Biology subjects

Freedman, E.

Publications and source records attributed to Freedman, E..

7 recordsLinked to original sources

bioRxiv2026

Neural and Gait Adaptations to Dual-Task Demands in Children and Young Adults: A Mobile Brain-Body Imaging (MoBI) Study.

Cognitive-motor interactions describe the complex interplay underlying how the brain manages concurrent demands on motor and cognitive processing. Yet, how cognitive-motor interactions present across childhood and young adulthood remains understudied, particularly through multi-modal methods which include neurophysiology. We investigated development of cognitive-motor interactions using a dual-task study design including simultaneous motor (walking) and cognitive (visual Go-NoGo) tasks. Using mobile brain-body imaging, (MoBI), we recorded simultaneous EEG, gait kinematics, and task performance. 61 neurotypical 8-to-30-year-olds completed the Go-NoGo while seated or walking on a treadmill. With increased age, participants became faster and more accurate on the task, walking became less variable, and N200 and P300 ERP amplitudes increased. Two distinct effects of cognitive-motor interactions emerged with age. An N200 amplitude attenuation when walking became exaggerated with age, suggesting older participants engaged greater neurophysiological flexibility to support their improved task performances, whereas children performed less well and may not have needed to recruit the same adaptive neural mechanisms. Additionally, an attenuation of stride variability during dual-task walking lessened with age, demonstrating robust motor development under dual-task conditions. These findings demonstrate a distinct pattern of changes to cognitive-motor interactions through development. Future research can examine how this pattern varies in different developmental conditions.

neuroscience↗

bioRxiv2025

Organelle Development and Inheritance are Driven by Independent Nuclear and Organellar Mechanisms in Malaria Parasites

The apicoplast organelle of Plasmodium falciparum is essential for parasites replication, however the details of its biogenesis, inheritance and regulation throughout the cell cycle are unknown. Here, we report the development of a dynamic imaging platform coupled with an analytical pipeline that enables us to follow and measure subcellular structures throughout the 48-hour cell cycle of live parasites. We reveal a predetermined sequence of four discrete morphological steps in organelle development, which are tightly correlated with nuclear replication. We show that one of these steps, which we term the Crown morphology, is required for nucleus-apicoplast attachment. During Crown, apicoplast is stretched over multiple nuclei, fastened by centriolar tubulin. A complementary molecular approach was used to discover the basic ploidy of apicoplast and mitochondrial genomes, their replication rates and association with nuclear DNA replication. We inhibited nuclear DNA replication and found that it completely blocks apicoplast biogenesis in its most initial stages, demonstrating dependency on S-phase initiation. Conversely, specific inhibition of apicoplast genome replication resulted in an almost-undisturbed organelle development and division. However, it affected the Crown step, preventing association to tubulin-nuclear structures, leading to failure in accurate organelle sorting into daughter cells. Collectively, these experiments reveal a central cellular pathway linking apicoplast development to the parasites cell cycle, and a second independent organellar mechanism responsible for segregation into daughter cells.

microbiology↗

bioRxiv2024

Brain-body circuit by which midbrain dopamine neuronal activity modulates splenic immunity

Midbrain dopamine neurons are well-known to shape central nervous system function, yet there is growing evidence for their influence on the peripheral immune system. Here we demonstrate that midbrain dopamine neurons form a circuit to the spleen via a multi-synaptic pathway from the dorsal vagal complex (DVC) through the celiac ganglion. Midbrain dopamine neurons modulate the activity of D1- and D2-like dopamine receptor-expressing DVC neurons. In vivo activation of midbrain dopamine neurons induced dopamine release in the DVC and increased immediate early gene expression in both the DVC and celiac ganglion. Activation of this midbrain-to-spleen circuit reduced spleen weight and decreased naive CD4+ T-cell populations without affecting total T-cell numbers. These findings unveil a functional midbrain- DVC-celiac ganglion-spleen pathway, through which midbrain dopamine neurons modulate splenic immunity. These novel insights into the neural regulation of the immune system have important implications for diseases involving altered dopamine neurotransmission and highlight potential targets for immunotherapeutic interventions.

