A type II protein arginine methyltransferase regulates merozoite invasion in Plasmodium falciparum.

Protein arginine methyltransferases (PRMTs) regulate many important cellular processes, such as transcription and RNA processing in model organisms but their functions in human malaria parasites are not elucidated. Here, we characterize PfPRMT5 in Plasmodium falciparum, which catalyzes symmetric dimethylation of histone H3 at R2 (H3R2me2s) and R8, and histone H4 at R3 in vitro. PfPRMT5 disruption results in asexual stage growth defects primarily due to lower invasion efficiency of the merozoites.

The Plasmodium falciparum Nuclear Protein Phosphatase NIF4 Is Required for Efficient Merozoite Invasion and Regulates Artemisinin Sensitivity.

Artemisinin resistance in Plasmodium falciparum has been associated with a mutation in the NLI-interacting factor-like phosphatase PfNIF4, in addition to the mutations in the Kelch13 protein as the major determinant. We found that PfNIF4 was predominantly expressed at the schizont stage and localized in the nuclei of the parasite. To elucidate the functions of PfNIF4 in P.

A Leak-Free Inducible CRISPRi/a System for Gene Functional Studies in Plasmodium falciparum.

By fusing catalytically dead Cas9 (dCas9) to active domains of histone deacetylase (Sir2a) or acetyltransferase (GCN5), this CRISPR interference/activation (CRISPRi/a) system allows gene regulation at the transcriptional level without causing permanent changes in the parasite genome. However, the constitutive expression of dCas9 poses a challenge for studying essential genes, which may lead to adaptive changes in the parasite, masking the true phenotypes. Here, we developed a leak-free inducible CRISPRi/a system by integrating the DiCre/ regulon to allow the expression of dCas9-GCN5/-Sir2a upon transient induction with rapamycin, which allows convenient transcriptional regulation of a gene of interest by introducing a guide RNA targeting its transcription start region.

Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook.

Emergence and spread of resistance in Plasmodium falciparum to the frontline treatment artemisinin-based combination therapies (ACTs) in the epicenter of multidrug resistance of Southeast Asia threaten global malaria control and elimination. Artemisinin (ART) resistance (or tolerance) is defined clinically as delayed parasite clearance after treatment with an ART drug. The resistance phenotype is restricted to the early ring stage and can be measured in vitro using a ring-stage survival assay.

Role of Plasmodium falciparum Kelch 13 Protein Mutations in P. falciparum Populations from Northeastern Myanmar in Mediating Artemisinin Resistance.

Mutations in the Kelch 13 (PfK13) protein are associated with artemisinin resistance. PfK13 is essential for asexual erythrocytic development, but its function is not known. We tagged the PfK13 protein with green fluorescent protein in to study its expression and localization in asexual and sexual stages.

Evolution of the Plasmodium vivax multidrug resistance 1 gene in the Greater Mekong Subregion during malaria elimination.

Background: The malaria elimination plan of the Greater Mekong Subregion (GMS) is jeopardized by the increasing number of Plasmodium vivax infections and emergence of parasite strains with reduced susceptibility to the frontline drug treatment chloroquine/primaquine. This study aimed to determine the evolution of the P. vivax multidrug resistance 1 (Pvmdr1) gene in P.

Strategies for Accurate Diagnosis of Fetal Aortic Arch Anomalies: Benefits of Three-Dimensional Sonography With Spatiotemporal Image Correlation and a Novel Algorithm for Volume Analysis.

Background: Obtaining an accurate diagnosis of fetal aortic arch anomalies is often difficult with traditional two-dimensional (2D) sonography. Thus, the aim of this study was to assess the value of three-dimensional (3D) sonography with spatiotemporal image correlation for diagnosing fetal aortic arch anomalies using a novel algorithm for 3D volume analysis.

Methods: Two-dimensional and 3D echocardiographic image data from 300 normal fetuses and 30 fetuses with aortic arch anomalies were retrospectively reviewed.

Prenatal diagnosis of fetal absent pulmonary valve syndrome by two- and three-dimensional echocardiography.

Absent pulmonary valve syndrome (APVS) is a rare congenital cardiac anomaly characterized by hypoplastic or even absent pulmonary valve, to-and-fro flow across the pulmonary valve annulus, and dilatation of main pulmonary artery and branches. It is crucial to evaluate the degree of dilatation of pulmonary arteries and the presence of associated malformation and chromosomal anomalies affecting pregnancy decision. We described two- and three-dimensional (3D) echocardiographic findings of one fetus with APVS and indicated the beneficial contribution of 3D technology in understanding the anatomy.

