3,520 research outputs found
Fast and flexible selection with a single switch
Selection methods that require only a single-switch input, such as a button
click or blink, are potentially useful for individuals with motor impairments,
mobile technology users, and individuals wishing to transmit information
securely. We present a single-switch selection method, "Nomon," that is general
and efficient. Existing single-switch selection methods require selectable
options to be arranged in ways that limit potential applications. By contrast,
traditional operating systems, web browsers, and free-form applications (such
as drawing) place options at arbitrary points on the screen. Nomon, however,
has the flexibility to select any point on a screen. Nomon adapts automatically
to an individual's clicking ability; it allows a person who clicks precisely to
make a selection quickly and allows a person who clicks imprecisely more time
to make a selection without error. Nomon reaps gains in information rate by
allowing the specification of beliefs (priors) about option selection
probabilities and by avoiding tree-based selection schemes in favor of direct
(posterior) inference. We have developed both a Nomon-based writing application
and a drawing application. To evaluate Nomon's performance, we compared the
writing application with a popular existing method for single-switch writing
(row-column scanning). Novice users wrote 35% faster with the Nomon interface
than with the scanning interface. An experienced user (author TB, with > 10
hours practice) wrote at speeds of 9.3 words per minute with Nomon, using 1.2
clicks per character and making no errors in the final text.Comment: 14 pages, 5 figures, 1 table, presented at NIPS 2009 Mini-symposi
A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling.
Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes1,2, and regulate cellular functions such as metabolism3-5 and transcription6. An important 'sensor' protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF27,8, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1-NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases
Fully covered self-expanding metal stents placed temporarily in the bile duct: safety profile and histologic classification in a porcine model
<p>Abstract</p> <p>Background</p> <p>Fully covered Self-Expanding metal stents (FCSEMS) have been shown efficacious in palliating malignant biliary obstructions. There is little data analyzing mucosal response to their temporary placement in the bile duct.</p> <p>Methods</p> <p>Ten mini pigs underwent endoscopic placement of a FCSEMS (Wallflex, Boston Scientific). FCSEMS were kept in place for three months. At the end of the 3 months, FCSEMS were removed endoscopically. Five pigs were euthanized and their bile ducts harvested. The other five were kept alive for another month post removal. A single pathologist, created a scoring system (to determine degree of inflammation, fibrosis, and epithelial injury), examined all specimens in a blinded fashion.</p> <p>Results</p> <p>Four FCSEMS spontaneously migrated in the duodenum. On post mortem examination, mild mucosal thickness was noted in three bile duct specimens while superficial inflammation of the bile duct was noted in five animals. Histologic examination of the bile duct revealed focal acute inflammation in both groups. For the 5 animals euthanized immediately after stent removal, there was a tendency to have superficial mucosal erosion and fibrosis. In contrast, increased chronic inflammation was more commonly seen in the animals 1 month post stent removal, with all animals in this group showing moderate degrees of mononuclear inflammatory cell mucosal infiltrates. No severe inflammatory or fibrotic duct injury was observed in any of the study animals, with degree of injury graded as mild to moderate.</p> <p>Conclusion</p> <p>FCSEMS appear to induce minimal tissue overgrowth or fibrosis post placement. Ease of removability and no significant histologic injury are advantages noted with FCSEMS., however, further studies are needed to evaluate treating benign biliary strictures with FCSEMS in humans.</p
Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain
Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results: In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Eva Birosova, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid V Rauch, Christina Uhlmann, Harald Kugel and Udo Dannlowsk
Dual Beneficial Effects of (-)-Epigallocatechin-3-Gallate on Levodopa Methylation and Hippocampal Neurodegeneration: In Vitro and In Vivo Studies
A combination of levodopa (L-DOPA) and carbidopa is the most commonly-used treatment for symptom management in Parkinson's disease. Studies have shown that concomitant use of a COMT inhibitor is highly beneficial in controlling the wearing-off phenomenon by improving L-DOPA bioavailability as well as brain entry. The present study sought to determine whether (-)-epigallocatechin-3-gallate (EGCG), a common tea polyphenol, can serve as a naturally-occurring COMT inhibitor that also possesses neuroprotective actions.Using both in vitro and in vivo models, we investigated the modulating effects of EGCG on L-DOPA methylation as well as on chemically induced oxidative neuronal damage and degeneration. EGCG strongly inhibited human liver COMT-mediated O-methylation of L-DOPA in a concentration-dependent manner in vitro, with an average IC50 of 0.36 microM. Oral administration of EGCG moderately lowered the accumulation of 3-O-methyldopa in the plasma and striatum of rats treated with L-DOPA+carbidopa. In addition, EGCG also reduced glutamate-induced oxidative cytotoxicity in cultured HT22 mouse hippocampal neuronal cells through inactivation of the nuclear factor kappaB-signaling pathway. Under in vivo conditions, administration of EGCG exerted a strong protective effect against kainic acid-induced oxidative neuronal death in the hippocampus of rats.These observations suggest that oral administration of EGCG may have significant beneficial effects in Parkinson's patients treated with L-DOPA and carbidopa by exerting a modest inhibition of L-DOPA methylation plus a strong neuroprotection against oxidative damage and degeneration
Strong Ultraviolet Pulse From a Newborn Type Ia Supernova
Type Ia supernovae are destructive explosions of carbon oxygen white dwarfs.
Although they are used empirically to measure cosmological distances, the
nature of their progenitors remains mysterious, One of the leading progenitor
models, called the single degenerate channel, hypothesizes that a white dwarf
accretes matter from a companion star and the resulting increase in its central
pressure and temperature ignites thermonuclear explosion. Here we report
observations of strong but declining ultraviolet emission from a Type Ia
supernova within four days of its explosion. This emission is consistent with
theoretical expectations of collision between material ejected by the supernova
and a companion star, and therefore provides evidence that some Type Ia
supernovae arise from the single degenerate channel.Comment: Accepted for publication on the 21 May 2015 issue of Natur
Search for Pair Production of Scalar Top Quarks Decaying to a tau Lepton and a b Quark in ppbar Collisions at sqrt{s}=1.96 TeV
We search for pair production of supersymmetric top quarks (~t_1), followed
by R-parity violating decay ~t_1 -> tau b with a branching ratio beta, using
322 pb^-1 of ppbar collisions at sqrt{s}=1.96 TeV collected by the CDF II
detector at Fermilab. Two candidate events pass our final selection criteria,
consistent with the standard model expectation. We set upper limits on the
cross section sigma(~t_1 ~tbar_1)*beta^2 as a function of the stop mass
m(~t_1). Assuming beta=1, we set a 95% confidence level limit m(~t_1)>153
GeV/c^2. The limits are also applicable to the case of a third generation
scalar leptoquark (LQ_3) decaying LQ_3 -> tau b.Comment: 7 pages, 2 eps figure
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