We replicated and extended treatment procedures described by Lennox, Miltenberger, and Donnelly (1987) designed to reduce rapid eating. The participant was a 17‐year‐old girl with developmental ...disabilities who engaged in dangerously high rates of food ingestion. The procedure involved an adjusting differential‐reinforcement‐of‐low‐rate‐responding (DRL) schedule, response blocking, and prompts. We evaluated a continuation of the treatment despite initial negative side effects that were similar to those reported by Lennox et al. Results showed that the treatment package was effective and negative side effects eventually decreased.
The nuances of small non-coding RNA biology continue to be discovered. The most characterized species of non-coding RNAs are microRNA (miRNA). miRNA largely function to modulate gene expression by ...repressing the translation of mRNA into protein. It is now known that miRNA participate in regulating nearly every type of cellular process and their importance in brain development, function, and disease continues to be uncovered. Recently RNA sequencing revealed that miRNA are often produced in detectable levels with slight sequence variations. Several steps are involved in the biogenesis of miRNA and slight changes in these processes can lead to a variety of extensions, deletions, or alterations in the final mature sequence. The name isomiR for these isoforms of canonically described miRNA sequences was coined in 2008. Research demonstrates that these miRNA variants have altered stability and in some cases distinct functions from their close sequence relatives. Recent findings also indicate that altered isomiR expression is associated with disease states. To date little research has characterized the expression of isomiRs in the brain, however alterations in canonical miRNA expression and miRNA biogenesis have been reproducibly associated with schizophrenia, suggesting that the biogenesis of isomiRs may also be altered. Therefore, we characterized isomiR expression in 92 postmortem dorsolateral prefrontal cortex (DLPFC) human brain samples, including 30 samples from patients with schizophrenia and 62 from healthy controls. Using small RNA sequencing, we profiled the expression of both canonical miRNAs and isomiRs. We utilized the BIOO Scientific NextFlex small RNA sequencing kit, with 500 ng of starting total RNA and ran 50 base pair sequencing on the HiSeq 3000. We achieved a sequencing depth of over 20 million reads per sample. Reads were aligned to miRNA and isomiR sequences using miRge. First, we assessed the overall magnitude and diversity of isomiR expression, however no differences were found between cases and controls. We then assessed the influence of diagnosis on the expression of individual miRNAs and isomiRs. Seven canonical miRNAs and 52 isomiRs, derived from 22 canonically described miRNA sequences, were identified to be differentially expressed between cases and controls. Importantly many of these isomiRs had alterations in the 5 prime portion of their sequence. Such alterations have been shown to shift the repertoire of binding partners to be distinct from that of the canonical sequence. Therefore, altered expression of these isomiRs may especially indicate modifications in gene expression regulation in schizophrenia. More research is necessary to decipher the role of these miRNA variants in schizophrenia and the brain. However, our study suggests that such variation should not be ignored.
Accurate, RNA-seq based, microRNA (miRNA) expression estimates from primary cells have recently been described. However, this in vitro data is mainly obtained from cell culture, which is known to ...alter cell maturity/differentiation status, significantly changing miRNA levels. What is needed is a robust method to obtain in vivo miRNA expression values directly from cells. We introduce expression microdissection miRNA small RNA sequencing (xMD-miRNA-seq), a method to isolate cells directly from formalin fixed paraffin-embedded (FFPE) tissues. xMD-miRNA-seq is a low-cost, high-throughput, immunohistochemistry-based method to capture any cell type of interest. As a proof-of-concept, we isolated colon epithelial cells from two specimens and performed low-input small RNA-seq. We generated up to 600,000 miRNA reads from the samples. Isolated epithelial cells, had abundant epithelial-enriched miRNA expression (miR-192; miR-194; miR-200b; miR-200c; miR-215; miR-375) and overall similar miRNA expression patterns to other epithelial cell populations (colonic enteroids and flow-isolated colon epithelium). xMD-derived epithelial cells were generally not contaminated by other adjacent cells of the colon as noted by t-SNE analysis. xMD-miRNA-seq allows for simple, economical, and efficient identification of cell-specific miRNA expression estimates. Further development will enhance rapid identification of cell-specific miRNA expression estimates in health and disease for nearly any cell type using archival FFPE material.
In feminist sociocultural models of rape, extreme adherence to the masculine gender role is implicated in the perpetuation of sexual assault against women in that it encourages men to be dominant and ...aggressive, and it teaches that women are inferior to men and are sometimes worthy of victimization. Many researchers have linked components of masculine ideology to self-reports of past sexual aggression or future likelihood to rape. Thirty-nine effect sizes were examined in this meta-analysis across 11 different measures of masculine ideology to determine how strongly each index of masculine ideology was associated with sexual aggression. Although 10 of the 11 effect sizes were statistically significant, the 2 largest effects were for Malamuth's construct of "hostile masculinity" (e.g., Malamuth, Sockloskie, Koss, & Tanaka, 1991) and Mosher's construct of "hypermasculinity" (e.g., Mosher & Sirkin, 1984), both of which measure multiple components of masculine ideology including acceptance of aggression against women and negative, hostile beliefs about women. The next strongest relationships concerned measures of agreement that men are dominant over women and measures of hostility toward women. Scores on general measures of gender-role adherence, such as the Bem Sex Role Inventory (Bem, 1974), were not strong predictors of sexual aggression. Sociocultural models that link patriarchal masculine ideology and situational factors to sexual aggression should prove most predictive in future research.
