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Sinister : once you see him, nothing can save you
Ten years ago, true crime writer Ellison Oswald made his reputation with a best-selling account of a notorious murder. Now, desperate to replicate the success of his first book, he moves his family into a home where the previous occupants were brutally executed and a child disappeared, hoping to find inspiration in the crime scene. In the home, Ellison discovers a cache of terrifying home movies, unwittingly opening the door into a nightmarish mystery.
DVD
Inference of cell type content from human brain transcriptomic datasets illuminates the effects of age, manner of death, dissection, and psychiatric diagnosis
Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data.
Journal Article
Cecal Ligation and Puncture Results in Long-Term Central Nervous System Myeloid Inflammation
Survivors of sepsis often experience long-term cognitive and functional decline. Previous studies utilizing lipopolysaccharide injection and cecal ligation and puncture in rodent models of sepsis have demonstrated changes in depressive-like behavior and learning and memory after sepsis, as well as evidence of myeloid inflammation and cytokine expression in the brain, but the long-term course of neuroinflammation after sepsis remains unclear. Here, we utilize cecal ligation and puncture with greater than 80% survival as a model of sepsis. We found that sepsis survivor mice demonstrate deficits in extinction of conditioned fear, but no acquisition of fear conditioning, nearly two months after sepsis. These cognitive changes occur in the absence of neuronal loss or changes in synaptic density in the hippocampus. Sepsis also resulted in infiltration of monocytes and neutrophils into the CNS at least two weeks after sepsis in a CCR2 independent manner. Cellular inflammation is accompanied by long-term expression of pro-inflammatory cytokine and chemokine genes, including TNFα and CCR2 ligands, in whole brain homogenates. Gene expression analysis of microglia revealed that while microglia do express anti-microbial genes and damage-associated molecular pattern molecules of the S100A family of genes at least 2 weeks after sepsis, they do not express the cytokines observed in whole brain homogenates. Our results indicate that in a naturalistic model of infection, sepsis results in long-term neuroinflammation, and that this sustained inflammation is likely due to interactions among multiple cell types, including resident microglia and peripherally derived myeloid cells.
Journal Article
Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome
Synaptic abnormalities and learning dysfunction are prominent characteristics of Down's syndrome. Now Huaxi Xu and colleagues show that expression of the protein SNX27 is reduced in Down's syndrome brains and that restoring its expression can ameliorate learning dysfunction in a mouse model of the disease.
Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that
Snx27
−/−
mice have severe neuronal deficits in the hippocampus and cortex. Although
Snx27
+/−
mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein β (C/EBPβ) in Down's syndrome brains and identify C/EBPβ as a transcription factor for
SNX27
. Down's syndrome causes overexpression of miR-155, a chromosome 21–encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Down's syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome pathogenesis.
Journal Article
Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription
Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD). Insulin modulates metabolism of β-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of β-amyloid (Aβ) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (GlucophageR), affects APP metabolism and Aβ generation in various cell models. We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular Aβ species. Furthermore, the effect of metformin on Aβ generation is mediated by transcriptional up-regulation of β-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on Aβ degradation. In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on Aβ. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on Aβ generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on Aβ generation, in combined use, metformin enhances insulin's effect in reducing Aβ levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients.
Journal Article
Combined microRNA and mRNA detection in mammalian retinas by in situ hybridization chain reaction
Improved
in situ
hybridization methods for mRNA detection in tissues have been developed based on the hybridization chain reaction (HCR). We show that
in situ
HCR methods can be used for the detection of microRNAs in tissue sections from mouse retinas.
In situ
HCR can be used for the detection of two microRNAs simultaneously or for the combined detection of microRNA and mRNA. In addition, miRNA
in situ
HCR can be combined with immunodetection of proteins. We use these methods to characterize cells expressing specific microRNAs in the mouse retina. We find that miR-181a is expressed in amacrine cells during development and in adult retinas, and it is present in both GABAergic and glycinergic amacrine cells. The detection of microRNAs with
in situ
HCR should facilitate studies of microRNA function and gene regulation in the retina and other tissues.
Journal Article
Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques
Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to determine whether a gain-of-function nonsynonymous OXTR SNP interacted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavioral differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.
Journal Article
Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry
Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects [almost equal to]1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 x 10⁻⁶. We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P [almost equal to] 10⁻⁷: 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 x 10⁻⁷) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.
Journal Article
NGSQC: cross-platform quality analysis pipeline for deep sequencing data
Background
While the accuracy and precision of deep sequencing data is significantly better than those obtained by the earlier generation of hybridization-based high throughput technologies, the digital nature of deep sequencing output often leads to unwarranted confidence in their reliability.
Results
The NGSQC (
N
ext
G
eneration
S
equencing
Q
uality
C
ontrol) pipeline provides a set of novel quality control measures for quickly detecting a wide variety of quality issues in deep sequencing data derived from two dimensional surfaces, regardless of the assay technology used. It also enables researchers to determine whether sequencing data related to their most interesting biological discoveries are caused by sequencing quality issues.
Conclusions
Next generation sequencing platforms have their own share of quality issues and there can be significant lab-to-lab, batch-to-batch and even within chip/slide variations. NGSQC can help to ensure that biological conclusions, in particular those based on relatively rare sequence alterations, are not caused by low quality sequencing.
Journal Article
Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals
Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety- and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders.
Journal Article