Human erythroid progenitors express antigen presentation machinery.

Early-life immune exposures can profoundly impact lifelong health. However, functional mechanisms underlying fetal immune development remain incomplete. Erythrocytes are not typically considered active immune mediators, primarily because erythroid precursors discard their organelles as they mature, thus losing the ability to alter gene expression in response to stimuli. Erythroid progenitors and precursors circulate in human fetuses and neonates. Although there is limited evidence that erythroid precursors are immunomodulatory, our understanding of the underlying mechanisms remains inadequate. To define the immunobiological role of fetal and perinatal erythroid progenitors and precursors, we analyzed single cell RNA-sequencing data and found that transcriptomics support erythroid progenitors as putative immune mediators. Unexpectedly, we discovered that human erythroid progenitors constitutively express Major Histocompatibility Complex (MHC) class II antigen processing and presentation machinery, which are hallmarks of specialized antigen presenting immune cells. Furthermore, we demonstrate that erythroid progenitors internalize and cleave foreign proteins into peptide antigens. Unlike conventional antigen presenting cells, erythroid progenitors express atypical costimulatory molecules and immunoregulatory cytokines that direct the development of regulatory T cells, which are critical for establishing maternal-fetal tolerance. Expression of MHC II in definitive erythroid progenitors begins during the second trimester, coinciding with the appearance of mature T cells in the fetus, and is absent in primitive progenitors. Lastly, we demonstrate physical and molecular interaction potential of erythroid progenitors and T cells in the fetal liver. Our findings shed light on a unique orchestrator of fetal immunity and provide insight into the mechanisms by which erythroid cells contribute to host defense.

Human red blood cells express the RNA sensor TLR7.

Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs.

Simultaneous cortical, subcortical, and brainstem mapping of sensory activation.

Nonpainful tactile sensory stimuli are processed in the cortex, subcortex, and brainstem. Recent functional magnetic resonance imaging studies have highlighted the value of whole-brain, systems-level investigation for examining sensory processing. However, whole-brain functional magnetic resonance imaging studies are uncommon, in part due to challenges with signal to noise when studying the brainstem. Furthermore, differentiation of small sensory brainstem structures such as the cuneate and gracile nuclei necessitates high-resolution imaging. To address this gap in systems-level sensory investigation, we employed a whole-brain, multi-echo functional magnetic resonance imaging acquisition at 3T with multi-echo independent component analysis denoising and brainstem-specific modeling to enable detection of activation across the entire sensory system. In healthy participants, we examined patterns of activity in response to nonpainful brushing of the right hand, left hand, and right foot (n = 10 per location), and found the expected lateralization, with distinct cortical and subcortical responses for upper and lower limb stimulation. At the brainstem level, we differentiated the adjacent cuneate and gracile nuclei, corresponding to hand and foot stimulation respectively. Our findings demonstrate that simultaneous cortical, subcortical, and brainstem mapping at 3T could be a key tool to understand the sensory system in both healthy individuals and clinical cohorts with sensory deficits.

Simultaneous cortical, subcortical, and brainstem mapping of sensory activation.

Non-painful tactile sensory stimuli are processed in the cortex, subcortex, and brainstem. Recent functional magnetic resonance imaging (fMRI) studies have highlighted the value of whole-brain, systems-level investigation for examining pain processing. However, whole-brain fMRI studies are uncommon, in part due to challenges with signal to noise when studying the brainstem. Furthermore, the differentiation of small sensory brainstem structures such as the cuneate and gracile nuclei necessitates high resolution imaging. To address this gap in systems-level sensory investigation, we employed a whole-brain, multi-echo fMRI acquisition at 3T with multi-echo independent component analysis (ME-ICA) denoising and brainstem-specific modeling to enable detection of activation across the entire sensory system. In healthy participants, we examined patterns of activity in response to non-painful brushing of the right hand, left hand, and right foot, and found the expected lateralization, with distinct cortical and subcortical responses for upper and lower limb stimulation. At the brainstem level, we were able to differentiate the small, adjacent cuneate and gracile nuclei, corresponding to hand and foot stimulation respectively. Our findings demonstrate that simultaneous cortical, subcortical, and brainstem mapping at 3T could be a key tool to understand the sensory system in both healthy individuals and clinical cohorts with sensory deficits.

Acute effects of high-intensity exercise on brain mechanical properties and cognitive function.

