Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins

Diverse optogenetic tools have allowed versatile control over neural activity. Many depolarizing and hyperpolarizing tools have now been developed in multiple laboratories and tested across different preparations, presenting opportunities but also making it difficult to draw direct comparisons. This challenge has been compounded by the dependence of performance on parameters such as vector, promoter, expression time, illumination, cell type and many other variables. As a result, it has become increasingly complicated for end users to select the optimal reagents for their experimental needs. For a rapidly growing field, critical figures of merit should be formalized both to establish a framework for further development and so that end users can readily understand how these standardized parameters translate into performance. Here we systematically compared microbial opsins under matched experimental conditions to extract essential principles and identify key parameters for the conduct, design and interpretation of experiments involving optogenetic techniques

Beyond the Red, Purple, and Blue: Election Law Issues in 2012

The Symposium Welcome was given by Clint A. Nichols, the Allen Chair Editor for the University of Richmond Law Review, and Wendy C. Perdue, Dean & Professor of Law at the University of Richmond School of Law. The “Get out the vote?” session was presented by Keesha M. Gaskins, Senior Counsel with the Brennan Center for Justice at New York University; Steven F. Huefner, Professor of Law and Director of Clinical Programs at The Ohio State University Moritz College of Law; Joshua N. Lief, Senior Assistant Attorney General for the Commonwealth of Virginia; and Michael J. Pitts, Professor of Law and Dean’s Fellow at Indiana University’s Robert H. McKinney School of Law. The “Third Parties to the Process” session was presented by Jocelyn F. Benson, Associate Professor of Law at Wayne State University Law School; Joshua A. Douglas, Assistant Professor of Law at the University of Kentucky College of Law; and Rebecca Green, Professor of the Practice of Law and Co-Director of the Election Law Program at the William & Mary Law School. The “Drawing the Lines” session was presented by Keesha M. Gaskins, Senior Counsel with the Brennan Center for Justice at New York University; Dale Ho, Assistant Counsel with the NAACP Legal Defense and Educational Fund; Dr. Michael P. McDonald, Associate Professor of Government and Politics at George Mason University; Donald Palmer, Secretary of the Virginia State Board of Elections; and Rob Richie, Executive Director of FairVote

Organic matter and carbon isotope composition of carbonate nodules and associated sediments from middle valley, leg 139

Carbonate nodules and associated sediments from Ocean Drilling Program Leg 139 sites of the Middle Valley, Juan de Fuca Ridge, were studied using a combination of inorganic and organic geochemical techniques. The mineralogy and stable isotopic compositions defined three types of nodules, reflecting the conditions of carbonate precipitation. Nodule ingrowth has entrapped the sedimentary organic matter, and concomitant displacement of the sedimentary mineral matrix and associated organic matter resulted in decreased bitumen extract yields from the nodules. Molecular organic geochemical analyses of the bitumen by gas chromatography-mass spectrometry revealed that polycyclic aromatic hydrocarbons are major constituents in the total extracts, reflecting the high-temperature origin of the entrapped hydrothermal organic products. Strong reducing conditions are evident during the hydrothermal alteration of biomarker precursors to products. The oxygen isotope data reflect the lower fluid temperatures during carbonate precipitation

Making space for empathy: supporting doctors in the emotional labour of clinical care

BACKGROUND: The academic and medical literature highlights the positive effects of empathy for patient care. Yet, very little attention has been given to the impact of the requirement for empathy on the physicians themselves and on their emotional wellbeing. DISCUSSION: The medical profession requires doctors to be both clinically competent and empathetic towards the patients. In practice, accommodating both requirements can be difficult for physicians. The image of the technically skilful, rational, and emotionally detached doctor dominates the profession, and inhibits physicians from engaging emotionally with their patients and their own feelings, which forms the basis for empathy. This inhibition has a negative impact not only on the patients but also on the physicians. The expression of emotions in medical practice is perceived as unprofessional and many doctors learn to supress and ignore their feelings. When facing stressful situations, these physicians are more likely to suffer from depression and burnout than those who engage with and reflect on their feelings. Physicians should be supported in their emotional work, which will help them develop empathy. Methods could include questionnaires that aid self-reflection, and discussion groups with peers and supervisors on emotional experiences. Yet, in order for these methods to work, the negative image associated with the expression of emotions should be questioned. Also, the work conditions of physicians should improve to allow them to make use of these tools. SUMMARY: Empathy should not only be expected from doctors but should be actively promoted, assisted and cultivated in the medical profession

Amygdala circuitry mediating reversible and bidirectional control of anxiety

Anxiety—a sustained state of heightened apprehension in the absence of immediate threat—becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)—achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA—exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA–CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease

The Rule of Law is Dead! Long Live the Rule of Law!

