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PubMed2025

Strategies for mitigating emerging artemisinin-based antimalarial drug resistance in Rwanda: a promising approach for managing therapies in malaria-endemic countries.

Malaria treatment failures associated with reduced efficacy of chloroquine (CQ) and amodiaquine (AQ) antimalarial drugs emerged in Rwanda during the 1980s, prompting the policy shift towards adopting artemisinin-based combination therapies in 2006 as an alternative. However, recent findings from malaria surveillance and therapeutic efficacy studies have revealed a countrywide increase in antimalarial drug resistance. Particularly, artemether-lumefantrine (AL) efficacy has significantly decreased, probably due to the emergence of Plasmodium falciparum (Pf) genomic mutations. To mitigate the current drug resistance, Rwanda has adopted targeted multiple first-line therapies. Through the national malaria control program, antimalarial drugs were deployed in accordance with the reported resistance profile. A significant rise in Pfkelch13 mutations, particularly A675V associated with AL resistance, was mainly reported in the western region; therefore, artesunate-pyronaridine was recommended. Dihydroartemisinin-piperaquine was considered in eastern and central regions, where R561H mutations were predominant. On the contrary, AL was maintained in the southern region, where the prevalence of the R561H mutation was low. Insights from this data-driven model will inform its extension to other malaria-endemic countries facing emerging Pf genetic diversity.

Antimalarials↗

PubMed2025

Acetyl-CoA synthetase mutations affect the susceptibility of Plasmodium falciparum to antimalarial drugs.

Plasmodium falciparum acetyl-CoA synthetase (PfAcAS) is an important source of acetyl-CoA. We detected mutations S868G and V950I in PfAcAS by whole-genome sequencing analysis in certain recrudescent parasites after treatment with artesunate and dihydroartemisinin-piperaquine. Using CRISPR/Cas9 technology, we engineered parasite lines to carry the PfAcAS S868G and V950I mutations in two genetic backgrounds and evaluated their susceptibilities to antimalarial drugs in vitro. The results demonstrated that PfAcAS S868G and V950I mutations alone or in combination affected the susceptibility of P. falciparum to several antimalarial drugs, including the artemisinin derivatives (dihydroartemisinin, artesunate, and artemether) and chloroquine, although absolute changes in susceptibilities were modest.IMPORTANCEMalaria, an infectious disease caused by Plasmodium parasites and transmitted by mosquitoes, continues to be one of the most pressing public health challenges worldwide. P. falciparum has demonstrated reduced sensitivity to artemisinin-based combination therapies (ACTs), thereby intensifying the difficulties associated with malaria management. Currently, only a limited number of molecular markers exist for identifying drug resistance in P. falciparum, and these markers do not fully elucidate the mechanisms behind this resistance. In this study, we performed whole-genome sequencing analysis on P. falciparum strains that reemerged following ACT treatment. We aim to identify molecules potentially associated with drug resistance, which may provide new molecular markers for monitoring drug resistance in P. falciparum.

Plasmodium falciparum↗

PubMed2026

Genome-Guided Discovery of Antimalarial 4-Amino-2,4-Pentadienoate-Containing Cyclolipodepsipeptides.

4-Amino-2,4-pentadienoate-containing cyclolipodepsipeptides (APD-CLDs) represent a structurally distinctive family of natural products known for their selective activity against hypoxic cancer cells. To explore the structural diversity of APD-CLDs, we have identified and prioritized cryptic APD-CLD biosynthetic gene clusters (BGCs) for compound discovery. Using a combination of genetic and chemical methods, we successfully activated three dormant BGCs, leading to the discovery of 12 new APD-CLDs. These newly discovered metabolites significantly expanded the diversity of the APD-CLD family, with chloromalamides and arabimalamides representing the first halogenated and glycosylated members, respectively. Unexpectedly, chloromalamides and arabimalamides exhibited potent antiplasmodial activity, with IC50 values in the 25-161 nM range against drug-sensitive and multidrug-resistant Plasmodium falciparum strains. Phenotypic studies revealed arabimalamide B halted parasite development during the asexual blood stage life cycle, resulting in enlarged digestive vacuoles, dispersed hemozoin, and ultimately reduced reinvasion efficiency. These phenotypes are reminiscent of the effect of chloroquine and other 4-aminoquinoline drugs, suggesting that arabimalamides may disrupt the parasite's heme detoxification mechanism. Biosynthetic studies identified key scaffold-forming and modifying enzymes, including a rare membrane glycosyltransferase in arabimalamide biosynthesis. Together, these findings unveil APD-CLDs as new antimalarial lead scaffolds and set the stage for structural diversification and optimization.

