Sequential perturbations to mouse corticogenesis following in utero maternal immune activation.

In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time-course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates.

Background: Maternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through which MIA imparts risk remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for studying underlying molecular correlates.

Baseline immunoreactivity before pregnancy and poly(I:C) dose combine to dictate susceptibility and resilience of offspring to maternal immune activation.

Despite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, current approaches using these models ignore two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal viral infection and (ii) susceptible pregnancies can lead to different combinations of phenotypes in offspring. Here, we report two new sources of variability-the baseline immunoreactivity (BIR) of isogenic females prior to pregnancy and differences in immune responses in C57BL/6 dams across vendors-that contribute to resilience and susceptibility to distinct combinations of behavioral and biological outcomes in offspring. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all pregnancies and a combination of poly(I:C) dose and BIR predicts susceptibility and resilience of pregnancies to aberrant repetitive behaviors and alterations in striatal protein levels in offspring.

Increasing access to microfluidics for studying fungi and other branched biological structures.

Background: Microfluidic systems are well-suited for studying mixed biological communities for improving industrial processes of fermentation, biofuel production, and pharmaceutical production. The results of which have the potential to resolve the underlying mechanisms of growth and transport in these complex branched living systems. Microfluidics provide controlled environments and improved optical access for real-time and high-resolution imaging studies that allow high-content and quantitative analyses.

Brain, Immunity, Gut: "BIG" Links between Pregnancy and Autism.

Although dysregulation of brain, immune, and gut physiology during pregnancy have each been implicated in neuropsychiatric disorders, whether and how these presumably distinct systems are linked to cause disease is unclear. Kim et al. (2017) and Shin Yim et al.

Maternal immune activation: Implications for neuropsychiatric disorders.

Epidemiological evidence implicates maternal infection as a risk factor for autism spectrum disorder and schizophrenia. Animal models corroborate this link and demonstrate that maternal immune activation (MIA) alone is sufficient to impart lifelong neuropathology and altered behaviors in offspring. This Review describes common principles revealed by these models, highlighting recent findings that strengthen their relevance for schizophrenia and autism and are starting to reveal the molecular mechanisms underlying the effects of MIA on offspring.

Immune mediators in the brain and peripheral tissues in autism spectrum disorder.

Increasing evidence points to a central role for immune dysregulation in autism spectrum disorder (ASD). Several ASD risk genes encode components of the immune system and many maternal immune system-related risk factors--including autoimmunity, infection and fetal reactive antibodies--are associated with ASD. In addition, there is evidence of ongoing immune dysregulation in individuals with ASD and in animal models of this disorder.

Alterations in immune cells and mediators in the brain: it's not always neuroinflammation!

Neuroinflammation was once a clearly defined term denoting pathological immune processes within the central nervous system (CNS). Historically, this term was used to indicate the four hallmarks of peripheral inflammaton that occur following severe CNS injuries, such as stroke, injury or infection. Recently, however, the definition of neuroinflammation has relaxed to the point that it is often now assumed to be present when even only a single classical hallmark of inflammation is measured.

MHCI requires MEF2 transcription factors to negatively regulate synapse density during development and in disease.

Major histocompatibility complex class I (MHCI) molecules negatively regulate cortical connections and are implicated in neurodevelopmental disorders, including autism spectrum disorders and schizophrenia. However, the mechanisms that mediate these effects are unknown. Here, we report a novel MHCI signaling pathway that requires the myocyte enhancer factor 2 (MEF2) transcription factors.

Flow cytometric identification and functional characterization of immature and mature circulating endothelial cells.

Objective: We sought to identify and characterize 2 distinct populations of bona fide circulating endothelial cells, including the endothelial colony-forming cell (ECFC), by polychromatic flow cytometry (PFC), colony assays, immunomagnetic selection, and electron microscopy.

Methods And Results: Mononuclear cells from human umbilical cord blood and peripheral blood were analyzed using our recently published PFC protocol. A population of cells containing both ECFCs and mature circulating endothelial cells was determined by varying expressions of CD34, CD31, and CD146 but not AC133 and CD45.

Application of polychromatic flow cytometry to identify novel subsets of circulating cells with angiogenic potential.

Defining whether human circulating proangiogenic cells represent a subset of the hematopoietic system and express CD45 or are hematopoietic derivatives that do not express CD45 (and are called endothelial progenitor cells) remains controversial. We have previously developed a polychromatic flow cytometry (PFC) protocol to isolate subsets of hematopoietic cells and we now identify the circulating pool of CD34(+)CD45(dim) cells representing functional circulating hematopoietic stem and progenitor cells (CHSPCs) that can be separated on the basis of AC133 expression and report that the AC133(+) subset of the CHSPCs enhances the growth of tumor blood vessels in vivo in immunodeficient mice. In addition, the ratio of AC133(+) proangiogenic CHSPCs to AC133(-) nonangiogenic CHSPCs unambiguously correlates with the severity of the clinical state of patients with peripheral arterial disease.

Identification of endothelial cells and progenitor cell subsets in human peripheral blood.

An assay for circulating cell subsets in human peripheral blood by flow cytometry is used as a biomarker to determine cardiovascular disease risk and tumor responsiveness to chemotherapy since endothelial progenitor cells (EPCs) function in vasculogenesis and angiogenesis. Despite analytical advances in polychromatic flow cytometry (PFC), conventional approaches are routinely utilized to enumerate and isolate EPCs, which has led to varied results in clinical studies, potential cellular misidentification, and thus a lack of a plausible biological explanation for how purported EPCs function. Herein, a reproducible PFC protocol is provided to identify a rare circulating endothelial colony-forming cell (ECFC) with proliferative potential, along with a population of circulating progenitor cells (CPCs) in which the ratio analysis distinguishes between healthy and disease populations.

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans.

Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear.

Src family kinases promote AML cell survival through activation of signal transducers and activators of transcription (STAT).

We investigated the role of Src family kinases (SFKs) in the regulation of STAT activation in myeloid leukemia cells. Two of 6 AML cell lines displayed constitutive STAT5 activation, whereas four cell lines had constitutive SFK activity. Treatment with the SFK inhibitors suppressed STAT5 activation and decreased viability.