FXN promoter silencing in the humanized mouse model of Friedreich Ataxia

Background - Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues. Methodology / Principal Findings - The humanized mouse model of Friedreich ataxia (YG8sR), which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R). We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse. Conclusions / Significance- Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.This research was supported by grants from the National Institutes of Health (R01 NS072418), and the Muscular Dystrophy Association to S.I.B. Y.K.C. is supported by a postdoctoral research fellowship from the Million Dollar Bike Ride Grant Program of the Orphan Disease Center at University of Pennsylvania. T.T.H. was supported by the American College of Medical Genetics Foundation. A.C.P. and M.G.M. were supported by the SURE and OSCTR programs at OUHSC, respectively

Screening disability insurance applications

This paper investigates the effects of stricter screening of disability insurance applications. A large-scale experiment was setup where in two of the 26 Dutch regions case workers of the disability insurance administration were instructed to screen applications more stringently. The empirical results show that stricter screening reduces long-term sickness absenteeism and disability insurance applications. We find evidence for direct effects of stricter screening on work resumption during the period of sickness absence and for self-screening by potential disability insurance applicants. Stricter screening seems to improve targeting efficiency, without inducing negative spillover effects to the inflow into unemployment insurance. The costs of stricter screening are only a small fraction of the monetary benefits.Disability insurance; experiment; policy evaluation; sickness absenteeism; self-screening

Intimal hyperplasia following implantation of helical-centreline and straight-centreline stents in common carotid arteries in healthy pigs: influence of intraluminal flow

Intimal hyperplasia (IH) is a leading cause of obstruction of vascular interventions, including arterial stents, bypass grafts and arteriovenous grafts and fistulae. Proposals to account for arterial stent-associated IH include wall damage, low wall shear stress (WSS), disturbed flow and, although not widely recognized, wall hypoxia. The common non-planarity of arterial geometry and flow, led us to develop a bare-metal, nitinol, self-expanding stent with three-dimensional helical-centreline geometry. This was deployed in one common carotid artery of healthy pigs, with a straight-centreline, but otherwise identical (conventional) stent deployed contralaterally. Both stent types deformed the arteries, but the helical-centreline device additionally deformed them helically and caused swirling of intraluminal flow. At sacrifice, one month post stent deployment, histology revealed significantly less IH in the helical-centreline than straight-centreline stented vessels. Medial cross-sectional area was not significantly different in helical-centreline than straight-centreline stented vessels. By contrast, luminal cross-sectional area was significantly larger in helical-centreline than straight-centreline stented vessels. Mechanisms considered to account for those results include enhanced intraluminal WSS and enhanced intraluminal blood–vessel wall mass transport, including of oxygen, in the helical-centreline stented vessels. Consistent with the latter proposal, adventitial microvessel density was lower in the helical-centreline stented than straight-centreline stented vessels

The Impact of Central and Peripheral Cyclooxygenase Enzyme Inhibition on Exercise-induced Core Body Temperature Elevations.

PURPOSE: Exercise increases core body temperature (TC) due to metabolic heat production. However, the exercise-induced release of inflammatory cytokines including interleukin-6 may also contribute to the rise in TC by increasing the hypothalamic temperature setpoint. We aimed to investigate whether the exercise-induced increase in TC is partly caused by an altered hypothalamic temperature setpoint. METHODS: 15 healthy, active male subjects aged 36±14 years were recruited. Subjects performed submaximal treadmill exercise in 3 randomized test conditions: (1) ibuprofen 400mg and acetaminophen 1000mg (IBU/APAP), (2) acetaminophen 1000mg (APAP) and (3) a control condition (CTRL). Acetaminophen and ibuprofen were used to block the effect of interleukin-6 at a central and peripheral level, respectively. TC, skin temperature and heart rate were measured continuously during the submaximal exercise tests. RESULTS: Baseline values of TC, skin temperature and heart rate did not differ across conditions. Serum interleukin-6 concentrations increased in all three conditions. A significantly lower peak TC was observed in IBU/APAP (38.8±0.4°C) versus CTRL (39.2±0.5°C, p=0.02), but not in APAP (38.9±0.4°C) versus CTRL. Similarly, a lower ΔTC was observed in IBU/APAP (1.7±0.3°C) versus CTRL (2.0±0.5°C, p<0.02), but not in APAP (1.7±0.5°C) versus CTRL. No differences were observed in skin temperature and heart rate responses across conditions. CONCLUSIONS: The combined administration of acetaminophen and ibuprofen resulted in an attenuated increase in TC during exercise when compared to a control condition. This observation suggests that a prostaglandin E2 induced elevated hypothalamic temperature setpoint may contribute to the exercise-induced rise in TC

Coffee consumption and prostate cancer risk: further evidence for inverse relationship

<p>Abstract</p> <p>Background</p> <p>Higher consumption of coffee intake has recently been linked with reduced risk of aggressive prostate cancer (PC) incidence, although meta-analysis of other studies that examine the association between coffee consumption and overall PC risk remains inconclusive. Only one recent study investigated the association between coffee intake and grade-specific incidence of PC, further evidence is required to understand the aetiology of aggressive PCs. Therefore, we conducted a prospective study to examine the relationship between coffee intake and overall as well as grade-specific PC risk.</p> <p>Methods</p> <p>We conducted a prospective cohort study of 6017 men who were enrolled in the Collaborative cohort study in the UK between 1970 and 1973 and followed up to 31st December 2007. Cox Proportional Hazards Models were used to evaluate the association between coffee consumption and overall, as well as Gleason grade-specific, PC incidence.</p> <p>Results</p> <p>Higher coffee consumption was inversely associated with risk of high grade but not with overall risk of PC. Men consuming 3 or more cups of coffee per day experienced 55% lower risk of high Gleason grade disease compared with non-coffee drinkers in analysis adjusted for age and social class (HR 0.45, 95% CI 0.23-0.90, p value for trend 0.01). This association changed a little after additional adjustment for Body Mass Index, smoking, cholesterol level, systolic blood pressure, tea intake and alcohol consumption.</p> <p>Conclusion</p> <p>Coffee consumption reduces the risk of aggressive PC but not the overall risk.</p