Increasing evidence suggests that hyperphosphorylation and aggregation of microtubule-associated protein tau (MAPT or tau) correlates with the development of cognitive impairment in Alzheimer's ...disease (AD) and related tauopathies. While numerous attempts have been made to model AD-relevant tau pathology in various animal models, there has been very limited success for these models to fully recapitulate the progression of disease as seen in human tauopathies. Here, we performed whole genome gene expression in a genomic mouse model of tauopathy that expressed human
gene under the control of endogenous human
promoter and also were complete knockout for endogenous mouse tau referred to as 'hTau
' mice. First, whole genome expression analysis revealed 64 genes, which were differentially expressed (32 up-regulated and 32 down-regulated) in the hippocampus of 6-month-old hTau
mice compared to age-matched non-transgenic controls. Genes relevant to neuronal function or neurological disease include up-regulated genes: PKC-alpha (
), MECP2 (
), STRN4 (
), SLC40a1 (
), POLD2 (
), PCSK2 (
), and down-regulated genes: KRT12 (
), LASS1 (
), PLAT (
), and NRXN1 (
). Second, network analysis suggested anatomical structure development, cellular metabolic process, cell death, signal transduction, and stress response were significantly altered biological processes in the hTau
mice as compared to age-matched non-transgenic controls. Further characterization of a sub-group of significantly altered genes revealed elevated phosphorylation of MECP2 (methyl-CpG-binding protein-2), which binds to methylated CpGs and associates with chromatin, in hTau
mice compared to age-matched controls. Third, phoshpho-MECP2 was elevated in autopsy brain samples from human AD compared to healthy controls. Finally, siRNA-mediated knockdown of MECP2 in human tau expressing N2a cells resulted in a significant decrease in total and phosphorylated tau. Together, these results suggest that MECP2 is a potential novel regulator of tau pathology relevant to AD and tauopathies.
•We examine how the microRNA-137-associated variant rs1625579 affects subcortical volumes in schizophrenia.•In patients, the homozygous risk genotype confers lesser reduction of callosal ...volume.•Results are robust after considering possible multi-site and ethnicity confounds.•Results suggest variant does not mediate schizophrenia risk through corpus callosum volume reduction.
Genome-wide association studies implicate the MIR137HG risk variant rs1625579 (MIR137HGrv) within the host gene for microRNA-137 as a potential regulator of schizophrenia susceptibility. We examined the influence of MIR137HGrv genotype on 17 subcortical and callosal volumes in a large sample of individuals with schizophrenia and healthy controls (n=841). Although the volumes were overall reduced relative to healthy controls, for individuals with schizophrenia the homozygous MIR137HGrv risk genotype was associated with attenuated reduction of mid-posterior corpus callosum volume (p=0.001), along with trend-level effects in the adjacent central and posterior corpus callosum. These findings are unique in the literature and remain robust after analysis in ethnically homogenous and single-scanner subsets of the larger sample. Thus, our study suggests that the mechanisms whereby MIR137HGrv works to increase schizophrenia risk are not those that generate the corpus callosum volume reductions commonly found in the disorder.
A single nucleotide polymorphism (SNP) within MIR137, the host gene for miR-137, has been identified repeatedly as a risk factor for schizophrenia. Previous genetic pathway analyses suggest that ...potential targets of this microRNA (miRNA) are also highly enriched in schizophrenia-relevant biological pathways, including those involved in nervous system development and function.
In this study, we evaluated the schizophrenia risk of miR-137 target genes within these pathways. Gene set enrichment analysis of pathway-specific miR-137 targets was performed using the stage 1 (21,856 subjects) schizophrenia genome wide association study data from the Psychiatric Genomics Consortium and a small independent replication cohort (244 subjects) from the Mind Clinical Imaging Consortium and Northwestern University.
Gene sets of potential miR-137 targets were enriched with variants associated with schizophrenia risk, including target sets involved in axonal guidance signaling, Ephrin receptor signaling, long-term potentiation, PKA signaling, and Sertoli cell junction signaling. The schizophrenia-risk association of SNPs in PKA signaling targets was replicated in the second independent cohort.
These results suggest that these biological pathways may be involved in the mechanisms by which this MIR137 variant enhances schizophrenia risk. SNPs in targets and the miRNA host gene may collectively lead to dysregulation of target expression and aberrant functioning of such implicated pathways. Pathway-guided gene set enrichment analyses should be useful in evaluating the impact of other miRNAs and target genes in different diseases.
Using a procedure similar to the one described by Le and Smith (in press), we evaluated the effects of protective equipment during a functional analysis for 2 individuals who engaged in severe ...self‐injurious behavior (SIB). Results of our analyses revealed that the use of protective equipment during functional analyses of SIB suppressed levels of responding such that a behavioral function could not be identified.
Typically, functional analyses of severe problem behavior have been conducted in two ways: (a) The target response is reinforced immediately after it occurs, or (b) the target response is reinforced ...on some schedule thought to mimic a naturally occurring schedule. We evaluated the effects of contingency strength in reducing levels of problem behavior with 2 participants who had been diagnosed with developmental disabilities. Results showed that under a neutral contingency, one in which the probability of reinforcement for aggression was equal to the probability of reinforcement for the nonoccurrence of aggression, rates of aggression were suppressed to low levels for both participants.
We compared the effects of extinction (EXT) and fixed‐time (FT) schedules as treatment for severe problem behavior displayed by 3 individuals with developmental disabilities. First, functional ...analyses identified the reinforcers maintaining aberrant behavior for all 3 individuals. Next, EXT and FT schedules were compared using a multielement design. During EXT, the reinforcer maintaining problem behavior was withheld. During FT, the reinforcers were presented response independently at preset intervals. Results showed that FT schedules were generally more effective than EXT schedules in reducing aberrant behavior. FT schedules may be used in situations when extinction‐induced phenomena are problematic.
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