The Role of Intrinsically Unstructured Proteins in Neurodegenerative Diseases

The number and importance of intrinsically disordered proteins (IUP), known to be involved in various human disorders, are growing rapidly. To test for the generalized implications of intrinsic disorders in proteins involved in Neurodegenerative diseases, disorder prediction tools have been applied to three datasets comprising of proteins involved in Huntington Disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD). Results show, in general, proteins in disease datasets possess significantly enhanced intrinsic unstructuredness. Most of these disordered proteins in the disease datasets are found to be involved in neuronal activities, signal transduction, apoptosis, intracellular traffic, cell differentiation etc. Also these proteins are found to have more number of interactors and hence as the proportion of disorderedness (i.e., the length of the unfolded stretch) increased, the size of the interaction network simultaneously increased. All these observations reflect that, “Moonlighting” i.e. the contextual acquisition of different structural conformations (transient), eventually may allow these disordered proteins to act as network “hubs” and thus they may have crucial influences in the pathogenecity of neurodegenerative diseases

Magnitude of observer error using cone beam CT for prostate interfraction motion estimation: effect of reducing scan length or increasing exposure.

Objective Cone beam CT (CBCT) enables soft-tissue registration to planning CT for position verification in radiotherapy. The aim of this study was to determine the interobserver error (IOE) in prostate position verification using a standard CBCT protocol, and the effect of reducing CBCT scan length or increasing exposure, compared with standard imaging protocol.Methods CBCT images were acquired using a novel 7 cm length image with standard exposure (1644 mAs) at Fraction 1 (7), standard 12 cm length image (1644 mAs) at Fraction 2 (12) and a 7 cm length image with higher exposure (2632 mAs) at Fraction 3 (7H) on 31 patients receiving radiotherapy for prostate cancer. Eight observers (two clinicians and six radiographers) registered the images. Guidelines and training were provided. The means of the IOEs were compared using a Kruzkal-Wallis test. Levene's test was used to test for differences in the variances of the IOEs and the independent prostate position.Results No significant difference was found between the IOEs of each image protocol in any direction. Mean absolute IOE was the greatest in the anteroposterior direction. Standard deviation (SD) of the IOE was the least in the left-right direction for each of the three image protocols. The SD of the IOE was significantly less than the independent prostate motion in the anterior-posterior (AP) direction only (1.8 and 3.0 mm, respectively: p = 0.017). IOEs were within 1 SD of the independent prostate motion in 95%, 77% and 96% of the images in the RL, SI and AP direction.Conclusion Reducing CBCT scan length and increasing exposure did not have a significant effect on IOEs. To reduce imaging dose, a reduction in CBCT scan length could be considered without increasing the uncertainty in prostate registration. Precision of CBCT verification of prostate radiotherapy is affected by IOE and should be quantified prior to implementation.Advances in knowledge This study shows the importance of quantifying the magnitude of IOEs prior to CBCT implementation

The role of the pion cloud in the interpretation of the valence light-cone wavefunction of the nucleon

The pion cloud renormalises the light-cone wavefunction of the nucleon which is measured in hard, exclusive photon-nucleon reactions. We discuss the leading twist contributions to high-energy exclusive reactions taking into account both the pion cloud and perturbative QCD physics. The nucleon's electromagnetic form-factor at high $Q^2$ is proportional to the bare nucleon probability $Z$ and the cross-sections for hard (real at large angle or deeply virtual) Compton scattering are proportional to $Z^2$. Our present knowledge of the pion-nucleon system is consistent with $Z = 0.7 \pm 0.2$. If we apply just perturbative QCD to extract a light-cone wavefunction directly from these hard exclusive cross-sections, then the light-cone wavefunction that we extract measures the three valence quarks partially screened by the pion cloud of the nucleon. We discuss how this pion cloud renormalisation effect might be understood at the quark level in terms of the (in-)stability of the perturbative Dirac vacuum in low energy QCD.Comment: Expanded Discussion of Phenomenology and Spin Physic

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

Effects of Methoxyisoflavone, Ecdysterone, and Sulfo-Polysaccharide Supplementation on Training Adaptations in Resistance-Trained Males

