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Immunity Aug 2023Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have...
Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have been intensively investigated but are still not fully understood as their phenotypes, especially in the DC2 lineage and the recently described human DC3s, overlap with monocytes. Here, using LEGENDScreen to profile DC vs. monocyte lineages, we found sustained expression of FLT3 and CD45RB through the whole DC lineage, allowing DCs and their precursors to be distinguished from monocytes. Using fate mapping models, single-cell RNA sequencing and adoptive transfer, we identified a lineage of murine CD16/32CD172a DC3, distinct from DC2, arising from Ly6C monocyte-DC progenitors (MDPs) through Lyz2Ly6CCD11c pro-DC3s, whereas DC2s develop from common DC progenitors (CDPs) through CD7Ly6CCD11c pre-DC2s. Corresponding DC subsets, developmental stages, and lineages exist in humans. These findings reveal DC3 as a DC lineage phenotypically related to but developmentally different from monocytes and DC2s.
Topics: Mice; Humans; Animals; Monocytes; Stem Cells; Phenotype; Cells, Cultured; Dendritic Cells; Cell Differentiation
PubMed: 37506694
DOI: 10.1016/j.immuni.2023.07.001 -
Journal of the American Academy of... Jan 2024As children age, there are set milestones that we follow clinically to help track fine motor, gross motor, social, and language development. Because we know what a...
As children age, there are set milestones that we follow clinically to help track fine motor, gross motor, social, and language development. Because we know what a 2-month-old vs 4-month-old vs 1-year-old child should be able to do, we are able to assess whether a given child is on track developmentally. In pediatrics, three developmental stages are assessed and, if, behind there is a clear next step, often to involve early intervention. In child psychiatry, work has been done to establish stages of development as well, seen through the work of Piaget, Erickson, and others. These stages help to define the thoughts and behaviors expected for different-aged children, and thus can help with putting together our diagnostic formulation. The difficulty is that these stages are much broader temporally then the early motor, social, and language developmental milestones. Students may also be participating in the same experiences, such as the same grade level, even though they are at different developmental levels based on their age when they started school, as there could be as much as a year difference between those in a given grade. This has led to concerns about being able to distinguish a child struggling with attention-deficit/hyperactivity disorder (ADHD) relative to a child who is younger than his peers, as teachers may compare a young child to their older peers when filling out assessment forms. These are the developmental questions that we often must ponder as child psychiatrists, inasmuch as mental health and behavioral development are complex and influenced by many factors. In this month's Book Forum, Rishab Chawla looks more into these questions in the review of Nasty, Brutish and Short by Scott Hershovitz, pointing out that there is an overlap between the skills of a child psychiatrist to assess the behavioral impact of these developmental questions and the philosophical questions that younger children start to ponder. The child's developmental understanding of right and wrong will better help us to assess the behaviors that present to us in the office. As Rishab points out in the review, we must ask more about these children whom we see regarding these philosophical questions to better understand some of the behaviors present. Looking more deeply into a student's understanding of these questions may better help us to distinguish developmentally appropriate or inappropriate behaviors.
Topics: Child; Humans; Aged; Infant; Attention Deficit Disorder with Hyperactivity; Schools; Mental Health; Peer Group
PubMed: 37805068
DOI: 10.1016/j.jaac.2023.09.542 -
Drug Resistance Updates : Reviews and... Sep 2023We investigated the stage-specific mechanisms of partial resistance to artemisinin (ART, an antimalarial drug) in Plasmodium falciparum (P. falciparum) carrying the...
AIMS
We investigated the stage-specific mechanisms of partial resistance to artemisinin (ART, an antimalarial drug) in Plasmodium falciparum (P. falciparum) carrying the Kelch13 C580Y mutation.
METHODS
Using fluorescence labeling and activity-based protein profiling, we systematically profile the ART activation levels in P. falciparum during the entire intra-erythrocytic developmental cycle (IDC), and determined the ART-targets profile of the ART-sensitive and -resistant strains at different stages. We retrieved and integrated datasets of single-cell transcriptomics and label-free proteomics across three IDC stages of wild-type P. falciparum. We also employed lipidomics to validate lipid metabolic reprogramming in the resistant strain.
RESULTS
The activation and expression patterns of genes and proteins of ART-targets in both ART-sensitive and resistant strains varied at different stages and periods of P. falciparum development, with the late trophozoite stage harboring the largest number of ART targets. We identified and validated 36 overlapping targets, such as GAPDH, EGF-1a, and SpdSyn, during the IDC stages in both strains. We revealed the ART-insensitivity of fatty acid-associated activities in the partially resistant strain at both the early ring and early trophozoite stages.
CONCLUSIONS
Our multi-omics strategies provide novel insights into the mechanisms of ART partial resistance in Kelch13 mutant P. falciparum, demonstrating the stage-specific interaction between ART and malaria parasites.
