Type-I IFNs induce GBPs and lysosomal defense in hepatocytes to control malaria.

parasites undergo development and replication within the hepatocytes before infecting the erythrocytes and initiating clinical malaria. Although type-I interferons (IFNs) are known to hinder infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria.

Multi-center improvement in screening for dystonia in young people with cerebral palsy.

Background And Objectives: Dystonia is a common, debilitating, and often treatment refractory motor symptom of cerebral palsy (CP), affecting 70-80% of this population based on research assessments. However, routine clinical evaluation for dystonia in CP has failed to match these expected numbers. Addressing this diagnostic gap is a medical imperative because the presence of dystonia rules in or out certain treatments for motor symptoms in CP.

Delayed colonization of spp. and low prevalence of among infants of Asian ancestry born in Singapore: insights from the GUSTO cohort study.

Background: The loss of ancestral microbes, or the "disappearing microbiota hypothesis" has been proposed to play a critical role in the rise of inflammatory and immune diseases in developed nations. The effect of this loss is most consequential during early-life, as initial colonizers of the newborn gut contribute significantly to the development of the immune system.

Methods: In this longitudinal study (day 3, week 3, and month 3 post-birth) of infants of Asian ancestry born in Singapore, we studied how generational immigration status and common perinatal factors affect bifidobacteria and subsp.

Optimization of diastereomeric dihydropyridines as antimalarials.

The increase in research funding for the development of antimalarials since 2000 has led to a surge of new chemotypes with potent antimalarial activity. High-throughput screens have delivered several thousand new active compounds in several hundred series, including the 4,7-diphenyl-1,4,5,6,7,8-hexahydroquinolines, hereafter termed dihydropyridines (DHPs). We optimized the DHPs for antimalarial activity.

The influence of oviposition status on measures of transmission potential in malaria-infected mosquitoes depends on sugar availability.

Background: Like other oviparous organisms, the gonotrophic cycle of mosquitoes is not complete until they have selected a suitable habitat to oviposit. In addition to the evolutionary constraints associated with selective oviposition behavior, the physiological demands relative to an organism's oviposition status also influence their nutrient requirement from the environment. Yet, studies that measure transmission potential (vectorial capacity or competence) of mosquito-borne parasites rarely consider whether the rates of parasite replication and development could be influenced by these constraints resulting from whether mosquitoes have completed their gonotrophic cycle.

Extended blood stage sensitivity profiles of to doxycycline and tafenoquine, as a model for .

Testing antimicrobial sensitivity is limited to schizont maturation assays, which preclude determining the IC50s of delayed action antimalarials such as doxycycline. Using as a model for , we determined the physiologically significant delayed death effect induced by doxycycline [IC, 1,401 ± 607 nM]. As expected, IC to chloroquine (20.

In Vitro Antimalarial Activity of Trichothecenes against Liver and Blood Stages of Species.

Trichothecenes (TCNs) are a large group of tricyclic sesquiterpenoid mycotoxins that have intriguing structural features and remarkable biological activities. Herein, we focused on three TCNs (anguidine, verrucarin A, and verrucarol) and their ability to target both the blood and liver stages of species, the parasite responsible for malaria. Anguidine and verrucarin A were found to be highly effective against the blood and liver stages of malaria, while verrucarol had no effect at the highest concentration tested.

Circulating microRNAs as biomarkers of Chagas cardiomyopathy.

Background: Chagas cardiomyopathy (CHCM) is the most important clinical manifestation of Chagas disease. The analysis of cardiac miRNAs may contribute to predicting the progression to CHCM in Chagas indeterminate phase and/or to the differential diagnosis for cardiomyopathy.

Methods: We carried out a case-control study to identify circulating miRNAs associated with CHCM.

Blood meals from 'dead-end' vertebrate hosts enhance transmission potential of malaria-infected mosquitoes.

Ingestion of an additional blood meal(s) by a hematophagic insect can accelerate development of several vector-borne parasites and pathogens. Most studies, however, offer blood from the same vertebrate host species as the original challenge (for e.g.

Corrigendum: Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes.

[This corrects the article DOI: 10.3389/fmicb.2023.

