139 research outputs found
Approximation by the Dickman distribution and quasi-logarithmic combinatorial structures
Quasi-logarithmic combinatorial structures are a class of decomposable
combinatorial structures which extend the logarithmic class considered by
Arratia, Barbour and Tavar\'{e} (2003). In order to obtain asymptotic
approximations to their component spectrum, it is necessary first to establish
an approximation to the sum of an associated sequence of independent random
variables in terms of the Dickman distribution. This in turn requires an
argument that refines the Mineka coupling by incorporating a blocking
construction, leading to exponentially sharper coupling rates for the sums in
question. Applications include distributional limit theorems for the size of
the largest component and for the vector of counts of the small components in a
quasi-logarithmic combinatorial structure.Comment: 22 pages; replaces earlier paper [arXiv:math/0609129] with same title
by Bruno Nietlispac
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Compressed sensing: Reconstruction of non-uniformly sampled multidimensional NMR data
© 2018 Wiley Periodicals, Inc. Nuclear magnetic resonance (NMR) spectroscopy is widely used across the physical, chemical, and biological sciences. A core component of NMR studies is multidimensional experiments, which enable correlation of properties from one or more NMR-active nuclei. In high-resolution biomolecular NMR, common nuclei are1H,15N, and13C, and triple resonance experiments using these three nuclei form the backbone of NMR structural studies. In other fields, a range of other nuclei may be used. Multidimensional NMR experiments provide unparalleled information content, but this comes at the price of long experiment times required to achieve the necessary resolution and sensitivity. Non-uniform sampling (NUS) techniques to reduce the required data sampling have existed for many decades. Recently, such techniques have received heightened interest due to the development of compressed sensing (CS) methods for reconstructing spectra from such NUS datasets. When applied jointly, these methods provide a powerful approach to dramatically improve the resolution of spectra per time unit and under suitable conditions can also lead to signal-to-noise ratio improvements. In this review, we explore the basis of NUS approaches, the fundamental features of NUS reconstruction using CS and applications based on CS approaches including the benefits of expanding the repertoire of biomolecular NMR experiments into higher dimensions. We discuss some of the recent algorithms and software packages and provide practical tips for recording and processing NUS data by CS
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Improving resolution in multidimensional NMR using random quadrature detection with compressed sensing reconstruction.
NMR spectroscopy is central to atomic resolution studies in biology and chemistry. Key to this approach are multidimensional experiments. Obtaining such experiments with sufficient resolution, however, is a slow process, in part since each time increment in every indirect dimension needs to be recorded twice, in quadrature. We introduce a modified compressed sensing (CS) algorithm enabling reconstruction of data acquired with random acquisition of quadrature components in gradient-selection NMR. We name this approach random quadrature detection (RQD). Gradient-selection experiments are essential to the success of modern NMR and with RQD, a 50 % reduction in the number of data points per indirect dimension is possible, by only acquiring one quadrature component per time point. Using our algorithm (CSRQD), high quality reconstructions are achieved. RQD is modular and combined with non-uniform sampling we show that this provides increased flexibility in designing sampling schedules leading to improved resolution with increasing benefits as dimensionality of experiments increases, with particular advantages for 4- and higher dimensional experiments.Part of this work was performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/), provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England and funding from the Science and Technology Facilities Council.This is the final version of the article. It first appeared from Springer via https://doi.org/10.1007/s10858-016-0062-
Integral membrane protein structure determination using pseudocontact shifts.