PURPOSE: Methoxyisoflavone (M), 20-hydroxyecdysone (E), and sulfo-polysaccharide (CSP3) have been marketed to athletes as dietary supplements that can increase strength and muscle mass during resistancetraining. However, little is known about their potential ergogenic value. The purpose of this study was to determine whether these supplements affect training adaptations and/or markers of muscle anabolism/catabolism in resistance-trained athletes. METHODS: Forty-five resistance-trained males (20.5±3 yrs; 179±7 cm, 84±16 kg, 17.3±9 % body fat) were matched according to FFM and randomly assigned to ingest in a double blind manner supplements containing either a placebo (P); 800 mg/day of M; 200 mg of E; or, 1,000 mg/day of CSP3 for 8-weeks during training. At 0, 4, and 8-weeks, subjects donated fasting blood samples and completed comprehensive muscular strength, muscular endurance, anaerobic capacity, and body composition analysis. Data were analyzed by repeated measures ANOVA. RESULTS: No significant differences (p>0.05) were observed in training adaptations among groups in the variables FFM, percent body fat, bench press 1RM, leg press 1RM or sprint peak power. Anabolic/catabolic analysis revealed no significant differences among groups in active testosterone (AT), free testosterone (FT), cortisol, the AT to cortisol ratio, urea nitrogen, creatinine, the blood urea nitrogen to creatinine ratio. In addition, no significant differences were seen from pr

Autocrine Activation of the MET Receptor Tyrosine Kinase in Acute Myeloid Leukemia

Although the treatment of acute myeloid leukemia (AML) has improved significantly, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified aberrant expression of the hepatocyte growth factor (HGF) as a critical factor in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance due to compensatory upregulation of HGF expression, leading to restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked compensatory HGF upregulation, resulting in sustained logarithmic cell kill both in vitro and in xenograft models in vivo. Our results demonstrate widespread dependence of AML cells on autocrine activation of MET, as well as the importance of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers

An Ensemble Analysis of Electromyographic Activity during Whole Body Pointing with the Use of Support Vector Machines

We explored the use of support vector machines (SVM) in order to analyze the ensemble activities of 24 postural and focal muscles recorded during a whole body pointing task. Because of the large number of variables involved in motor control studies, such multivariate methods have much to offer over the standard univariate techniques that are currently employed in the field to detect modifications. The SVM was used to uncover the principle differences underlying several variations of the task. Five variants of the task were used. An unconstrained reaching, two constrained at the focal level and two at the postural level. Using the electromyographic (EMG) data, the SVM proved capable of distinguishing all the unconstrained from the constrained conditions with a success of approximately 80% or above. In all cases, including those with focal constraints, the collective postural muscle EMGs were as good as or better than those from focal muscles for discriminating between conditions. This was unexpected especially in the case with focal constraints. In trying to rank the importance of particular features of the postural EMGs we found the maximum amplitude rather than the moment at which it occurred to be more discriminative. A classification using the muscles one at a time permitted us to identify some of the postural muscles that are significantly altered between conditions. In this case, the use of a multivariate method also permitted the use of the entire muscle EMG waveform rather than the difficult process of defining and extracting any particular variable. The best accuracy was obtained from muscles of the leg rather than from the trunk. By identifying the features that are important in discrimination, the use of the SVM permitted us to identify some of the features that are adapted when constraints are placed on a complex motor task

Modelling Vesicular Release at Hippocampal Synapses

We study local calcium dynamics leading to a vesicle fusion in a stochastic, and spatially explicit, biophysical model of the CA3-CA1 presynaptic bouton. The kinetic model for vesicle release has two calcium sensors, a sensor for fast synchronous release that lasts a few tens of milliseconds and a separate sensor for slow asynchronous release that lasts a few hundred milliseconds. A wide range of data can be accounted for consistently only when a refractory period lasting a few milliseconds between releases is included. The inclusion of a second sensor for asynchronous release with a slow unbinding site, and thereby a long memory, affects short-term plasticity by facilitating release. Our simulations also reveal a third time scale of vesicle release that is correlated with the stimulus and is distinct from the fast and the slow releases. In these detailed Monte Carlo simulations all three time scales of vesicle release are insensitive to the spatial details of the synaptic ultrastructure. Furthermore, our simulations allow us to identify features of synaptic transmission that are universal and those that are modulated by structure