Spatial regulation of NSUN2-mediated tRNA m5C installation in cognitive function.

Enzyme-mediated modifications of tRNA, such as 5-methylcytosine (m5C) installed by nuclear-enriched NOP2/Sun RNA methyltransferase 2 (NSUN2), play a critical role in neuronal development and function. However, our understanding of these modifications' spatial installation and biological functions remains incomplete. In this study, we demonstrate that a nucleoplasm-localized G679R NSUN2 mutant, linked to intellectual disability, diminishes NSUN2-mediated tRNA m5C in human cell lines and Drosophila.

Mettl3-catalyzed mA regulates histone modifier and modification expression in self-renewing somatic tissue.

-methyladenosine (mA) is the most abundant modification on messenger RNAs (mRNAs) and is catalyzed by methyltransferase-like protein 3 (Mettl3). To understand the role of mA in a self-renewing somatic tissue, we deleted in epidermal progenitors in vivo. Mice lacking demonstrate marked features of dysfunctional development and self-renewal, including a loss of hair follicle morphogenesis and impaired cell adhesion and polarity associated with oral ulcerations.

Noncatalytic regulation of 18 rRNA methyltransferase DIMT1 in acute myeloid leukemia.

Several rRNA-modifying enzymes install rRNA modifications while participating in ribosome assembly. Here, we show that 18 rRNA methyltransferase DIMT1 is essential for acute myeloid leukemia (AML) proliferation through a noncatalytic function. We reveal that targeting a positively charged cleft of DIMT1, remote from the catalytic site, weakens the binding of DIMT1 to rRNA and mislocalizes DIMT1 to the nucleoplasm, in contrast to the primarily nucleolar localization of wild-type DIMT1.

Microwaves can kill malaria parasites non-thermally.

Malaria, which infected more than 240 million people and killed around six hundred thousand only in 2021, has reclaimed territory after the SARS-CoV-2 pandemic. Together with parasite resistance and a not-yet-optimal vaccine, the need for new approaches has become critical. While earlier, limited, studies have suggested that malaria parasites are affected by electromagnetic energy, the outcomes of this affectation vary and there has not been a study that looks into the mechanism of action behind these responses.

The lncRNA ALPHA specifically targets chikungunya virus to control infection.

Arthropod-borne viruses, including the alphavirus chikungunya virus (CHIKV), cause acute disease in millions of people and utilize potent mechanisms to antagonize and circumvent innate immune pathways including the type I interferon (IFN) pathway. In response, hosts have evolved antiviral counterdefense strategies that remain incompletely understood. Recent studies have found that long noncoding RNAs (lncRNAs) regulate classical innate immune pathways; how lncRNAs contribute to additional antiviral counterdefenses remains unclear.

Global-run on sequencing identifies as an Akt-dependent long noncoding RNA involved in insulin sensitivity.

The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and refeeding as well as define the specific role of hepatic Akt and FoxO1 signaling in mediating this response. We identified 599 feeding-regulated transcripts, as well as over 6,000 eRNAs, and mapped their dependency on Akt and FoxO1 signaling.

CLIP-Seq to identify targets and interactions of RNA binding proteins and RNA modifying enzymes.

The study of RNA chemical modifications is currently one of the most rapid-growing fields. Many types of RNA modifications in diverse RNA species have been shown to play versatile roles in a wide array of cellular processes. These modifications are installed and erased by writer and eraser enzymes, respectively.

Human DIMT1 generates NA-dimethylation-containing small RNAs.

Dimethyladenosine transferase 1 (DIMT1) is an evolutionarily conserved RNA N-dimethyladenosine (mA) methyltransferase. DIMT1 plays an important role in ribosome biogenesis, and the catalytic activity of DIMT1 is indispensable for cell viability and protein synthesis. A few RNA-modifying enzymes can install the same modification in multiple RNA species.

Treatment of Plasmodium falciparum merozoites with the protease inhibitor E64 and mechanical filtration increases their susceptibility to complement activation.

Plasmodium falciparum malaria killed 451,000 people in 2017. Merozoites, the stage of the parasite that invades RBCs, are a logical target for vaccine development. Treatment with the protease inhibitor E64 followed by filtration through a 1.

Structural and catalytic roles of the human 18 rRNA methyltransferases DIMT1 in ribosome assembly and translation.

rRNA-modifying enzymes participate in ribosome assembly. However, whether the catalytic activities of these enzymes are important for the ribosome assembly and other cellular processes is not fully understood. Here, we report the crystal structure of WT human dimethyladenosine transferase 1 (DIMT1), an 18 rRNA -dimethyladenosine (mA) methyltransferase, and results obtained with a catalytically inactive DIMT1 variant.

