Keeping track of worm trackers

C. elegans is used extensively as a model system in the neurosciences due to its well defined nervous system. However, the seeming simplicity of this nervous system in anatomical structure and neuronal connectivity, at least compared to higher animals, underlies a rich diversity of behaviors. The usefulness of the worm in genome-wide mutagenesis or RNAi screens, where thousands of strains are assessed for phenotype, emphasizes the need for computational methods for automated parameterization of generated behaviors. In addition, behaviors can be modulated upon external cues like temperature, O2 and CO2 concentrations, mechanosensory and chemosensory inputs. Different machine vision tools have been developed to aid researchers in their efforts to inventory and characterize defined behavioral “outputs”. Here we aim at providing an overview of different worm-tracking packages or video analysis tools designed to quantify different aspects of locomotion such as the occurrence of directional changes (turns, omega bends), curvature of the sinusoidal shape (amplitude, body bend angles) and velocity (speed, backward or forward movement)

Hypofractionated SBRT versus conventionally fractionated EBRT for prostate cancer: comparison of PSA slope and nadir.

BackgroundPatients with early stage prostate cancer have a variety of curative radiotherapy options, including conventionally-fractionated external beam radiotherapy (CF-EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Although results of CF-EBRT are well known, the use of SBRT for prostate cancer is a more recent development, and long-term follow-up is not yet available. However, rapid post-treatment PSA decline and low PSA nadir have been linked to improved clinical outcomes. The purpose of this study was to compare the PSA kinetics between CF-EBRT and SBRT in newly diagnosed localized prostate cancer.Materials/methods75 patients with low to low-intermediate risk prostate cancer (T1-T2; GS 3 + 3, PSA < 20 or 3 + 4, PSA < 15) treated without hormones with CF-EBRT (>70.2 Gy, <76 Gy) to the prostate only, were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997-2012). Patients were excluded if they failed therapy by the Phoenix definition or had less than 1 year of follow-up or <3 PSAs. 43 patients who were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. PSA nadir and rate of change in PSA over time (slope) were calculated from the completion of RT to 1, 2 and 3 years post-RT.ResultsThe median PSA nadir and slope for CF-EBRT was 1.00, 0.72 and 0.60 ng/ml and -0.09, -0.04, -0.02 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadirs and slopes were 0.70, 0.40, 0.24 ng and -0.09, -0.06, -0.05 ng/ml/month, respectively. The PSA slope for SBRT was greater than CF-EBRT (p < 0.05) at 2 and 3 years following RT, although similar during the first year. Similarly, PSA nadir was significantly lower for SBRT when compared to EBRT for years 2 and 3 (p < 0.005).ConclusionPatients treated with SBRT experienced a lower PSA nadir and greater rate of decline in PSA 2 and 3 years following completion of RT than with CF-EBRT, consistent with delivery of a higher bioequivalent dose. Although follow-up for SBRT is limited, the improved PSA kinetics over CF-EBRT are promising for improved biochemical control

Microbial light-activatable proton pumps as neuronal inhibitors to functionally dissect neuronal networks in C. elegans

Essentially any behavior in simple and complex animals depends on neuronal network function. Currently, the best-defined system to study neuronal circuits is the nematode Caenorhabditis elegans, as the connectivity of its 302 neurons is exactly known. Individual neurons can be activated by photostimulation of Channelrhodopsin-2 (ChR2) using blue light, allowing to directly probe the importance of a particular neuron for the respective behavioral output of the network under study. In analogy, other excitable cells can be inhibited by expressing Halorhodopsin from Natronomonas pharaonis (NpHR) and subsequent illumination with yellow light. However, inhibiting C. elegans neurons using NpHR is difficult. Recently, proton pumps from various sources were established as valuable alternative hyperpolarizers. Here we show that archaerhodopsin-3 (Arch) from Halorubrum sodomense and a proton pump from the fungus Leptosphaeria maculans (Mac) can be utilized to effectively inhibit excitable cells in C. elegans. Arch is the most powerful hyperpolarizer when illuminated with yellow or green light while the action spectrum of Mac is more blue-shifted, as analyzed by light-evoked behaviors and electrophysiology. This allows these tools to be combined in various ways with ChR2 to analyze different subsets of neurons within a circuit. We exemplify this by means of the polymodal aversive sensory ASH neurons, and the downstream command interneurons to which ASH neurons signal to trigger a reversal followed by a directional turn. Photostimulating ASH and subsequently inhibiting command interneurons using two-color illumination of different body segments, allows investigating temporal aspects of signaling downstream of ASH