Antimalarials↗

PubMed2017

Hydrogen peroxide dynamics in subcellular compartments of malaria parasites using genetically encoded redox probes.

Redox balance is essential for the survival, growth and multiplication of malaria parasites and oxidative stress is involved in the mechanism of action of many antimalarial drugs. Hydrogen peroxide (H2O2) plays an important role in redox signalling and pathogen-host cell interactions. For monitoring intra- and subcellular redox events, highly sensitive and specific probes are required. Here, we stably expressed the ratiometric H2O2 redox sensor roGFP2-Orp1 in the cytosol and the mitochondria of Plasmodium falciparum (P. falciparum) NF54-attB blood-stage parasites and evaluated its sensitivity towards oxidative stress, selected antimalarial drugs, and novel lead compounds. In both compartments, the sensor showed reproducible sensitivity towards H2O2 in the low micromolar range and towards antimalarial compounds at pharmacologically relevant concentrations. Upon short-term exposure (4 h), artemisinin derivatives, quinine and mefloquine impacted H2O2 levels in mitochondria, whereas chloroquine and a glucose-6-phosphate dehydrogenase (G6PD) inhibitor affected the cytosol; 24 h exposure to arylmethylamino steroids and G6PD inhibitors revealed oxidation of mitochondria and cytosol, respectively. Genomic integration of an H2O2 sensor expressed in subcellular compartments of P. falciparum provides the basis for studying complex parasite-host cell interactions or drug effects with spatio-temporal resolution while preserving cell integrity, and sets the stage for high-throughput approaches to identify antimalarial agents perturbing redox equilibrium.

Antimalarials↗

PubMed2026

Malaria driven mechanisms shaping cancer risk and aggressiveness in African populations.

Malaria and cancer represent intersecting public health challenges in sub-Saharan Africa, where malaria remains endemic and cancer incidence is rapidly increasing. Emerging evidence indicates that chronic or recurrent malaria infection may influence carcinogenesis and tumour aggressiveness through complex biological mechanisms. This narrative review critically synthesizes data from PubMed, Scopus, and Web of Science to elucidate the mechanistic intersections between malaria and cancer risk, progression, and therapeutic response. The review highlights five principal axes linking malaria to oncogenesis: malaria-induced oxidative stress and chronic inflammation driving genomic instability; gut microbiome dysbiosis altering systemic immunity and tumour microenvironment; exploitation of shared molecular targets such as the endothelial protein C receptor (EPCR) and oncofetal chondroitin sulfate by Plasmodium parasites and cancer cells; cooperative interactions between malaria and oncogenic viruses like Epstein-Barr virus in lymphomagenesis; and malaria-associated vitamin D deficiency impairing immune surveillance. Furthermore, pharmacological evidence reveals that several antimalarial agents, including artemisinin derivatives, chloroquine, and quinacrine, possess anticancer properties, while some anticancer drugs exhibit antimalarial activity, underscoring opportunities for dual-action or repurposed therapeutics. The convergence of malaria and cancer biology underscores the urgent need for integrative, multidisciplinary research spanning molecular epidemiology, immunology, and pharmacology. Unveiling these mechanisms may unveil novel biomarkers and therapeutic targets, guiding context-specific interventions to reduce the disproportionate cancer burden in malaria-endemic African populations.

