Stemming the Tide: Strategies to Reduce the Growth and Cut the Cost of the Federal Prison System

The federal prison population has escalated from under 25,000 inmates in 1980 to over 219,000 today. This growth has come at great expense to taxpayers and other important fiscal priorities. As policymakers consider the array of options to stem the tide of inmates, our research concludes that a combination of strategies is the best way to make a real impact. In this report, we evaluate various policy options for cutting the size and costs of the burgeoning federal prison system

Alternative processing of human HTT mRNA with implications for Huntington's disease therapeutics

Huntington disease is caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that is translated into a polyglutamine stretch in the huntingtin protein (HTT). We previously showed that HTT mRNA carrying an expanded CAG repeat was incompletely spliced to generate HTT1a, an exon 1 only transcript, which was translated to produce the highly aggregation-prone and pathogenic exon 1 HTT protein. This occurred in all knock-in mouse models of Huntington's disease and could be detected in patient cell lines and post-mortem brains. To extend these findings to a model system expressing human HTT, we took advantage of YAC128 mice that are transgenic for a yeast artificial chromosome carrying human HTT with an expanded CAG repeat. We discovered that the HTT1a transcript could be detected throughout the brains of YAC128 mice. We implemented RNAscope to visualise HTT transcripts at the single molecule level and found that full-length HTT and HTT1a were retained together in large nuclear RNA clusters, as well as being present as single transcripts in the cytoplasm. Homogeneous time-resolved fluorescence analysis demonstrated that the HTT1a transcript had been translated to produce the exon 1 HTT protein. The levels of exon 1 HTT in YAC128 mice, correlated with HTT aggregation, supportive of the hypothesis that exon 1 HTT initiates the aggregation process. Huntingtin-lowering strategies are a major focus of therapeutic development for Huntington's disease. These approaches often target full-length HTT alone and would not be expected to reduce pathogenic exon 1 HTT levels. We have established YAC128 mouse embryonic fibroblast lines and shown that, together with our QuantiGene multiplex assay, these provide an effective screening tool for agents that target HTT transcripts. The effects of current targeting strategies on nuclear RNA clusters are unknown, structures that may have a pathogenic role, or alternatively could be protective by retaining HTT1a in the nucleus and preventing it from being translated. In light of recently halted antisense oligonucleotide trials, it is vital that agents targeting HTT1a are developed, and that the effects of HTT-lowering strategies on the subcellular levels of all HTT transcripts and their various HTT protein isoforms are understood

COMMENT: Pressure to Pray? Thinking beyond the Coercion Test for Legislator-Led Prayer

The First Amendment to the Constitution commands that “Congress shall make no law respecting an establishment of religion.” This provision is now generally interpreted to forbid a slew of policies and practices at the federal, state, and local levels that endorse or enshrine religion. One flash point in the Establishment Clause doctrine is prayer and government. Whereas one line of cases suggests that prayer offered at government-sponsored events is unconstitutional if it is coercive, another instructs that prayer offered in the legislative context is generally acceptable, at least if delivered by a third party. This Comment addresses a burgeoning circuit split regarding the intersection of these cases. Lower courts have struggled to come to an adequate answer to the question of whether prayer offered in an intimate, constituent-facing legislative context by councilmembers themselves is constitutional. This Comment analyzes the various prayer cases as two overlapping constitutional prophylactic rules designed to prevent intrusive and time-intensive fact-finding into hard-to-ascertain facts. There is also a parallel line of cases that militates against the constitutionality of legislative prayer—the government is supposed to refrain from practices that have the potential to be politically divisive. Because prayers delivered by legislators themselves are more potentially divisive than those offered by third parties, and because the Court prefers strong prophylactic rules designed to prevent judicial speculation into factors like the divisiveness of specific prayer content, legislatorled prayer should be per se forbidden

Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway

Malignant fibrous histiocytoma (MFH), now termed high-grade undifferentiated pleomorphic sarcoma, is a commonly diagnosed mesenchymal tumor, yet both the underlying molecular mechanisms of tumorigenesis and cell of origin remain unidentified. We present evidence demonstrating that human mesenchymal stem cells (hMSCs) are the progenitors of MFH. DKK1, a Wnt inhibitor and mediator of hMSC proliferation, is overexpressed in MFH. Using recombinant proteins, antibody depletion, and siRNA knockdown strategies of specific Wnt elements, we show that DKK1 inhibits hMSC commitment to differentiation via Wnt2/β-catenin canonical signaling and that Wnt5a/JNK noncanonical signaling regulates a viability checkpoint independent of Dkk1. Finally, we illustrate that hMSCs can be transformed via inhibition of Wnt signaling to form MFH-like tumors in nude mice, and conversely, MFH cells in which Wnt signaling is appropriately reestablished can differentiate along mature connective tissue lineages. Our results provide mechanistic insights regarding the cell of origin of MFH, establish what we believe is a novel tumor suppressor role for Wnt signaling, and identify a potential therapeutic differentiation strategy for sarcomas