A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape.The research leading to these results has received funding from the European Research Council under the European UnionÏs Seventh Framework Programme (FP7/2007–2013)/ ERC grant agreement no. [279337/DOS]. The authors also thank AstraZeneca, the EPSRC, the BBSRC, the MRC and the Wellcome Trust for funding. F.N. and D.L.K. thank the Gates Cambridge. F.N. also thanks Trinity College for a Krishnan-Ang Studentship. D.W. thanks the DFG for a postdoctoral fellowship (WI 4198/1-1). S.B. thanks the Herchel Smith Fund. The authors thank Dr John Davies for X-ray crystallography and Dr Andrew Bond for refinement (both from the University of Cambridge)

Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: is dose tapering practical in good responders?

OBJECTIVES: RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. METHODS: We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0-6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6-12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. RESULTS: Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0-6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6-12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). CONCLUSION: Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states

Wavelet Cycle Spinning Denoising of NDE Ultrasonic Signals Using a Random Selection of Shifts

Wavelets are a powerful tool for signal and image denoising. Most of the denoising applications in different fields were based on the thresholding of the discrete wavelet transform (DWT) coefficients. Nevertheless, DWT transform is not a time or shift invariant transform and results depend on the selected shift. Improvements on the denoising performance can be obtained using the stationary wavelet transform (SWT) (also called shift-invariant or undecimated wavelet transform). Denoising using SWT has previously shown a robust and usually better performance than denoising using DWT but with a higher computational cost. In this paper, wavelet shrinkage schemes are applied for reducing noise in synthetic and experimental non-destructive evaluation ultrasonic A-scans, using DWT and a cycle-spinning implementation of SWT. A new denoising procedure, which we call random partial cycle spinning (RPCS), is presented. It is based on a cycle-spinning over a limited number of shifts that are selected in a random way. Wavelet denoising based on DWT, SWT and RPCS have been applied to the same sets of ultrasonic A-scans and their performances in terms of SNR are compared. In all cases three well known threshold selection rules (Universal, Minimax and Sure), with decomposition level dependent selection, have been used. It is shown that the new procedure provides a good robust denoising performance, without the DWT fluctuating performance, and close to SWT but with a much lower computational cost.This work was partially supported by Spanish MCI Project DPI2011-22438San Emeterio Prieto, JL.; Rodríguez-Hernández, MA. (2015). Wavelet Cycle Spinning Denoising of NDE Ultrasonic Signals Using a Random Selection of Shifts. Journal of Nondestructive Evaluation. 34(1):1-8. https://doi.org/10.1007/s10921-014-0270-8S18341Galloway, R.L., McDermott, B.A., Thurstone, F.L.: A frequency diversity process for speckle reduction in real-time ultrasonic images. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 35, 45–49 (1988)Newhouse, V.L., Bilgutay, N.M., Saniie, J., Furgason, E.S.: Flaw-to-grain echo enhancement by split spectrum processing. Ultrasonics 20, 59–68 (1982)Karpur, P., Canelones, O.J.: Split spectrum processing: a new filtering approach for improved signal-to-noise ratio enhancement of ultrasonic signals. Ultrasonics 30, 351–357 (1992)Donoho, D.L., Johnstone, I.M.: Ideal spatial adaptation by wavelet shrinkage. Biometrika 81, 425–455 (1994)Donoho, D.L., Johnstone, I.M., Kerkyacharian, G., Picard, D.: Wavelet shrinkage: asymptotia? J. R Stat. Soc. Ser. B 57, 301–369 (1995)Donoho, D.L., Johnstone, I.M.: Adapting to unknown smoothness via wavelet shrinkage. J. Am. Stat. Assoc. 