Single-Cell RNA-seq Reveals Profound Alterations in Mechanosensitive Dorsal Root Ganglion Neurons with Vitamin E Deficiency.

Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa-/- mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa-/- DRGNs showed marked upregulation of voltage-gated Ca2+ and K+ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa-/- DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation

Search for optimal distance spectrum convolutional codes

In order to communicate reliably and to reduce the required transmitter power, NASA uses coded communication systems on most of their deep space satellites and probes (e.g. Pioneer, Voyager, Galileo, and the TDRSS network). These communication systems use binary convolutional codes. Better codes make the system more reliable and require less transmitter power. However, there are no good construction techniques for convolutional codes. Thus, to find good convolutional codes requires an exhaustive search over the ensemble of all possible codes. In this paper, an efficient convolutional code search algorithm was implemented on an IBM RS6000 Model 580. The combination of algorithm efficiency and computational power enabled us to find, for the first time, the optimal rate 1/2, memory 14, convolutional code

Neurochemical Characterization of the Tree Shrew Dorsal Striatum

The striatum is a major component of the basal ganglia and is associated with motor and cognitive functions. Striatal pathologies have been linked to several disorders, including Huntington’s, Tourette’s syndrome, obsessive–compulsive disorders, and schizophrenia. For the study of these striatal pathologies different animal models have been used, including rodents and non-human primates. Rodents lack on morphological complexity (for example, the lack of well defined caudate and putamen nuclei), which makes it difficult to translate data to the human paradigm. Primates, and especially higher primates, are the closest model to humans, but there are ever-increasing restrictions to the use of these animals for research. In our search for a non-primate animal model with a striatum that anatomically (and perhaps functionally) can resemble that of humans, we turned our attention to the tree shrew. Evolutionary genetic studies have provided strong data supporting that the tree shrews (Scadentia) are one of the closest groups to primates, although their brain anatomy has only been studied in detail for specific brain areas. Morphologically, the tree shrew striatum resembles the primate striatum with the presence of an internal capsule separating the caudate and putamen, but little is known about its neurochemical composition. Here we analyzed the expression of calcium-binding proteins, the presence and distribution of the striosome and matrix compartments (by the use of calbindin, tyrosine hydroxylase, and acetylcholinesterase immunohistochemistry), and the GABAergic system by immunohistochemistry against glutamic acid decarboxylase and Golgi impregnation. In summary, our results show that when compared to primates, the tree shrew dorsal striatum presents striking similarities in the distribution of most of the markers studied, while presenting some marked divergences when compared to the rodent striatum

Potential Impact of Revised Nci Eligibility Criteria Guidance: Prior Malignancy Exclusion in Breast Cancer Clinical Trials

BACKGROUND: Many individuals with cancer have survived a prior cancer and for this reason may have been excluded from clinical trials. Recent NCI guidance recommends including these individuals, especially when the risk of the prior malignancy interfering with either safety or efficacy endpoints is very low. Using breast cancer as an example, we determined the potential effect this policy change may have on clinical trial accrual. PATIENTS AND METHODS: We reviewed protocols of NCI-sponsored breast cancer clinical trials activated in 1991 through 2016. We quantified prevalence of prior cancer-related exclusion criteria and assessed the association with trial characteristics using Fisher\u27s exact tests. Using SEER data, we estimated the prevalence and timing of prior primary (nonbreast) cancer diagnoses among patients with breast cancer. RESULTS: Among 87 clinical trials (total target enrollment, 137,253 patients), 77% excluded individuals with prior cancer, most commonly (79%) within the preceding 5 years. Among trials with radiographic response or toxicity endpoints, 69% excluded prior cancer. In SEER data, the prevalence of a prior (nonbreast) cancer diagnosis ranged from 5.7% to 7.7%, depending on breast cancer stage, of which 39% occurred within 5 years of the incident breast cancer. For trials excluding prior cancer, the estimated proportion of patients excluded for this reason ranged from 1.3% to 5.8%, with the estimated number of excluded patients ranging from 1 to 288. CONCLUSIONS: More than three-fourths of NCI-sponsored breast cancer clinical trials exclude patients with prior cancer, including almost 70% of trials with response or toxicity endpoints. Given that \u3e5% of patients with breast cancer have a history of prior cancer, in large phase III trials this practice may exclude hundreds of patients. Following recent NCI eligibility guidance, the inclusion of patients with prior cancer on breast cancer trials may have a meaningful impact on accrual

Dopamine Pathology in Schizophrenia: Analysis of Total and Phosphorylated Tyrosine Hydroxylase in the Substantia Nigra

Introduction: Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. Objectives: In this study, we had three objectives: (1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. (2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. (3) Examine possible regional differences in TH expression anomalies within the SN/VTA. Methods: To achieve these objectives three independent studies were conducted: (1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. (2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. (3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. Results and Conclusion: Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic pathology rather than a treatment effect

Asymptotically-optimal path planning for manipulation using incremental sampling-based algorithms