Coordination of mRNA and tRNA methylations by TRMT10A.

The posttranscriptional modification of messenger RNA (mRNA) and transfer RNA (tRNA) provides an additional layer of regulatory complexity during gene expression. Here, we show that a tRNA methyltransferase, TRMT10A, interacts with an mRNA demethylase FTO (ALKBH9), both in vitro and inside cells. TRMT10A installs -methylguanosine (mG) in tRNA, and FTO performs demethylation on -methyladenosine (mA) and ,2'--dimethyladenosine (mA) in mRNA.

The chemical diversity of RNA modifications.

Nucleic acid modifications in DNA and RNA ubiquitously exist among all the three kingdoms of life. This trait significantly broadens the genome diversity and works as an important means of gene transcription regulation. Although mammalian systems have limited types of DNA modifications, over 150 different RNA modification types have been identified, with a wide variety of chemical diversities.

Plasmodium falciparum strains spontaneously switch invasion phenotype in suspension culture.

The extensive redundancy in the use of invasion ligands by Plasmodium falciparum, and its unique ability to switch between invasion pathways have hampered vaccine development. P. falciparum strains Dd2 and W2mef have been shown to change from sialic acid (SA)-dependent to SA-independent phenotypes when selected on neuraminidase-treated erythrocytes.

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection.

One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy.

Complement and Antibody-mediated Enhancement of Red Blood Cell Invasion and Growth of Malaria Parasites.

Plasmodium falciparum malaria is a deadly pathogen. The invasion of red blood cells (RBCs) by merozoites is a target for vaccine development. Although anti-merozoite antibodies can block invasion in vitro, there is no efficacy in vivo.

The HFE genotype and a formulated diet controlling for iron status attenuate experimental cerebral malaria in mice.

Plasmodium falciparum infects approximately 500million individuals each year. A small but significant number of infections lead to complications such as cerebral malaria. Cerebral malaria is associated with myelin damage and neurological deficits in survivors, and iron status is thought to impact the outcome of infection.

Analysis of Erythrocyte Invasion Mechanisms of Plasmodium falciparum Clinical Isolates Across 3 Malaria-Endemic Areas in Ghana.

Background: Plasmodium falciparum invades human erythrocytes by using an array of ligands that interact with several receptors, including sialic acid (SA), complement receptor 1 (CR1), and basigin. We hypothesized that in malaria-endemic areas, parasites vary invasion pathways under immune pressure. Therefore, invasion mechanisms of clinical isolates collected from 3 zones of Ghana with different levels of endemicity (from lowest to highest, Accra, Navrongo, and Kintampo) were compared using standardized methods.

Use of mosquito preventive measures is associated with increased RBC CR1 levels in a malaria holoendemic area of western Kenya.

Malaria is responsible for close to 1 million deaths each year, mostly among African children. Red blood cells (RBCs) of children with severe malarial anemia show loss of complement regulatory proteins such as complement receptor 1 (CR1). We carried out this study to identify socio-economic, environmental, and biological factors associated with the loss of RBC CR1.

Facile synthesis of antimalarial 1,2-disubstituted 4-quinolones from 1,3-bisaryl-monothio-1,3-diketones.

A new strategy was developed to synthesize 1,2-disubstituted 4-quinolones in good yield starting from 1,3-bisaryl-monothio-1,3-diketone substrates. The synthesized compounds were evaluated for antimalarial activity using Plasmodium falciparum strains. All compounds, except for two, showed good activity.

Complement activation in malaria: friend or foe?

Complement is activated during malaria infection, but there is little evidence that it benefits the host. On the contrary, growing evidence points to the central role of complement activation in the pathogenesis of complicated malaria. Recent evidence suggests a critical role for C5a and the membrane attack complex in the pathogenesis of cerebral malaria, and for C5a in the pathogenesis of placental malaria.

Use of telemedicine to diagnose tinea in Kenyan schoolchildren.

Objective: Internet-based telemedicine has the potential to alleviate the problem of limited access to healthcare in developing countries. The Mashavu project aims to deploy kiosks that transmit health data and pictures from patients in underdeveloped countries who have no immediate access to healthcare to clinics for analysis by trained personnel. To test this principle, we investigated whether dermatophytic fungal infections (tinea) could be diagnosed by Kenyan clinicians solely from pictures of the lesions.