Humans↗

PubMed2026

Discovery of Sphaeriaurantins as Rapid-Acting Antiplasmodials with Dual Activity in Blood and Liver Stages.

The rapid emergence of resistance in the malaria-causing protozoan Plasmodium falciparum has heightened the demand for treatments with novel modes of action. Having evolved to produce a myriad of structurally diverse natural products (NPs) as defenses against soil-dwelling parasites including protozoa, Actinomycetota strains are a promising source for the discovery of NPs as antiplasmodial drug leads. Herein, the selective inhibition of P. falciparum is reported for five distinct NP families from Actinomycetota, including an unprecedented family of glycosylated type II polyketides termed sphaeriaurantins (SPAs). The structures of SPAs were established through the combination of MS and NMR spectroscopic data analysis, derivatization and comparison of the deoxyhexose moieties to authentic standards, and quantum chemical calculations, including 1H and 13C NMR chemical shifts and electronic circular dichroism (ECD) spectra. The three isolated SPA congeners reveal that the characteristic pseudodimeric structure of the SPA family of NPs, likely introduced at a late stage of the SPA biosynthesis, is highly relevant for the observed low nanomolar activity. SPA A exhibits a rapid killing profile, with activities across all intraerythrocytic stages, and potent liver stage efficacy, as well as a low propensity for resistance development. Taken together, these results suggest a mode of action that most likely is distinct from the existing antimalarials, supporting SPA A as a promising antimalarial drug lead for further development.

Plasmodium falciparum↗

PubMed2025

The impact of Iso-mukaadial acetate on Plasmodium falciparum transcriptional gene regulation.

Malaria remains prevalent globally despite various intervention strategies aimed at preventing its transmission. With the decreasing effectiveness of antimalarial drugs, medicinal plant extracts have been proposed as alternatives. Iso-mukaadial acetate extracted from Warburgia salutaris has shown anti-plasmodial activity, but the mechanism of inhibition is unknown. In this study, RNA sequencing analysis of P. falciparum NF54 strain treated with IMA was conducted to determine the possible targets of IMA. The expression profiles of P. falciparum genes regulated by IMA and chloroquine (antimalarial control) during the intraerythrocytic stage were analyzed with gene ontology tools, including PlasmoDB, ShinyGO and g: Profiler. IMA and chloroquine upregulated genes linked to parasite biological processes and cell adhesion molecular binding functions, including PfEMP1, RIFIN, and STEVOR. Chloroquine specifically downregulated DNA replication processes involving DNA replication licensing factors MCM3 and DNA helicase, while IMA downregulated peptidyl-proline modification and glycolytic pathways. KEGG analysis suggested glycolysis-gluconeogenesis and pentose phosphate pathway enzymes (e.g., glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6-phosphate dehydrogenase (G6PD)-6-phosphogluconolactonase) as theoretical IMA targets, whose suppression could hypothetically reduce ATP and NADPH production, weakening parasite energy supply and antioxidant defenses. The inhibition of DNA replication components (MCM complex, DNA topoisomerases) by IMA, and the downregulation of DNA replication/repair proteins by chloroquine, may both impair genome integrity, contributing to the observed anti-plasmodial effects. IMA treatment was assumed to be associated with impairment of parasite energy metabolism, redox balance and DNA replication machinery. These effects differ from chloroquine, which primarily targeted DNA replication and repair processes, yet both drugs upregulated adhesion-associated gene families. Changes in the expression of metabolic and replication genes induced by IMA suggest the compounds potential as an anti-plasmodial candidate, warranting further biochemical validation of its mechanism of effect.

Plasmodium falciparum↗

PubMed2026

Population genomics of Plasmodium malariae from 4 African countries.

