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Genetic architecture of subcortical brain structures in 38,851 individuals
Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for
Drosophila
orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.
Journal Article
Community Health Centers
The aftermath of Hurricane Katrina has placed a national spotlight on the shameful state of healthcare for America's poor. In the face of this highly publicized disaster, public health experts are more concerned than ever about persistent disparities that result from income and race.This book tells the story of one groundbreaking approach to medicine that attacks the problem by focusing on the wellness of whole neighborhoods. Since their creation during the 1960s, community health centers have served the needs of the poor in the tenements of New York, the colonias of Texas, the working class neighborhoods of Boston, and the dirt farms of the South. As products of the civil rights movement, the early centers provided not only primary and preventive care, but also social and environmental services, economic development, and empowerment.Bonnie Lefkowitz-herself a veteran of community health administration-explores the program's unlikely transformation from a small and beleaguered demonstration effort to a network of close to a thousand modern health care organizations serving nearly 15 million people. In a series of personal accounts and interviews with national leaders and dozens of health care workers, patients, and activists in five communities across the United States, she shows how health centers have endured despite cynicism and inertia, the vagaries of politics, and ongoing discrimination.
eBook
Infection-induced plasmablasts are a nutrient sink that impairs humoral immunity to malaria
Plasmodium
parasite–specific antibodies are critical for protection against malaria, yet the development of long-lived and effective humoral immunity against
Plasmodium
takes many years and multiple rounds of infection and cure. Here, we report that the rapid development of short-lived plasmablasts during experimental malaria unexpectedly hindered parasite control by impeding germinal center responses. Metabolic hyperactivity of plasmablasts resulted in nutrient deprivation of the germinal center reaction, limiting the generation of memory B cell and long-lived plasma cell responses. Therapeutic administration of a single amino acid to experimentally infected mice was sufficient to overcome the metabolic constraints imposed by plasmablasts and enhanced parasite clearance and the formation of protective humoral immune memory responses. Thus, our studies not only challenge the current model describing the role and function of blood-stage
Plasmodium
-induced plasmablasts but they also reveal new targets and strategies to improve anti-
Plasmodium
humoral immunity.
Early humoral responses to malaria fail to induce durable protective antibodies. Butler and colleagues report that low-affinity, short-lived plasmablasts become nutrient sinks for glutamine and starve germinal center B and T cells, thereby reducing the generation of high-affinity B cells and long-lived plasma cells and memory B cells.
Journal Article