Topics: Humans; Plasmodium falciparum; Multiomics; Drug Resistance; Protozoan Proteins; Artemisinins; Antimalarials; Malaria, Falciparum; Mutation
PubMed: 37385107
DOI: 10.1016/j.drup.2023.100978 -
Trends in Parasitology Feb 2024Malaria is a life-threatening tropical disease caused by parasites of the genus Plasmodium, of which Plasmodium falciparum is the most lethal. Malaria parasites have a... (Review)
Review
Malaria is a life-threatening tropical disease caused by parasites of the genus Plasmodium, of which Plasmodium falciparum is the most lethal. Malaria parasites have a complex life cycle, with stages occurring in both the Anopheles mosquito vector and human host. Ring stages are the youngest form of the parasite in the intraerythrocytic developmental cycle and are associated with evasion of spleen clearance, temporary growth arrest (TGA), and drug resistance. This formidable ability to survive and develop into mature, sexual, or growth-arrested forms demonstrates the inherent population heterogeneity. Here we highlight the role of the ring stage as a crossroads in parasite development and as a reservoir of surviving cells in the human host via TGA survival mechanisms.
Topics: Animals; Humans; Antimalarials; Drug Resistance; Life Cycle Stages; Malaria; Malaria, Falciparum; Plasmodium falciparum
PubMed: 38104024
DOI: 10.1016/j.pt.2023.11.007 -
Cells Jul 2023In this review, advances in the understanding of epigenetic reprogramming from fertilization to the development of primordial germline cells in a mouse and embryo are... (Review)
Review
In this review, advances in the understanding of epigenetic reprogramming from fertilization to the development of primordial germline cells in a mouse and embryo are discussed. To gain insights into the molecular underpinnings of various diseases, it is essential to comprehend the intricate interplay between genetic, epigenetic, and environmental factors during cellular reprogramming and embryonic differentiation. An increasing range of diseases, including cancer and developmental disorders, have been linked to alterations in DNA methylation and histone modifications. Global epigenetic reprogramming occurs in mammals at two stages: post-fertilization and during the development of primordial germ cells (PGC). Epigenetic reprogramming after fertilization involves rapid demethylation of the paternal genome mediated through active and passive DNA demethylation, and gradual demethylation in the maternal genome through passive DNA demethylation. The de novo DNA methyltransferase enzymes, and , restore DNA methylation beginning from the blastocyst stage until the formation of the gastrula, and DNA maintenance methyltransferase, , maintains methylation in the somatic cells. The PGC undergo a second round of global demethylation after allocation during the formative pluripotent stage before gastrulation, where the imprints and the methylation marks on the transposable elements known as retrotransposons, including long interspersed nuclear elements (LINE-1) and intracisternal A-particle (IAP) elements are demethylated as well. Finally, DNA methylation is restored in the PGC at the implantation stage including sex-specific imprints corresponding to the sex of the embryo. This review introduces a novel perspective by uncovering how toxicants and stress stimuli impact the critical period of allocation during formative pluripotency, potentially influencing both the quantity and quality of PGCs. Furthermore, the comprehensive comparison of epigenetic events between and breaks new ground, empowering researchers to make informed decisions regarding the suitability of mouse models for their experiments.
Topics: Male; Female; Humans; Mice; Animals; Epigenesis, Genetic; Cell Differentiation; Germ Cells; Fertilization; DNA; Mammals
PubMed: 37508536
DOI: 10.3390/cells12141874 -
The Journal of Neuroscience : the... Nov 2023Environmentally appropriate social behavior is critical for survival across the lifespan. To support this flexible behavior, the brain must rapidly perform numerous... (Review)
Review
Environmentally appropriate social behavior is critical for survival across the lifespan. To support this flexible behavior, the brain must rapidly perform numerous computations taking into account sensation, memory, motor-control, and many other systems. Further complicating this process, individuals must perform distinct social behaviors adapted to the unique demands of each developmental stage; indeed, the social behaviors of the newborn would not be appropriate in adulthood and vice versa. However, our understanding of the neural circuit transitions supporting these behavioral transitions has been limited. Recent advances in neural circuit dissection tools, as well as adaptation of these tools for use at early time points, has helped uncover several novel mechanisms supporting developmentally appropriate social behavior. This review, and associated Minisymposium, bring together social neuroscience research across numerous model organisms and ages. Together, this work highlights developmentally regulated neural mechanisms and functional transitions in the roles of the sensory cortex, prefrontal cortex, amygdala, habenula, and the thalamus to support social interaction from infancy to adulthood. These studies underscore the need for synthesis across varied model organisms and across ages to advance our understanding of flexible social behavior.
Topics: Infant, Newborn; Humans; Social Behavior; Amygdala; Prefrontal Cortex; Brain
PubMed: 37940586
DOI: 10.1523/JNEUROSCI.1377-23.2023