Human multiple myeloma is a presently incurable hematologic malignancy, and novel biologically based therapies are urgently needed.

The extent to which RNA stability differs between individuals and its contribution to the interindividual expression variation remain unknown. We conducted a genome-wide analysis of RNA stability in seven human HapMap lymphoblastoid cell lines (LCLs) and analyzed the effect of DNA sequence variation on RNA half-life differences. Twenty-six percent of the expressed genes exhibited RNA half-life differences between LCLs at a false discovery rate (FDR) < 0.05, which accounted for ~ 37% of the gene expression differences between individuals. Nonsense polymorphisms were associated with reduced RNA half-lives. In genes presenting interindividual RNA half-life differences, higher coding GC3 contents (G and C percentages at the third-codon positions) were correlated with increased RNA half-life. Consistently, G and C alleles of single nucleotide polymorphisms (SNPs) in protein coding sequences were associated with enhanced RNA stability. These results suggest widespread interindividual differences in RNA stability related to DNA sequence and composition variation.

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.

Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves' disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e.g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia.

Background: Regulation of dopamine D2 receptor (DRD2) is pathophysiologically and pharmacologically important. Results: miR-9 and miR-326 target to the 3Ј-UTR of DRD2, and endogenously inhibit DRD2 expression. A functional single nucleotide polymorphism alters such regulation. Conclusion: DRD2 is post-transcriptionally regulated by miR-326 and miR-9. Significance: The study suggests a pathophysiological and pharmacological role of miR-9 and miR-326 in neuropsychiatric disorders.

The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had widespread effects on both cell growth and gene expression in LCLs. Overall, 1455 genes showed statistically significant differential DA response in SZ cases and controls. This set of differentially expressed genes is enriched for brain expression and for functions related to immune processes and apoptosis, suggesting that DA may play a role in SZ pathogenesis through modulating those systems. Moreover, we observed a non-significant enrichment of genes near genome-wide significant SZ loci and with genes spanned by SZ-associated copy number variants (CNVs), which suggests convergent pathogenic mechanisms detected by both genetic association and gene expression. The study suggests a novel role of DA in the biological processes of immune and apoptosis that may be relevant to SZ pathogenesis. Furthermore, our results show the utility of pathophysiologically relevant perturbation experiments to investigate the biology of complex mental disorders.

As a result of the international division of labor, the trade value distribution on different products substantiated by international trade flows can be regarded as one country’s strategy for competition. According to the empirical data of trade flows, countries may spend a large fraction of export values on ubiquitous and competitive products. Meanwhile, countries may also diversify their exports share on different types of products to reduce the risk. In this paper, we report that the export share distribution curves can be derived by maximizing the entropy of shares on different products under the product’s complexity constraint once the international market structure (the country-product bipartite network) is given. Therefore, a maximum entropy model provides a good fit to empirical data. The empirical data is consistent with maximum entropy subject to a constraint on the expected value of the product complexity for each country. One country’s strategy is mainly determined by the types of products this country can export. In addition, our model is able to fit the empirical export share distribution curves of nearly every country very well by tuning only one parameter.

Transcription factor NF-KB is linked to growth and survival of multiple myeloma (MM)cells; blockade of NF-KB activity is therefore an attractive therapeutic strategy. Here we describe NPI-1387, a potent inhibitor of NF-KB activation and its effects on MM cells, including those resistant to conventional agents dexamethasone or doxorubicin. Cell-based assays were used to screen a library of 200 semi-synthetic analogs derived from the pimarane diterpene, Acanthoic acid. Among these analogs, NPI-1387 inhibited LPS-induced TNF-A synthesis in the murine macrophage-like RAW 264.7 cells most potently. Importantly, NPI-1387 reduced TNF-A-induced NF-KB activation in a HEK293 NF-KB/luciferase reporter cell line. Therefore additional studies were initiated to define the biological activities in MM. Treatment of MM cells lines (MM.1S, MM.1R, OCI-My5, OPM1, Dox-40) with NPI-1347 for 48h induces a dose-dependent significant (P &lt; 0.004) decrease in cell viability in all cell lines at pharmacologically achievable concentrations (IC50 range 25–40 micromolar). To determine whether NPI-1387-decreased cell viability is due to apoptosis, various MM cell lines were treated at their respective IC50 for 48h; harvested; and analyzed for apoptosis. NPI-1387 triggered significant apoptosis in these cells, as measured by a marked increase in nuclear condensation reflected by dense pattern of DAPI stain under phase contrast microscopy. In contrast, untreated control cells exhibited homogeneous and intact nuclei. Besides nuclear condensation, NPI-1387 triggered proteolytic cleavage of poly (ADP ribose) polymerase (PARP), a hallmark of apoptosis. Examination of purified patient MM cells demonstrated similar results. Notably, NPI-1387 decreases the viability of cells obtained from Bortezomib-refractory MM patient. In contrast, no significant toxicity of NPI-1387 was observed against peripheral blood mononuclear cells from normal healthy donors or CD138− MM patient cells. Moreover, NPI-1387 does not affect the viability of MM patient-derived bone marrow stromal cells (BMSCs). Genetic and biochemical evidence indicates that apoptosis proceeds by two major cell death pathways: an intrinsic pathway that involves mitochondrial membrane permeabilization and release of several apoptogenic factors, followed by caspase-9 activation; and an extrinsic apoptotic signaling pathway that occurs via caspase-8 activation. Both caspase-8 and caspase-9 activate downstream caspase-3. We therefore next examined whether NPI-1387 triggers extrinsic or intrinsic apoptotic signaling pathways. Our results show that NPI-1387 (25 micromolar) induces activation of caspase-8, and caspase-9, followed by caspase-3 cleavage. These data suggest that NPI-1387-triggered MM cell apoptosis predominantly proceeds via caspase-8/caspase-9&gt;&gt;&gt;&gt;caspase-3 signaling pathway. Together, these findings provide the rationale for clinical evaluation of NPI-1387 to induce MM cell killing, overcome drug-resistance, and improve patient outcome in MM.