Ethics of the electrified mind: defining issues and perspectives on the principled use of brain stimulation in medical research and clinical care.

In recent years, non-pharmacologic approaches to modifying human neural activity have gained increasing attention. One of these approaches is brain stimulation, which involves either the direct application of electrical current to structures in the nervous system or the indirect application of current by means of electromagnetic induction. Interventions that manipulate the brain have generally been regarded as having both the potential to alleviate devastating brain-related conditions and the capacity to create unforeseen and unwanted consequences. Hence, although brain stimulation techniques offer considerable benefits to society, they also raise a number of ethical concerns. In this paper we will address various dilemmas related to brain stimulation in the context of clinical practice and biomedical research. We will survey current work involving deep brain stimulation, transcranial magnetic stimulation and transcranial direct current stimulation. We will reflect upon relevant similarities and differences between them, and consider some potentially problematic issues that may arise within the framework of established principles of medical ethics: nonmaleficence and beneficence, autonomy, and justice.

What Should Oversight of Clinical Decision Support Systems Look Like?

A learning health system provides opportunities to leverage data generated in the course of standard clinical care to improve clinical practice. One such opportunity includes a clinical decision support structure that would allow clinicians to query electronic health records (EHRs) such that responses from the EHRs could inform treatment recommendations. We argue that though using a clinical decision support system does not necessarily constitute a research activity subject to the Common Rule, it requires more ethical and regulatory oversight than activities of clinical practice are generally subjected to. In particular, we argue that the development and use of clinical decision support systems should be governed by a framework that (1) articulates appropriate conditions for their use, (2) includes processes for monitoring data quality and developing and validating algorithms, and (3) sufficiently protects patients' data.

Disruptions in AUX1-dependent auxin influx alter hypocotyl phototropism in Arabidopsis.

Phototropism represents a differential growth response by which plant organs can respond adaptively to changes in the direction of incident light to optimize leaf/stem positioning for photosynthetic light capture and root growth orientation for water/nutrient acquisition. Studies over the past few years have identified a number of components in the signaling pathway(s) leading to development of phototropic curvatures in hypocotyls. These include the phototropin photoreceptors (phot1 and phot2) that perceive directional blue-light (BL) cues and then stimulate signaling, leading to relocalization of the plant hormone auxin, as well as the auxin response factor NPH4/ARF7 that responds to changes in local auxin concentrations to directly mediate expression of genes likely encoding proteins necessary for development of phototropic curvatures. While null mutations in NPH4/ARF7 condition an aphototropic response to unidirectional BL, seedlings carrying the same mutations recover BL-dependent phototropic responsiveness if co-irradiated with red light (RL) or pre-treated with either ethylene. In the present study, we identify second-site enhancer mutations in the nph4 background that abrogate these recovery responses. One of these mutations--map1 (modifier of arf7 phenotypes 1)--was found to represent a missense allele of AUX1--a gene encoding a high-affinity auxin influx carrier previously associated with a number of root responses. Pharmacological studies and analyses of additional aux1 mutants confirmed that AUX1 functions as a modulator of hypocotyl phototropism. Moreover, we have found that the strength of dependence of hypocotyl phototropism on AUX1-mediated auxin influx is directly related to the auxin responsiveness of the seedling in question.

Signal transduction during light-quality acclimation in cyanobacteria: a model system for understanding phytochrome-response pathways in prokaryotes.

The colorful process of complementary chromatic adaptation (CCA), in which cyanobacteria dramatically alter their pigmentation in response to ambient light color changes, has intrigued scientists for more than a century. Over the past four decades, intensive research on the model organism Fremyella diplosiphon has revealed many details of the photobiology and molecular biology of this process, which includes restructuring of these organism's photosynthetic light-harvesting antennae, called phycobilisomes. This restructuring involves changes in transcription of genes encoding phycobilisome components. These genes have been cloned and their patterns of light-responsive expression characterized. In the past ten years, attention has focused on the signal transduction mechanism(s) through which cyanobacteria sense and respond to changes in ambient light color. Genetic approaches led to the isolation of signal transduction components that control light-color responses in F. diplosiphon. Several of these appear to be within a complex phosphorelay that is in part controlled by a photoreceptor called RcaE, the founding member of a large, novel class of prokaryotic photoreceptors with similarity to both plant phytochrome photoreceptors and sensor histidine kinases. The strong foundation of knowledge provided by years of research on CCA makes this a powerful model system for studying signal transduction systems controlled by prokaryotic phytochromes. In this regard, recent results demonstrate that multiple light sensing systems control this organism's responses to changes in light quality and that large numbers of genes are differentially regulated during this process.

Genomic DNA microarray analysis: identification of new genes regulated by light color in the cyanobacterium Fremyella diplosiphon.

Many cyanobacteria use complementary chromatic adaptation to efficiently utilize energy from both green and red regions of the light spectrum during photosynthesis. Although previous studies have shown that acclimation to changing light wavelengths involves many physiological responses, research to date has focused primarily on the expression and regulation of genes that encode proteins of the major photosynthetic light-harvesting antennae, the phycobilisomes. We have used two-dimensional gel electrophoresis and genomic DNA microarrays to expand our understanding of the physiology of acclimation to light color in the cyanobacterium Fremyella diplosiphon. We found that the levels of nearly 80 proteins are altered in cells growing in green versus red light and have cloned and positively identified 17 genes not previously known to be regulated by light color in any species. Among these are homologs of genes present in many bacteria that encode well-studied proteins lacking clearly defined functions, such as tspO, which encodes a tryptophan-rich sensory protein, and homologs of genes encoding proteins of clearly defined function in many species, such as nblA and chlL, encoding phycobilisome degradation and chlorophyll biosynthesis proteins, respectively. Our results suggest novel roles for several of these gene products and highly specialized, unique uses for others.