Predictive network analysis identifies JMJD6 and other potential key drivers in Alzheimer's disease.

Despite decades of genetic studies on late-onset Alzheimer's disease, the underlying molecular mechanisms remain unclear. To better comprehend its complex etiology, we use an integrative approach to build robust predictive (causal) network models using two large human multi-omics datasets. We delineate bulk-tissue gene expression into single cell-type gene expression and integrate clinical and pathologic traits, single nucleotide variation, and deconvoluted gene expression for the construction of cell type-specific predictive network models. Here, we focus on neuron-specific network models and prioritize 19 predicted key drivers modulating Alzheimer's pathology, which we then validate by knockdown in human induced pluripotent stem cell-derived neurons. We find that neuronal knockdown of 10 of the 19 targets significantly modulates levels of amyloid-beta and/or phosphorylated tau peptides, most notably JMJD6. We also confirm our network structure by RNA sequencing in the neurons following knockdown of each of the 10 targets, which additionally predicts that they are upstream regulators of REST and VGF. Our work thus identifies robust neuronal key drivers of the Alzheimer's-associated network state which may represent therapeutic targets with relevance to both amyloid and tau pathology in Alzheimer's disease.

Current liver biopsy practices for suspected parenchymal liver diseases in the United States: the evolving role of radiologists.

OBJECTIVE: The aim of this study was to determine current liver biopsy practices in the United States. METHODS: We mailed a questionnaire to 260 randomly selected members of the American Association for the Study of Liver Diseases. Statistical analysis was conducted using the chi2 test. RESULTS: A total of 128 members (49%) responded, with 106 responses suitable for inclusion. Of the respondents, 25% had a radiologist perform >50% of their patients' liver biopsies, whereas 38% personally performed all their patients' biopsies. During training, 87% of respondents were taught to perform liver biopsy using the "blind" technique, 2% with ultrasound (US) guidance, and 11% both. A total of 76% used US guidance during liver biopsy. More private practitioners than those practicing in academic centers used the "blind" technique (35% vs 18%; p = 0.02) and referred >50% of their patients for liver biopsy to Radiology (36% vs 17%; p = 0.01); desire for real-time US guidance was the main reason in 43% of cases. Of the respondents, 75% used US for safety reasons; 77% of those who did not use US believed that it was unnecessary. Overall, 87% of respondents indicated that patient safety was the most important issue during liver biopsy; only 2% thought that personal convenience and cost-effectiveness were most important. CONCLUSIONS: Respondents' chief concern was patient safety, and most used US for this reason. Private practitioners were less likely than those practicing in academic centers to use US guidance and were more likely to refer patients to Radiology.