Latent Sensitization in a Mouse Model of Ocular Neuropathic Pain

Purpose: Chronic ocular pain is poorly understood and difficult to manage. We developed a murine model of corneal surface injury (CSI)–induced chronic ocular neuropathic pain. The study focuses on changes in corneal nerve morphology and associated short- and long-term pain-like behavior after CSI. Methods: CSI was induced in mice by local application of an alkali solution (0.75 N NaOH). Corneal nerve architecture, morphology, density, and length were studied. Eye-wiping was evaluated before and after CSI in response to hypertonic saline (2 M NaCl). Naltrexone (NTX) or Naloxone-methiodide (NLX-me), opioid receptor antagonists, were given subcutaneously (s.c., 3 mg/kg) or topically (eye drop, 100 μM), and then an eye-wiping test was performed. Results: CSI caused partial corneal deinnervation followed by gradual reinnervation. Regenerated nerves displayed increased tortuosity, beading, and branching. CSI enhanced hypertonic saline-induced eye-wiping behavior compared to baseline or sham-injury (P \u3c 0.01). This hypersensitivity peaked at 10 days and subsided 14 days after CSI. Administration of NTX, or NLX-me, a selective peripheral opioid antagonist, reinstated eye-wiping behavior in the injury group, but not in the sham groups (P \u3c 0.05). Conclusions: This study introduces a model of chronic ocular pain and corneal neuropathy following CSI. CSI induces central and peripheral opioid receptor-dependent latent sensitization (LS) that is unmasked by systemic or topical administration of opioid antagonists. Translational Relevance: This model of chronic ocular pain establishes LS as a new inhibitory mechanism in the oculotrigeminal system and may be used for potential diagnostic and therapeutic interventions for ocular neuropathy

Quantum magneto-oscillations in a two-dimensional Fermi liquid

Quantum magneto-oscillations provide a powerfull tool for quantifying Fermi-liquid parameters of metals. In particular, the quasiparticle effective mass and spin susceptibility are extracted from the experiment using the Lifshitz-Kosevich formula, derived under the assumption that the properties of the system in a non-zero magnetic field are determined uniquely by the zero-field Fermi-liquid state. This assumption is valid in 3D but, generally speaking, erroneous in 2D where the Lifshitz-Kosevich formula may be applied only if the oscillations are strongly damped by thermal smearing and disorder. In this work, the effects of interactions and disorder on the amplitude of magneto-oscillations in 2D are studied. It is found that the effective mass diverges logarithmically with decreasing temperature signaling a deviation from the Fermi-liquid behavior. It is also shown that the quasiparticle lifetime due to inelastic interactions does not enter the oscillation amplitude, although these interactions do renormalize the effective mass. This result provides a generalization of the Fowler-Prange theorem formulated originally for the electron-phonon interaction.Comment: 4 pages, 1 figur

A measurement of the energy spectra of cosmic rays from 20 to 1000 GeV per amu

A group collaboration was made in the development of the Bristol University Gas Spectrometer number 4 (BUGS 4). The BUGS 4 detector is designed to measure the charge spectrum for species between oxygen and the iron peak as a function of energy per nucleon, between 20 and 1000 GeV/amu. It is particularly concerned with energies above 50 GeV/amu. The high energy component is considerably less affected by propagation through the interstellar medium than the lower energy component and is expected to approach the original charge spectrum of the source more closely. This information allows one to unravel the effects of cosmic ray production, acceleration, and propagation. The detector is described in total detail. The method of estimating the charge and energy of a cosmic ray depends on the energy of the particle. Calculations and experiments lead to the expectation of a nearly constant charge resolution of about 0.2 charge units over the whole energy range except 4.5 less than gamma less than 20. In this band, the experiment is insensitive to energy. A balloon flight is planned in 1993

A High Statistics Search for Ultra-High Energy Gamma-Ray Emission from Cygnus X-3 and Hercules X-1

We have carried out a high statistics (2 Billion events) search for ultra-high energy gamma-ray emission from the X-ray binary sources Cygnus X-3 and Hercules X-1. Using data taken with the CASA-MIA detector over a five year period (1990-1995), we find no evidence for steady emission from either source at energies above 115 TeV. The derived upper limits on such emission are more than two orders of magnitude lower than earlier claimed detections. We also find no evidence for neutral particle or gamma-ray emission from either source on time scales of one day and 0.5 hr. For Cygnus X-3, there is no evidence for emission correlated with the 4.8 hr X-ray periodicity or with the occurrence of large radio flares. Unless one postulates that these sources were very active earlier and are now dormant, the limits presented here put into question the earlier results, and highlight the difficulties that possible future experiments will have in detecting gamma-ray signals at ultra-high energies.Comment: 26 LaTeX pages, 16 PostScript figures, uses psfig.sty to be published in Physical Review

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

The AllWISE Motion Survey and the Quest for Cold Subdwarfs

The AllWISE processing pipeline has measured motions for all objects detected on Wide-field Infrared Survey Explorer (WISE) images taken between 2010 January and 2011 February. In this paper, we discuss new capabilities made to the software pipeline in order to make motion measurements possible, and we characterize the resulting data products for use by future researchers. Using a stringent set of selection criteria, we find 22,445 objects that have significant AllWISE motions, of which 3525 have motions that can be independently confirmed from earlier Two Micron All Sky Survey (2MASS) images, yet lack any published motions in SIMBAD. Another 58 sources lack 2MASS counterparts and are presented as motion candidates only. Limited spectroscopic follow-up of this list has already revealed eight new L subdwarfs. These may provide the first hints of a "subdwarf gap" at mid-L types that would indicate the break between the stellar and substellar populations at low metallicities (i.e., old ages). Another object in the motion list—WISEA J154045.67–510139.3—is a bright (J ≈ 9 mag) object of type M6; both the spectrophotometric distance and a crude preliminary parallax place it ~6 pc from the Sun. We also compare our list of motion objects to the recently published list of 762 WISE motion objects from Luhman. While these first large motion studies with WISE data have been very successful in revealing previously overlooked nearby dwarfs, both studies missed objects that the other found, demonstrating that many other nearby objects likely await discovery in the AllWISE data products