Minimizing the overlap problem in protein NMR: a computational framework for precision amino acid labeling

Motivation: Recent advances in cell-free protein expression systems allow specific labeling of proteins with amino acids containing stable isotopes (¹⁵N, ¹³C and ²H), an important feature for protein structure determination by nuclear magnetic resonance (NMR) spectroscopy. Given this labeling ability, we present a mathematical optimization framework for designing a set of protein isotopomers, or labeling schedules, to reduce the congestion in the NMR spectra. The labeling schedules, which are derived by the optimization of a cost function, are tailored to a specific protein and NMR experiment. Results: For 2D ¹⁵N-¹H HSQC experiments, we can produce an exact solution using a dynamic programming algorithm in under 2 h on a standard desktop machine. Applying the method to a standard benchmark protein, calmodulin, we are able to reduce the number of overlaps in the 500 MHZ HSQC spectrum from 10 to 1 using four samples with a true cost function, and 10 to 4 if the cost function is derived from statistical estimates. On a set of 448 curated proteins from the BMRB database, we are able to reduce the relative percent congestion by 84.9% in their HSQC spectra using only four samples. Our method can be applied in a high-throughput manner on a proteomic scale using the server we developed. On a 100-node cluster, optimal schedules can be computed for every protein coded for in the human genome in less than a month. Availability: A server for creating labeling schedules for ¹⁵N-¹H HSQC experiments as well as results for each of the individual 448 proteins used in the test set is available at http://nmr.proteomics.ics.uci.edu

3D MAS NMR Experiment Utilizing Through-Space

We demonstrate a novel 3D NNC magic angle spinning NMR experiment that generates ¹⁵N–¹⁵N internuclear contacts in protein systems using an optimized ¹⁵N–¹⁵N proton assisted recoupling (PAR) mixing period and a ¹³C dimension for improved resolution. The optimized PAR condition permits the acquisition of high signal-to-noise 3D data that enables backbone chemical shift assignments using a strategy that is complementary to current schemes. The spectra can also provide distance constraints. The utility of the experiment is demonstrated on an M₀Aβ₁₋₄₂ fibril sample that yields high-quality data that is readily assigned and interpreted. The 3D NNC experiment therefore provides a powerful platform for solid-state protein studies and is broadly applicable to a variety of systems and experimental conditions.National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant EB-001960)National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant EB-002026

CHILES: HI morphology and galaxy environment at z=0.12 and z=0.17

We present a study of 16 HI-detected galaxies found in 178 hours of observations from Epoch 1 of the COSMOS HI Large Extragalactic Survey (CHILES). We focus on two redshift ranges between 0.108 <= z <= 0.127 and 0.162 <= z <= 0.183 which are among the worst affected by radio frequency interference (RFI). While this represents only 10% of the total frequency coverage and 18% of the total expected time on source compared to what will be the full CHILES survey, we demonstrate that our data reduction pipeline recovers high quality data even in regions severely impacted by RFI. We report on our in-depth testing of an automated spectral line source finder to produce HI total intensity maps which we present side-by-side with significance maps to evaluate the reliability of the morphology recovered by the source finder. We recommend that this become a common place manner of presenting data from upcoming HI surveys of resolved objects. We use the COSMOS 20k group catalogue, and we extract filamentary structure using the topological DisPerSE algorithm to evaluate the \hi\ morphology in the context of both local and large-scale environments and we discuss the shortcomings of both methods. Many of the detections show disturbed HI morphologies suggesting they have undergone a recent interaction which is not evident from deep optical imaging alone. Overall, the sample showcases the broad range of ways in which galaxies interact with their environment. This is a first look at the population of galaxies and their local and large-scale environments observed in HI by CHILES at redshifts beyond the z=0.1 Universe.Comment: 23 pages, 12 figures, 1 interactive 3D figure, accepted to MNRA

The Regeneration Games: Commodities, Gifts and the Economics of London 2012

This paper considers contradictions between two concurrent and tacit conceptions of the Olympic ‘legacy’, setting out one conception that understands the games and their legacies as gifts alongside and as counterpoint to the prevailing discourse, which conceives Olympic assets as commodities. The paper critically examines press and governmental discussion of legacy, in order to locate these in the context of a wider perspective contrasting ‘gift’ and ‘commodity’ Olympics – setting anthropological conceptions of gift-based sociality as a necessary supplement to contractual and dis-embedded socioeconomic organizational assumptions underpinning the commodity Olympics. Costbenefit planning is central to modern city building and mega-event delivery. The paper considers the insufficiency of this approach as the exclusive paradigm within which to frame and manage a dynamic socio-economic and cultural legacy arising from the 2012 games

