A multi-looping chromatin signature predicts dysregulated gene expression in neurons with familial Alzheimer's disease mutations.

Mammalian genomes fold into tens of thousands of long-range loops, but their functional role and physiologic relevance remain poorly understood. Here, using human post-mitotic neurons with rare familial Alzheimer's disease (FAD) mutations, we identify hundreds of reproducibly dysregulated genes and thousands of miswired loops prior to amyloid accumulation and tau phosphorylation. Single loops do not predict expression changes; however, the severity and direction of change in mRNA levels and single-cell burst frequency strongly correlate with the number of FAD-gained or -lost promoter-enhancer loops. Classic architectural proteins CTCF and cohesin do not change occupancy in FAD-mutant neurons. Instead, we unexpectedly find TAATTA motifs amenable to binding by DLX homeodomain transcription factors and changing noncoding RNAPolII signal at FAD-dynamic promoter-enhancer loops. DLX1/5/6 mRNA levels are strongly upregulated in FAD-mutant neurons coincident with a shift in excitatory-to-inhibitory gene expression and miswiring of multi-loops connecting enhancers to neural subtype genes. DLX1 overexpression is sufficient for loop miswiring in wildtype neurons, including lost and gained loops at enhancers with tandem TAATTA arrays and singular TAATTA motifs, respectively. Our data uncover a genome structure-function relationship between multi-loop miswiring and dysregulated excitatory and inhibitory transcriptional programs during lineage commitment of human neurons homozygously-engineered with rare FAD mutations.

A review of the efficacy of a low-cost cancer screening test using cancer sniffing canines.

One of the most powerful tools in fighting cancer is early detection, as it has been strongly linked to greater chances of cancer survival. However, traditional cancer screening tests can cost hundreds if not thousands of dollars and are therefore not an affordable option for many marginalized populations. From a public health perspective, it is vital to research the use of inexpensive cancer detection so that low-resourced patients have greater access to affordable cancer screening. Numerous studies dating from the early 2000s to recent years have shown extensive evidence that the exceptional olfactory system of canines allows them to detect certain odors through exhaled breath condensate that are known to be biomarkers of a variety of cancers. In addition to providing a cheaper alternative to conventional cancer screening tests, the use of cancer sniffing dogs has other benefits, including great reliability and accuracy. There are a few major types of cancer for which the 'cancer dog test' proved to be remarkably effective, particularly colorectal, ovarian, and lung cancers. The test is non-invasive unlike most previous detection methods, meaning that it is also a safer option for individuals seeking cancer screening. Although the use of cancer sniffing dogs does have certain limitations and scope for error, it would provide a more affordable and accessible option for cancer screening, making it especially beneficial to low-resourced populations.