Beyond the Waste Land: Law Practice in the 1990s

Law practice has begun to resemble the world in T.S. Eliot\u27s enigmatic poem, The Waste Land. Professor Schuman suggests that the problem is confrontation: our basic misconception is that justice requires victors and vanquished, exclusion of the opponent rather than inclusion. Lawyers increasingly are unable to contain the aggressive and combative nature of the system and too often treat insensitivity, ruthlessness, and paranoia as professional virtues; virtues which then infect their personal lives. In stark contrast, observers throughout history Would have treated this isolation and defensive living as absurd or dangerous. This essay suggests that rather than fantasize about a Utopian alternative social context, lawyers heed the commands of The Waste Land\u27s thunder: to give, sympathize, control. By incorporating these directives into their professional lives, the author argues that lawyers may become more connected and whole within their existing world

An Extraterritorial FDA: Could the Food and Drug Administration Apply Its Informed Consent Requirement Abroad Consistent with International Law?

This paper addresses the regulatory challenges wrought by the increasing amount of human subject drug testing conducted in developing countries in support of new drug applications to the Food and Drug Administration. Specifically, it examines the difficulty of enforcing the “informed consent” requirement for ethical scientific research performed in foreign territory. In poorer regions, a lack of government oversight, lower regulatory standards, and barriers to communication have too frequently resulted in allegations of human experimentation performed without its participants’ informed consent. In order to solve this problem, some commentators have suggested that the FDA could apply its human subject protections to foreign clinical research, and enforce them through injunctions or criminal prosecutions. However, the international legal limits on states’ prescriptive jurisdiction may prohibit this exercise of extraterritoriality. After analyzing the proposed extraterritorial regulation of foreign drug testing under the traditional bases and limitations of prescriptive jurisdiction, this paper concludes that such regulation would likely violate international law. However, because nonconsensual clinical research has previously been regarded as a crime against humanity, the FDA might be able to bring criminal prosecutions under the principal of “universal jurisdiction” against investigators or sponsors who conducted studies without their subjects’ informed consent. This analysis offers both positive and normative conclusions regarding the international legal system and the human rights regime

Visualization of the distribution of autophosphorylated calcium/calmodulin-dependent protein kinase II after tetanic stimulation in the CA1 area of the hippocampus

Autophosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) at threonine-286 produces Ca2+-independent kinase activity and has been proposed to be involved in induction of long-term potentiation by tetanic stimulation in the hippocampus. We have used an immunocytochemical method to visualize and quantify the pattern of autophosphorylation of CaMKII in hippocampal slices after tetanization of the Schaffer collateral pathway. Thirty minutes after tetanic stimulation, autophosphorylated CaM kinase II (P-CaMKII) is significantly increased in area CA1 both in apical dendrites and in pyramidal cell somas. In apical dendrites, this increase is accompanied by an equally significant increase in staining for nonphosphorylated CaM kinase II. Thus, the increase in P-CaMKII appears to be secondary to an increase in the total amount of CaMKII. In neuronal somas, however, the increase in P-CaMKII is not accompanied by an increase in the total amount of CaMKII. We suggest that tetanic stimulation of the Schaffer collateral pathway may induce new synthesis of CaMKII molecules in the apical dendrites, which contain mRNA encoding its alpha-subunit. In neuronal somas, however, tetanic stimulation appears to result in long-lasting increases in P-CaMKII independent of an increase in the total amount of CaMKII. Our findings are consistent with a role for autophosphorylation of CaMKII in the induction and/or maintenance of long-term potentiation, but they indicate that the effects of tetanus on the kinase and its activity are not confined to synapses and may involve induction of new synthesis of kinase in dendrites as well as increases in the level of autophosphorylated kinase

Setting the Stage

4 pagesHorton vs. Oregon Health & Science University

Dave Frohnmayer – A Tribute

4 page

Mutant methionyl-tRNA synthetase from bacteria enables site-selective N-terminal labeling of proteins expressed in mammalian cells

