) and general health (r = −0.41) of SF-36 were negatively correlated with disease severity (p < 0.05). A significant, positive correlation was found between disease severity and direct cost (Spearman's rho = 0.39) and the cost of hiring a caregiver (Spearman's rho = 0.43).Conclusion: The mean cost for 6 months for patients with cerebellar ataxia in Hong Kong is HKD 146,832. Additional support, including employment, access to specialist consultants, informal home care and community participation, are some areas that should be addressed. Future study on a larger population with a prospective design is necessary to confirm the aforementioned claims.

Drug resistance remains a major obstacle to malaria control and eradication efforts, necessitating the development of novel therapeutic strategies to treat this disease. Drug combinations based on collateral sensitivity, wherein resistance to one drug causes increased sensitivity to the partner drug, have been proposed as an evolutionary strategy to suppress the emergence of resistance in pathogen populations. In this study, we explore collateral sensitivity between compounds targeting the Plasmodium dihydroorotate dehydrogenase (DHODH). We profiled the cross-resistance and collateral sensitivity phenotypes of several DHODH mutant lines to a diverse panel of DHODH inhibitors. We focus on one compound, TCMDC-125334, which was active against all mutant lines tested, including the DHODH C276Y line, which arose in selections with the clinical candidate DSM265. In six selections with TCMDC-125334, the most common mechanism of resistance to this compound was copy number variation of the dhodh locus, although we did identify one mutation, DHODH I263S, which conferred resistance to TCMDC-125334 but not DSM265. We found that selection of the DHODH C276Y mutant with TCMDC-125334 yielded additional genetic changes in the dhodh locus. These double mutant parasites exhibited decreased sensitivity to TCMDC-125334 and were highly resistant to DSM265. Finally, we tested whether collateral sensitivity could be exploited to suppress the emergence of resistance in the context of combination treatment by exposing wildtype parasites to both DSM265 and TCMDC-125334 simultaneously. This selected for parasites with a DHODH V532A mutation which were cross-resistant to both compounds and were as fit as the wildtype parent in vitro. The emergence of these cross-resistant, evolutionarily fit parasites highlights the mutational flexibility of the DHODH enzyme., Competing Interests: RM The work discussed in this article was performed by REKM elsewhere prior to becoming a federal employee. The article was written/edited by REKM in her private capacity. No official support or endorsement by the National Institute of Allergy and Infectious Diseases is intended or should be inferred, ML, MT, RM, SO, AL No competing interests declared, EW Sits on the advisory board of the Tres Cantos Open Lab Foundation, ML, FG GlaxoSmithKline employee, DW Sits on the advisory board of Medicines for Malaria Venture, (© 2023, Mandt et al.)

Antimalarial drug discovery has until recently been driven by high-throughput phenotypic cellular screening, allowing millions of compounds to be assayed and delivering clinical drug candidates. In this review, we will focus on target-based approaches, describing recent advances in our understanding of druggable targets in the malaria parasite. Targeting multiple stages of the Plasmodium lifecycle, rather than just the clinically symptomatic asexual blood stage, has become a requirement for new antimalarial medicines, and we link pharmacological data clearly to the parasite stages to which it applies. Finally, we highlight the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY, a web resource developed for the malaria research community that provides open and optimized access to published data on malaria pharmacology., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Multiple myeloma (MM) is a plasma cell malignancy characterised by aberrant production of immunoglobulins requiring survival mechanisms to adapt to proteotoxic stress. We here show that glutamyl-prolyl-tRNA synthetase (GluProRS) inhibition constitutes a novel therapeutic target. Genomic data suggest that GluProRS promotes disease progression and is associated with poor prognosis, while downregulation in MM cells triggers apoptosis. We developed NCP26, a novel ATP-competitive ProRS inhibitor that demonstrates significant anti-tumour activity in multiple in vitro and in vivo systems and overcomes metabolic adaptation observed with other inhibitor chemotypes. We demonstrate a complex phenotypic response involving protein quality control mechanisms that centers around the ribosome as an integrating hub. Using systems approaches, we identified multiple downregulated proline-rich motif-containing proteins as downstream effectors. These include CD138, transcription factors such as MYC, and transcription factor 3 (TCF3), which we establish as a novel determinant in MM pathobiology through functional and genomic validation. Our preclinical data therefore provide evidence that blockade of prolyl-aminoacylation evokes a complex pro-apoptotic response beyond the canonical integrated stress response and establish a framework for its evaluation in a clinical setting., (© 2023. The Author(s).)

The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world's most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl-tRNA synthetase, have emerged as attractive targets for malaria chemotherapy. We describe the development of a single-step biochemical assay for Plasmodium and human prolyl-tRNA synthetases that overcomes critical limitations of existing technologies and enables quantitative inhibitor profiling with high sensitivity and flexibility. Supported by this assay platform and co-crystal structures of representative inhibitor-target complexes, we develop a set of high-affinity prolyl-tRNA synthetase inhibitors, including previously elusive aminoacyl-tRNA synthetase triple-site ligands that simultaneously engage all three substrate-binding pockets. Several compounds exhibit potent dual-stage activity against Plasmodium parasites and display good cellular host selectivity. Our data inform the inhibitor requirements to overcome existing resistance mechanisms and establish a path for rational development of prolyl-tRNA synthetase-targeted anti-malarial therapies., (© 2022. The Author(s).)

The pace of progress in biomedical research directly depends on techniques that enable the quantitative interrogation of interactions between proteins and other biopolymers, or with their small-molecule ligands. Time-resolved Förster resonance energy transfer (TR-FRET) assay platforms offer high sensitivity and specificity. However, the paucity of accessible and biocompatible luminescent lanthanide complexes, which are essential reagents for TR-FRET-based approaches, and their poor cellular permeability have limited broader adaptation of TR-FRET beyond homogeneous and extracellular assay applications. Here, we report the development of CoraFluors, a new class of macrotricyclic terbium complexes, which are synthetically readily accessible, stable in biological media and exhibit photophysical and physicochemical properties that are desirable for biological studies. We validate the performance of CoraFluors in cell-free systems, identify cell-permeable analogs and demonstrate their utility in the quantitative domain-selective characterization of Keap1 ligands, as well as in isoform-selective target engagement profiling of HDAC1 inhibitors in live cells., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Proper disinfection using adequate disinfecting agents will be necessary for infection control strategies against coronavirus disease 2019 (COVID-19). However, limited guidance exists on effective surface disinfectants or best practices for their use against severe acute respiratory coronavirus 2. We outlined a process of fully characterizing over 350 products on the Environmental Protection Agency List N, including pH, method of delivery, indication for equipment sterilization, and purchase availability. We then developed a streamlined set of guidelines to help rapidly evaluate and select suitable disinfectants from List N, including practicality, efficacy, safety, and cost/availability. This resource guides the evaluation of ideal disinfectants amidst practical considerations posed by the COVID-19 pandemic., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)