131 research outputs found

    Functional and molecular analysis of proprioceptive sensory neuron excitability in mice

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    Neurons located in dorsal root ganglia (DRG) are crucial for transmitting peripheral sensations such as proprioception, touch, temperature, and nociception to the spinal cord before propagating these signals to higher brain structures. To date, difficulty in identifying modality-specific DRG neurons has limited our ability to study specific populations in detail. As the calcium-binding protein parvalbumin (PV) is a neurochemical marker for proprioceptive DRG cells we used a transgenic mouse line expressing green fluorescent protein (GFP) in PV positive DRGs, to study the functional and molecular properties of putative proprioceptive neurons. Immunolabeled DRGs showed a 100% overlap between GFP positive (GFP+) and PV positive cells, confirming the PVeGFP mouse accurately labeled PV neurons. Targeted patch-clamp recording from isolated GFP+ and GFP negative (GFP−) neurons showed the passive membrane properties of the two groups were similar, however, their active properties differed markedly. All GFP+ neurons fired a single spike in response to sustained current injection and their action potentials (APs) had faster rise times, lower thresholds and shorter half widths. A hyperpolarization-activated current (Ih) was observed in all GFP+ neurons but was infrequently noted in the GFP− population (100% vs. 11%). For GFP+ neurons, Ih activation rates varied markedly, suggesting differences in the underlying hyperpolarization-activated cyclic nucleotide-gated channel (HCN) subunit expression responsible for the current kinetics. Furthermore, quantitative polymerase chain reaction (qPCR) showed the HCN subunits 2, 1, and 4 mRNA (in that order) was more abundant in GFP+ neurons, while HCN 3 was more highly expressed in GFP− neurons. Likewise, immunolabeling confirmed HCN 1, 2, and 4 protein expression in GFP+ neurons. In summary, certain functional properties of GFP+ and GFP− cells differ markedly, providing evidence for modality-specific signaling between the two groups. However, the GFP+ DRG population demonstrates considerable internal heterogeneity when hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel) properties and subunit expression are considered. We propose this heterogeneity reflects the existence of different peripheral receptors such as tendon organs, muscle spindles or mechanoreceptors in the putative proprioceptive neuron population

    GRB 011121: A massive star progenitor

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    Of the cosmological gamma-ray bursts, GRB 011121 has the lowest redshift, z = 0.36. More importantly, the multicolor excess in the afterglow detected in the Hubble Space Telescope (HST) light curves is compelling observational evidence of an underlying supernova. Here we present near-infrared and radio observations of the afterglow, and from our comprehensive afterglow modeling, we find evidence favoring a wind-fed circumburst medium. Lacking X-ray data, we are unable to conclusively measure the mass-loss rate, M, but obtain an estimate, M ∼ 2 × 10-7/νw3 M⊙yr-1, where νw3 is the speed of the wind from the progenitor in units of 103 km s-1. This M is similar to that inferred for the progenitor of the Type Ibc supernova SN 1998bw that has been associated with the peculiar burst GRB 980425. Our data, taken in conjunction with the HST results of Bloom et al., provide a consistent picture: the long-duration GRB 011121 had a massive star progenitor that exploded as a supernova at about the same time as the gamma-ray burst event. Finally, we note that the gamma-ray profile of GRB 011121 is similar to that of GRB 980425

    Saturation of azimuthal anisotropy in Au + Au collisions at sqrt(s_NN) = 62 - 200 GeV

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    New measurements are presented for charged hadron azimuthal correlations at mid-rapidity in Au+Au collisions at sqrt(s_NN) = 62.4 and 200 GeV. They are compared to earlier measurements obtained at sqrt(s_NN) = 130 GeV and in Pb+Pb collisions at sqrt(s_NN) = 17.2 GeV. Sizeable anisotropies are observed with centrality and transverse momentum (p_T) dependence characteristic of elliptic flow (v_2). For a broad range of centralities, the observed magnitudes and trends of the differential anisotropy, v_2(p_T), change very little over the collision energy range sqrt(s_NN) = 62-200 GeV, indicating saturation of the excitation function for v_2 at these energies. Such a saturation may be indicative of the dominance of a very soft equation of state for sqrt(s_NN) = 62-200 GeV.Comment: 432 authors, 7 pages text, 4 figures, REVTeX4. To be submitted to Physical Review Letters. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

    Effects of Age, Temperature and Nitrogen Fertilizer on the Third Leaf of Wheat Plants

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    Meaningful Use of Pharmacogenetics

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