2,480 research outputs found
Interleukin-1 beta-converting enzyme-like protease cleaves DNA-dependent protein kinase in cytotoxic T cell killing.
Cytotoxic T cells (CTL) represent the major defense mechanism against the spread of virus infection. It is believed that the pore-forming protein, perforin, facilitates the entry of a series of serine proteases (particularly granzyme B) into the target cell which ultimately leads to DNA fragmentation and apoptosis. We demonstrate here that during CTL-mediated cytolysis the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an enzyme implicated in the repair of double strand breaks in DNA, is specifically cleaved by an interleukin (IL)-1 beta-converting enzyme (ICE)-like protease. A serine protease inhibitor, 3,4-dichloroisocoumarin (DCl), which is known to block granzyme B activity, inhibited CTL-induced apoptosis and prevented the degradation of DNA-PKcs in cells but failed to prevent the degradation of purified DNA-PKcs by CTL extracts. However, Tyr-Val-Ala-Asp-CH2Cl (YVAD-CMK) and other cysteine protease inhibitors prevented the degradation of purified DNA-PKcs by CTL extracts. Furthermore, incubation of DNA-PKcs with granzyme B did not produce the same cleavage pattern observed in cells undergoing apoptosis and when this substrate was incubated with either CTL extracts or the ICE-like protease, CPP32. Sequence analysis revealed that the cleavage site in DNA-PKcs during CTL killing was the same as that when this substrate was exposed to CPP32. This study demonstrates for the first time that the cleavage of DNA-PKcs in this intact cell system is exclusively due to an ICE-like protease
The midbrain to pons ratio: a simple and specific MRI sign of progressive supranuclear palsy.
MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP
The Effects of Acute Îâč-Tetrahydrocannabinol on Striatal Glutamatergic Function: A Proton Magnetic Resonance Spectroscopy Study
Background:
Cannabis and its main psychoactive component, Î9-tetrahydrocannabinol (THC), can elicit transient psychotic symptoms. A key candidate biological mechanism of how THC induces psychotic symptoms is the modulation of glutamate in the brain. We sought to investigate the effects of acute THC administration on striatal glutamate levels and its relationship to the induction of psychotic symptoms.
Methods:
We used proton magnetic resonance spectroscopy to measure glutamate levels in the striatum in 20 healthy participants after THC (15 mg, oral) and matched placebo administration in a randomized, double-blind, placebo-controlled design. Psychotic symptoms were measured using the Psychotomimetic States Inventory.
Results:
We found that THC administration did not significantly change glutamate (glutamate plus glutamine relative to creatine) concentration in the striatum (p = .58; scaled Jeffreys-Zellner-Siow Bayes factor = 4.29). THC increased psychotic symptoms, but the severity of these symptoms was not correlated with striatal glutamate levels.
Conclusions:
These findings suggest that oral administration of 15 mg of THC does not result in altered striatal glutamate levels. Further work is needed to clarify the effects of THC on striatal glutamate
Analysis of temporal transcription expression profiles reveal links between protein function and developmental stages of Drosophila melanogaster
Accurate gene or protein function prediction is a key challenge in the post-genome era. Most current methods perform well on molecular function prediction, but struggle to provide useful annotations relating to biological process functions due to the limited power of sequence-based features in that functional domain. In this work, we systematically evaluate the predictive power of temporal transcription expression profiles for protein function prediction in Drosophila melanogaster. Our results show significantly better performance on predicting protein function when transcription expression profile-based features are integrated with sequence-derived features, compared with the sequence-derived features alone. We also observe that the combination of expression-based and sequence-based features leads to further improvement of accuracy on predicting all three domains of gene function. Based on the optimal feature combinations, we then propose a novel multi-classifier-based function prediction method for Drosophila melanogaster proteins, FFPred-fly+. Interpreting our machine learning models also allows us to identify some of the underlying links between biological
processes and developmental stages of Drosophila melanogaster
Co-morbidity and polypharmacy in Parkinson's Disease:insights from a large Scottish primary care database
Background: Parkinsonâs disease is complicated by comorbidity and polypharmacy, but the extent and patterns of
these are unclear. We describe comorbidity and polypharmacy in patients with and without Parkinsonâs disease
across 31 other physical, and seven mental health conditions.
Methods: We analysed primary health-care data on 510,502 adults aged 55 and over. We generated standardised
prevalence rates by age-groups, gender, and neighbourhood deprivation, then calculated age, sex and deprivation
adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for those with PD compared to those without, for
the prevalence, and number of conditions.
Results: Two thousand six hundred forty (0.5%) had Parkinsonâs disease, of whom only 7.4% had no other conditions
compared with 22.9% of controls (adjusted OR [aOR] 0.43, 95% 0.38â0.49). The Parkinsonâs group had more conditions,
with the biggest difference found for seven or more conditions (PD 12.1% vs. controls 3.9%; aOR 2.08 95% CI 1.84â2.35).
12 of the 31 physical conditions and five of the seven mental health conditions were significantly more prevalent in the
PD group. 44.5% with Parkinsonâs disease were on five to nine repeat prescriptions compared to 24.5% of controls (aOR
1.40; 95% CI 1.28 to 1.53) and 19.2% on ten or more compared to 6.2% of controls (aOR 1.90; 95% CI 1.68 to 2.15).
Conclusions: Parkinsonâs disease is associated with substantial physical and mental co-morbidity. Polypharmacy is also a
significant issue due to the complex nature of the disease and associated treatments
A search for the decay modes B+/- to h+/- tau l
We present a search for the lepton flavor violating decay modes B+/- to h+/-
tau l (h= K,pi; l= e,mu) using the BaBar data sample, which corresponds to 472
million BBbar pairs. The search uses events where one B meson is fully
reconstructed in one of several hadronic final states. Using the momenta of the
reconstructed B, h, and l candidates, we are able to fully determine the tau
four-momentum. The resulting tau candidate mass is our main discriminant
against combinatorial background. We see no evidence for B+/- to h+/- tau l
decays and set a 90% confidence level upper limit on each branching fraction at
the level of a few times 10^-5.Comment: 15 pages, 7 figures, submitted to Phys. Rev.
Evidence for an excess of B -> D(*) Tau Nu decays
Based on the full BaBar data sample, we report improved measurements of the
ratios R(D(*)) = B(B -> D(*) Tau Nu)/B(B -> D(*) l Nu), where l is either e or
mu. These ratios are sensitive to new physics contributions in the form of a
charged Higgs boson. We measure R(D) = 0.440 +- 0.058 +- 0.042 and R(D*) =
0.332 +- 0.024 +- 0.018, which exceed the Standard Model expectations by 2.0
sigma and 2.7 sigma, respectively. Taken together, our results disagree with
these expectations at the 3.4 sigma level. This excess cannot be explained by a
charged Higgs boson in the type II two-Higgs-doublet model. We also report the
observation of the decay B -> D Tau Nu, with a significance of 6.8 sigma.Comment: Expanded section on systematics, text corrections, improved the
format of Figure 2 and included the effect of the change of the Tau
polarization due to the charged Higg
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