A desirable property of path planning for robotic manipulation is the ability to identify solutions in a sufficiently short amount of time to be usable. This is particularly challenging for the manipulation problem due to the need to plan over high-dimensional configuration spaces and to perform computationally expensive collision checking procedures. Consequently, existing planners take steps to achieve desired solution times at the cost of low quality solutions. This paper presents a planning algorithm that overcomes these difficulties by augmenting the asymptotically-optimal RRT* with a sparse sampling procedure. With the addition of a collision checking procedure that leverages memoization, this approach has the benefit that it quickly identifies low-cost feasible trajectories and takes advantage of subsequent computation time to refine the solution towards an optimal one. We evaluate the algorithm through a series of Monte Carlo simulations of seven, twelve, and fourteen degree of freedom manipulation planning problems in a realistic simulation environment. The results indicate that the proposed approach provides significant improvements in the quality of both the initial solution and the final path, while incurring almost no computational overhead compared to the RRT algorithm. We conclude with a demonstration of our algorithm for single-arm and dual-arm planning on Willow Garage's PR2 robot

First Study of a HEXITEC Detector for Secondary Particle Characterisation during Proton Beam Therapy

Online proton range verification is a rapidly emerging field characterised by its ability to reduce the error margins during proton beam therapy, as it is patient-specific and in vivo. In particular, secondary prompt gamma detection is a promising tool to monitor the dose delivery. The present research evaluates the capability of a HEXITEC detector to identify the prompt gammas produced during proton beam therapy, and assesses its potential for online range verification. To achieve this, the detector is placed at one side of a water phantom, which is irradiated at different proton energies in the University College London Hospital Proton Centre. For further analysis, Monte Carlo simulations are performed using Geant4 and the same geometry as the experiment. The results show that HEXITEC has the potential to be part of a detection system that could identify secondary prompt gammas within the secondary field produced inside the target, allowing for the in-detector discrimination of these particles via cluster size analysis. The comparison between data sets shows that there is a high level of accuracy between the model and the experimental measurements in terms of secondary flux and charge diffusion inside the detector, which poses the model as a fundamental tool for future optimisation studies

Genetic and Biophysical Modelling Evidence of Generational Connectivity in the Intensively Exploited, Western North Atlantic Red Grouper (Epinephelus morio)

Understanding the connectivity of reef organisms is important to assist in the conservation of biological diversity and to facilitate sustainable fisheries in these ecosystems. Common methods to assess reef connectivity include both population genetics and biophysical modelling. Individually, these techniques can offer insight into population structure; however, the information acquired by any singular analysis is often subject to limitations, underscoring the need for a multi-faceted approach. To assess the connectivity dynamics of the red grouper (Epinephelus morio), an economically important reef fish species found throughout the Gulf of Mexico and USA western Atlantic, we utilized two sets of genetic markers (12 microsatellite loci and 632 single nucleotide polymorphisms) to resolve this species’ population genetic structure, along with biophysical modelling to deliver a spatial forecast of potential larval “sources” and “sinks” across these same regions and spatial scale. Our genetic survey indicates little, if any, evidence of population genetic structure and modelling efforts indicate the potential for ecological connectivity between sampled regions over multiple generations. We offer that using a dual empirical and theoretical approach lessens the error associated with the use of any single method and provides an important step towards the validation of either of these methodologies

Mapping The Interstellar Medium With Near-Infrared Diffuse Interstellar Bands

We map the distribution and properties of the Milky Way's interstellar medium as traced by diffuse interstellar bands (DIBs) detected in near-infrared stellar spectra from the SDSS-III/APOGEE survey. Focusing exclusively on the strongest DIB in the H band, at lambda similar to 1.527 mu m, we present a projected map of the DIB absorption field in the Galactic plane, using a set of about 60,000 sightlines that reach up to 15 kpc from the Sun and probe up to 30 mag of visual extinction. The strength of this DIB is linearly correlated with dust reddening over three orders of magnitude in both DIB equivalent width (Wpm) and extinction, with a power law index of 1.01 +/- 0.01, a mean relationship of W-DIB/A(v) = 0.1 angstrom mag(-1) and a dispersion of similar to 0.05 angstrom mag(-1) at extinctions characteristic of the Galactic midplane. These properties establish this DIB as a powerful, independent probe of dust extinction over a wide range of Av values. The subset of about 14,000 robustly detected DIB features have a W-DIB distribution that follows an exponential trend. We empirically determine the intrinsic rest wavelength of this transition to be lambda(0) = 15 272.42 angstrom and use it to calculate absolute radial velocities of the carrier, which display the kinematical signature of the rotating Galactic disk. We probe the DIB carrier distribution in three dimensions and show that it can be characterized by an exponential disk model with a scale height of about 100 pc and a scale length of about 5 kpc. Finally, we show that the DIB distribution also traces large-scale Galactic structures, including the Galactic long bar and the warp of the outer disk.NSF Astronomy & Astrophysics Postdoctoral Fellowship AST-1203017NSF AST-1109665Alfred P. Sloan FoundationNational Science FoundationU.S. Department of Energy Office of ScienceUniversity of ArizonaBrazilian Participation GroupBrookhaven National LaboratoryUniversity of CambridgeCarnegie Mellon UniversityUniversity of FloridaFrench Participation GroupGerman Participation GroupHarvard UniversityInstituto de Astrofisica de CanariasMichigan State/Notre Dame/JINA Participation GroupJohns Hopkins UniversityLawrence Berkeley National LaboratoryMax Planck Institute for AstrophysicsMax Planck Institute for Extraterrestrial PhysicsNew Mexico State UniversityNew York UniversityOhio State UniversityPennsylvania State UniversityUniversity of PortsmouthPrinceton UniversitySpanish Participation GroupUniversity of TokyoUniversity of UtahVanderbilt UniversityUniversity of VirginiaUniversity of WashingtonYale UniversitySpanish Ministry of Economy and Competitiveness AYA-2011-27754McDonald Observator