Polls show that a significant proportion of the public considers judges to be political. This result holds whether Americans are asked about Supreme Court justices, federal judges, state judges, or judges in general. At the same time, a large majority of the public also believes that judges are fair and impartial arbiters, and this belief also applies across the board. In this paper, I consider what this half-law-half-politics understanding of the courts means for judicial legitimacy and the public confidence on which that legitimacy rests. Drawing on the Legal Realists, and particularly on the work of Thurman Arnold, I argue against the notion that the contradictory views must be resolved in order for judicial legitimacy to remain intact. A rule of law built on contending legal and political beliefs is not necessarily fair or just. But it can be stable. At least in the context of law and courts, a house divided may stand

Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis

Immunoglobulin light-chain (AL) amyloidosis is a rare, incurable plasma cell disorder. Its therapy has benefited immensely from the expanding drug armamentarium available for multiple myeloma. Pomalidomide in combination with weekly dexamethasone (Pom/dex) is active among patients with relapsed myeloma. In the present study, we explored the Pom/dex combination in patients with previously treated AL. Patients were eligible for this prospective phase 2 trial if they had had at least one prior regimen and if they had reasonably preserved organ function. Patients were treated with oral Pom/dex. Thirty-three patients were enrolled. The median age was 66 years. Median time from diagnosis to on-study was 37 months. Eighty-two percent had cardiac involvement. The confirmed hematologic response rate was 48%, with a median time to response of 1.9 months. Organ improvement was documented in 5 patients. The median overall and progression-free survival rates were 28 and 14 months, respectively; the 1-year overall and progression-free survival rates were 76% and 59%, respectively. There was a discordance between the hematologic response and the N-terminal probrain natriuretic peptide response. The most common grade 3-5 adverse events, regardless of attribution, were neutropenia and fatigue. We conclude that pomalidomide appears to be a valuable drug covering an unmet clinical need in patients with previously treated AL. The trial is registered at www.clinicaltrials.gov as NCT00558896. (Blood. 2012;119(23): 5397-5404

SNCA Triplication Parkinson's Patient's iPSC-derived DA Neurons Accumulate α-Synuclein and Are Susceptible to Oxidative Stress

Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the α-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of α-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain

Expanding the role of supervision in child psychiatric education

Despite the burgeoning of available therapeutic interventions, the sparse literature devoted to child psychiatric supervision concentrates on individual psychotherapy. The non-cognitive aspects of the expanding supervisory challenge continues to converge on the clinician's personality, which is a focus of educational attention only in sequestered or haphazard parts of programs. The unidimensional supervisory literature addresses this issue by questioning the extent to which supervision should resemble traditional pedagogy or personal psychotherapy. In contrast to this emphasis on elusive unconscious influences on clinical work, scant attention has been devoted to other influences stemming from the clinician's current experiences, affiliations, identifications, aspirations and similar more easily modifiable factors that exert considerable leverage and tend to be more accessible to rational scrutiny in supervision. The latter half of this paper discusses these factors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43974/1/10578_2005_Article_BF01463219.pd

Fashioning Entitlements: A Comparative Law and Economic Analysis of the Judicial Role in Environmental Centralization in the U.S. and Europe

This paper identifies and evaluates, from an economic point of view, the role of the judiciary the steady shift of environmental regulatory authority to higher, more centralized levels of government in both the U.S. and Europe. We supply both a positive analysis of how the decisions made by judges have affected the incentives of both private and public actors to pollute the natural environment, and normative answers to the question of whether judges have acted so as to create incentives that move levels of pollution in an efficient direction, toward their optimal, cost-minimizing (or net-benefit-maximizing) levels. Highlights of the analysis include the following points: 1) Industrial-era local (state or national) legislation awarding entitlements to pollute was almost certainly inefficient due to a fundamental economic obstacle faced by those who suffer harm from the over-pollution of publicly owned natural resources: the inability to monetize and credibly commit to repay the future economic value of reducing pollution. 2) When industrial era pollution spilled across state lines in the US, the federal courts, in particular the Supreme Court, fashioned a federal common law of interstate nuisance that set up essentially the same sort of blurry, uncertain entitlements to pollute or be free of pollution that had been created by the state courts in resolving local pollution disputes. We argue that for the typical pollution problem, a legal regime of blurry interstate entitlements - with neither jurisdiction having a clear right either to pollute or be free of pollution from the other - is likely to generate efficient incentives for interjursidictional bargaining, even despite the public choice problems besetting majority-rule government. Interestingly, a very similar system of de facto entitlements arose and often stimulated interjursidictional bargaining in Europe as well as in the U.S. 3) The US federal courts have generally interpreted the federal environmental statutes in ways that give clear primacy to federal regulators. Through such judicial interpretation, state and local regulators face a continuing risk of having their decisions overridden by federal regulators. This reduces the incentives for regulatory innovation at the state and local level. Judicial authorization of federal overrides has thus weakened the economic rationale for cooperative federalism suggested by economic models of principal-agent relationships. As a result of the principle of attribution, there is less risk in Europe that (like in the US) courts would enlarge the federal purview and thereby limit the powers of the Member States. Despite this principle, the power of the European bureaucracy (that is, the European Commission) has steadily increased and led to a steady shift of environmental regulatory competencies to the European level. This shift is only sometimes normatively desirable, and yet there is little that the ECJ can or will do to slow it