Interview with Patrick Leahy by Brien Williams

Biographical NotePatrick Joseph Leahy was born in Montpelier, Vermont, on March 31, 1940. He was graduated from Saint Michael’s College in 1961 and Georgetown Law in 1964. Beginning in 1966, he was elected to four consecutive terms as Vermont state’s attorney in Chittenden County. At the age of 34, he became the youngest U.S. senator ever elected by Vermont, and he is the only elected Democrat from Vermont ever to serve in the U.S. Senate. During the 1980s, he was vice chairman of the Senate Select Committee on Intelligence and chairman of the Agriculture, Nutrition and Forestry Committee. At the time of this interview, he was chairman of the Senate Judiciary Committee and a senior member of the Agriculture and Appropriations Committees, ranking second in seniority in the Senate. SummaryInterview includes discussion of: Mitchell’s arrival in the Senate and his perceived qualities, especially his negotiating skills; Mitchell’s quick rise to Senate leadership; Mitchell’s decision to retire from the Senate; Mitchell’s potential as a Supreme Court justice

Advice and Consent: Ensuring Judicial Freedom

Throughout this nation\u27s history, Americans have turned to the Supreme Court to protect their rights against excesses of the legislative and executive branches. To protect this crucial role of the Court, the Framers realized that neither the executive nor the legislature should have the power to cast the Court in its own image. To prevent this usurpation of one branch by another, the Framers wisely required the President to obtain the advice and consent of the Senate in making appointments to the Supreme Court

Embryonic and post-embryonic utilization and subcellular localization of the nuclear receptor SpSHR2 in the sea urchin

SpSHR2 (Strongylocentrotus purpuratus steroid hormone receptor 2) is a nuclear receptor, encoded by a maternal RNA in the sea urchin embryo. These maternal SpSHR2 transcripts, which are present in all cells, persist until the blastula stage and then are rapidly turned over. A small fraction of the embryonic SpSHR2 protein is maternal, but the majority of this nuclear receptor in the embryo is the product of new synthesis, presumably from the maternal RNA after fertilization. In agreement with the mRNA distribution, the SpSHR2 protein is also detected in all embryonic cells. Contrary to the RNA though, the SpSHR2 protein persists throughout embryonic development to the pluteus stage, long after the mRNA is depleted. Following fertilization and as soon as the 2-cell stage, the cytoplasmic SpSHR2 protein enters rapidly into the embryonic nuclei where it appears in the form of speckles. During subsequent stages (from fourth cleavage onward), SpSHR2 resides in speckled form in both the nucleus and the cytoplasm of the embryonic cells. The cytoplasmic localization of SpSHR2 differs between polarized and non-polarized cells, maintaining an apical position in the ectoderm and endoderm versus a uniform distribution in mesenchyme cells. Following the end of embryonic development (pluteus stage), the SpSHR2 protein is depleted from all tissues. During the ensuing four weeks of larval development, the SpSHR2 is not detected in either the larval or the rudiment cells which will give rise to the adult. Just prior to metamorphosis, at about 35 days post-fertilization, the protein is detected again but in contrast to the uniform distribution in the early embryo, the larval SpSHR2 is specifically expressed in cells of the mouth epithelium and the epaulettes. In adult ovaries and testes, SpSHR2 is specifically detected in the myoepithelial cells surrounding the ovarioles and the testicular acini. Nuclear SpSHR2 in blastula extracts binds to the C1R hormone response element in the upstream promoter region of the CyIIIb actin gene indicating that the latter may be a target of this nuclear receptor in the sea urchin embryo