90, 1200–1224 (1995)Johnstone, I.M., Silverman, B.W.: Wavelet threshold estimators for data with correlated noise. J. R Stat. Soc. 59, 319–351 (1997)Jansen, M.: Noise Reduction by Wavelet Thresholding. Lecture Notes in Statistics 161. Springer, New York (2001). doi: 10.1007/978-1-4613-0145-5Nason, G.P., Silverman, B.W.:The stationary wavelet transform and some statistical applications. In: Antoniadis, A., Oppenheim, G. (eds.) Wavelets and Statistics. Lecture Notes in Statistics, Vol. 103, pp 281–299. Springer, New York (1995)Lang, M., Guo, H., Odegard, J.E., Burrus, C.S.: Noise reduction using an undecimated discrete wavelet transform. IEEE Signal Proc. Lett. 3, 10–12 (1996)Coifman, R.R., Donoho, D.L.: Translation-invariant de-noising. In: Antoniadis, A., Oppenheim, G. (eds.) Wavelets and Statistics. Lecture Notes in Statistics, vol. 103, pp 125–150, Springer, New York (1995) .Abbate, A., Koay, J., Frankel, J., Schroeder, S.C., Das, P.: Signal detection and noise suppression using a wavelet transform signal processor: application to ultrasonic flaw detection. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 44, 14–26 (1997)Lázaro, J.C., San Emeterio, J.L., Ramos, A., Fernandez, J.L.: Influence of thresholding procedures in ultrasonic grain noise reduction using wavelets. Ultrasonics 40, 263–267 (2002)Matz, V., Smid, R., Starman, S., Kreidl, M.: Signal-to-noise ratio enhancement based on wavelet filtering in ultrasonic testing. Ultrasonics 49, 752–759 (2009)Kubinyi, M., Kreibich, O., Neuzil, J., Smid, R.: EMAT noise suppression using information fusion in stationary wavelet packets. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 58, 1027–1036 (2011)Shi, G.M., Chen, X.Y., Song, X.X., Qui, F., Ding, A.L.: Signal matching wavelet for ultrasonic flaw detection in high background noise. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 58, 776–787 (2011)Song, S.P., Que, P.W.: Wavelet based noise suppression technique and its application to ultrasonic flaw detection. Ultrasonics 44, 188–193 (2006)Rodriguez, M.A., San Emeterio, J.L., Lázaro, J.C., Ramos, A.: Ultrasonic flaw detection in NDE of highly scattering materials using wavelet and Wigner-Ville transform processing. Ultrasonics 42, 847–851 (2004)Zhang, G.M., Zhang, S.Y., Wang, Y.W.: Application of adaptive time-frequency decomposition in ultrasonic NDE of highly-scattering materials. Ultrasonics 38, 961–964 (2000)Drai, R., Khelil, M., Benchaala, A.: Time frequency and wavelet transform applied to selected problems in ultrasonics NDE. NDT & E Int. 35, 567–572 (2002)Pardo, E., San Emeterio, J.L.: Noise reduction in ultrasonic NDT using undecimated wavelet transforms. Ultrasonics 44, e1063–e1067 (2006)Kechida, A., Drai, R., Guessoum, A.: Texture analysis for flaw detection in ultrasonic images. J. Nondestruct. Eval. 31, 108–116 (2012). doi: 10.1007/s10921-011-0126-4Rucka, M., Wilde, K.: Experimental study on ultrasonic monitoring of splitting failure in reinforced concrete. J. Nondestruct. Eval. 32, 372–383 (2013). doi: 10.1007/s10921-013-0191-yHosseini, S.M.H., Duczek, S., Gabbert, U.: Damage localization in plates using mode conversion characteristics of ultrasonic guided waves. J. Nondestruct. Eval. 33, 152–165 (2014). doi: 10.1007/s10921-013-0211-yMohammed, M.S., Ki-Seong, K.: Shift-invariant wavelet packet for signal de-noising in ultrasonic testing. Insight 54, 366–370 (2012)San Emeterio, J.L., Rodriguez-Hernandez, M.A.: Wavelet denoising of ultrasonic A-scans by random partial cycle spinning. 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Does child weight influence how mothers report their feeding practices?