BACKGROUNDMalaria caused by Plasmodium malariae is geographically widespread and sometimes associated with prolonged infection, yet little is known about its genomic epidemiology.METHODSWe performed hybrid capture and whole-genome sequencing of 77 isolates collected from Cameroon (n = 7), the Democratic Republic of the Congo (n = 16), Nigeria (n = 4), and Tanzania (n = 50) between 2015 and 2021, analyzing parasite genetic population structure and demography.RESULTSThere is no evidence of geographic population structure. Nucleotide diversity was significantly lower than in colocalized P. falciparum isolates, while linkage disequilibrium was significantly higher. Genome-wide selection scans identified no erythrocyte invasion ligands or antimalarial resistance orthologs as top hits; however, targeted analyses of these loci revealed evidence of selective sweeps around 4 erythrocyte invasion ligands and 6 antimalarial resistance orthologs. Demographic inference modeling suggests that African P. malariae is recovering from a bottleneck.CONCLUSIONP. malariae is genomically atypical among human Plasmodium spp. and lacks strong population structure in Africa. The low diversity has potential impacts on understanding persistent versus new infection through genomic epidemiology.FUNDINGBill & Melinda Gates Foundation (grant 002202), USAID/PMI through Jhpiego and CDC, NIH (T32AI007151, T32AI070114, R01AI107949, R01AI129812, R21 AI148579, R01AI137395, R21AI152260, R01AI132547, and K24AI134990), and the DELTAS Africa initiative (DELGEME grant 107740/Z/15/Z).

Plasmodium malariae↗

PubMed2026

Dual plasmepsin IX and X inhibitors are refractory to development of resistance.

Artemisinin-based combination therapies (ACTs) remain the cornerstone of malaria treatment, but emerging resistance threatens their efficacy. The potential for the development of drug resistance against plasmepsin X (PMX)-selective inhibitors and dual plasmepsin IX/X (PMIX/X) inhibitors was investigated in Plasmodium falciparum. A series of PMX-selective (WM4, WM76, WM92) and PMIX/X dual inhibitors (WM382, WM09, WM42) were characterised for potency against parasite growth and enzyme inhibition. In vitro selection experiments showed that all compounds had a high barrier to resistance, although parasites with reduced sensitivity to PMX‑selective inhibitors could still be selected. Resistance mechanisms involved pmx gene amplification and point mutations (D245N, S315P, S359P, I363L) that alter inhibitor binding. Recombinant expression and Michaelis-Menten kinetics demonstrated that these mutations impair drug binding whilst preserving PMX catalytic function. Reverse genetics confirmed that introducing these mutations into the pmx gene resulted in decreased potency of the inhibitors. In this study, resistance to the PMIX/X dual inhibitors evaluated here could not be selected, despite prolonged selection pressure. Antimalarial Resistome Barcoding (AReBar) assays confirmed the absence of pre-existing resistance to either inhibitor class. Critically, PMIX/X dual inhibitors maintained efficacy against parasites with decreased sensitivity to PMX-selective compounds. These findings demonstrate that dual PMIX/X inhibitors present a substantially higher barrier to resistance than PMX-selective inhibitors, informing antimalarial drug development strategies and highlighting dual-target inhibition as a promising approach to mitigate resistance risks.

Aspartic Acid Endopeptidases↗

PubMed2025

Influence of genetic factors of humans, mosquitoes and parasites, on the evolution of Plasmodium falciparum infections, malaria transmission and genetic control methods: a review of the literature.

Despite significant progress, malaria remains a public health problem in many regions, particularly in sub-Saharan Africa. This situation is partly explained by the mosquito's resistance to insecticides and the emergence of parasite resistance to antimalarial drugs. Indeed, in spite of the various vectors' controls, insecticide resistance emerges from multi-generational selection and poses worldwide concern. In parallel, artemisinin resistance unfortunately emerged independently in multiple countries in eastern Africa. Since 2014, artemisinin resistance has been observed in 6 countries in Africa and, more concerningly, the evidence from longitudinal molecular surveys in these countries suggests that it is spreading. While phenotypic evidence of treatment failure is still limited, the increasing reports of validated artemisinin resistance mutations are alarming. Unlike the emergence of artemisinin resistance in South-East Asia, our understanding of the genetic determinants of artemisinin resistance and our ability to sequence and map the spread of resistance are significantly greater. In addition to mosquito and parasite genetics affecting malaria evolution, many human individual variants have been identified that are associated with malaria protection, but the most important of all relates to the structure or function of red blood cells, the classical polymorphisms that causes sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants. In that biological complex context, there is a need to characterize the various genetic factors in Plasmodium falciparum, humans and mosquitoes that are potentially associated with resistance to antimalarial drugs and insecticides, and their involvement in the evolution, severity and transmission of malaria. In this direction, A comprehensive literature review was conducted to capture the objectives highlighted above. The advances in genomic surveillance and emerging genetic control strategies, such as gene drive technology were also considered in this review. We used search engines such as PubMed and Google scholar to retrieve articles useful to the objective of this paper and information on the knowledge of genetic factors and methods that contributed to malaria control were synthesized.