The Linear-Size Evolution of Classical Double Radio Sources

Recent investigations of how the median size of extragalactic radio sources change with redshift have produced inconsistent results. Eales compared the radio and optical properties of a bright 3C and faint 6C sample and concluded that $D\propto(1+z)^{-1.1\pm0.5}$ ($\Omega_0 = 0$), with $D$ being the median size of the radio sources at a given epoch and z the redshift. Oort, Katgert, and Windhorst, on the other hand, from a comparison of the properties of a number of radio samples, found much stronger evolution, with $D\propto(1+z)^{-3.3 \pm0.5}$. In this paper we attempt to resolve the difference. We have repeated the analysis of Eales using the virtually complete redshift information that now exists for the 6C sample. Confining our analysis to FR2 sources, which we argue is the best-understood class of radio sources and the least likely to be affected by selection effects, we find $D\propto(1+z)^{-1.2\pm0.5}$ ($\Omega_0 = 0$) and $D\propto(1+z)^{-1.7\pm0.4}$ ($\Omega_0 = 1$). Our complete redshift information allows us to gain insight into our result by plotting a radio luminosity-size (P-D) diagram for the 6C sample. The most obvious difference between the 3C and 6C P-D diagrams is the clump of sources in the 6C diagram at $D\sim 100 kpc, P_{151}\sim 5x10^{27} WHz^{-1}sr^{-1}$. These clump sources have similar sizes to the emission-line regions found around high-redshift radio galaxies, suggesting that the presence of dense line-emitting gas around high-redshift radio galaxies is responsible for the size evolution. We show that this explanation can quantitatively explain the observed size evolution, as long as there is either little X-ray emitting gas around these objects or, if there is, it is distributed in a similar way to the emission-line gas: highly anisotropic and inhomogeneous.Comment: compressed and uuencoded postscript file. 33 pages including 5 figures (441951 bytes). Accepted for publication in September Ap

The FRET Signatures of Noninteracting Proteins in Membranes: Simulations and Experiments

AbstractFörster resonance energy transfer (FRET) experiments are often used to study interactions between integral membrane proteins in cellular membranes. However, in addition to the FRET of sequence-specific interactions, these experiments invariably record a contribution due to proximity FRET, which occurs when a donor and an acceptor approach each other by chance within distances of ∼100 Å. This effect does not reflect specific interactions in the membrane and is frequently unappreciated, despite the fact that its magnitude can be significant. Here we develop a computational description of proximity FRET, simulating the cases of proximity FRET when fluorescent proteins are used to tag monomeric, dimeric, trimeric, and tetrameric membrane proteins, as well as membrane proteins existing in monomer-dimer equilibria. We also perform rigorous experimental measurements of this effect, by identifying membrane receptors that do not associate in mammalian membranes. We measure the FRET efficiencies between yellow fluorescent protein and mCherry-tagged versions of these receptors in plasma-membrane-derived vesicles as a function of receptor concentration. Finally, we demonstrate that the experimental measurements are well described by our predictions. The work presented here brings additional rigor to FRET-based studies of membrane protein interactions, and should have broad utility in membrane biophysics research

Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming.

The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGFβ2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming. Cells undergoing early adaptive drug escape are in proliferative-metabolic quiescent, with enhanced EMT-ness and stem cell signaling, exhibiting global bioenergetics suppression including reverse Warburg, and are susceptible to glutamine deprivation and TGFβ2 inhibition. Our study further supports a preemptive therapeutic targeting of bioenergetics and mitochondrial priming to impact early drug-escape emergence using EGFR precision inhibitor combined with broad BH3-mimetic to interrupt BCL-2/BCL-xL together, but not BCL-2 alone

Using Global Positioning System Technology to Manage Human-Black Bear Incidents at Yosemite National Park

Managing human–bear (Ursus spp.) incidents is a top management priority in national parks inhabited by bears. Yosemite National Park (Yosemite), located in the Sierra Nevada in California, USA, receives up to 5 million visitors annually. It is also home to 300–500 black bears (U. americanus). Yosemite has an extensive history of black bear research, educational programs, and innovative solutions for reducing human–bear incidents. Despite this, human–bear incidents peaked in 1998 at 1,584. The resulting political fallout led to Yosemite receiving funds to expand its bear management program, including increasing its staffing and garbage pick-up, and improving the park’s bear-resistant infrastructure. In 2011, Yosemite reached a milestone when it recorded only 114 human–bear incidents—a 93% decrease from the 1998 high. To sustain this lower level of incidents while facing shrinking budgets and increasing visitation, bear managers turned to more modern technology. From 2014–2018, we evaluated the effectiveness of using global positioning system (GPS) collars to manage bears more proactively, increase staff and public engagement with bears, and gain insight into the bears’ spatial and temporal movements. The GPS collars were effective in achieving these goals, while also improving both our time management and our communication with park management. By the end of November 2018, Yosemite had recorded only 22 human–bear incidents—a 99% decrease from the 1998 high. The GPS collars are now an integral part of the Yosemite bear management program. We provide recommendations on how GPS technology may help other parks reduce human–bear incidents