Urban domestic cat (Felis catus) populations can attain exceedingly high densities and are not limited by natural prey availability. This has generated concerns that they may negatively affect prey ...populations, leading to calls for management. We enlisted cat-owners to record prey returned home to estimate patterns of predation by free-roaming pets in different localities within the town of Reading, UK and questionnaire surveys were used to quantify attitudes to different possible management strategies. Prey return rates were highly variable: only 20% of cats returned ≥4 dead prey annually. Consequently, approximately 65% of owners received no prey in a given season, but this declined to 22% after eight seasons. The estimated mean predation rate was 18.3 prey cat⁻¹ year⁻¹ but this varied markedly both spatially and temporally: per capita predation rates declined with increasing cat density. Comparisons with estimates of the density of six common bird prey species indicated that cats killed numbers equivalent to adult density on c. 39% of occasions. Population modeling studies suggest that such predation rates could significantly reduce the size of local bird populations for common urban species. Conversely, most urban residents did not consider cat predation to be a significant problem. Collar-mounted anti-predation devices were the only management action acceptable to the majority of urban residents (65%), but were less acceptable to cat-owners because of perceived risks to their pets; only 24% of cats were fitted with such devices. Overall, cat predation did appear to be of sufficient magnitude to affect some prey populations, although further investigation of some key aspects of cat predation is warranted. Management of the predation behavior of urban cat populations in the UK is likely to be challenging and achieving this would require considerable engagement with cat owners.
Chronic pain is a global problem affecting up to 20% of the world’s population and has a significant economic, social and personal cost to society. Sensory neurons of the dorsal root ganglia (DRG) ...detect noxious stimuli and transmit this sensory information to regions of the central nervous system (CNS) where activity is perceived as pain. DRG neurons express multiple voltage-gated sodium channels that underlie their excitability. Research over the last 20 years has provided valuable insights into the critical roles that two channels, Na
V
1.7 and Na
V
1.9, play in pain signalling in man. Gain of function mutations in Na
V
1.7 cause painful conditions while loss of function mutations cause complete insensitivity to pain. Only gain of function mutations have been reported for Na
V
1.9. However, while most Na
V
1.9 mutations lead to painful conditions, a few are reported to cause insensitivity to pain. The critical roles these channels play in pain along with their low expression in the CNS and heart muscle suggest they are valid targets for novel analgesic drugs.
A central hallmark of Alzheimer’s disease is the presence of extracellular amyloid plaques chiefly consisting of amyloid-β (Aβ) peptides in the brain interstitium. Aβ largely exists in two isoforms, ...40 and 42 amino acids long, but a large body of evidence points to Aβ(1–42) rather than Aβ(1–40) as the cytotoxic form. One proposed mechanism by which Aβ exerts toxicity is the formation of ion channel pores that disrupt intracellular Ca2+ homeostasis. However, previous studies using membrane mimetics have not identified any notable difference in the channel forming properties between Aβ(1–40) and Aβ(1–42). Here, we tested whether a more physiological environment, membranes excised from HEK293 cells of neuronal origin, would reveal differences in the relative channel forming ability of monomeric, oligomeric, and fibrillar forms of both Aβ(1–40) and Aβ(1–42). Aβ preparations were characterized with transmission electron microscopy and thioflavin T fluorescence. Aβ was then exposed to the extracellular face of excised membranes, and transmembrane currents were monitored using patch clamp. Our data indicated that Aβ(1–42) assemblies in oligomeric preparations form voltage-independent, non-selective ion channels. In contrast, Aβ(1–40) oligomers, fibers, and monomers did not form channels. Ion channel conductance results suggested that Aβ(1–42) oligomers, but not monomers and fibers, formed three distinct pore structures with 1.7-, 2.1-, and 2.4-nm pore diameters. Our findings demonstrate that only Aβ(1–42) contains unique structural features that facilitate membrane insertion and channel formation, now aligning ion channel formation with the differential neurotoxic effect of Aβ(1–40) and Aβ(1–42) in Alzheimer’s disease.
Voltage-gated sodium channels (VGSCs) play a key role in the initiation and propagation of action potentials in neurons. Na(V)1.8 is a tetrodotoxin (TTX) resistant VGSC expressed in nociceptors, ...peripheral small-diameter neurons able to detect noxious stimuli. Na(V)1.8 underlies the vast majority of sodium currents during action potentials. Many studies have highlighted a key role for Na(V)1.8 in inflammatory and chronic pain models. Lipid rafts are microdomains of the plasma membrane highly enriched in cholesterol and sphingolipids. Lipid rafts tune the spatial and temporal organisation of proteins and lipids on the plasma membrane. They are thought to act as platforms on the membrane where proteins and lipids can be trafficked, compartmentalised and functionally clustered. In the present study we investigated Na(V)1.8 sub-cellular localisation and explored the idea that it is associated with lipid rafts in nociceptors. We found that Na(V)1.8 is distributed in clusters along the axons of DRG neurons in vitro and ex vivo. We also demonstrated, by biochemical and imaging studies, that Na(V)1.8 is associated with lipid rafts along the sciatic nerve ex vivo and in DRG neurons in vitro. Moreover, treatments with methyl-β-cyclodextrin (MβCD) and 7-ketocholesterol (7KC) led to the dissociation between rafts and Na(V)1.8. By calcium imaging we demonstrated that the lack of association between rafts and Na(V)1.8 correlated with impaired neuronal excitability, highlighted by a reduction in the number of neurons able to conduct mechanically- and chemically-evoked depolarisations. These findings reveal the sub-cellular localisation of Na(V)1.8 in nociceptors and highlight the importance of the association between Na(V)1.8 and lipid rafts in the control of nociceptor excitability.