Two- and four-dimensional echocardiography with high-definition flow imaging and spatiotemporal image correlation in the diagnosis of fetal isolated partial anomalous pulmonary venous connection.

Partial anomalous pulmonary venous connection (PAPVC) is a rare malformation. We describe a case of PAPVC, in which the left pulmonary veins coursed to the left innominate vein through a vertical vein and finally drained into the right superior vena cava; the right pulmonary veins were connected to the left atrium. Tracing the origin and destination of abnormal vessels presented at the three-vessel and trachea view is useful for the diagnosis.

Genetic diversity of the Plasmodium vivax phosphatidylinositol 3-kinase gene in two regions of the China-Myanmar border.

Artemisinin resistance in Plasmodium falciparum was associated with mutations in the propeller domain of the PfK13 gene and increased phosphatidylinositol-3'-kinase (PfPI3K) activity. Assessment of the genetic diversity of the PfK13 ortholog PvK12 in Plasmodium vivax field samples from the same hotspots of P. falciparum artemisinin resistance revealed a limited genetic diversity of PvK12.

Prenatal screening of fetal ventriculoarterial connections: benefits of 4D technique in fetal heart imaging.

Background: Identification of prenatal ventriculoarterial connections in fetuses with conotruncal anomalies (CTA) remains one of the greatest challenges for sonographers performing screening examinations. Herein, we propose a novel protocol of 4D volume analysis that identifies ventriculoarterial connections and evaluate its clinical utility in routine screenings.

Methods: Twenty-nine cases of transposition of the great arteries (TGA), 22 cases of double-outlet right ventricle (DORV), 36 cases of tetralogy of Fallot (TOF), 14 cases of truncus arteriosus (TCA), and randomly selected 70 normal fetuses were reviewed in this study.

Role of four-dimensional echocardiography with high-definition flow imaging and spatiotemporal image correlation in detecting fetal pulmonary veins.

Background: Prenatal diagnosis of fetal total anomalous pulmonary vein connection (TAPVC) remains challenging for most screening sonographers. The purpose of this study was to evaluate the use of four-dimensional echocardiography with high-definition flow imaging and spatiotemporal image correlation (4D-HDFI) in identifying pulmonary veins in normal and TAPVC fetuses.

Material & Methods: We retrospectively reviewed and performed 4D-HDFI in 204 normal and 12 fetuses with confirmed diagnosis of TAPVC.

Limited genetic diversity in the PvK12 Kelch protein in Plasmodium vivax isolates from Southeast Asia.

Background: Artemisinin resistance in Plasmodium falciparum has emerged as a major threat for malaria control and elimination worldwide. Mutations in the Kelch propeller domain of PfK13 are the only known molecular markers for artemisinin resistance in this parasite. Over 100 non-synonymous mutations have been identified in PfK13 from various malaria endemic regions.

Evaluation of fetal cardiac valve anomalies by four-dimensional echocardiography with spatiotemporal image correlation (4DSTIC).

Background: Prenatal diagnosis of cardiac valve anomalies challenged most screening sonographers. The purpose of the study was to evaluate the use of four-dimensional echocardiography with spatiotemporal image correlation (4DSTIC) in detecting normal and abnormal fetal cardiac valves.

Methods: Forty-three cases of confirmed cardiac valve anomalies identified by two-dimensional echocardiography (2DE) were retrospectively reviewed in this study.

Design, synthesis and biological evaluation of small molecules as potent glucosidase inhibitors.

Herein we have reported design, synthesis and in vitro biological evaluation of a library of bicyclic lactams that led to the discovery of compounds 6 and 7 as a novel class of α-glucosidase inhibitors. They inhibited α-glucosidase (yeast origin) in a mixed type of inhibition with an IC50 of ∼150 nM. Molecular docking studies further substantiated screening results.

The central role of cAMP in regulating Plasmodium falciparum merozoite invasion of human erythrocytes.

All pathogenesis and death associated with Plasmodium falciparum malaria is due to parasite-infected erythrocytes. Invasion of erythrocytes by P. falciparum merozoites requires specific interactions between host receptors and parasite ligands that are localized in apical organelles called micronemes.

A thrombospondin structural repeat containing rhoptry protein from Plasmodium falciparum mediates erythrocyte invasion.

Host cell invasion by Plasmodium falciparum requires multiple molecular interactions between host receptors and parasite ligands. A family of parasite proteins, which contain the conserved thrombospondin structural repeat motif (TSR), has been implicated in receptor binding during invasion. In this study we have characterized the functional role of a TSR containing blood stage protein referred to as P.