Previous studies have shown that engagement in even a single session of exercise can improve cognitive performance in the short term. However, the underlying physiological mechanisms contributing to this effect are still being studied. Recently, with improvements to advanced quantitative neuroimaging techniques, brain tissue mechanical properties can be sensitively and noninvasively measured with magnetic resonance elastography (MRE) and regional brain mechanical properties have been shown to reflect individual cognitive performance. Here we assess brain mechanical properties before and immediately after engagement in a high-intensity interval training (HIIT) regimen, as well as one-hour post-exercise. We find that immediately after exercise, subjects in the HIIT group had an average global brain stiffness decrease of 4.2% (p < 0.001), and an average brain damping ratio increase of 3.1% (p = 0.002). In contrast, control participants who did not engage in exercise showed no significant change over time in either stiffness or damping ratio. Changes in brain mechanical properties with exercise appeared to be regionally dependent, with the hippocampus decreasing in stiffness by 10.4%. We also found that one-hour after exercise, brain mechanical properties returned to initial baseline values. The magnitude of changes to brain mechanical properties also correlated with improvements in reaction time on executive control tasks (Eriksen Flanker and Stroop) with exercise. Understanding the neural changes that arise in response to exercise may inform potential mechanisms behind improvements to cognitive performance with acute exercise.

Mechanical Property Based Brain Age Prediction using Convolutional Neural Networks.

Brain age is a quantitative estimate to explain an individual's structural and functional brain measurements relative to the overall population and is particularly valuable in describing differences related to developmental or neurodegenerative pathology. Accurately inferring brain age from brain imaging data requires sophisticated models that capture the underlying age-related brain changes. Magnetic resonance elastography (MRE) is a phase contrast MRI technology that uses external palpations to measure brain mechanical properties. Mechanical property measures of viscoelastic shear stiffness and damping ratio have been found to change across the entire life span and to reflect brain health due to neurodegenerative diseases and even individual differences in cognitive function. Here we develop and train a multi-modal 3D convolutional neural network (CNN) to model the relationship between age and whole brain mechanical properties. After training, the network maps the measurements and other inputs to a brain age prediction. We found high performance using the 3D maps of various mechanical properties to predict brain age. Stiffness maps alone were able to predict ages of the test group subjects with a mean absolute error (MAE) of 3.76 years, which is comparable to single inputs of damping ratio (MAE: 3.82) and outperforms single input of volume (MAE: 4.60). Combining stiffness and volume in a multimodal approach performed the best, with an MAE of 3.60 years, whereas including damping ratio worsened model performance. Our results reflect previous MRE literature that had demonstrated that stiffness is more strongly related to chronological age than damping ratio. This machine learning model provides the first prediction of brain age from brain biomechanical data-an advancement towards sensitively describing brain integrity differences in individuals with neuropathology.

Identification of basal complex protein that is essential for maturation of transmission-stage malaria parasites.

Malaria remains a global driver of morbidity and mortality. To generate new antimalarials, one must elucidate the fundamental cell biology of Plasmodium falciparum, the parasite responsible for the deadliest cases of malaria. A membranous and proteinaceous scaffold called the inner membrane complex (IMC) supports the parasite during morphological changes, including segmentation of daughter cells during asexual replication and formation of transmission-stage gametocytes. The basal complex lines the edge of the IMC during segmentation and likely facilitates IMC expansion. It is unknown, however, what drives IMC expansion during gametocytogenesis. We describe the discovery of a basal complex protein, PfBLEB, which we find to be essential for gametocytogenesis. Parasites lacking PfBLEB harbor defects in IMC expansion and are unable to form mature gametocytes. This article demonstrates a role for a basal complex protein outside of asexual division, and, importantly, highlights a potential molecular target for the ablation of malaria transmission.

The ONETEP linear-scaling density functional theory program.

We present an overview of the onetep program for linear-scaling density functional theory (DFT) calculations with large basis set (plane-wave) accuracy on parallel computers. The DFT energy is computed from the density matrix, which is constructed from spatially localized orbitals we call Non-orthogonal Generalized Wannier Functions (NGWFs), expressed in terms of periodic sinc (psinc) functions. During the calculation, both the density matrix and the NGWFs are optimized with localization constraints. By taking advantage of localization, onetep is able to perform calculations including thousands of atoms with computational effort, which scales linearly with the number or atoms. The code has a large and diverse range of capabilities, explored in this paper, including different boundary conditions, various exchange-correlation functionals (with and without exact exchange), finite electronic temperature methods for metallic systems, methods for strongly correlated systems, molecular dynamics, vibrational calculations, time-dependent DFT, electronic transport, core loss spectroscopy, implicit solvation, quantum mechanical (QM)/molecular mechanical and QM-in-QM embedding, density of states calculations, distributed multipole analysis, and methods for partitioning charges and interactions between fragments. Calculations with onetep provide unique insights into large and complex systems that require an accurate atomic-level description, ranging from biomolecular to chemical, to materials, and to physical problems, as we show with a small selection of illustrative examples. onetep has always aimed to be at the cutting edge of method and software developments, and it serves as a platform for developing new methods of electronic structure simulation. We therefore conclude by describing some of the challenges and directions for its future developments and applications.

Viscoelasticity of reward and control systems in adolescent risk taking.

