Enhancing the catalytic repertoire of nucleic acids: a systematic study of linker length and rigidity

The incorporation of potentially catalytic groups in DNA is of interest for the in vitro selection of novel deoxyribozymes, A series of 10 C5-modified analogues of 2'-deoxyuridine triphosphate have been synthesised that possess side chains of differing flexibility and bearing a primary amino or imidazole functionality, For each series of nucleotide analogues differing degrees of flexibility of the C5 side chain was achieved through the use of alkynyl, alkenyl and alkyl moieties, The imidazole function was conjugated to these CS-amino-modified nucleotides using either imidazole 4-acetic acid or imidazole 4-acrylic acid (urocanic acid), The substrate properties of the nucleotides (fully replacing dTTP) with Taq polymerase during PCR have been investigated in order to evaluate their potential applications for in vitro selection experiments, 5-(3-Aminopropynyl)dUTP and 5-(E-3-aminopropenyl)dUTP and their imidazole 4-acetic acid- and urocanic acid-modified conjugates were found to be substrates, In contrast, C5-amino-modified dUTPs with alkane or Z-alkene linkers and their corresponding conjugates were not substrates, The incorporation of these analogues during PCR has been confirmed by inhibition of restriction enzyme digestion using XbaI and by mass spectrometry of the PCR products.

Climate spectrum estimation in the presence of timescale errors.

We introduce an algorithm (called REDFITmc2) for spectrum estimation in the presence of timescale errors. It is based on the Lomb-Scargle periodogram for unevenly spaced time series, in combination with the Welch's Overlapped Segment Averaging procedure, bootstrap bias correction and persistence estimation. The timescale errors are modelled parametrically and included in the simulations for determining (1) the upper levels of the spectrum of the red-noise AR(1) alternative and (2) the uncertainty of the frequency of a spectral peak. Application of REDFITmc2 to ice core and stalagmite records of palaeoclimate allowed a more realistic evaluation of spectral peaks than when ignoring this source of uncertainty. The results support qualitatively the intuition that stronger effects on the spectrum estimate (decreased detectability and increased frequency uncertainty) occur for higher frequencies. The surplus information brought by algorithm REDFITmc2 is that those effects are quantified. Regarding timescale construction, not only the fixpoints, dating errors and the functional form of the age-depth model play a role. Also the joint distribution of all time points (serial correlation, stratigraphic order) determines spectrum estimation.

The Asian summer monsoon: an intercomparison of CMIP5 vs. CMIP3 simulations of the late 20th century

The boreal summer Asian monsoon has been evaluated in 25 Coupled Model Intercomparison Project-5 (CMIP5) and 22 CMIP3 GCM simulations of the late 20th Century. Diagnostics and skill metrics have been calculated to assess the time-mean, climatological annual cycle, interannual variability, and intraseasonal variability. Progress has been made in modeling these aspects of the monsoon, though there is no single model that best represents all of these aspects of the monsoon. The CMIP5 multi-model mean (MMM) is more skillful than the CMIP3 MMM for all diagnostics in terms of the skill of simulating pattern correlations with respect to observations. Additionally, for rainfall/convection the MMM outperforms the individual models for the time mean, the interannual variability of the East Asian monsoon, and intraseasonal variability. The pattern correlation of the time (pentad) of monsoon peak and withdrawal is better simulated than that of monsoon onset. The onset of the monsoon over India is typically too late in the models. The extension of the monsoon over eastern China, Korea, and Japan is underestimated, while it is overestimated over the subtropical western/central Pacific Ocean. The anti-correlation between anomalies of all-India rainfall and Niño-3.4 sea surface temperature is overly strong in CMIP3 and typically too weak in CMIP5. For both the ENSO-monsoon teleconnection and the East Asian zonal wind-rainfall teleconnection, the MMM interannual rainfall anomalies are weak compared to observations. Though simulation of intraseasonal variability remains problematic, several models show improved skill at representing the northward propagation of convection and the development of the tilted band of convection that extends from India to the equatorial west Pacific. The MMM also well represents the space-time evolution of intraseasonal outgoing longwave radiation anomalies. Caution is necessary when using GPCP and CMAP rainfall to validate (1) the time-mean rainfall, as there are systematic differences over ocean and land between these two data sets, and (2) the timing of monsoon withdrawal over India, where the smooth southward progression seen in India Meteorological Department data is better realized in CMAP data compared to GPCP data.

