191 research outputs found
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OPR-PPR, a Computer Program for Assessing Data Importance to Model Predictions Using Linear Statistics
The OPR-PPR program calculates the Observation-Prediction (OPR) and Parameter-Prediction (PPR) statistics that can be used to evaluate the relative importance of various kinds of data to simulated predictions. The data considered fall into three categories: (1) existing observations, (2) potential observations, and (3) potential information about parameters. The first two are addressed by the OPR statistic; the third is addressed by the PPR statistic. The statistics are based on linear theory and measure the leverage of the data, which depends on the location, the type, and possibly the time of the data being considered. For example, in a ground-water system the type of data might be a head measurement at a particular location and time. As a measure of leverage, the statistics do not take into account the value of the measurement. As linear measures, the OPR and PPR statistics require minimal computational effort once sensitivities have been calculated. Sensitivities need to be calculated for only one set of parameter values; commonly these are the values estimated through model calibration. OPR-PPR can calculate the OPR and PPR statistics for any mathematical model that produces the necessary OPR-PPR input files. In this report, OPR-PPR capabilities are presented in the context of using the ground-water model MODFLOW-2000 and the universal inverse program UCODE_2005. The method used to calculate the OPR and PPR statistics is based on the linear equation for prediction standard deviation. Using sensitivities and other information, OPR-PPR calculates (a) the percent increase in the prediction standard deviation that results when one or more existing observations are omitted from the calibration data set; (b) the percent decrease in the prediction standard deviation that results when one or more potential observations are added to the calibration data set; or (c) the percent decrease in the prediction standard deviation that results when potential information on one or more parameters is added
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Final Technical Report on Radioxenon Event Analysis
This is a final deliverable report for the Advanced Spectral Analysis for Radioxenon project with a focus on radioxenon event categorization
The biogenesis and characterization of mammalian microRNAs of mirtron origin
Mirtrons, short hairpin pre-microRNA (miRNA) mimics directly produced by intronic splicing, have recently been identified and experimentally confirmed in invertebrates. While there is evidence to suggest several mammalian miRNAs have mirtron origins, this has yet to be experimentally demonstrated. Here, we characterize the biogenesis of mammalian mirtrons by ectopic expression of splicing-dependent mirtron precursors. The putative mirtrons hsa-miR-877, hsa-miR-1226 and mmu-miR-1224 were designed as introns within eGFP. Correct splicing and function of these sequences as introns was shown through eGFP fluorescence and RT–PCR, while all mirtrons suppressed perfectly complementary luciferase reporter targets to levels similar to that of corresponding independently expressed pre-miRNA controls. Splicing-deficient mutants and disruption of key steps in miRNA biogenesis demonstrated that mirtron-mediated gene knockdown was splicing-dependent, Drosha-independent and had variable dependence on RNAi pathway elements following pre-miRNA formation. The silencing effect of hsa-miR-877 was further demonstrated to be mediated by the generation of short anti-sense RNA species expressed with low abundance. Finally, the mammalian mirtron hsa-miR-877 was shown to reduce mRNA levels of an endogenous transcript containing hsa-miR-877 target sites in neuronal SH-SY5Y cells. This work confirms the mirtron origins of three mammalian miRNAs and suggests that they are a functional class of splicing-dependent miRNAs which are physiologically active
Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition
Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell–mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR–HLA-B*4405EENLLDFVRF complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes
Phosphate Starvation Triggers Production and Secretion of an Extracellular Lipoprotein in Caulobacter crescentus
Life in oligotrophic environments necessitates quick adaptive responses to a sudden lack of nutrients. Secretion of specific degradative enzymes into the extracellular medium is a means to mobilize the required nutrient from nearby sources. The aquatic bacterium Caulobacter crescentus must often face changes in its environment such as phosphate limitation. Evidence reported in this paper indicates that under phosphate starvation, C. crescentus produces a membrane surface-anchored lipoprotein named ElpS subsequently released into the extracellular medium. A complete set of 12 genes encoding a type II secretion system (T2SS) is located adjacent to the elpS locus in the C. crescentus genome. Deletion of this T2SS impairs release of ElpS in the environment, which surprisingly remains present at the cell surface, indicating