Obtaining enough experimental restraints can be a limiting factor in the NMR structure determination of larger proteins. This is particularly the case for large assemblies such as membrane proteins that have been solubilized in a membrane-mimicking environment. Whilst in such cases extensive deuteration strategies are regularly utilised with the aim to improve the spectral quality, these schemes often limit the number of NOEs obtainable, making complementary strategies highly beneficial for successful structure elucidation. Recently, lanthanide-induced pseudocontact shifts (PCSs) have been established as a structural tool for globular proteins. Here, we demonstrate that a PCS-based approach can be successfully applied for the structure determination of integral membrane proteins. Using the 7TM α-helical microbial receptor pSRII, we show that PCS-derived restraints from lanthanide binding tags attached to four different positions of the protein facilitate the backbone structure determination when combined with a limited set of NOEs. In contrast, the same set of NOEs fails to determine the correct 3D fold. The latter situation is frequently encountered in polytopical α-helical membrane proteins and a PCS approach is thus suitable even for this particularly challenging class of membrane proteins. The ease of measuring PCSs makes this an attractive route for structure determination of large membrane proteins in general.This work was supported by the Biotechnology and Biological Sciences Research Council BBSRC [BB/K01983X/1].This paper was originally published in the Journal of Bimolecular NMR (Crick DJ, Wang JX, Graham B, Swarbrick JD, Mott HR, Nietlispach D, Journal of Biomolecular NMR 2015, doi:10.1007/s10858-015-9899-6)
Repositionable Versus Balloon-Expandable Devices for Transcatheter Aortic Valve Implantation in Patients With Aortic Stenosis.
The safety and effectiveness of the fully repositionable LOTUS valve system as compared with the balloon-expandable Edwards SAPIEN 3 prosthesis for the treatment of aortic stenosis has not been evaluated to date.
All patients undergoing transcatheter aortic valve implantation with the Edwards SAPIEN 3 or the LOTUS valve system were included into the Swiss Transcatheter Aortic Valve Implantation Registry. An adjusted analysis was performed to compare the early clinical safety outcome according to the Valve Academic Research Consortium-2 definition. Between February 2014 and September 2015, 140 and 815 patients were treated with the LOTUS and the Edwards SAPIEN 3 valve, respectively. There was no difference in crude and adjusted analyses of the early safety outcome between patients treated with LOTUS (14.3%) and those treated with Edwards SAPIEN 3 (14.6%) (crude hazard ratio, 0.97; 95% CI, 0.61-1.56 [P=0.915]; adjusted hazard ratio, 1.03; 95% CI, 0.64-1.67 [P=0.909]). More than mild aortic regurgitation was <2% for both devices. A total of 34.3% of patients treated with LOTUS and 14.1% of patients treated with Edwards SAPIEN 3 required a permanent pacemaker (HR, 2.76; 95% CI, 1.97-3.87 [P<0.001]).
The repositionable LOTUS valve system and the balloon-expandable Edwards SAPIEN 3 prosthesis appeared comparable in regard to the Valve Academic Research Consortium-2 early safety outcome, and the rates of more than mild aortic regurgitation were exceedingly low for both devices. The need for new permanent pacemaker implantation was more frequent among patients treated with the LOTUS valve
Diabetes and baseline glucose are associated with inflammation, left ventricular function and short- and long-term outcome in acute coronary syndromes: role of the novel biomarker Cyr 61.
Hyperglycemia in the setting of an acute coronary syndrome (ACS) impacts short term outcomes, but little is known about longer term effects. We therefore designed this study to firstly determine the association between hyperglycemia and short term and longer term outcomes in patients presenting with ACS and secondly evaluate the prognostic role of diabetes, body mass index (BMI) and the novel biomarker Cyr61 on outcomes.
The prospective Special Program University Medicine-Acute Coronary Syndrome (SPUM-ACS) cohort enrolled 2168 patients with ACS between December 2009 and October 2012, of which 2034 underwent PCI (93.8%). Patients were followed up for 12 months. Events were independently adjudicated by three experienced cardiologists. Participants were recruited from four tertiary hospitals in Switzerland: Zurich, Geneva, Lausanne and Bern. Participants presenting with acute coronary syndromes and who underwent coronary angiography were included in the analysis. Patients were grouped according to history of diabetes (or HbA1c greater than 6%), baseline blood sugar level (BSL; < 6, 6-11.1 and > 11.1 mmol/L) and body mass index (BMI). The primary outcome was major adverse cardiac events (MACE) which was a composite of myocardial infarction, stroke and all-cause death. Secondary outcomes included the individual components of the primary endpoint, revascularisations, bleeding events (BARC classification) and cerebrovascular events (ischaemic or haemorrhagic stroke or TIA).