The lower limit of metal hydride nanoconfinement is demonstrated through the coordination of a molecular hydride species to binding sites inside the pores of a metal–organic framework (MOF). ...Magnesium borohydride, which has a high hydrogen capacity, is incorporated into the pores of UiO-67bpy (Zr6O4(OH)4(bpydc)6 with bpydc2– = 2,2′-bipyridine-5,5′-dicarboxylate) by solvent impregnation. The MOF retained its long-range order, and transmission electron microscopy and elemental mapping confirmed the retention of the crystal morphology and revealed a homogeneous distribution of the hydride within the MOF host. Notably, the B-, N-, and Mg-edge XAS data confirm the coordination of Mg(II) to the N atoms of the chelating bipyridine groups. In situ 11B MAS NMR studies helped elucidate the reaction mechanism and revealed that complete hydrogen release from Mg(BH4)2 occurs as low as 200 °C. Sieverts and thermogravimetric measurements indicate an increase in the rate of hydrogen release, with the onset of hydrogen desorption as low as 120 °C, which is approximately 150 °C lower than that of the bulk material. Furthermore, density functional theory calculations support the improved dehydrogenation properties and confirm the drastically lower activation energy for B–H bond dissociation.
Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain ...with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene
SCN9A, which encodes hNa
v1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na
v1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in
SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE). Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant. PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy.
Xylan, a hemicellulosic component of the plant cell wall, is one of the most abundant polysaccharides in nature. In contrast to dicots, xylan in grasses is extensively modified by α-(1,2)– and ...α-(1,3)–linked arabinofuranose. Despite the importance of grass arabinoxylan in human and animal nutrition and for bioenergy, the enzymes adding the arabinosyl substitutions are unknown. Here we demonstrate that knocking-down glycosyltransferase (GT) 61 expression in wheat endosperm strongly decreases α-(1,3)–linked arabinosyl substitution of xylan. Moreover, heterologous expression of wheat and rice GT61s in Arabidopsis leads to arabinosylation of the xylan, and therefore provides gain-of-function evidence for α-(1,3)-arabinosyltransferase activity. Thus, GT61 proteins play a key role in arabinoxylan biosynthesis and therefore in the evolutionary divergence of grass cell walls.
Lung endothelial cell apoptosis and injury occur throughout all stages of acute lung injury/acute respiratory distress syndrome and impact disease progression. Caspases 1, 4, and 5 are essential for ...completion of the apoptotic program known as pyroptosis that also involves proinflammatory cytokines. Because gasdermin D (GSDMD) mediates pyroptotic death and is essential for pore formation, we hypothesized that it might direct caspase 1-encapsulated microparticle (MP) release and mediate endothelial cell death. Our present work provides evidence that GSDMD is released by LPS-stimulated THP-1 monocytic cells, where it is packaged into microparticles together with active caspase 1. Furthermore, only MP released from stimulated monocytic cells that contain both cleaved GSDMD and active caspase 1 induce endothelial cell apoptosis. MPs pretreated with caspase 1 inhibitor Y-VAD or pan-caspase inhibitor Z-VAD do not contain cleaved GSDMD. MPs from caspase 1-knockout cells are also deficient in p30 active GSDMD, further confirming that caspase 1 regulates GSDMD function. Although control MPs contained cleaved GSDMD without caspase 1, these fractions were unable to induce cell death, suggesting that encapsulation of both caspase 1 and GSDMD is essential for cell death induction. Release of microparticulate active caspase 1 was abrogated in GSDMD knockout cells, although cytosolic caspase 1 activation was not impaired. Last, higher concentrations of microparticulate GSDMD were detected in the plasma of septic patients with acute respiratory distress syndrome than in that of healthy donors. Taken together, these findings suggest that GSDMD regulates the release of microparticulate active caspase 1 from monocytes essential for induction of cell death and thereby may play a critical role in sepsis-induced endothelial cell injury.
The activity of voltage-gated sodium channels has long been linked to disorders of neuronal excitability such as epilepsy and chronic pain. Recent genetic studies have now expanded the role of sodium ...channels in health and disease, to include autism, migraine, multiple sclerosis, cancer as well as muscle and immune system disorders. Transgenic mouse models have proved useful in understanding the physiological role of individual sodium channels, and there has been significant progress in the development of subtype selective inhibitors of sodium channels. This review will outline the functions and roles of specific sodium channels in electrical signalling and disease, focusing on neurological aspects. We also discuss recent advances in the development of selective sodium channel inhibitors.
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