Objectives. The present study aimed to ascertain whether parental reports of their feeding practices are associated with independent observations of these behaviours, and whether the reliability of maternal report depends upon the child's weight. Methods. A total of 56 mothers and their children ate a lunch to satiety which was videotaped and coded for maternal use of control during feeding. Mothers also completed questionnaires about their feeding practices and children were weighed and measured. Results. Maternal reports of controlling feeding practices were poorly related to independent observations of these behaviours in the laboratory. However, there was a significant interaction between child BMI z score and observed pressure to eat in predicting maternally reported pressure to eat. There was also a significant interaction between child BMI z score and observed maternal restriction with food in predicting maternally reported restriction. When decomposed, these interactions suggested that only mothers of relatively underweight children were accurate at reporting their use of pressure to eat when compared to independent observations. For mothers of relatively overweight children there was a significant negative relationship between observed and reported restriction over food. Conclusions. Overall there was poor correspondence between maternal reports and independent observations of the use of controlling feeding practices. Further research is needed to replicate these findings and to ascertain whether parents who are inaccurate at reporting their use of these feeding practices are unaware that they are using controlling feeding practices or whether they are responding in socially desirable ways to questionnaires assessing their feeding behaviour. © 2011 Informa Healthcare

Compared to conventional, ecological intensive management promotes beneficial proteolytic soil microbial communities for agro-ecosystem functioning under climate change-induced rain regimes

Projected climate change and rainfall variability will affect soil microbial communities, biogeochemical cycling and agriculture. Nitrogen (N) is the most limiting nutrient in agroecosystems and its cycling and availability is highly dependent on microbial driven processes. In agroecosystems, hydrolysis of organic nitrogen (N) is an important step in controlling soil N availability. We analyzed the effect of management (ecological intensive vs. conventional intensive) on N-cycling processes and involved microbial communities under climate change-induced rain regimes. Terrestrial model ecosystems originating from agroecosystems across Europe were subjected to four different rain regimes for 263 days. Using structural equation modelling we identified direct impacts of rain regimes on N-cycling processes, whereas N-related microbial communities were more resistant. In addition to rain regimes, management indirectly affected N-cycling processes via modifications of N-related microbial community composition. Ecological intensive management promoted a beneficial N-related microbial community composition involved in N-cycling processes under climate change-induced rain regimes. Exploratory analyses identified phosphorus-associated litter properties as possible drivers for the observed management effects on N-related microbial community composition. This work provides novel insights into mechanisms controlling agro-ecosystem functioning under climate change

Does intensive management improve remission rates in patients with intermediate rheumatoid arthritis? (the TITRATE trial): study protocol for a randomised controlled trial.

BACKGROUND: Uncontrolled active rheumatoid arthritis can lead to increasing disability and reduced quality of life over time. 'Treating to target' has been shown to be effective in active established disease and also in early disease. However, there is a lack of nationally agreed treatment protocols for patients with established rheumatoid arthritis who have intermediate disease activity. This trial is designed to investigate whether intensive management of disease leads to a greater number of remissions at 12 months. Levels of disability and quality of life, and acceptability and cost-effectiveness of the intervention will also be examined. METHODS: The trial is a 12-month, pragmatic, randomised, open-label, two-arm, parallel-group, multicentre trial undertaken at specialist rheumatology centres across England. Three hundred and ninety-eight patients with established rheumatoid arthritis will be recruited. They will currently have intermediate disease activity (disease activity score for 28 joints assessed using an erythrocyte sedimentation rate of 3.2 to 5.1 with at least three active joints) and will be taking at least one disease-modifying anti-rheumatic drug. Participants will be randomly selected to receive intensive management or standard care. Intensive management will involve monthly clinical reviews with a specialist health practitioner, where drug treatment will be optimised and an individualised treatment support programme delivered based on several principles of motivational interviewing to address identified problem areas, such as pain, fatigue and adherence. Standard care will follow standard local pathways and will be in line with current English guidelines from the National Institute for Health and Clinical Excellence. Patients will be assessed initially and at 6 and 12 months through self-completed questionnaires and clinical evaluation. DISCUSSION: The trial will establish whether the known benefits of intensive treatment strategies in active rheumatoid arthritis are also seen in patients with established rheumatoid arthritis who have moderately active disease. It will evaluate both the clinical and cost-effectiveness of intensive treatment. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN70160382 . Registered on 16 January 2014.MRC Funding: MC_UP_1302/3 NIHR Funding: RP-PG-0610-1006