Heightened risk-taking tendencies during adolescence have been hypothesized to be attributable to physiological differences of maturation in key brain regions. The socioemotional system (e.g., nucleus accumbens), which is instrumental in reward response, shows a relatively earlier development trajectory than the cognitive control system (e.g., medial prefrontal cortex), which regulates impulse response. This developmental imbalance between heightened reward seeking and immature cognitive control potentially makes adolescents more susceptible to engaging in risky activities. Here, we assess brain structure in the socioemotional and cognitive control systems through viscoelastic stiffness measured with magnetic resonance elastography (MRE) and volumetry, as well as risk-taking tendencies measured using two experimental tasks in 40 adolescents (mean age â€‹= â€‹13.4 years old). MRE measures of regional brain stiffness reflect brain health and development via myelin content and glial matrix makeup, and have been shown to be highly sensitive to cognitive processes as compared to measures of regional brain volume and diffusion weighted imaging metrics. We find here that the viscoelastic and volumetric differences between the nucleus accumbens and the prefrontal cortex are correlated with increased risk-taking behavior in adolescents. These differences in development between the two brain systems can be used as an indicator of those adolescents who are more prone to real world risky activities and a useful measure for characterizing response to intervention.

A Novel Antiparasitic Compound Kills Ring-Stage Plasmodium falciparum and Retains Activity Against Artemisinin-Resistant Parasites.

Spreading antimalarial resistance threatens effective treatment of malaria, an infectious disease caused by Plasmodium parasites. We identified a compound, BCH070, that inhibits asexual growth of multiple antimalarial-resistant strains of Plasmodium falciparum (half maximal inhibitory concentration [IC50] = 1-2 µM), suggesting that BCH070 acts via a novel mechanism of action. BCH070 preferentially kills early ring-form trophozoites, and, importantly, equally inhibits ring-stage survival of wild-type and artemisinin-resistant parasites harboring the PfKelch13:C580Y mutation. Metabolomic analysis demonstrates that BCH070 likely targets multiple pathways in the parasite. BCH070 is a promising lead compound for development of new antimalarial combination therapy that retains activity against artemisinin-resistant parasites.

FoxO1 Is Required for Most of the Metabolic and Hormonal Perturbations Produced by Hepatic Insulin Receptor Deletion in Male Mice.

Insulin coordinates the complex response to feeding, affecting numerous metabolic and hormonal pathways. Forkhead box protein O1 (FoxO1) is one of several signaling molecules downstream of insulin; FoxO1 drives gluconeogenesis and is suppressed by insulin. To determine the role of FoxO1 in mediating other actions of insulin, we studied mice with hepatic deletion of the insulin receptor, FoxO1, or both. We found that mice with deletion of the insulin receptor alone showed not only hyperglycemia but also a 70% decrease in plasma insulin-like growth factor 1 and delayed growth during the first 2 months of life, a 24-fold increase in the soluble leptin receptor and a 19-fold increase in plasma leptin levels. Deletion of the insulin receptor also produced derangements in fatty acid metabolism, with a decrease in the expression of the lipogenic enzymes, hepatic diglycerides, and plasma triglycerides; in parallel, it increased expression of the fatty acid oxidation enzymes. Mice with deletion of both insulin receptor and FoxO1 showed a much more modest phenotype, with normal or near-normal glucose levels, growth, leptin levels, hepatic diglycerides, and fatty acid oxidation gene expression; however, lipogenic gene expression remained low. Taken together, these data reveal the pervasive role of FoxO1 in mediating the effects of insulin on not only glucose metabolism but also other hormonal signaling pathways and even some aspects of lipid metabolism.

Visual-motor association learning in undergraduate students as a function of the autism-spectrum quotient.

We examined how performance on an associative learning task changes in a sample of undergraduate students as a function of their autism-spectrum quotient (AQ) score. The participants, without any prior knowledge of the Japanese language, learned to associate hiragana characters with button responses. In the novel condition, 50 participants learned visual-motor associations without any prior exposure to the stimuli's visual attributes. In the familiar condition, a different set of 50 participants completed a session in which they first became familiar with the stimuli's visual appearance prior to completing the visual-motor association learning task. Participants with higher AQ scores had a clear advantage in the novel condition; the amount of training required reaching learning criterion correlated negatively with AQ. In contrast, participants with lower AQ scores had a clear advantage in the familiar condition; the amount of training required to reach learning criterion correlated positively with AQ. An examination of how each of the AQ subscales correlated with these learning patterns revealed that abilities in visual discrimination-which is known to depend on the visual ventral-stream system-may have afforded an advantage in the novel condition for the participants with the higher AQ scores, whereas abilities in attention switching-which are known to require mechanisms in the prefrontal cortex-may have afforded an advantage in the familiar condition for the participants with the lower AQ scores.