Characterization of the extracellular vesicles, ultrastructural morphology, and intercellular interactions of multiple clinical isolates of the brain-eating amoeba, .

Introduction: As global temperatures rise to unprecedented historic levels, so too do the latitudes of habitable niches for the pathogenic free-living amoeba, . This opportunistic parasite causes a rare, but >97% fatal, neurological infection called primary amoebic meningoencephalitis. Despite its lethality, this parasite remains one of the most neglected and understudied parasitic protozoans.

Sheptide A: an antimalarial cyclic pentapeptide from a fungal strain in the Herpotrichiellaceae.

As part of ongoing efforts to isolate biologically active fungal metabolites, a cyclic pentapeptide, sheptide A (1), was discovered from strain MSX53339 (Herpotrichiellaceae). The structure and sequence of 1 were determined primarily by analysis of 2D NMR and HRMS/MS data, while the absolute configuration was assigned using a modified version of Marfey's method. In an in vitro assay for antimalarial potency, 1 displayed a pEC value of 5.

Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes.

species, , and are opportunistic pathogens that cause a range of brain, skin, eye, and disseminated diseases in humans and animals. These pathogenic free-living amoebae (pFLA) are commonly misdiagnosed and have sub-optimal treatment regimens which contribute to the extremely high mortality rates (>90%) when they infect the central nervous system. To address the unmet medical need for effective therapeutics, we screened kinase inhibitor chemotypes against three pFLA using phenotypic drug assays involving CellTiter-Glo 2.

Pf7: an open dataset of genome variation in 20,000 worldwide samples.

We describe the MalariaGEN Pf7 data resource, the seventh release of genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Hypnozoites.

Radical cure of malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against and hypnozoites.

Effects of probiotic and synbiotic supplementation on ponderal and linear growth in severely malnourished young infants in a randomized clinical trial.

Severe acute malnutrition (SAM) is a major global public health problem. We aimed to assess the effects of probiotic and synbiotic supplementation on rate of weight gain and change in length in young SAM infants. This study was substudy of a single-blind randomized clinical trial (NCT0366657).

AIM2 sensors mediate immunity to infection in hepatocytes.

Malaria, caused by parasites is a severe disease affecting millions of people around the world. undergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening blood-stage of malaria. Although the natural immune responses impeding infection and development in the liver are key to controlling clinical malaria and transmission, those remain relatively unknown.

Cryopreservation of Sporozoites.

Malaria is a deadly disease caused by the parasite, , and impacts the lives of millions of people around the world. Following inoculation into mammalian hosts by infected mosquitoes, the sporozoite stage of undergoes obligate development in the liver before infecting erythrocytes and causing clinical malaria. The most promising vaccine candidates for malaria rely on the use of attenuated live sporozoites to induce protective immune responses.

Integrative Genetic Manipulation of Plasmodium cynomolgi Reveals Multidrug Resistance-1 Y976F Associated With Increased In Vitro Susceptibility to Mefloquine.

The lack of a long-term in vitro culture method has severely restricted the study of Plasmodium vivax, in part because it limits genetic manipulation and reverse genetics. We used the recently optimized Plasmodium cynomolgi Berok in vitro culture model to investigate the putative P. vivax drug resistance marker MDR1 Y976F.

Intramyocardial Dissecting Hematoma: A Mechanical Complication Needing Surgical Therapy?

Intramyocardial dissecting hematoma is a form of cardiac rupture caused by myocardial infarction, percutaneous coronary intervention, or trauma. It is a cavity between myocardial fibers caused by partial rupture of the ventricular wall. Therapeutic management, including the timing for surgical approach, has not been standardized.

Liver-stage fate determination in parasites: Characterization of schizont growth and hypnozoite fating from patient isolates.

, one species of parasite causing human malaria, forms a dormant liver stage, termed the hypnozoite, which activate weeks, months or years after the primary infection, causing relapse episodes. Relapses significantly contribute to the vivax malaria burden and are only killed with drugs of the 8-aminoquinoline class, which are contraindicated in many vulnerable populations. Development of new therapies targeting hypnozoites is hindered, in part, by the lack of robust methods to continuously culture and characterize this parasite.