that the T2SS is not involved in the translocation of ElpS to the outer membrane but rather in its release. Accordingly, treatment with protease inhibitors prevents release of ElpS in the extracellular medium suggesting that ElpS secretion relies on a T2SS-secreted protease. Finally, secretion of ElpS is associated with an increase in alkaline phosphatase activity in culture supernatants, suggesting a role of the secreted protein in inorganic phosphate mobilization. In conlusion, we have shown that upon phosphate starvation, C. crescentus produces an outer membrane bound lipoprotein, ElpS, which is further cleaved and released in the extracellular medium in a T2SS-dependent manner. Our data suggest that ElpS is associated with an alkaline phosphatase activity, thereby allowing the bacterium to gather inorganic phosphates from a poor environment
Prophylactic Melatonin for Delirium in Intensive Care (Pro-MEDIC): Study protocol for a randomised controlled trial
Background: Delirium is an acute state of brain dysfunction characterised by fluctuating inattention and cognitive disturbances, usually due to illness. It occurs commonly in the intensive care unit (ICU), and it is associated with greater morbidity and mortality. It is likely that disturbances of sleep and of the day-night cycle play a significant role. Melatonin is a naturally occurring, safe and cheap hormone that can be administered to improve sleep. The main aim of this trial will be to determine whether prophylactic melatonin administered to critically ill adults, when compared with placebo, decreases the rate of delirium. Methods: This trial will be a multi-centre, randomised, placebo-controlled study conducted in closed ICUs in Australia. Our aim is to enrol 850 adult patients with an expected ICU length of stay (LOS) of 72h or more. Eligible patients for whom there is consent will be randomised to receive melatonin 4mg enterally or placebo in a 1:1 ratio according to a computer-generated randomisation list, stratified by site. The study drug will be indistinguishable from placebo. Patients, doctors, nurses, investigators and statisticians will be blinded. Melatonin or placebo will be administered once per day at 21:00 until ICU discharge or 14days after enrolment, whichever occurs first. Trained staff will assess patients twice daily to determine the presence or absence of delirium using the Confusion Assessment Method for the ICU score. Data will also be collected on demographics, the overall prevalence of delirium, duration and severity of delirium, sleep quality, participation in physiotherapy sessions, ICU and hospital LOS, morbidity and mortality, and healthcare costs. A subgroup of 100 patients will undergo polysomnographic testing to further evaluate the quality of sleep. Discussion: Delirium is a significant issue in ICU because of its frequency and associated poorer outcomes. This trial will be the largest evaluation of melatonin as a prophylactic agent to prevent delirium in the critically ill population. This study will also provide one of the largest series of polysomnographic testing done in ICU. Trial registration: Australian New Zealand Clinical Trial Registry (ANZCTR) number: ACTRN12616000436471. Registered on 20 December 2015
Detection of Cosmic Structures using the Bispectrum Phase. II. First Results from Application to Cosmic Reionization Using the Hydrogen Epoch of Reionization Array
Characterizing the epoch of reionization (EoR) at via the
redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern
astrophysics and cosmology, and thus a key science goal of many current and
planned low-frequency radio telescopes. The primary challenge to detecting this
signal is the overwhelmingly bright foreground emission at these frequencies,
placing stringent requirements on the knowledge of the instruments and
inaccuracies in analyses. Results from these experiments have largely been
limited not by thermal sensitivity but by systematics, particularly caused by
the inability to calibrate the instrument to high accuracy. The interferometric
bispectrum phase is immune to antenna-based calibration and errors therein, and
presents an independent alternative to detect the EoR HI fluctuations while
largely avoiding calibration systematics. Here, we provide a demonstration of
this technique on a subset of data from the Hydrogen Epoch of Reionization
Array (HERA) to place approximate constraints on the brightness temperature of
the intergalactic medium (IGM). From this limited data, at we infer
"" upper limits on the IGM brightness temperature to be
"pseudo" mK at "pseudo" Mpc (data-limited)
and "pseudo" mK at "pseudo" Mpc
(noise-limited). The "pseudo" units denote only an approximate and not an exact
correspondence to the actual distance scales and brightness temperatures. By
propagating models in parallel to the data analysis, we confirm that the
dynamic range required to separate the cosmic HI signal from the foregrounds is
similar to that in standard approaches, and the power spectrum of the
bispectrum phase is still data-limited (at dynamic range)
indicating scope for further improvement in sensitivity as the array build-out
continues.Comment: 22 pages, 12 figures (including sub-figures). Published in PhRvD.
