Alcohol use disorder causes global changes in splicing in the human brain.

Alcohol use disorder (AUD) is a widespread disease leading to the deterioration of cognitive and other functions. Mechanisms by which alcohol affects the brain are not fully elucidated. Splicing constitutes a nuclear process of RNA maturation, which results in the formation of the transcriptome. We tested the hypothesis as to whether AUD impairs splicing in the superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). To evaluate splicing, bam files from STAR alignments were indexed with samtools for use by rMATS software. Computational analysis of affected pathways was performed using Gene Ontology Consortium, Gene Set Enrichment Analysis, and LncRNA Ontology databases. Surprisingly, AUD was associated with limited changes in the transcriptome: expression of 23 genes was altered in SFC, 14 in NA, 102 in BLA, and 57 in CNA. However, strikingly, mis-splicing in AUD was profound: 1421 mis-splicing events were detected in SFC, 394 in NA, 1317 in BLA, and 469 in CNA. To determine the mechanism of mis-splicing, we analyzed the elements of the spliceosome: small nuclear RNAs (snRNAs) and splicing factors. While snRNAs were not affected by alcohol, expression of splicing factor heat shock protein family A (Hsp70) member 6 (HSPA6) was drastically increased in SFC, BLA, and CNA. Also, AUD was accompanied by aberrant expression of long noncoding RNAs (lncRNAs) related to splicing. In summary, alcohol is associated with genome-wide changes in splicing in multiple human brain regions, likely due to dysregulation of splicing factor(s) and/or altered expression of splicing-related lncRNAs.

Generalized finite mixture of multivariate regressions with applications to therapeutic biomarker identification.

Finite mixtures of regressions have been used to analyze data that come from a heterogeneous population. When more than one response is observed, accommodating a multivariate response can be useful. In this article, we go a step further and introduce a multivariate extension that includes a latent overlapping cluster indicator variable that allows for potential overdispersion. A generalized mixture of multivariate regressions in connection with the proposed model and a new EM algorithm for fitting are provided. In addition, we allow for high-dimensional predictors via shrinkage estimation. This model proves particularly useful in the analysis of complex data like the search for cancer therapeutic biomarkers. We demonstrate this using the genomics of drug sensitivity in cancer resource.

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

Forced expiratory flow in uninfected infants and children born to HIV-infected mothers.

The Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV (P(2)C(2) HIV) Study is a multicenter study examining pulmonary and cardiac outcomes in offspring of HIV-infected mothers. This portion of the P(2)C(2) study tests the hypothesis that infants exposed to, but uninfected by, maternal HIV have normal maximal expiratory flow at functional residual capacity (V'max,(FRC)). We obtained 500 measurements of V'max,(FRC) by rapid thoracic compression in 285 children ages 6-30 mo in five U.S. centers. The data were compared with those from a healthy cohort of children described elsewhere. V'max,(FRC) rose with height in a linear relationship. The slope of the regression line in the exposed infants did not differ statistically from the slope in the comparison group, but the intercept was about 20% lower (p < 0.001). Height and weight were comparable in the two cohorts, and the differences between intercepts persisted after adjusting for birth weight and gestational age. However, maternal HIV infection cannot be assumed to be the cause as the cohorts may have differed in other variables, such as socioeconomic status and frequency of maternal smoking and drug use. Also, measurements varied substantially within and between our five centers, probably in part because of different racial and ethnic distributions. In summary, maternal HIV infection probably has only a modest effect, if any, on maximal expiratory flow at functional residual capacity in uninfected infants.