Humans↗

PubMed2025

The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels.

Spreading resistance to front-line treatments necessitate the search for new classes of antimalarials. Limitations of standard screening conditions lead us to develop an assay using culture media that more closely reflects nutrient levels in human serum to reveal new therapeutically relevant parasite pathways. Our approach was validated by testing 22k compounds followed by a full 750k compound screen and identified 29 chemotypes with higher activity in nutrient restricted media that were further characterized. Through a combination of chemo-genomics and innovative photocatalytic proximity labeling proteomics, we identified the target of two compounds as the CLAG3 component of the plasmodial surface anion channel (PSAC). Strikingly, every one of the other 29 chemotypes selected was also found to block PSAC activity, highlighting the importance of this nutrient channel for parasite survival under physiological conditions. The effect of PSAC inhibitors in the in vivo humanized mouse model was confirmed.

Animals↗

PubMed2026

Plasmodium thiamine pyrophosphokinase is essential for sporozoite formation and activation of an antiplasmodial thiamine analogue.

Oxythiamine, a thiamine analogue, inhibits Plasmodium falciparum proliferation by acting as an antimetabolite of vitamin B1. To elucidate in more detail its underlying mechanism of action, in vitro drug pressure was employed to generate oxythiamine-resistant P. falciparum lines. Whole-genome sequencing revealed that resistance was conferred by a single-point mutation in the thiamine pyrophosphokinase (TPK) gene. The mutated TPK has reduced activity, thereby likely limiting the conversion of oxythiamine into its active toxic form. To investigate the functional role of TPK across the parasite life cycle, a TPK-knockout line was generated in Plasmodium berghei. TPK-knockout parasites displayed a minor fitness cost during intraerythrocytic proliferation that could be overcome by infecting reticulocytes, but their sensitivity to oxythiamine was reduced fivefold in vivo, consistent with the hypothesis that activation of oxythiamine via TPK is essential for its antiplasmodial activity. In the Anopheles vector, TPK-knockout parasites produced a similar number of oocysts as wild-type parasites, but oocyst maturation was impaired and sporozoite formation was completely inhibited. These findings underscore an essential role for TPK in mediating the antiplasmodial activity of oxythiamine and reveal its critical function in sporogony within the mosquito, supporting its potential as a transmission-blocking target for antimalarial intervention.

Animals↗

PubMed2025

14 days of high-dose versus low-dose primaquine treatment in patients with Plasmodium vivax infection in Cambodia: a randomised, single-centre, open-label efficacy study.

