The spinal dorsal horn receives input from primary afferent axons, which terminate in a modality-specific fashion in different laminae. The incoming somatosensory information is processed through ...complex synaptic circuits involving excitatory and inhibitory interneurons, before being transmitted to the brain via projection neurons for conscious perception. The dorsal horn is important, firstly because changes in this region contribute to chronic pain states, and secondly because it contains potential targets for the development of new treatments for pain. However, at present, we have only a limited understanding of the neuronal circuitry within this region, and this is largely because of the difficulty in defining functional populations among the excitatory and inhibitory interneurons. The recent discovery of specific neurochemically defined interneuron populations, together with the development of molecular genetic techniques for altering neuronal function in vivo, are resulting in a dramatic improvement in our understanding of somatosensory processing at the spinal level.
Neurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous ...potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organization and circuitry of this complex region.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in ...gastrointestinal disorders
. Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility
, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health.
Circuit-level analytical models for hard-switching, soft-switching, and dv/dt-induced false turn on of SiC MOSFETs and their experimental validation are described. The models include the ...high-frequency parasitic components in the circuit and enable fast, accurate simulation of the switching behavior using only datasheet parameters. To increase the accuracy of models, nonlinearities in the junction capacitances of the devices are incorporated by fitting their nonlinear curves to a simple equation. The numerical solutions of the analytical models provide more accurate prediction than an LTspice simulation with a threefold reduction in the simulation time. The analytical models are evaluated at 25 °C and 125 °C. The effect of snubber capacitors on the soft-switching waveforms is explained analytically and validated experimentally, which enables the techniques to be used to evaluate future soft-switching solutions. Finally, the dv/dt-induced false turn-on conditions are predicted analytically and validated experimentally. It was observed that consideration of nonlinearities in the junction capacitances ensures accurate prediction of false turn on, and that the small shoot-through current due to false turn on can increase the switching loss by 8% for an off-state gate bias of -2 V.
The compatible solute dimethylsulphoniopropionate (DMSP) has important roles in marine environments. It is an anti-stress compound made by many single-celled plankton, some seaweeds and a few land ...plants that live by the shore. Furthermore, in the oceans it is a major source of carbon and sulphur for marine bacteria that break it down to products such as dimethyl sulphide, which are important in their own right and have wide-ranging effects, from altering animal behaviour to seeding cloud formation. In this Review, we describe how recent genetic and genomic work on the ways in which several different bacteria, and some fungi, catabolize DMSP has provided new and surprising insights into the mechanisms, regulation and possible evolution of DMSP catabolism in microorganisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying ...neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5−/− mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.
•Spinal B5-I interneurons function to inhibit itch•B5-I neurons release the kappa opioid dynorphin•Kappa opioid signaling bidirectionally modulates itch within the spinal cord•Spinal B5-I interneurons mediate the inhibition of itch by menthol
Kardon et al. identify a population of spinal interneurons that function to inhibit itch. Release of the kappa opioid dynorphin from these neurons mediates the inhibition of itch by chemical counterstimuli such as menthol, suggesting that kappa opioids may be a broadly effective therapy for pathological itch.
The dorsal horns of the spinal cord and the trigeminal nuclei in the brainstem contain neuron populations that are critical to process sensory information. Neurons in these areas are highly ...heterogeneous in their morphology, molecular phenotype and intrinsic properties, making it difficult to identify functionally distinct cell populations, and to determine how these are engaged in pathophysiological conditions. There is a growing consensus concerning the classification of neuron populations, based on transcriptomic and transductomic analyses of the dorsal horn. These approaches have led to the discovery of several molecularly defined cell types that have been implicated in cutaneous mechanical allodynia, a highly prevalent and difficult-to-treat symptom of chronic pain, in which touch becomes painful. The main objective of this review is to provide a contemporary view of dorsal horn neuronal populations, and describe recent advances in our understanding of on how they participate in cutaneous mechanical allodynia.
Convergent evolution is a process that has occurred throughout the tree of life, but the historical genetic and biochemical context promoting the repeated independent origins of a trait is rarely ...understood. The well-known stimulant caffeine, and its xanthine alkaloid precursors, has evolved multiple times in flowering plant history for various roles in plant defense and pollination. We have shown that convergent caffeine production, surprisingly, has evolved by two previously unknown biochemical pathways in chocolate, citrus, and guaraná plants using either caffeine synthase- or xanthine methyltransferase-like enzymes. However, the pathway and enzyme lineage used by any given plant species is not predictable from phylogenetic relatedness alone. Ancestral sequence resurrection reveals that this convergence was facilitated by co-option of genes maintained over 100 million y for alternative biochemical roles. The ancient enzymes of the Citrus lineage were exapted for reactions currently used for various steps of caffeine biosynthesis and required very few mutations to acquire modern-day enzymatic characteristics, allowing for the evolution of a complete pathway. Future studies aimed at manipulating caffeine content of plants will require the use of different approaches given the metabolic and genetic diversity revealed by this study.
Abstract
We analyze new far-ultraviolet spectra of 13 quasars from the
COS-Halos survey that cover the H
i
Lyman limit of 14 circumgalactic medium (CGM) systems. These data yield precise estimates or ...more constraining limits than previous COS-Halos measurements on the H
i
column densities
. We then apply a Monte-Carlo Markov chain approach on 32 systems from COS-Halos to estimate the metallicity of the cool (
K) CGM gas that gives rise to low-ionization state metal lines, under the assumption of photoionization equilibrium with the extragalactic UV background. The principle results are: (1) the CGM of field
L
* galaxies exhibits a declining H
i
surface density with impact parameter
(at
confidence), (2) the transmission of ionizing radiation through CGM gas alone is 70 ± 7%; (3) the metallicity distribution function of the cool CGM is unimodal with a median of
and a 95% interval
to
; the incidence of metal-poor (
) gas is low, implying any such gas discovered along quasar sightlines is typically unrelated to
L
* galaxies; (4) we find an unexpected increase in gas metallicity with declining
(at
confidence) and, therefore, also with increasing
; the high metallicity at large radii implies early enrichment; and (5) a non-parametric estimate of the cool CGM gas mass is
, which together with new mass estimates for the hot CGM may resolve the galactic missing baryons problem. Future analyses of halo gas should focus on the underlying astrophysics governing the CGM, rather than processes that simply expel the medium from the halo.
ABSTRACT The total contribution of diffuse halo gas to the galaxy baryon budget strongly depends on its dominant ionization state. In this paper, we address the physical conditions in the highly ...ionized circumgalactic medium (CGM) traced by absorption lines observed in COS-Halos spectra. We analyze the observed ionic column densities, absorption-line widths and relative velocities, along with the ratios of / for 39 fitted Voigt profile components of O vi. We compare these quantities with the predictions given by a wide range of ionization models. Photoionization models that include only extragalactic UV background radiation are ruled out; conservatively, the upper limits to / and measurements of imply unphysically large path lengths 100 kpc. Furthermore, very broad absorption (b > 40 km s−1) is a defining characteristic of the CGM of star-forming L* galaxies. We highlight two possible origins for the bulk of the observed : (1) highly structured gas clouds photoionized primarily by local high-energy sources or (2) gas radiatively cooling on large scales behind a supersonic wind. Approximately 20% of circumgalactic O vi does not align with any low-ionization state gas within 50 km s−1 and is found only in halos with < 1012 . We suggest that this type of unmatched O vi absorption traces the hot corona itself at a characteristic temperature of K. We discuss the implications of these very distinct physical origins for the dynamical state, gas cooling rates, and total baryonic content of L* gaseous halos.
PDF