neuroscience↗

bioRxiv2022

Plasmodium falciparum genetic diversity in coincident human and mosquito hosts

Population genetic diversity of P. falciparum antigenic loci is high despite large bottlenecks in population size during the parasite life cycle. The extent of this diversity in human blood-stage infections, following expansion from a small number of liver-stage schizonts, has been well described. However, little is known about parasite genetic diversity in the vector, where a similar bottleneck and expansion occurs following parasite mating and where parasite genotypes from several different human infections may accumulate. We assessed parasite genetic diversity within human and mosquito P. falciparum infections collected from the same households during a 14-month longitudinal cohort study using amplicon deep sequencing of two antigenic gene fragments (ama1 and csp). To a prior set of infected humans (n=1175/2813; 86.2% sequencing success) and mosquito abdomens (n=199/1448; 95.5% sequencing success), we added sequences from infected mosquito heads (n=134/1448; 98.5% sequencing success). Across all sample types we observed 456 ama1 and 289 csp unique haplotypes. While both hosts contained many rare haplotypes, population genetic metrics indicated that the overall and sample-level parasite populations were more diverse in mosquitoes than in humans, and infections were more likely to harbor a dominant haplotype in humans than in mosquitoes (based on relative read abundance). Finally, within a given mosquito there was little overlap in genetic composition of abdomen and head infections, suggesting that infections may be cleared from the abdomen during a mosquitos lifespan. Taken together, our observations provide evidence for the role of the mosquito vector in maintaining sequence diversity of malaria parasite populations. Significance statementConcurrent infections with multiple strains of Plasmodium falciparum, the leading causative agent of death due to malaria, are common in highly endemic regions. During transitions within and between the parasites mosquito and human hosts, population bottlenecks occur, and distinct parasite strains may have differential fitness in the various environments encountered. These bottlenecks and fitness differences may lead to differences in strain prevalence and diversity between hosts. We investigated differences in genetic diversity between P. falciparum parasites in human and mosquito hosts and found that, compared to human parasite populations and infections, mosquito populations and infections were more diverse. This suggests that the mosquito vector may play a role in in maintaining sequence diversity in malaria parasite populations.

microbiology↗

bioRxiv2021

Impact of sickle cell trait hemoglobin on the intraerythrocytic transcriptional program of Plasmodium falciparum

Sickle-trait hemoglobin (HbAS) confers near-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 parasites 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 Maurers 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. ImportanceSickle-trait hemoglobin (HbAS) confers near-complete protection from severe, life-threatening malaria, yet the molecular mechanisms that underlie HbAS protection from severe malaria remain incompletely understood. Here, we use 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. falciparums 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.

genetics↗

bioRxiv2019

High-resolution micro-epidemiology of parasite spatial and temporal dynamics in a high malaria transmission setting in Kenya

Novel interventions that leverage the heterogeneity of parasite transmission are needed to push malaria further towards elimination. To better understand spatial and temporal dynamics of transmission, we applied amplicon NGS of two polymorphic gene regions (csp and ama1) to a cohort identified via reactive case detection in a high-transmission setting in western Kenya. From 4/2013-6/2014, we enrolled 442 symptomatic children with malaria, 442 matched controls, and all household members of both groups. We evaluated genetic similarity between infected individuals using three novel indices: sharing of parasite haplotypes on binary and proportional scales and the L1 norm. Symptomatic children more commonly shared haplotypes with their own household members. Furthermore, we identified robust temporal structuring of parasite genetic similarity that we exploited to identify the molecular signature of an outbreak. These findings of both micro- and macro-scale organization of parasite populations might be harnessed to inform next-generation malaria control measures.

microbiology↗

bioRxiv2019

Auditory sensory memory span for duration is severely curtailed in females with Rett Syndrome.

Rett syndrome (RTT), a rare neurodevelopmental disorder caused by mutations in the MECP2 gene, is typified by profound cognitive impairment and severe language impairment, rendering it very difficult to accurately measure auditory processing capabilities behaviorally in this population. Here we leverage the mismatch negativity (MMN) component of the event-related potential to measure the ability of RTT patients to decode and store occasional duration deviations in a stream of auditory stimuli. Sensory memory for duration, crucial for speech comprehension, has not been studied in RTT.\n\nHigh-density EEG was successfully recorded in 18 females with RTT and 27 age-matched typically developing (TD) controls (aged 6-22 years). Data from 7 RTT and 3 TD participants were excluded for excessive noise. Stimuli were 1kHz tones with a standard duration of 100ms and deviant duration of 180ms. To assess the sustainability of sensory memory, stimulus presentation rate was varied with stimulus onset asynchronies (SOAs) of 450, 900 and 1800ms. MMNs with maximum negativity over fronto-central scalp and a latency of 220-230ms were clearly evident for each presentation rate in the TD group, but only for the shortest SOA in the RTT group. Repeated-measures ANOVA revealed a significant group by SOA interaction. MMN amplitude correlated with age in the TD group only. MMN amplitude was not correlated with the Rett Syndrome Severity Scale. This study indicates that while RTT patients can decode deviations in auditory duration, the span of this sensory memory system is severely foreshortened, with likely implications for speech decoding abilities.

neuroscience↗