'Thou glorious kingdome, thou chiefe of empires': Persia in seventeenth-century travel literature

This article discusses a series of texts by or about travellers to Safavid Persia in the early seventeenth century, and in particular the literature surrounding the Sherley brothers. It looks at the ways in which, in order to encourage support for the voyages they described, English travel writers emphasised the potential for closer Anglo-Persian relations. In doing so, such narratives took advantage of a developing awareness of sectarian division within Islam in order to differentiate Persia from the Ottoman Empire. The article then examines how The Travailes of the Three English Brothers (1607) by Day, Rowley and Wilkins, built on the possibilities suggested by the travel writings, and specifically their recognition of Islamic sectarian division, to develop an idealised model of how relations between Persia and England might function. More broadly, these texts demonstrate travellers’ interest in looking for potential correlation between Christian and Muslim identities during this period.

Regional performance and characteristics of Indian manufacturing industry

This paper investigates the regional characteristics of Indian manufacturing industry. Its aim is to assess whether geography plays any major role in determining the performance or characteristics of Indian manufacturing firms, and in order to do this, it presents the results of cross-section regressions estimated on the basis of a balanced sample of 1607 firms across the 30 Indian states. The results suggest that firm performance and characteristics are related to many of the expected industrial organization variables. However, there is also evidence of significant region–state influences on both the performance and characteristics of Indian manufacturing industry. As such, the results demonstrate that analyses which focus solely on standard non-spatial industrial organization variables will fail to explain much of the cross-sectional variation in firm performance and characteristics. In particular, while there are no systematic simple centre–periphery variations in the Indian regional economic system, there is evidence to suggest that industrial spatial concentration, regional specialization, and regional market size play a key role in determining the performance and characteristics of Indian manufacturing industry.

20th century intraseasonal Asian monsoon dynamics viewed from Isomap

The Asian summer monsoon is a high dimensional and highly nonlinear phenomenon involving considerable moisture transport towards land from the ocean, and is critical for the whole region. We have used daily ECMWF reanalysis (ERA-40) sea-level pressure (SLP) anomalies to the seasonal cycle, over the region 50-145°E, 20°S-35°N to study the nonlinearity of the Asian monsoon using Isomap. We have focused on the two-dimensional embedding of the SLP anomalies for ease of interpretation. Unlike the unimodality obtained from tests performed in empirical orthogonal function space, the probability density function, within the two-dimensional Isomap space, turns out to be bimodal. But a clustering procedure applied to the SLP data reveals support for three clusters, which are identified using a three-component bivariate Gaussian mixture model. The modes are found to appear similar to active and break phases of the monsoon over South Asia in addition to a third phase, which shows active conditions over the Western North Pacific. Using the low-level wind field anomalies the active phase over South Asia is found to be characterised by a strengthening and an eastward extension of the Somali jet whereas during the break phase the Somali jet is weakened near southern India, while the monsoon trough in northern India also weakens. Interpretation is aided using the APHRODITE gridded land precipitation product for monsoon Asia. The effect of large-scale seasonal mean monsoon and lower boundary forcing, in the form of ENSO, is also investigated and discussed. The outcome here is that ENSO is shown to perturb the intraseasonal regimes, in agreement with conceptual ideas.

