On the extent and role of the small proteome in the parasitic eukaryote Trypanosoma brucei

Background: Although technical advances in genomics and proteomics research have yielded a better understanding of the coding capacity of a genome, one major challenge remaining is the identification of all expressed proteins, especially those less than 100 amino acids in length. Such information can be particularly relevant to human pathogens, such as Trypanosoma brucei, the causative agent of African trypanosomiasis, since it will provide further insight into the parasite biology and life cycle. Results: Starting with 993 T. brucei transcripts, previously shown by RNA-Sequencing not to coincide with annotated coding sequences (CDS), homology searches revealed that 173 predicted short open reading frames in these transcripts are conserved across kinetoplastids with 13 also conserved in representative eukaryotes. Mining mass spectrometry data sets revealed 42 transcripts encoding at least one matching peptide. RNAi-induced down-regulation of these 42 transcripts revealed seven to be essential in insect-form trypanosomes with two also required for the bloodstream life cycle stage. To validate the specificity of the RNAi results, each lethal phenotype was rescued by co-expressing an RNAi-resistant construct of each corresponding CDS. These previously non-annotated essential small proteins localized to a variety of cell compartments, including the cell surface, mitochondria, nucleus and cytoplasm, inferring the diverse biological roles they are likely to play in T. brucei. We also provide evidence that one of these small proteins is required for replicating the kinetoplast (mitochondrial) DNA. Conclusions: Our studies highlight the presence and significance of small proteins in a protist and expose potential new targets to block the survival of trypanosomes in the insect vector and/or the mammalian host

Beyond ‘ignorance’: using the cultural stereotypes of Americans studying in the UK as a resource for learning and teaching about British culture

A course introducing British culture is a standard component of many study abroad programmes running in this country that are aimed at international students who will be spending a limited amount of time in the United Kingdom. However, it is not often acknowledged that such students possess a range of strong pre-conceptions about British culture and society prior to their arrival. Conventional teaching strategies assume student ignorance of the subject. However, an alternative approach which makes us of pre-arrival stereotypes can be more productive in terms of engaging students in active processes of comparative analysis of their new and existing knowledge. A case study of American student stereotypes of the British monarchy is presented and it is suggested that these can be used as the basis for refining student understanding of cultural politics in the United Kingdom. International students, therefore, should not be treated as being culturally ignorant of Britain in the sense of having no knowledge or opinions at all. Rather, it should be understood that they possess a culturally mediated state of subjectivity which I refer to as ‘ignorance’ and that this can become a valuable resource for teaching and learning

Early twentieth-century Vogue, George Wolfe Plank and the "Freaks of Mayfair"

Vogue was one of the most influential fashion magazines of the twentieth century. In the 1920s its British edition, launched in 1916, became a focus for various forms of queer visual and cultural expression. The origins of the related ‘amusing style’, which delighted in camp display, can be traced to the romantic and artistic collaboration between the American artist George Wolfe Plank and the British writer E. F. Benson during World War One. The illustrations that Plank produced for Benson’s book of satirical sketches of life in London’s high society, The Freaks of Mayfair (1916), shed light on the camp images that Plank designed for the covers of both the American and British editions of the magazine. Therefore, Plank can be understood to have played a key role in the development of queer visual culture during the early twentieth century

Clinical and neurophysiological effects of botulinum neurotoxin type a in chronic migraine

Chronic pain syndromes present a subversion of both functional and structural nociceptive networks. We used transcranial magnetic stimulation (TMS) to evaluate changes in cortical excitability and plasticity in patients with chronic migraine (CM) treated with botulinum neurotoxin type A (BoNT/A). We enrolled 11 patients with episodic migraine (EM) and 11 affected by CM. Baseline characteristics for both groups were recorded using single-and paired-pulse TMS protocols. The same TMS protocol was repeated in CM patients after four cycles of BoNT/A completed in one year. At baseline, compared with EM patients, patients with CM had a lower threshold in both hemispheres (right hemisphere: 46% \ub1 7.8 vs. 52% \ub1 4.28, p = 0.03; left hemisphere: 52% \ub1 4.28 vs. 53.54% \ub1 6.58, p = 0.02). In EM, paired-pulse stimulation elicited a physiologically shaped response, whereas in CM, physiological intracortical inhibition (ICI) between 1 and 3 ms intervals was absent at baseline. On the contrary, increasing intracortical facilitation (ICF) was observed for all interstimulus intervals (ISIs). In CM, cortical excitability was partially reduced after BoNT/A treatment, along with a significant decrease observed in MIDAS score (from 20.7 to 9.8; p = 0.008). The lower motor threshold in CM reflects a higher cortical hyperexcitability. The lack of physiological ICI in CM could indicate sensitisation of the trigeminovascular system. Although reduced, this type of response is still observable after treatment, despite a marked clinical improvement. Our study suggests a long-term alteration of cortical plasticity due to chronic pain

Maximal entropy inference of oncogenicity from phosphorylation signaling

Point mutations in the phosphorylation domain of the Bcr-Abl fusion oncogene give rise to drug resistance in chronic myelogenous leukemia patients. These mutations alter kinase-mediated signaling function and phenotypic outcome. An information theoretic analysis of the correlation of phosphoproteomic profiling and transformation potency of the oncogene in different mutants is presented. The theory seeks to predict the leukemic transformation potency from the observed signaling by constructing a distribution of maximal entropy of site-specific phosphorylation events. The theory is developed with special reference to systems biology where high throughput measurements are typical. We seek sets of phosphorylation events most contributory to predicting the phenotype by determining the constraints on the signaling system. The relevance of a constraint is measured by how much it reduces the value of the entropy from its global maximum, where all events are equally likely. Application to experimental phospho-proteomics data for kinase inhibitor-resistant mutants shows that there is one dominant constraint and that other constraints are not relevant to a similar extent. This single constraint accounts for much of the correlation of phosphorylation events with the oncogenic potency and thereby usefully predicts the trends in the phenotypic output. An additional constraint possibly accounts for biological fine structure

