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(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na(v)1.7 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.

Abstract-Motivated by the current interest in ultra-reliable, low-latency, machine-type communication systems, we investigate the tradeoff between reliability, throughput, and latency in the transmission of information over multiple-antenna Rayleigh blockfading channels. Specifically, we obtain finite-blocklength, finite-SNR upper and lower bounds on the maximum coding rate achievable over such channels for a given constraint on the packet error probability. Numerical evidence suggests that our bounds delimit tightly the maximum coding rate already for short blocklengths (packets of about 100 symbols). Furthermore, our bounds reveal the existence of a tradeoff between the rate gain obtainable by spreading each codeword over all available time-frequency-spatial degrees of freedom, and the rate loss caused by the need of estimating the fading coefficients over these degrees of freedom. In particular, our bounds allow us to determine the optimal number of transmit antennas and the optimal number of time-frequency diversity branches that maximize the rate. Finally, we show that infinite-blocklength performance metrics such as the ergodic capacity and the outage capacity yield inaccurate throughput estimates.

Persistent tetrodotoxin-resistant (TTX-r) sodium currents up-regulated by intracellular GTP have been invoked as the site of action of peripheral inflammatory mediators that lower pain thresholds, and ascribed to the Na V 1.9 sodium channel. Here we describe the properties of a global knock-out of Na V 1.9 produced by replacing exons 4 and 5 in SCN11A with a neomycin resistance cassette, deleting the domain 1 voltage sensor and introducing a frameshift mutation. Recordings from small (< 25 μm apparent diameter) sensory neurones indicated that channel loss eliminates a TTX-r persistent current. Intracellular dialysis of GTP-γ-S did not cause an up-regulation of persistent Na + current in Na V 1.9-null neurones and the concomitant negative shift in voltage-threshold seen in wild-type and heterozygous neurones. Heterologous hNa V 1.9 expression in Na V 1.9 knock-out sensory neurones confirms that the human clone can restore the persistent Na + current. Taken together, these findings demonstrate that Na V 1.9 underlies the G-protein pathway-regulated TTX-r persistent Na + current in small diameter sensory neurones that may drive spontaneous discharge in nociceptive nerve fibres during inflammation.

In amyloid diseases, it is not evident which protein aggregates induce cell death via specific molecular mechanisms and which cause damage because of their mass accumulation and mechanical properties. We showed that equine lysozyme assembles into soluble amyloid oligomers and protofilaments at pH 2.0 and 4.5, 57°C. They bind thioflavin-T and Congo red similar to common amyloid structures, and their morphology was monitored by atomic force microscopy. Molecular volume evaluation from microscopic measurements allowed us to identify distinct types of oligomers, ranging from tetramer to octamer and 20-mer. Monomeric lysozyme and protofilaments are not cytotoxic, whereas the oligomers induce cell death in primary neuronal cells, primary fibroblasts, and the neuroblastoma IMR-32 cell line. Cytotoxicity was accessed by ethidium bromide staining, MTT reduction, and TUNEL assays. Primary cultures were more susceptible to the toxic effect induced by soluble amyloid oligomers than the neuroblastoma cell line. The cytotoxicity correlates with the size of oligomers; the sample incubated at pH 4.5 and containing larger oligomers, including 20-mer, appears to be more cytotoxic than the lysozyme sample kept at pH 2.0, in which only tetramers and octamers were found. Soluble amyloid oligomers may assemble into rings; however, there was no correlation between the quantity of rings in the sample and its toxicity. The cytotoxicity of transient oligomeric species of the ubiquitous protein lysozyme indicates that this is an intrinsic feature of protein amyloid aggregation, and therefore soluble amyloid oligomers can be used as a primary therapeutic target and marker of amyloid disease.The molecular basis of the pathogenicity of amyloid aggregates is a central theme in understanding the causes of a wide range of amyloid-related diseases, including Alzheimer's, Parkinson's, prion diseases, type II diabetes, and familial amyloidotic polyneuropathy (1-4). There is a striking difference between the amounts of amyloid depositions in various types of amyloid disorders. In systemic lysozyme amyloidosis, for example, the deposits can grow to kilogram quantities in the liver (5, 6). In neurodegenerative diseases, by contrast, there is no clear correlation between the amount of amyloid deposition and the clinical severity of disease. Significant cognitive impairment of Alzheimer's patients was observed without noticeable amyloid deposits in the brain, although the level of readily soluble amyloid oligomeric assemblies in the Alzheimer's brain was found to be greatly elevated (7,8).The evidence is accumulating that prefibrillar aggregates are cytotoxic both in vivo and in vitro (4,8,9), although this question is still open to debate. Moreover, aggregates of the proteins, which are not related to clinical amyloidoses, such as human ␣-lactalbumin (10), SH3 domain, or HypF-N protein, have also been found to be cytotoxic, which implies a common mechanism for cytotoxicity of misfolded proteins (11). By contrast, it has been shown that the mature amyl...

A number of studies have linked citizens' involvement in user-generated content (UGC) on the internet to democratic engagement. Whereas previous research implies a view of UGC involvement as the processing of political information, this study conceptualizes and operationalizes UGC involvement in terms of a distinct audience experience based on expressivity, performance and collaboration. Analysis of survey data from Swedish adolescents in the 13-17 age range shows that UGC involvement predicts offline as well as online political participation. In contrast to informational media use, however, UGC involvement is negatively related to political knowledge. The findings are compatible with recent theories suggesting that the expressive, performative and collaborative features of UGC involvement can promote political participation. Implications of the findings for youth democratic engagement are discussed. Keywords internet use, political knowledge, political participation, user-generated content, youthThe idea that people's experiences as media audiences are important to democratic engagement is central in media and communication studies. On the one hand, the media