Patients with hyperglycemia, i.e. BSL ≥ 11.1 mmol/L, had higher levels of C-reactive protein (CRP), white blood cell count (WBC), creatinine kinase (CK), higher heart rates and lower left ventricular ejection fraction (LVEF) and increased N-terminal pro-brain natriuretic peptide. At 30 days and 12 months, those with BSL ≥ 11.1 mmol/L had more MACE and death compared to those with BSL < 6.0 mmol/L or 6.0-11.1 mmol/L (HR-ratio 4.78 and 6.6; p < 0.001). The novel biomarker Cyr61 strongly associated with high BSL and STEMI and was independently associated with 1 year outcomes (HR 2.22; 95% CI 1.33-3.72; Tertile 3 vs. Tertile 1).
In this large, prospective, independently adjudicated cohort of in all comers ACS patients undergoing PCI, both a history of diabetes and elevated entry glucose was associated with inflammation and increased risk of MACE both at short and long-term. The mediators might involve increased sympathetic activation, inflammation and ischemia as reflected by elevated Cyr61 levels leading to larger levels of troponin and lower LVEF. Trial registration Clinical Trial Registration Number: NCT01000701. Registered October 23, 2009
NUScon: a community-driven platform for quantitative evaluation of nonuniform sampling in NMR
Although the concepts of nonuniform sampling (NUS) and non-Fourier spectral reconstruction in multidimensional NMR began to emerge 4 decades ago (Bodenhausen and Ernst, 1981; Barna and Laue, 1987), it is only relatively recently that NUS has become more commonplace. Advantages of NUS include the ability to tailor experiments to reduce data collection time and to improve spectral quality, whether through detection of closely spaced peaks (i.e., “resolution”) or peaks of weak intensity (i.e., “sensitivity”). Wider adoption of these methods is the result of improvements in computational performance, a growing abundance and flexibility of software, support from NMR spectrometer vendors, and the increased data sampling demands imposed by higher magnetic fields. However, the identification of best practices still remains a significant and unmet challenge. Unlike the discrete Fourier transform, non-Fourier methods used to reconstruct spectra from NUS data are nonlinear, depend on the complexity and nature of the signals, and lack quantitative or formal theory describing their performance. Seemingly subtle algorithmic differences may lead to significant variabilities in spectral qualities and artifacts. A community-based critical assessment of NUS challenge problems has been initiated, called the “Nonuniform Sampling Contest” (NUScon), with the objective of determining best practices for processing and analyzing NUS experiments. We address this objective by constructing challenges from NMR experiments that we inject with synthetic signals, and we process these challenges using workflows submitted by the community. In the initial rounds of NUScon our aim is to establish objective criteria for evaluating the quality of spectral reconstructions. We present here a software package for performing the quantitative analyses, and we present the results from the first two rounds of NUScon. We discuss the challenges that remain and present a roadmap for continued community-driven development with the ultimate aim of providing best practices in this rapidly evolving field. The NUScon software package and all data from evaluating the challenge problems are hosted on the NMRbox platform
NUScon: a community-driven platform for quantitative evaluation of nonuniform sampling in NMR
Although the concepts of nonuniform sampling (NUS) and non-Fourier spectral reconstruction in multidimensional NMR began to emerge 4 decades ago (Bodenhausen and Ernst, 1981; Barna and Laue, 1987), it is only relatively recently that NUS has become more commonplace. Advantages of NUS include the ability to tailor experiments to reduce data collection time and to improve spectral quality, whether through detection of closely spaced peaks (i.e., “resolution”) or peaks of weak intensity (i.e., “sensitivity”). Wider adoption of these methods is the result of improvements in computational performance, a growing abundance and flexibility of software, support from NMR spectrometer vendors, and the increased data sampling demands imposed by higher magnetic fields. However, the identification of best practices still remains a significant and unmet challenge. Unlike the discrete Fourier transform, non-Fourier methods used to reconstruct spectra from NUS data are nonlinear, depend on the complexity and nature of the signals, and lack quantitative or