Impact of Sickle Cell Trait Hemoglobin on the Intraerythrocytic Transcriptional Program of Plasmodium falciparum.

Sickle-trait hemoglobin (HbAS) confers nearly complete protection from severe, life-threatening falciparum malaria in African children. Despite this clear protection, the molecular mechanisms by which HbAS confers these protective phenotypes remain incompletely understood. As a forward genetic screen for aberrant parasite transcriptional responses associated with parasite neutralization in HbAS red blood cells (RBCs), we performed comparative transcriptomic analyses of Plasmodium falciparum in normal (HbAA) and HbAS erythrocytes during both in vitro cultivation of reference parasite strains and naturally occurring P. falciparum infections in Malian children with HbAA or HbAS. During in vitro cultivation, parasites matured normally in HbAS RBCs, and the temporal expression was largely unperturbed of the highly ordered transcriptional program that underlies the parasite's maturation throughout the intraerythrocytic development cycle (IDC). However, differential expression analysis identified hundreds of transcripts aberrantly expressed in HbAS, largely occurring late in the IDC. Surprisingly, transcripts encoding members of the Maurer's clefts were overexpressed in HbAS despite impaired parasite protein export in these RBCs, while parasites in HbAS RBCs underexpressed transcripts associated with the endoplasmic reticulum and those encoding serine repeat antigen proteases that promote parasite egress. Analyses of P. falciparum transcriptomes from 32 children with uncomplicated malaria identified stage-specific differential expression: among infections composed of ring-stage parasites, only cyclophilin 19B was underexpressed in children with HbAS, while trophozoite-stage infections identified a range of differentially expressed transcripts, including downregulation in HbAS of several transcripts associated with severe malaria in collateral studies. Collectively, our comparative transcriptomic screen in vitro and in vivo indicates that P. falciparum adapts to HbAS by altering its protein chaperone and folding machinery, oxidative stress response, and protein export machinery. Because HbAS consistently protects from severe P. falciparum, modulation of these responses may offer avenues by which to neutralize P. falciparum parasites. IMPORTANCE Sickle-trait hemoglobin (HbAS) confers nearly complete protection from severe, life-threatening malaria, yet the molecular mechanisms that underlie HbAS protection from severe malaria remain incompletely understood. Here, we used transcriptome sequencing (RNA-seq) to measure the impact of HbAS on the blood-stage transcriptome of Plasmodium falciparum in in vitro time series experiments and in vivo samples from natural infections. Our in vitro time series data reveal that, during its blood stage, P. falciparum's gene expression in HbAS is impacted primarily through alterations in the abundance of gene products as opposed to variations in the timing of gene expression. Collectively, our in vitro and in vivo data indicate that P. falciparum adapts to HbAS by altering its protein chaperone and folding machinery, oxidative stress response, and protein export machinery. Due to the persistent association of HbAS and protection from severe disease, these processes that are modified in HbAS may offer strategies to neutralize P. falciparum.

Yoga led by a physical therapist for individuals with Essential Tremor: An explorative pilot study.

PURPOSE: The purpose of this pilot study is to evaluate the outcomes for individuals with Essential Tremor (ET) who participate in a community-based yoga class, led by a neurologic physical therapist. METHODS: Six subjects with ET completed an 8-week intervention consisting of weekly 1-h yoga classes (in the Vinyasa style) guided by an instructor (200-h registered yoga teacher, physical therapist, and neurological resident). RESULTS: Five subjects demonstrated improvements on the Tremor Research Group Essential Tremor Rating Scale (mean 15.3%, range 8.3-34.7%). The mean improvement on the Fullerton Advanced Balance Scale was 10.8% (range 2.5-20%). Five subjects maintained pre-intervention anxiety levels ("very low") while one reported increased anxiety secondary to a non-study related factor. Minimal improvements were noted in the McGill Quality of Life Questionnaire. CONCLUSION: This pilot study offers support for further examining the benefits of integration of yoga into an exercise program for individuals with ET and specific suggestions for future research are offered. There were no adverse events with participation in yoga.

Source genotype influence on cross species transmission of transmissible spongiform encephalopathies evaluated by RT-QuIC.

Scrapie is a naturally occurring transmissible spongiform encephalopathy of sheep and goats. This fatal neurodegenerative disease is caused by misfolding of the cellular prion protein to pathogenic ß-rich conformers (PrPSc) that accumulate in higher order structures of the brain and other tissues. This conversion has been used for in vitro assays including serial protein misfolding amplification and real-time quaking induced conversion (RT-QuIC). RT-QuIC can be used for the detection of prions and for strain discrimination in a variety of biological tissues from humans and animals. In this study, we evaluated how PrPSc isolated from sheep of different genotypes after inoculation with the scrapie agent influence the fibril formation in vitro using RT-QuIC. We found that reaction mixtures seeded with PrPSc from genotype VRQ/VRQ sheep brains have better conversion efficiency with 132M elk substrate compared to reactions seeded with PrPSc from the brains of sheep with the ARQ/ARQ genotype no matter which strain of scrapie was used to seed the reactions. We also inoculated transgenic mice expressing 132M elk PRNP (Tg12) with the scrapie agent from different genotypes of sheep to compare with our RT-QuIC results. The bioassays support the data showing a significantly shorter incubation period for inoculum from VRQ/VRQ sheep when compared to inoculum from ARQ/ARQ sheep. Thus, we conclude that the genotype of both source and recipient can strongly influence transmission.

Social dominance in preschool classrooms.

The authors examined preschoolers' aggressive and cooperative behaviors and their associations with social dominance. First and as predicted, directly observed aggressive interactions decreased across the school year, and same-sex aggression occurred more frequently than cross-sex aggression. Next, the authors examined the relation between aggression and reconciliation, cooperation, and social display variables. Teacher ratings of children's aggression related to observed aggression but not to observed "wins" of aggressive bouts. Instead, wins were related to cooperation and display variables. Finally, they examined the relative power of wins and cooperation in predicting 2 measures of social dominance. After age was controlled, wins alone predicted teacher-rated social dominance. Results are discussed in terms of different forms of competition and how school ethos affects these forms.