Abstract may be slightly abridged compared to the actual manuscript due to
length limitations on arXi
Design of RNAi Hairpins for Mutation-Specific Silencing of Ataxin-7 and Correction of a SCA7 Phenotype
Spinocerebellar ataxia type 7 is a polyglutamine disorder caused by an expanded CAG repeat mutation that results in neurodegeneration. Since no treatment exists for this chronic disease, novel therapies such post-transcriptional RNA interference-based gene silencing are under investigation, in particular those that might enable constitutive and tissue-specific silencing, such as expressed hairpins. Given that this method of silencing can be abolished by the presence of nucleotide mismatches against the target RNA, we sought to identify expressed RNA hairpins selective for silencing the mutant ataxin-7 transcript using a linked SNP. By targeting both short and full-length tagged ataxin-7 sequences, we show that mutation-specific selectivity can be obtained with single nucleotide mismatches to the wild-type RNA target incorporated 3′ to the centre of the active strand of short hairpin RNAs. The activity of the most effective short hairpin RNA incorporating the nucleotide mismatch at position 16 was further studied in a heterozygous ataxin-7 disease model, demonstrating significantly reduced levels of toxic mutant ataxin-7 protein with decreased mutant protein aggregation and retention of normal wild-type protein in a non-aggregated diffuse cellular distribution. Allele-specific mutant ataxin7 silencing was also obtained with the use of primary microRNA mimics, the most highly effective construct also harbouring the single nucleotide mismatch at position 16, corroborating our earlier findings. Our data provide understanding of RNA interference guide strand anatomy optimised for the allele-specific silencing of a polyglutamine mutation linked SNP and give a basis for the use of allele-specific RNA interference as a viable therapeutic approach for spinocerebellar ataxia 7
What does an interferometer really measure? Including instrument and data characteristics in the reconstruction of the 21cm power spectrum
Combining the visibilities measured by an interferometer to form a
cosmological power spectrum is a complicated process in which the window
functions play a crucial role. In a delay-based analysis, the mapping between
instrumental space, made of per-baseline delay spectra, and cosmological space
is not a one-to-one relation. Instead, neighbouring modes contribute to the
power measured at one point, with their respective contributions encoded in the
window functions. To better understand the power spectrum measured by an
interferometer, we assess the impact of instrument characteristics and analysis
choices on the estimator by deriving its exact window functions, outside of the
delay approximation. Focusing on HERA as a case study, we find that
observations made with long baselines tend to correspond to enhanced low-k
tails of the window functions, which facilitate foreground leakage outside the
wedge, whilst the choice of bandwidth and frequency taper can help narrow them
down. With the help of simple test cases and more realistic visibility
simulations, we show that, apart from tracing mode mixing, the window functions
can accurately reconstruct the power spectrum estimator of simulated
visibilities. We note that the window functions depend strongly on the
chromaticity of the beam, and less on its spatial structure - a Gaussian
approximation, ignoring side lobes, is sufficient. Finally, we investigate the
potential of asymmetric window functions, down-weighting the contribution of
low-k power to avoid foreground leakage. The window functions presented in this
work correspond to the latest HERA upper limits for the full Phase I data. They
allow an accurate reconstruction of the power spectrum measured by the
instrument and can be used in future analyses to confront theoretical models
and data directly in cylindrical space.Comment: 18 pages, 18 figures, submitted to MNRAS. Comments welcome
Characterization Of Inpaint Residuals In Interferometric Measurements of the Epoch Of Reionization
Radio Frequency Interference (RFI) is one of the systematic challenges
preventing 21cm interferometric instruments from detecting the Epoch of
Reionization. To mitigate the effects of RFI on data analysis pipelines,
numerous inpaint techniques have been developed to restore RFI corrupted data.
We examine the qualitative and quantitative errors introduced into the
visibilities and power spectrum due to inpainting. We perform our analysis on
simulated data as well as real data from the Hydrogen Epoch of Reionization
Array (HERA) Phase 1 upper limits. We also introduce a convolutional neural
network that capable of inpainting RFI corrupted data in interferometric
instruments. We train our network on simulated data and show that our network
is capable at inpainting real data without requiring to be retrained. We find
that techniques that incorporate high wavenumbers in delay space in their
modeling are best suited for inpainting over narrowband RFI. We also show that
with our fiducial parameters Discrete Prolate Spheroidal Sequences (DPSS) and
CLEAN provide the best performance for intermittent ``narrowband'' RFI while
Gaussian Progress Regression (GPR) and Least Squares Spectral Analysis (LSSA)
provide the best performance for larger RFI gaps. However we caution that these
qualitative conclusions are sensitive to the chosen hyperparameters of each
inpainting technique. We find these results to be consistent in both simulated
and real visibilities. We show that all inpainting techniques reliably
reproduce foreground dominated modes in the power spectrum. Since the
inpainting techniques should not be capable of reproducing noise realizations,
we find that the largest errors occur in the noise dominated delay modes. We
show that in the future, as the noise level of the data comes down, CLEAN and
DPSS are most capable of reproducing the fine frequency structure in the
visibilities of HERA data.Comment: 26 pages, 18 figure
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