BACKGROUND: Most malaria-endemic countries, including Cambodia, use a total dose of 3·5 mg/kg of primaquine to eliminate Plasmodium vivax hypnozoites and prevent relapses. There are, however, indications that the lower dose of 3·5 mg/kg is insufficient for tropical P vivax isolates, particularly in southeast Asia, and WHO now recommends a total dose of 7·0 mg/kg in most countries. We aimed to determine the most effective regimen to eliminate P vivax hypnozoites to support elimination efforts of this malaria parasite. METHODS: We conducted an open-label, randomised controlled trial in Kampong Speu province, western Cambodia. Patients infected with P vivax aged at least 15 years were offered to participate. Exclusion criteria were severe malaria or other diseases requiring treatment, low haemoglobin (<8·0 g/dL), pregnancy or breastfeeding, sensitivity to study drugs, and use of antimalarials in the preceding month. Enrolled patients were treated with an artesunate regimen of 2 mg/kg per day for 7 days. Patients with normal glucose-6-phosphate dehydrogenase (G6PD) levels were randomly assigned (2:2:1) to receive 3·5 mg/kg (low dose [0·25 mg/kg per day]), 7·0 mg/kg (high dose [0·5 mg/kg per day]), or no primaquine for 14 days. Patients with deficient G6PD levels were assigned to the no primaquine comparator arm. Patients were relocated to the study site in Aoral town where no malaria transmission occurs to ensure that they were not reinfected during their 90-day follow-up. After 90 days of relocation, G6PD-normal patients in the no primaquine arm were provided 3·5 mg/kg of primaquine for 14 days to be taken unsupervised. At day 90, relocation was terminated, and patients were followed up monthly for 3 months until day 180. The primary outcome was P vivax recurrence within 90 days of relocated follow-up, assessed in all patients who completed treatment and complied with relocation without interruption. All patients enrolled and assigned to an intervention arm were included in the safety analysis. The study is registered on ClinicalTrials.gov and recruitment is completed (NCT04706130). FINDINGS: Between Nov 10, 2021, and Feb 10, 2024, 160 patients were enrolled and 147 were included in the primary analysis-59 were assigned to the no primaquine arm (37 assigned as G6PD deficient [median age 22 years, IQR 18-28]; 22 randomly assigned [18, 17-25]), 45 to the low-dose primaquine arm (23, 19-30), and 43 to the high-dose primaquine arm (22, 18-25). Participants were mostly male (135 [92%] of 147) and all Cambodian. 48 (81% [95% CI 69·6-89·2]) participants in the no primaquine arm had at least one P vivax recurrence within 90 days, as did 11 (24%, 14·2-38·7) in the low-dose group and two (5%, 0·8-15·5) in the high-dose group (p=0·0141 for high vs low). After imputation for missing data, low-dose primaquine remained associated with more recurrences than high-dose primaquine (hazard ratio 0·17 [95% CI 0·04-0·79], p=0·0229). Both primaquine regimens were well tolerated with no serious adverse events reported. INTERPRETATION: Not providing primaquine to patients led to a considerable rate of P vivax recurrence. The risk of P vivax recurrence was substantially lower for 7·0 mg/kg primaquine treatment compared with 3·5 mg/kg. Tolerability and safety of both primaquine regimens in G6PD normal individuals was comparable. FUNDING: US National Institutes of Health (R01AI146590).

Humans↗

PubMed2026

Molecular characterization and genome sequence analysis of Dichroa emaravirus, a putative novel member of the genus Emaravirus.

Hydrangea febrifuga (syn. Dichroa febrifuga) is a traditional medicinal plant distributed in China and Southeast Asia, and febrifugine, one of its principal bioactive constituents, has served as an important lead compound for antimalarial drug development. Viral infections may adversely affect the quality of medicinal plants; however, no emaravirus has previously been reported from H. febrifuga. Here, high-throughput sequencing was performed on H. febrifuga leaves exhibiting mosaic symptoms collected in Yunnan Province, China. Combined with RT-PCR, Sanger sequencing, and 5'/3' rapid amplification of cDNA ends (RACE), five full-length genomic RNA segments of a putative novel emaravirus, tentatively designated Dichroa emaravirus (DEV), were identified and characterized. The five negative-sense single-stranded RNA (-ssRNA) segments have a combined length of 12,971 nt and encode an RNA-dependent RNA polymerase (RdRp), glycoprotein precursor (GP), nucleocapsid protein (NP), movement protein (MP), and an uncharacterized accessory protein, P5. The maximum amino acid sequence identities of DEV P1-P4 with recognized emaraviruses were 73.90%, 51.82%, 65.60%, and 81.30%, respectively, whereas P5 showed a maximum identity of 49.16% with its closest homolog. Thus, three of the four core proteins had maximum identities below 80%, consistent with the current ICTV species demarcation criterion for the genus Emaravirus. Maximum-likelihood phylogenetic analyses based on the four core proteins further supported the placement of DEV within the genus Emaravirus (family Fimoviridae). These results support DEV as a putative novel emaravirus and represent the first report of an emaravirus associated with H. febrifuga.

