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Maternal Fetal Medicine. Medical Records - Washington Twp. Outpatient Medical Imaging - Wash. Search form Search. Elizabeth A. Population genetic studies dating back to the midth century first proposed that erythrocytes red blood cells , the host cell for P.
Hemoglobinopathies, thalassemias, ovalocytosis, and G6PD deficiency are all examples of red cell disorders that appear to provide protection against severe malaria. Although the notion that malaria has helped shape the human genome is well- accepted, the lack of a nucleus in human erythrocytes has hindered our ability to study genetic interactions between these unusual host cells and P. Recently, we developed a hematopoietic stem cell-based approach to tackle this issue, in which we can genetically alter nucleated hematopoietic precursor cells and differentiate them ex-vivo to mature erythrocytes that can be infected by P.
Using this approach, we performed a forward genetic screen of human blood groups to identify critical host factors for P. We found that the Cromer blood group antigen CD55 DAF is essential for parasite invasion and is necessary for proper attachment of merozoites to the erythrocyte surface. Importantly the requirement for CD55 appears to be strain-transcendent, suggesting that it may act as a critical receptor during malaria infection. We are currently pursuing fundamental questions related to host-pathogen interactions in malaria, with the host erythrocyte as a focal point.
We employ a variety of approaches spanning molecular parasitology, stem cell biology, cell biology, biochemistry and genomics.
We welcome self-motivated individuals interested in joining us as we seek to learn more about the fascinating biology underlying host-pathogen interactions in malaria. The replication of Plasmodium falciparum parasites within red blood cells RBCs causes severe disease in humans, especially in Africa. Deleterious alleles like hemoglobin S are well-known to confer strong resistance to malaria, but the effects of common RBC variation are largely undetermined.
Here we collected fresh blood samples from healthy donors, most with African ancestry, and performed exome sequencing, detailed RBC phenotyping, and parasite fitness assays. Over one third of healthy donors unknowingly carried alleles for G6PD deficiency or hemoglobinopathies, which were associated with characteristic RBC phenotypes.
Among non-carriers alone, variation in RBC hydration, membrane deformability, and volume was strongly associated with P. Interestingly, we observed little or negative evidence for divergent selection on non-pathogenic RBC variation between Africans and Europeans. These findings suggest a model in which globally widespread variation in a moderate number of genes and phenotypes modulates P. View details for DOI View details for PubMedID View details for Web of Science ID Biophysical separation promises label-free, less-invasive methods to manipulate the diverse properties of live cells, such as density, magnetic susceptibility, and morphological characteristics.
However, some cellular changes are so minute that they are undetectable by current methods. We developed a multiparametric cell-separation approach to profile cells with simultaneously changing density and magnetic susceptibility.
We demonstrated this approach with the natural biophysical phenomenon of Plasmodium falciparum infection, which modifies its host erythrocyte by simultaneously decreasing density and increasing magnetic susceptibility. Current approaches have used these properties separately to isolate later-stage infected cells, but not in combination. We present biophysical separation of infected erythrocytes by balancing gravitational and magnetic forces to differentiate infected cell stages, including early stages for the first time, using magnetic levitation.
We quantified height distributions of erythrocyte populations ring-stage synchronized samples and 35 uninfected controls-and quantified their unique biophysical signatures.
This platform can thus enable multidimensional biophysical measurements on unique cell types. Invasion of human erythrocytes by the malaria parasite Plasmodium falciparum is a multi-step process. Previously, a forward genetic screen for P. Pre-invasion kinetics, erythrocyte deformability, and echinocytosis were not influenced by CD55, but entry was inhibited when CD55 was blocked or absent.
Our findings demonstrate that CD55 acts after discharge of the parasite's rhoptry organelles, and plays a unique role relative to all other invasion receptors.
As the requirement for CD55 is strain-transcendent, these results suggest that CD55 or its interacting partners may hold potential as therapeutic targets for malaria. Mitochondrial dysfunction results in an imbalance between energy supply and demand in a failing heart. An innovative therapy that targets the intracellular bioenergetics directly through mitochondria transfer may be necessary.
The purpose of this study was to establish a preclinical proof-of-concept that extracellular vesicle EV -mediated transfer of autologous mitochondria and their related energy source enhance cardiac function through restoration of myocardial bioenergetics. Human-induced pluripotent stem cell-derived cardiomyocytes iCMs were employed. Electron microscopy revealed healthy-shaped mitochondria inside M-EVs. Confocal microscopy showed that M-EV-derived mitochondria were transferred into the recipient iCMs and fused with their endogenous mitochondrial networks.
Treatment with 1. Finally, intramyocardial injection of 1. M-EVs facilitated immediate transfer of their mitochondrial and nonmitochondrial cargos, contributing to improved intracellular energetics in vitro.
This therapy can be developed as a novel, precision therapeutic for mitochondria-related diseases including heart failure. Anthracycline-induced cardiomyopathy AIC is a significant source of morbidity and mortality in cancer survivors.
Malaria caused by the apicomplexan parasite Plasmodium falciparum has served as a strong evolutionary force throughout human history, selecting for red blood cell polymorphisms that confer innate protection against severe disease. Recently, gain-of-function mutations in the mechanosensitive ion channel PIEZO1 were shown to ameliorate Plasmodium parasite growth, blood-brain barrier dysfunction, and mortality in a mouse model of malaria.
In humans, the gain-of-function allele PIEZO1 Edel is highly prevalent and enriched in Africans, raising the possibility that it is under positive selection due to malaria. Here we used a case-control study design to test for an association between PIEZO1 Edel and malaria severity among children in Gabon.
We found that the Edel variant is strongly associated with protection against severe malaria in heterozygotes. In subjects with sickle cell trait, heterozygosity for PIEZO1 Edel did not confer additive protection and homozygosity was associated with an elevated risk of severe disease, suggesting an epistatic relationship between hemoglobin S and PIEZO1 Edel.
Using donor blood samples, we show that red cells heterozygous for PIEZO1 Edel are not dehydrated and can support the intracellular growth of P. However, surface expression of the P.
Our findings demonstrate that PIEZO1 is an important innate determinant of malaria susceptibility in humans and suggest that the mechanism of protection may be related to impaired export of P. Severe malaria is caused by the Apicomplexan parasite Plasmodium falciparum, and results in significant global morbidity and mortality, particularly among young children and pregnant women.
Since erythrocytes are enucleated and lack DNA, genetic approaches to understand erythrocyte determinants of malaria infection have historically been limited. This review highlights recent advances in the use of hematopoietic stem cells to facilitate genetic screening for malaria host factors.
While challenges still exist, this approach holds promise for gaining new insights into host-pathogen interactions in malaria. Lan null individuals are asymptomatic, and the function of ABCB6 in mature erythrocytes is not understood. Here, we assessed ABCB6 as a host factor for Plasmodium falciparum malaria parasites during erythrocyte invasion.
We show that Lan null erythrocytes are highly resistant to invasion by P. Although both Lan null and Jr a- erythrocytes harbor excess porphyrin, only Lan null erythrocytes exhibit a P. Further, the zoonotic parasite P. Using tandem mass tag-based proteomics, we find that the only consistent difference in membrane proteins between Lan null and control cells is absence of ABCB6.
Last Name. Share this page. Follow Ballotpedia. Click here to follow election results! Report an officeholder change. Egan assumed office on January 4, Egan's current term ends on January 4, Egan won election for judge of the Superior Court of Fresno County in California outright in the primary on March 3, , after the general election was canceled.
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