The N-P-K soil nutrient balance of portuguese cropland in the 1950s: the transition from organic to chemical fertilization

Agricultural nutrient balances have been receiving increasing attention in both historical and nutrient management research. The main objectives of this study were to further develop balance methodologies and to carry out a comprehensive assessment of the functioning and nutrient cycling of 1950s agroecosystems in Portugal. Additionally, the main implications for the history of agriculture in Portugal were discussed from the standpoint of soil fertility. We used a mass balance approach that comprises virtually all nitrogen (N), phosphorus (P) and potassium (K) inputs and outputs from cropland topsoil for average conditions in the period 1951–56. We found a consistent deficit in N, both for nationwide (−2.1 kg.ha−1.yr−1) and arable crops (−1.6 kg.ha−1.yr−1) estimates, that was rectified in the turn to the 1960 decade. P and K were, in contrast, accumulating in the soil (4.2–4.6 kg.ha−1.yr−1 and 1.0–3.0 kg.ha−1.yr−1, respectively). We observed that the 1950s is the very moment of inflection from an agriculture fertilized predominantly through reused N in biomass (livestock excretions plus marine, plant and human waste sources) to one where chemical fertilizers prevailed. It is suggested that N deficiency played an important role in this transitioninfo:eu-repo/semantics/publishedVersio

The regional and global significance of nitrogen removal in lakes and reservoirs

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Biogeochemistry 93 (2009): 143-157, doi:10.1007/s10533-008-9272-x.Human activities have greatly increased the transport of biologically available N through watersheds to potentially sensitive coastal ecosystems. Lentic water bodies (lakes and reservoirs) have the potential to act as important sinks for this reactive N as it is transported across the landscape because they offer ideal conditions for N burial in sediments or permanent loss via denitrification. However, the patterns and controls on lentic N removal have not been explored in great detail at large regional to global scales. In this paper we describe, evaluate, and apply a new, spatially explicit, annual-scale, global model of lentic N removal called NiRReLa (Nitrogen Retention in Reservoirs and Lakes). The NiRReLa model incorporates small lakes and reservoirs than have been included in previous global analyses, and also allows for separate treatment and analysis of reservoirs and natural lakes. Model runs for the mid-1990s indicate that lentic systems are indeed important sinks for N and are conservatively estimated to remove 19.7 Tg N yr-1 from watersheds globally. Small lakes (< 50 km2) were critical in the analysis, retaining almost half (9.3 Tg N yr-1) of the global total. In model runs, capacity of lakes and reservoirs to remove watershed N varied substantially (0-100%) both as a function of climate and the density of lentic systems. Although reservoirs occupy just 6% of the global lentic surface area, we estimate they retain approximately 33% of the total N removed by lentic systems, due to a combination of higher drainage ratios (catchment surface area : lake or reservoir surface area), higher apparent settling velocities for N, and greater N loading rates in reservoirs than in lakes. Finally, a sensitivity analysis of NiRReLa suggests that, on-average, N removal within lentic systems will respond more strongly to changes in land use and N loading than to changes in climate at the global scale.The NSF26 Research Coordination Network on denitrification for support for collaboration (award number DEB0443439 to S.P. Seitzinger and E.A. Davidson). This project was also supported by grants to J.A. Harrison from California Sea Grant (award number RSF8) and from the U.S. Geological Survey 104b program and R. Maranger (FQRNT Strategic Professor)