23 High Redshift Supernovae from the IfA Deep Survey: Doubling the SN Sample at z>0.7

We present photometric and spectroscopic observations of 23 high redshift supernovae spanning a range of z=0.34-1.03, 9 of which are unambiguously classified as Type Ia. These supernovae were discovered during the IfA Deep Survey, which began in September 2001 and observed a total of 2.5 square degrees to a depth of approximately m=25-26 in RIZ over 9-17 visits, typically every 1-3 weeks for nearly 5 months, with additional observations continuing until April 2002. We give a brief description of the survey motivations, observational strategy, and reduction process. This sample of 23 high-redshift supernovae includes 15 at z>0.7, doubling the published number of objects at these redshifts, and indicates that the evidence for acceleration of the universe is not due to a systematic effect proportional to redshift. In combination with the recent compilation of Tonry et al. (2003), we calculate cosmological parameter density contours which are consistent with the flat universe indicated by the CMB (Spergel et al. 2003). Adopting the constraint that Omega_total = 1.0, we obtain best-fit values of (Omega_m, Omega_Lambda)=(0.33, 0.67) using 22 SNe from this survey augmented by the literature compilation. We show that using the empty-beam model for gravitational lensing does not eliminate the need for Omega_Lambda > 0. Experience from this survey indicates great potential for similar large-scale surveys while also revealing the limitations of performing surveys for z>1 SNe from the ground.Comment: 67 pages, 12 figures, 12 tables, accepted for publication in the Astrophysical Journa

Financing Direct Democracy: Revisiting the Research on Campaign Spending and Citizen Initiatives

The conventional view in the direct democracy literature is that spending against a measure is more effective than spending in favor of a measure, but the empirical results underlying this conclusion have been questioned by recent research. We argue that the conventional finding is driven by the endogenous nature of campaign spending: initiative proponents spend more when their ballot measure is likely to fail. We address this endogeneity by using an instrumental variables approach to analyze a comprehensive dataset of ballot propositions in California from 1976 to 2004. We find that both support and opposition spending on citizen initiatives have strong, statistically significant, and countervailing effects. We confirm this finding by looking at time series data from early polling on a subset of these measures. Both analyses show that spending in favor of citizen initiatives substantially increases their chances of passage, just as opposition spending decreases this likelihood

Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis

Background More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+)to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination.Methods In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks.Findings We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+.After 5\u20138 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0\ub717, 95% CI 0\ub711\u20130\ub725) among girls aged 13\u201319 years, and decreased significantly by 66% (RR 0\ub734, 95% CI 0\ub723\u20130\ub749) among women aged 20\u201324 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0\ub746, 95% CI 0\ub733\u20130\ub766) among girls aged 13\u201319 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0\ub733, 95% CI 0\ub724\u20130\ub746) among girls aged 15\u201319 years, decreased significantly by 54% (RR 0\ub746, 95% CI 0.36\u20130.60) among women aged 20\u201324 years, and decreased significantly by 31% (RR 0\ub769, 95% CI 0\ub753\u20130\ub789) among women aged 25\u201329 years. Among boys aged 15\u201319 years anogenital wart diagnoses decreased significantly by 48% (RR 0\ub752, 95% CI 0\ub737\u20130\ub775) and among men aged 20\u201324 years they decreased significantly by 32% (RR 0\ub768, 95% CI 0\ub747\u20130\ub798). After 5\u20139 years of vaccination, CIN2+ decreased significantly by 51% (RR 0\ub749, 95% CI 0\ub742\u20130\ub758) among screened girls aged 15\u201319 years and decreased significantly by 31% (RR 0\ub769, 95% CI 0\ub757\u20130\ub784) among women aged 20\u201324 years.Interpretation This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects

A Multi-Institutional Analysis of Adjuvant Chemotherapy and Radiation Sequence in Women With Stage IIIC Endometrial Cancer

PURPOSE: Our purpose was to evaluate the effect of sequence and type of adjuvant therapy for patients with stage IIIC endometrial carcinoma (EC) on outcomes. METHODS AND MATERIALS: In a multi-institutional retrospective cohort study, patients with stage IIIC EC who had surgical staging and received both adjuvant chemotherapy and radiation therapy (RT) were included. Adjuvant treatment regimens were classified as adjuvant chemotherapy followed by sequential RT (upfront chemo), which was predominant sequence; RT with concurrent chemotherapy followed by chemotherapy (concurrent); systemic chemotherapy before and after RT (sandwich); adjuvant RT followed by chemotherapy (upfront RT); or chemotherapy concurrent with vaginal cuff brachytherapy alone (chemo-brachy). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. RESULTS: A total of 686 eligible patients were included with a median follow-up of 45.3 months. The estimated 5-year OS and RFS rates were 74% and 66%, respectively. The sequence and type of adjuvant therapy were not correlated with OS or RFS (adjusted P = .68 and .84, respectively). On multivariate analysis, black race, nonendometrioid histology, grade 3 tumor, stage IIIC2, and presence of adnexal and cervical involvement were associated with worse OS and RFS (all P \u3c .05). Regardless of the sequence of treatment, the most common site of first recurrence was distant metastasis (20.1%). Vaginal only, pelvic only, and paraortic lymph node (PALN) recurrences occurred in 11 (1.6%),15 (2.2 %), and 43 (6.3 %) patients, respectively. Brachytherapy alone was associated with a higher rate of PALN recurrence (15%) compared with external beam radiation therapy (5%) P \u3c .0001. CONCLUSIONS: The sequence and type of combined adjuvant therapy did not affect OS or RFS rates. Brachytherapy alone was associated with a higher rate of PALN recurrence, emphasizing the role of nodal radiation for stage IIIC EC. The vast proportion of recurrences were distant despite systemic chemotherapy, highlighting the need for novel regimens