Multiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo

Abstract Alternative polyadenylation (APA) is strikingly dysregulated in many cancers. Although global APA dysregulation is frequently associated with poor prognosis, the importance of most individual APA events is controversial simply because few have been functionally studied. Here, we address this gap by developing a CRISPR-Cas9-based screen to manipulate endogenous polyadenylation and systematically quantify how APA events contribute to tumor growth in vivo. Our screen reveals individual APA events that control mouse melanoma growth in an immunocompetent host, with concordant associations in clinical human cancer. For example, forced Atg7 3′ UTR lengthening in mouse melanoma suppresses ATG7 protein levels, slows tumor growth, and improves host survival; similarly, in clinical human melanoma, a long ATG7 3′ UTR is associated with significantly prolonged patient survival. Overall, our study provides an easily adaptable means to functionally dissect APA in physiological systems and directly quantifies the contributions of recurrent APA events to tumorigenic phenotypes

In Vivo Measurement of Internal and Global Macromolecular Motions in Escherichia coli

We present direct quasielastic neutron scattering measurements, in vivo, of macromolecular dynamics in Escherichia coli. The experiments were performed on a wide range of timescales to cover the large panel of internal and self-diffusion motions. Three major internal processes were extracted at physiological temperature: a fast picosecond process that corresponded to restricted jump diffusion motions and two slower processes that resulted from reorientational motions occurring in ∼40 ps and 90 ps, respectively. The analysis of the fast process revealed that the cellular environment leads to an appreciable increase in internal molecular flexibility and diffusive motion rates compared with those evaluated in fully hydrated powders. The result showed that the amount of cell water plays a decisive role in internal molecular dynamics. Macromolecular interactions and confinement, however, attenuate slightly the lubricating effect of water, as revealed by the decrease of the in vivo parameters compared with those measured in solution. The study demonstrated that standard sample preparations do not mimic accurately the physiological environment and suggested that intracellular complexity participates in functional dynamics necessary for biological activity. Furthermore, the method allowed the extraction of the self-diffusion of E. coli macromolecules, which presented similar parameters as those extracted for hemoglobin in red blood cells

Rethinking Conditional Release as an Assumption-Based Test of Offender Readiness

While many great strides have been made in supervision generally toward more evidence-based practices, the primary tenets of conditional release have remained unchanged, untested, and assumption based. This essay examines the fundamental tenets of conditional release and how they have been widely overlooked in spite of the evidence-based movement. By laying out the problems in practice, recording, and definition, as well as gaps in the literature, I display several areas where future research can progress both knowledge and policy. I argue that the crux of issues surrounding conditional release is the notion that it is a test of readiness and should be regarded as such. By viewing the practice from this perspective, the inadequacies of state systems to address criminogenic needs become glaringly apparent. Following this explication, it is consequently clear as to why the released person may not be ready and how successful reentry may have less to do with individual accountability and more to do with a rehabilitative ideal