In Search of a Rational Sentence: A Return to the Concept of Appellate Review

I. Introduction II. Origin and Development of the Non-Review Doctrine … A. Appellate Jurisdiction: Early Judicial Construction … B. Supreme Court Precedents: Emerging Requirement of Individualized Sentences … C. Current Circuit Positions on Individualized Sentences … D. Abandonment of the Non-Review Doctrine III. Sources for a Doctrine of Appellate Review of Sentencing … A. Existing Statutory Exceptions … B. Pending Legislation … C. Reexamination of Judicial Arguments against Review … 1. Does the Trial Judge Have an Advantage? … 2. Should the Trial Judge State His Reasons? … D. Other Non-Legislative Recommendations … E. Recent Congressional Hearings IV. Conclusion and Recommendation Postscript Appendi

Assessing the Safety and Efficacy of the FDA: The Case of the Prescription Drug User Fee Acts

The US Food and drug Administration (FDA) is estimated to regulate markets accounting for about 20% of consumer spending in the US. This paper proposes a general methodology to evaluate FDA policies, in general, and the central speed-safety tradeoff it faces, in particular. We apply this methodology to estimate the welfare effects of a major piece of legislation affecting this tradeoff, the Prescription Drug User Fee Acts (PDUFA). We find that PDUFA raised the private surplus of producers, and thus innovative returns, by about $11 to$13 billion. Dependent on the market power assumed of producers while having patent protection, we find that PDUFA raised consumer welfare between $5 to$19 billion; thus the combined social surplus was raised between $18 to$31 billions. Converting these economic gains into equivalent health benefits, we find that the more rapid access of drugs on the market enabled by PDUFA saved the equivalent of 180 to 310 thousand life-years. Additionally, we estimate an upper bound on the adverse effects of PDUFA based on drugs submitted during PDUFA I/II and subsequently withdrawn for safety reasons, and find that an extreme upper bound of about 56 thousand life-years were lost. We discuss how our general methodology could be used to perform a quantitative and evidence-based evaluation of the desirability of other FDA policies in the future, particularly those affecting the speed-safety tradeoff.

Contribution of seasonal sub-Antarctic surface water variability to millennial-scale changes in atmospheric CO<inf>2</inf> over the last deglaciation and Marine Isotope Stage 3

The Southern Ocean is thought to have played a key role in past atmospheric carbon dioxide (CO2,atm) changes. Three main factors are understood to control the Southern Ocean's influence on CO2,atm, via their impact on surface ocean pCO2 and therefore regional ocean–atmosphere CO2 fluxes: 1) the efficiency of air–sea gas exchange, which may be attenuated by seasonal- or annual sea-ice coverage or the development of a shallow pycnocline; 2) the supply of CO2-rich water masses from the sub-surface and the deep ocean, which is associated with turbulent mixing and surface buoyancy- and/or wind forcing; and 3) biological carbon fixation, which depends on nutrient availability and is therefore influenced by dust deposition and/or upwelling. In order to investigate the possible contributions of these processes to millennial-scale CO2,atm variations during the last glacial and deglacial periods, we make use of planktonic foraminifer census counts and stable oxygen- and carbon isotope measurements in the planktonic foraminifera Globigerina bulloides and Neogloboquadrina pachyderma (sinistral) from marine sediment core MD07-3076Q in the sub-Antarctic Atlantic. These data are interpreted on the basis of a comparison of core-top and modern seawater isotope data, which permits an assessment of the seasonal biases and geochemical controls on the stable isotopic compositions of G. bulloides and N. pachyderma (s.). Based on a comparison of our down-core results with similar data from the Southeast Atlantic (Cape Basin) we infer past basin-wide changes in the surface hydrography of the sub-Antarctic Atlantic. We find that millennial-scale rises in CO2,atm over the last 70 ka are consistently linked with evidence for increased spring upwelling, and enhanced summer air–sea exchange in the sub-Antarctic Atlantic. Parallel evidence for increased summer export production would suggest that seasonal changes in upwelling and air–sea exchange exerted a dominant influence on surface pCO2 in the sub-Antarctic Atlantic. These results underline the role of Southern Ocean dynamics, in particular their seasonal variations, in driving millennial-scale variations in CO2,atm.This work was supported by the Gates Cambridge Trust, the Royal Society and NERC grant NE/J010545/1.This was originally published in Earth and Planetary Science Letters (J Gottschalk, LC Skinner, C Waelbroeck, Earth and Planetary Science Letters 2015, 411, 87-99