Genome, Viral↗

PubMed2026

Clinical features and outcomes of patients with anti-neutrophil cytoplasmic antibody-positive systemic lupus erythematosus from a single-center retrospective study.

INTRODUCTION: The role of anti-neutrophil cytoplasmic antibodies (ANCA) in systemic lupus erythematosus (SLE) remains unclear. ANCA positivity has been linked to more severe disease and possible overlap with ANCA-associated vasculitis, but available data are inconsistent. METHODS: We conducted a retrospective single-center study of SLE patients treated at the University Hospital in Kraków (2012-2022). Patients fulfilled the 2019 EULAR/ACR criteria. ANCA positivity (anti-MPO or anti-PR3) was confirmed by ELISA. Clinical features, laboratory findings, treatment, and outcomes were analyzed. RESULTS: Among 1039 SLE patients, 18 (1.73%) were ANCA-positive (anti-MPO, 72.22%; anti-PR3, 27.78%). Most ANCA-positive SLE patients were female (88.89%), with a median age at disease onset of 35.5 years. The most common manifestations in ANCA-positive cases were hematological abnormalities (100%), constitutional symptoms (88.89%), and joint involvement (88.89%). Renal involvement was observed in 72.22% (n = 13) of ANCA-positive SLE patients; however, lupus nephritis was confirmed by kidney biopsy in only seven cases. Vasculitis was rare (5.56%). Anti-dsDNA (61.11%) and anti-SSA (50%) were the most frequent autoantibodies. No significant differences were found between anti-MPO and anti-PR3 subgroups. Most ANCA-positive patients received glucocorticoids (94.44%), cyclophosphamide (61.11%), and antimalarials (61.11%). No statistically significant differences were observed between the ANCA-positive and ANCA-negative groups (p > 0.05 for all parameters). CONCLUSIONS: ANCA positivity in SLE is rare and predominantly associated with anti-MPO antibodies. It is linked to frequent renal involvement but infrequent vasculitis. No differences were observed between ANCA subtypes, suggesting no distinct clinical phenotype. Key Points • ANCA positivity was rare in this systemic lupus erythematosus cohort (1.73%) and was predominantly associated with anti-MPO antibodies rather than anti-PR3 antibodies. • No significant differences in demographic characteristics, clinical manifestations, comorbidities, or autoantibody profiles were observed between ANCA-positive and ANCA-negative patients. Similarly, no significant differences were identified between the anti-PR3-positive and anti-MPO-positive groups. • ANCA-positive SLE was commonly associated with the need for intensive immunosuppressive treatment, highlighting its potential relevance as a marker of severe disease course.

Humans↗

PubMed2025

Replication stress increases de novo CNVs across the malaria parasite genome.

Changes in the copy number of large genomic regions, termed copy number variations (CNVs), contribute to important phenotypes. CNVs are readily identified using conventional approaches when present in a large fraction of the cell population. However, CNVs in only a few genomes are often overlooked but important; if beneficial, a de novo CNV that arises in a single genome can expand during selection to create a population of cells with novel characteristics. While single cell methods for studying de novo CNVs are increasing, we continue to lack information about CNV dynamics in rapidly evolving microbial populations. Here, we investigated de novo CNVs in the genome of the Plasmodium parasite that causes human malaria. The highly AT-rich P. falciparum genome readily accumulates CNVs that facilitate rapid adaptation. We employed low-input genomics and specialized computational tools to evaluate the impact of sub-lethal stress on the de novo CNV rate. We observed a significant increase in genome-wide de novo CNVs following treatment with an antimalarial compound that inhibits replication. De novo CNVs encompassed genes from various cellular pathways participating in human infection. This snapshot of CNV dynamics emphasizes the connection between replication stress, DNA repair, and CNV generation in this important microbial pathogen.