A Gyrochronology and Microvariability Survey of the Milky Way's Older Stars Using Kepler's Two-Wheels Program

Even with the diminished precision possible with only two reaction wheels, the Kepler spacecraft can obtain mmag level, time-resolved photometry of tens of thousands of sources. The presence of such a rich, large data set could be transformative for stellar astronomy. In this white paper, we discuss how rotation periods for a large ensemble of single and binary main- sequence dwarfs can yield a quantitative understanding of the evolution of stellar spin-down over time. This will allow us to calibrate rotation-based ages beyond ~1 Gyr, which is the oldest benchmark that exists today apart from the Sun. Measurement of rotation periods of M dwarfs past the fully-convective boundary will enable extension of gyrochronology to the end of the stellar main-sequence, yielding precise ages ({\sigma} ~10%) for the vast majority of nearby stars. It will also help set constraints on the angular momentum evolution and magnetic field generation in these stars. Our Kepler-based study would be supported by a suite of ongoing and future ground-based observations. Finally, we briefly discuss two ancillary science cases, detection of long-period low-mass eclipsing binaries and microvariability in white dwarfs and hot subdwarf B stars that the Kepler Two-Wheels Program would facilitate.Comment: Kepler white pape

Cerebrovascular risk in restless legs syndrome: Intima-media thickness and cerebral vasomotor reactivity: A case\u2013control study

Purpose: Although some studies have suggested an association between cardiovascular disease and restless legs syndrome (RLS), the mechanisms underlying this relationship remain unclear. The intima-media thickness (IMT) and vasomotor reactivity are two simple, non-invasive tools to investigate preclinical atherosclerosis and microangiopathy, respectively. The aims of this study were to evaluate carotid IMT and to explore vasomotor reactivity in idiopathic RLS (iRLS) patients. Patients and Methods: We enrolled 44 iRLS after exclusion of patients with secondary causes of RLS, history of vascular events, known uncontrolled vascular risk factors and other neurological disorders. Forty-four age and sex matched controls were therefore recruited. No significant differences in demographic data and vascular risk factors were found between the two groups. Carotid IMT was measured with a high-resolution B-mode ultrasound on the far-wall of common carotid artery, 10 mm and 30 mm to the carotid bulb. Vasomotor reactivity to hypo-and hypercapnia was assessed, by right middle cerebral artery transcranial Doppler, accordingly to the changes in peak systolic velocity, peak diastolic velocity and mean blood flow velocity. Results: Mean IMT was significantly increased in patients with iRLS when measured immediately proximally to carotid bifurcation (0.73; sd=0.17), versus controls (0.65; sd=0.13); p=0.035. Patients showed higher cerebrovascular flow velocities (CBFVs) compared to controls. After multivariate analysis, age, hypertension and iRLS proved to be independent IMT predictors. Conclusion: Increased IMT and higher CBFVs in iRLS support the association of iRLS with vascular damage, possibly through enhanced atherogenesis and sympathetic hyperactivity. However, to clarify a causal relationship, further longitudinal assessment of these parameters is needed, trying to control all their physiological modifying factors

XO-2b: Transiting Hot Jupiter in a Metal-rich Common Proper Motion Binary

We report on a V=11.2 early K dwarf, XO-2 (GSC 03413-00005), that hosts a Rp=0.98+0.03/-0.01 Rjup, Mp=0.57+/-0.06 Mjup transiting extrasolar planet, XO-2b, with an orbital period of 2.615857+/-0.000005 days. XO-2 has high metallicity, [Fe/H]=0.45+/-0.02, high proper motion, mu_tot=157 mas/yr, and has a common proper motion stellar companion with 31" separation. The two stars are nearly identical twins, with very similar spectra and apparent magnitudes. Due to the high metallicity, these early K dwarf stars have a mass and radius close to solar, Ms=0.98+/-0.02 Msolar and Rs=0.97+0.02/-0.01 Rsolar. The high proper motion of XO-2 results from an eccentric orbit (Galactic pericenter, Rper<4 kpc) well confined to the Galactic disk (Zmax~100 pc). In addition, the phase space position of XO-2 is near the Hercules dynamical stream, which points to an origin of XO-2 in the metal-rich, inner Thin Disk and subsequent dynamical scattering into the solar neighborhood. We describe an efficient Markov Chain Monte Carlo algorithm for calculating the Bayesian posterior probability of the system parameters from a transit light curve.Comment: 14 pages, 10 Figures, Accepted in ApJ. Negligible changes to XO-2 system properties. Removed Chi^2 light curve analysis section, and simplified MCMC light curve analysis discussio

The protein C pathway: implications for the design of the RESPOND study

The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome. Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial indicate that administration of drotrecogin alfa (activated; DrotAA) leads to an increase in endogenous protein C levels in severe sepsis patients. In a group as heterogeneous as sepsis patients, the currently approved dose and duration of administration (24 μg/kg per hour for 96 hours) might not be optimal in some individuals. The RESPOND (Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]) trial is a phase II study being conducted to explore the use of endogenous protein C level as both a biomarker and a steering parameter for administration of DrotAA. Eligible patients will receive DrotAA either at the normal, currently approved dose and duration of administration ('standard therapy') or at a higher dose with variable infusion duration or variable infusion duration only ('alternative therapy'). The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C. The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA