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Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. These anaesthetics block sodium channels and thereby the excitability of all neurons, not just sensory neurons. We tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. Here we show that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability. Inhibition by co-applied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 h) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits. 相似文献
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Bis JC DeCarli C Smith AV van der Lijn F Crivello F Fornage M Debette S Shulman JM Schmidt H Srikanth V Schuur M Yu L Choi SH Sigurdsson S Verhaaren BF DeStefano AL Lambert JC Jack CR Struchalin M Stankovich J Ibrahim-Verbaas CA Fleischman D Zijdenbos A den Heijer T Mazoyer B Coker LH Enzinger C Danoy P Amin N Arfanakis K van Buchem MA de Bruijn RF Beiser A Dufouil C Huang J Cavalieri M Thomson R Niessen WJ Chibnik LB Gislason GK Hofman A Pikula A Amouyel P Freeman KB Phan TG Oostra BA Stein JL 《Nature genetics》2012,44(5):545-551
Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia. 相似文献
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Cited are names and combinations within the woody species of Atriplex as they occur in North America. Types and their repositories are included for all taxa except those for which that information could not be located. New nomenclatural proposals include Atriplex gardneri var. aptera (A. Nelson) Welsh & Crompton, comb. nov.; A. garrettii var. navajoensis (C. A. Hanson) Welsh & Crompton, comb. nov.; Atriplex acanthocarpa var. coahuilensis (Henrickson) Welsh & Crompton, comb. nov. A lectotype is designated for A. breweri S. Watson. 相似文献
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Ultrasensitive solution-cast quantum dot photodetectors 总被引:4,自引:0,他引:4
Konstantatos G Howard I Fischer A Hoogland S Clifford J Klem E Levina L Sargent EH 《Nature》2006,442(7099):180-183
Solution-processed electronic and optoelectronic devices offer low cost, large device area, physical flexibility and convenient materials integration compared to conventional epitaxially grown, lattice-matched, crystalline semiconductor devices. Although the electronic or optoelectronic performance of these solution-processed devices is typically inferior to that of those fabricated by conventional routes, this can be tolerated for some applications in view of the other benefits. Here we report the fabrication of solution-processed infrared photodetectors that are superior in their normalized detectivity (D*, the figure of merit for detector sensitivity) to the best epitaxially grown devices operating at room temperature. We produced the devices in a single solution-processing step, overcoating a prefabricated planar electrode array with an unpatterned layer of PbS colloidal quantum dot nanocrystals. The devices showed large photoconductive gains with responsivities greater than 10(3) A W(-1). The best devices exhibited a normalized detectivity D* of 1.8 x 10(13) jones (1 jones = 1 cm Hz(1/2) W(-1)) at 1.3 microm at room temperature: today's highest performance infrared photodetectors are photovoltaic devices made from epitaxially grown InGaAs that exhibit peak D* in the 10(12) jones range at room temperature, whereas the previous record for D* from a photoconductive detector lies at 10(11) jones. The tailored selection of absorption onset energy through the quantum size effect, combined with deliberate engineering of the sequence of nanoparticle fusing and surface trap functionalization, underlie the superior performance achieved in this readily fabricated family of devices. 相似文献
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Subtypes of medulloblastoma have distinct developmental origins 总被引:2,自引:0,他引:2
Gibson P Tong Y Robinson G Thompson MC Currle DS Eden C Kranenburg TA Hogg T Poppleton H Martin J Finkelstein D Pounds S Weiss A Patay Z Scoggins M Ogg R Pei Y Yang ZJ Brun S Lee Y Zindy F Lindsey JC Taketo MM Boop FA Sanford RA Gajjar A Clifford SC Roussel MF McKinnon PJ Gutmann DH Ellison DW Wechsler-Reya R Gilbertson RJ 《Nature》2010,468(7327):1095-1099
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1(+) precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer. 相似文献
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Aflatoxin: a site of action in the rat liver cell 总被引:17,自引:0,他引:17
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Clifford G. Rice 《西北部美国博物学家》2011,63(2)
Call counts and brood counts are frequently used to evaluate Ring-necked Pheasant ( Phasianus colchicus ) populations and to forecast harvest. Given the variability commonly observed in these counts, I evaluated their utility in performing these functions in the state of Washington. Pheasant harvest, call counts, and brood counts have all declined in Washington State since 1982. Power for detecting trends in call counts was higher than for brood counts, but substantial sampling was required to reliably detect even large changes in the short term (e.g., power=0.9 for a 40% decline between 2 years with 12 routes). Brood counts predicted harvest with greater precision than did call counts, but predictions were meaningful only at the statewide scale (i.e., not for counties or major river basins). This was true for predicting total harvest and relative harvest (high, medium, or low). 相似文献
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