Newly synthesized cellular proteins can be tagged with a variety of metabolic labels that distinguish them from preexisting proteins and allow them to be identified and tracked. Many such labels are incorporated into proteins via the endogenous cellular machinery and can be used in numerous cell types and organisms. Though broad applicability has advantages, we aimed to develop a strategy to restrict protein labeling to specified mammalian cells that express a transgene. Here we report that heterologous expression of a mutant methionyl-tRNA synthetase from Escherichia coli permits incorporation of azidonorleucine (Anl) into proteins made in mammalian (HEK293) cells. Anl is incorporated site-selectively at N-terminal positions (in competition with initiator methionines) and is not found at internal sites. Site selectivity is enabled by the fact that the bacterial synthetase aminoacylates mammalian initiator tRNA, but not elongator tRNA. N-terminally labeled proteins can be selectively conjugated to a variety of useful probes; here we demonstrate use of this system in enrichment and visualization of proteins made during various stages of the cell cycle. N-terminal incorporation of Anl may also be used to engineer modified proteins for therapeutic and other applications

Development and Mechanistic Investigation of Potassium Tert-Butoxide Catalyzed C–H Silylation

The synthetic organic community has a long history of concurrent development of new methods, total syntheses, and mechanistic investigations. For example, new methods may allow the synthesis of previously inaccessible synthetic targets or a challenging transformation in a total synthesis may lead to the development of new reaction methods. Understanding the mechanism of a reaction may lead to the development of new methods or application in total synthesis. Historically, the Stoltz group has found great success focusing on the synergistic development of reaction methods, total synthesis, and mechanistic investigation. This thesis focuses on the mechanistic investigation of a novel method developed by our group and a number of new methods inspired by this better understanding of the reaction mechanism. Initially, an overview of transition-metal-free, catalytic C–H silylation reactions is presented. Next, a detailed mechanistic investigation into the KOt-Bu-catalyzed C–H silylation reaction of aromatic heterocycles is presented. This investigation covers a series of experimental, computational, and analytic techniques to probe possible radical or ionic reaction mechanisms. The development of a number of new methods is presented including the catalytic trimethylsilylation of aromatic heterocycles and catalytic silylation of terminal alkynes. Finally, the current progress of our efforts toward the total synthesis of the natural product illisimonin A are presented.</p

Cleavable Biotin Probes for Labeling of Biomolecules via Azide−Alkyne Cycloaddition

The azide−alkyne cycloaddition provides a powerful tool for bio-orthogonal labeling of proteins, nucleic acids, glycans, and lipids. In some labeling experiments, e.g., in proteomic studies involving affinity purification and mass spectrometry, it is convenient to use cleavable probes that allow release of labeled biomolecules under mild conditions. Five cleavable biotin probes are described for use in labeling of proteins and other biomolecules via azide−alkyne cycloaddition. Subsequent to conjugation with metabolically labeled protein, these probes are subject to cleavage with either 50 mM Na_2S_2O_4, 2% HOCH_2CH_2SH, 10% HCO_2H, 95% CF_3CO_2H, or irradiation at 365 nm. Most strikingly, a probe constructed around a dialkoxydiphenylsilane (DADPS) linker was found to be cleaved efficiently when treated with 10% HCO_2H for 0.5 h. A model green fluorescent protein was used to demonstrate that the DADPS probe undergoes highly selective conjugation and leaves a small (143 Da) mass tag on the labeled protein after cleavage. These features make the DADPS probe especially attractive for use in biomolecular labeling and proteomic studies

State-Selective Metabolic Labeling of Cellular Proteins

Transcriptional activity from a specified promoter can provide a useful marker for the physiological state of a cell. Here we introduce a method for selective tagging of proteins made in cells in which specified promoters are active. Tagged proteins can be modified with affinity reagents for enrichment or with fluorescent dyes for visualization. The method allows state-selective analysis of the proteome, whereby proteins synthesized in predetermined physiological states can be identified. The approach is demonstrated by proteome-wide labeling of bacterial proteins upon activation of the P_(BAD) promoter and the SoxRS regulon and provides a basis for analysis of more complex systems including spatially heterogeneous microbial cultures and biofilms

Transcript: Session 2: The Problem of State Judicial Campaign “Arms Races”—What Can Be Done in the State Legislatures and State Courts?

Many years ago, when my hair was still thick, this justice spoke at a conference on state court judicial elections. I was not there, but the story goes that when it came to an audience question, an idealistic young man asked this West Virginia supreme court justice: How do you go about becoming a state supreme court justice? Do you have to go to a good law school? Do you have to become involved in the state bar association? Do you have to become involved in civic organizations? Do you have to become a trial judge, then an appellate judge, and then tender your resume to the governor and hope that merit is the measure? Is that how you have to do it? Without pausing for an ethical second, the bold justice from West Virginia said, “Money, my man, money.” This is the realist backdrop or subtext for much of the discussion about Caperton and also White. At least some of the subtext includes an animosity to judicial elections and an attempt to defang them