formal theory describing their performance. Seemingly subtle algorithmic differences may lead to significant variabilities in spectral qualities and artifacts. A community-based critical assessment of NUS challenge problems has been initiated, called the “Nonuniform Sampling Contest” (NUScon), with the objective of determining best practices for processing and analyzing NUS experiments. We address this objective by constructing challenges from NMR experiments that we inject with synthetic signals, and we process these challenges using workflows submitted by the community. In the initial rounds of NUScon our aim is to establish objective criteria for evaluating the quality of spectral reconstructions. We present here a software package for performing the quantitative analyses, and we present the results from the first two rounds of NUScon. We discuss the challenges that remain and present a roadmap for continued community-driven development with the ultimate aim of providing best practices in this rapidly evolving field. The NUScon software package and all data from evaluating the challenge problems are hosted on the NMRbox platform
Acute kidney injury following transcatheter aortic valve implantation: predictive factors, prognostic value, and comparison with surgical aortic valve replacement
Aims: Very few data exist on the occurrence of acute kidney injury (AKI) associated with transcatheter aortic valve implantation (TAVI). The objectives of the present study were (i) to determine the incidence, predictive factors, and prognostic value of AKI following TAVI, and (ii) to compare the occurrence of AKI in TAVI vs. surgical aortic valve replacement (SAVR) in patients with pre-procedural chronic kidney disease (CKD).
Methods and results: A total of 213 patients (mean age 82 ± 8 years) undergoing TAVI for the treatment of severe aortic stenosis were included in the study. Acute kidney injury was defined as a reduction of >25% in estimated glomerular filtration rate (eGFR) within 48 h following the procedure or the need for haemodialysis during index hospitalization. Those patients with pre-procedural CKD (eGFR <60 mL/min/1.73 m2, n = 119) were compared with 104 contemporary patients with CKD who underwent isolated SAVR. The incidence of AKI following TAVI was 11.7%, with 1.4% of the patients requiring haemodialysis. Predictive factors of AKI were hypertension (OR: 4.66; 95% CI: 1.04–20.87), chronic obstructive pulmonary disease (OR: 2.64, 95% CI: 1.10–6.36), and peri-operative blood transfusion (OR: 3.47, 95% CI: 1.30–9.29). Twenty-one patients (9.8%) died during index hospitalization, and the logistic EuroSCORE (OR: 1.03 for each increase of 1%; 95% CI: 1.01–1.06) and occurrence of AKI (OR: 4.14, 95% CI: 1.42–12.13) were identified as independent predictors of postoperative mortality. Patients with CKD who underwent TAVI were older, had a higher logistic EuroSCORE and lower pre-procedural eGFR values compared with those who underwent SAVR (P < 0.0001 for all). The incidence of AKI was lower (P = 0.001; P = 0.014 after propensity score adjustment) in CKD patients who underwent TAVI (9.2%, need for haemodialysis: 2.5%) compared with those who underwent SAVR (25.9%, need for haemodialysis: 8.7%).
Conclusion: Acute kidney injury occurred in 11.7% of the patients following TAVI and was associated with a greater than four-fold increase in the risk of postoperative mortality. Hypertension, chronic obstructive pulmonary disease, and blood transfusion were predictive factors of AKI. In those patients with pre-procedural CKD, TAVI was associated with a significant reduction of AKI compared with SAVR
Local Cooperativity in an Amyloidogenic State of Human Lysozyme Observed at Atomic Resolution
The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild-type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal unfolding under amyloidogenic solution conditions involves a cooperative loss of native tertiary structure, followed by progressive unfolding of a compact, molten globule-like denatured state ensemble as the temperature is increased. The width of the temperature window over which the denatured ensemble progressively unfolds correlates with the relative amyloidogenicity and stability of these variants, and the region of lysozyme that unfolds first maps to that which forms the core of the amyloid fibrils formed under similar conditions. Together, these results present a coherent picture at atomic resolution of the initial events underlying amyloid formation by a globular protein
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