Journal Article↗

PubMed2026

Tandem duplication-driven expansion and UV-B stress adaptation of the LHC gene family in Artemisia annua L.

BACKGROUND: Artemisia annua L., is the primary natural source of the antimalarial drug artemisinin. In nature, fluctuating light is a major environmental stress that affects plant growth and artemisinin biosynthesis. Although the light-harvesting chlorophyll a/b-binding (LHC) superfamily plays a key role in mediating plant responses to fluctuating light, systematic research of this gene family in A. annua has not yet been conducted, limiting our understanding of light adaptation in this medicinally important species. RESULTS: This study investigated the evolutionary dynamics and functional adaptation of the light-harvesting chlorophyll a/b-binding (LHC) superfamily in A. annua, with a focus on the early light‑induced protein (ELIP) subfamily. Comparative genomics of 24 plant species showed that the LHC superfamily recently expanded in the examined Asteraceae lineages through duplication events. In A. annua, 229 LHC genes identified from four haplotype genomes comprised 205 allelic and 24 haplotype-specific loci, with the ELIP subfamily expanding significantly via tandem duplication. Notably, compared to non-Asteraceae plants, ELIPs exhibited a uniform single-exon architecture, indicating it is a genomic feature unique to Asteraceae plants. Population genomics of 41 individuals showed dynamic copy number variations ranging from 1 to 4 copies per locus. Interestingly, a structurally disrupted ELIP allele remained transcriptionally active and produced long aberrant transcripts, showing that this subfamily is still actively evolving. Under UV-B stress, AaELIP loci showed synchronized induction trend but differed in expression levels, suggesting a division into major and auxiliary roles within the expanded tandem cluster. Overall, while the response of ELIPs to light stress is evolutionarily conserved, this dramatic expansion and structural streamlining of AaELIPs may represent a key evolutionary adaptation that enhances the plant's ability to cope with intense light and radiation stress. CONCLUSIONS: Collectively, this study demonstrates a significant expansion of the LHC superfamily in A. annua, especially within the ELIP subfamily, as well as its robust response to UV-B treatment, underscoring the essential role of ELIPs in mediating light stress responses. These findings provide a valuable foundation for future research to uncover the molecular mechanisms underlying A. annua's adaptation to complex light environments.

Artemisia annua↗

PubMed2025

A common DNA deletion altering the 3'UTR of mdr1 is associated with reduced mefloquine susceptibility in P. vivax parasites from Cambodian patients.

Artemisinin-combination therapies (ACTs) are now recommended for the treatment of uncomplicated malaria caused by Plasmodium vivax, the parasite responsible for the majority of malaria infections outside of Africa. We analyzed the genome sequences of 206 P. vivax parasites collected from Cambodian malaria patients and showed that more than 80% of them carried a DNA deletion located immediately downstream of the multidrug resistance 1 gene (mdr1). This 837 bp deletion overlapped with a different deletion present at low frequency in South American isolates, suggesting a functional role despite not altering the coding sequence of mdr1. Using RNA sequencing, we showed that these deletions altered the transcripts expressed from mdr1 and resulted in mRNAs with different 3' untranslated regions. In Cambodian isolates, the deletion was significantly associated with a higher expression of mdr1 and a lower ex vivo susceptibility to mefloquine. Finally, we genotyped 592 Cambodian isolates collected between 2014 and 2024 and showed that the mdr1 deletion increased in frequency in Cambodia since the introduction of mefloquine as ACT partner drug. Overall, these findings indicate that a common deletion of a non-coding sequence affects the transcription, stability, or translation of mdr1 in P. vivax parasites and could mediate reduced susceptibility to antimalarial drug(s) currently used for the treatment of uncomplicated vivax malaria.

Journal Article↗