Invasion speeds for structured populations in fluctuating environments

We live in a time where climate models predict future increases in environmental variability and biological invasions are becoming increasingly frequent. A key to developing effective responses to biological invasions in increasingly variable environments will be estimates of their rates of spatial spread and the associated uncertainty of these estimates. Using stochastic, stage-structured, integro-difference equation models, we show analytically that invasion speeds are asymptotically normally distributed with a variance that decreases in time. We apply our methods to a simple juvenile-adult model with stochastic variation in reproduction and an illustrative example with published data for the perennial herb, \emph{Calathea ovandensis}. These examples buttressed by additional analysis reveal that increased variability in vital rates simultaneously slow down invasions yet generate greater uncertainty about rates of spatial spread. Moreover, while temporal autocorrelations in vital rates inflate variability in invasion speeds, the effect of these autocorrelations on the average invasion speed can be positive or negative depending on life history traits and how well vital rates ``remember'' the past

Controlling passively-quenched single photon detectors by bright light

Single photon detectors based on passively-quenched avalanche photodiodes can be temporarily blinded by relatively bright light, of intensity less than a nanowatt. I describe a bright-light regime suitable for attacking a quantum key distribution system containing such detectors. In this regime, all single photon detectors in the receiver Bob are uniformly blinded by continuous illumination coming from the eavesdropper Eve. When Eve needs a certain detector in Bob to produce a click, she modifies polarization (or other parameter used to encode quantum states) of the light she sends to Bob such that the target detector stops receiving light while the other detector(s) continue to be illuminated. The target detector regains single photon sensitivity and, when Eve modifies the polarization again, produces a single click. Thus, Eve has full control of Bob and can do a successful intercept-resend attack. To check the feasibility of the attack, 3 different models of passively-quenched detectors have been tested. In the experiment, I have simulated the intensity diagrams the detectors would receive in a real quantum key distribution system under attack. Control parameters and side effects are considered. It appears that the attack could be practically possible.Comment: Experimental results from a third detector model added. Minor corrections and edits made. 11 pages, 10 figure

Using genetic algorithms to generate test sequences for complex timed systems

The generation of test data for state based specifications is a computationally expensive process. This problem is magnified if we consider that time con- straints have to be taken into account to govern the transitions of the studied system. The main goal of this paper is to introduce a complete methodology, sup- ported by tools, that addresses this issue by represent- ing the test data generation problem as an optimisa- tion problem. We use heuristics to generate test cases. In order to assess the suitability of our approach we consider two different case studies: a communication protocol and the scientific application BIPS3D. We give details concerning how the test case generation problem can be presented as a search problem and automated. Genetic algorithms (GAs) and random search are used to generate test data and evaluate the approach. GAs outperform random search and seem to scale well as the problem size increases. It is worth to mention that we use a very simple fitness function that can be eas- ily adapted to be used with other evolutionary search techniques

International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) - the propagation of knowledge in ultrasound for the improvement of OB/GYN care worldwide: experience of basic ultrasound training in Oman.

BACKGROUND: The aim of this study is to evaluate effectiveness of a new ISUOG (International Society of Ultrasound in Obstetrics and Gynecology) Outreach Teaching and Training Program delivered in Muscat, Oman. METHODS: Quantitative assessments to evaluate knowledge and practical skills were administered before and after an ultrasound course for sonologists attending the ISUOG Outreach Course, which took place in November, 2017, in Oman. Trainees were selected from each region of the country following a national vetting process conducted by the Oman Ministry of Health. Twenty-eight of the participants were included in the analysis. Pre- and post-training practical and theoretical scores were evaluated and compared. RESULTS: Participants achieved statistically significant improvements, on average by 47% (p < 0.001), in both theoretical knowledge and practical skills. Specifically, the mean score in the theoretical knowledge test significantly increased from 55.6% (± 14.0%) to 81.6% (± 8.2%), while in the practical test, the mean score increased from 44.6% (± 19.5%) to 65.7% (± 23.0%) (p < 0.001). Performance was improved post-course among 27/28 participants (96.4%) in the theoretical test (range: 14 to 200%) and among 24/28 (85.7%) trainees in the practical skills test (range: 5 to 217%). CONCLUSION: Application of the ISUOG Basic Training Curriculum and Outreach Teaching and Training Course improved the theoretical knowledge and practical skills of local health personnel. Long-term re-evaluation is, however, considered imperative to ascertain and ensure knowledge retention

The SKA and "High-Resolution" Science

"High-resolution", or "long-baseline", science with the SKA and its precursors covers a broad range of topics in astrophysics. In several research areas, the coupling between improved brightness sensitivity of the SKA and a sub-arcsecond resolution would uncover truly unique avenues and opportunities for studying extreme states of matter, vicinity of compact relativistic objects, and complex processes in astrophysical plasmas. At the same time, long baselines would secure excellent positional and astrometric measurements with the SKA and critically enhance SKA image fidelity at all scales. The latter aspect may also have a substantial impact on the survey speed of the SKA, thus affecting several key science projects of the instrument.Comment: JENAM-2010: Invited talk at JENAM session S7: The Square Kilometre Array: Paving the way for the new 21st century radio astronomy paradigm; 9 page