Summary We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.

2 SUMMARYWe previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.

Older adults exhibit global reductions in cortical surface area, but little is known about the regional patterns of reductions or how these relate to other measures of brain structure. This knowledge is critical to understanding the dynamic relationship between different macrostructural properties of the cortex throughout adult life. Here, cortical arealization, local gyrification index (LGI), and cortical thickness were measured vertex wise across the brain surface in 322 healthy adults (20-85 years), with the aims of 1) characterizing age patterns of the three separate cortical measures and 2) testing the age-independent relationships among cortical surface area, gyrification, and thickness. Surface area showed strong age-related decreases, particularly pronounced in dorsomedial prefrontal, lateral temporal, and fusiform cortices, independently of total white matter volume. LGI decreased with age independently of regional surface area, with strongest effects laterally, extending from the angular gyrus in all directions. As expected, regional surface area and LGI were positively related. However, both measures correlated negatively with thickness, indicating increasing local arealization and gyrification with decreasing cortical thickness. We suggest that this pattern of regional "cortical stretching" reflects the well-established phylogenetic principle of maximizing surface area and gyrification rather than increase thickness to facilitate brain connectivity and functional development.

Bacterial community acquisition in the infant gut impacts immune education and disease susceptibility. We compared bacterial strains across and within families in a prospective birth cohort of 44 infants and their mothers, sampled longitudinally in the first months of each child's life. We identified mother-to-child bacterial transmission events and describe the incidence of family-specific antibiotic resistance genes. We observed two inheritance patterns across multiple species, where often the mother's dominant strain is transmitted to the child, but occasionally her secondary strains colonize the infant gut. In families where the secondary strain of B. uniformis was inherited, a starch utilization gene cluster that was absent in the mother's dominant strain was identified in the child, suggesting the selective advantage of a mother's secondary strain in the infant gut. Our findings reveal mother-to-child bacterial transmission events at high resolution and give insights into early colonization of the infant gut.