Fibroblast growth factor 2 maintains the neurogenic capacity of embryonic neural progenitor cells in vitro but changes their neuronal subtype specification

Many in vitro systems used to examine multipotential neural progenitor cells (NPCs) rely on mitogens including fibroblast growth factor 2 (FGF2) for their continued expansion. However, FGF2 has also been shown to alter the expression of transcription factors (TFs) that determine cell fate. Here, we report that NPCs from the embryonic telencephalon grown without FGF2 retain many of their in vivo characteristics, making them a good model for investigating molecular mechanisms involved in cell fate specification and differentiation. However, exposure of cortical NPCs to FGF2 results in a profound change in the types of neurons generated, switching them from a glutamatergic to a GABAergic phenotype. This change closely correlates with the dramatic upregulation of TFs more characteristic of ventral telencephalic NPCs. In addition, exposure of cortical NPCs to FGF2 maintains their neurogenic potential in vitro, and NPCs spontaneously undergo differentiation following FGF2 withdrawal. These results highlight the importance of TFs in determining the types of neurons generated by NPCs in vitro. In addition, they show that FGF2, as well as acting as a mitogen, changes the developmental capabilities of NPCs. These findings have implications for the cell fate specification of in vitro-expanded NPCs and their ability to generate specific cell types for therapeutic applications. Disclosure of potential conflicts of interest is found at the end of this article.

Forecasters priorities for improving probabilistic flood forecasts.

Hydrological ensemble prediction systems (HEPS) have in recent years been increasingly used for the operational forecasting of floods by European hydrometeorological agencies. The most obvious advantage of HEPS is that more of the uncertainty in the modelling system can be assessed. In addition, ensemble prediction systems generally have better skill than deterministic systems both in the terms of the mean forecast performance and the potential forecasting of extreme events. Research efforts have so far mostly been devoted to the improvement of the physical and technical aspects of the model systems, such as increased resolution in time and space and better description of physical processes. Developments like these are certainly needed; however, in this paper we argue that there are other areas of HEPS that need urgent attention. This was also the result from a group exercise and a survey conducted to operational forecasters within the European Flood Awareness System (EFAS) to identify the top priorities of improvement regarding their own system. They turned out to span a range of areas, the most popular being to include verification of an assessment of past forecast performance, a multi-model approach for hydrological modelling, to increase the forecast skill on the medium range (>3 days) and more focus on education and training on the interpretation of forecasts. In light of limited resources, we suggest a simple model to classify the identified priorities in terms of their cost and complexity to decide in which order to tackle them. This model is then used to create an action plan of short-, medium- and long-term research priorities with the ultimate goal of an optimal improvement of EFAS in particular and to spur the development of operational HEPS in general.

Endocannabinoids in neuroendopsychology: multiphasic control of mitochondrial function

The endocannabinoid system (ECS) is a construct based on the discovery of receptors that are modulated by the plant compound tetrahydrocannabinol and the subsequent identification of a family of nascent ligands, the 'endocannabinoids'. The function of the ECS is thus defined by modulation of these receptors-in particular, by two of the best-described ligands (2-arachidonyl glycerol and anandamide), and by their metabolic pathways. Endocannabinoids are released by cell stress, and promote both cell survival and death according to concentration. The ECS appears to shift the immune system towards a type 2 response, while maintaining a positive energy balance and reducing anxiety. It may therefore be important in resolution of injury and inflammation. Data suggest that the ECS could potentially modulate mitochondrial function by several different pathways; this may help explain its actions in the central nervous system. Dose-related control of mitochondrial function could therefore provide an insight into its role in health and disease, and why it might have its own pathology, and possibly, new therapeutic directions.

Effects of a web-based personalized intervention on physical activity in European adults: a randomized controlled trial

Background: The high prevalence of physical inactivity worldwide calls for innovative and more effective ways to promote physical activity (PA). There are limited objective data on the effectiveness of Web-based personalized feedback on increasing PA in adults. Objective: It is hypothesized that providing personalized advice based on PA measured objectively alongside diet, phenotype, or genotype information would lead to larger and more sustained changes in PA, compared with nonpersonalized advice. Methods: A total of 1607 adults in seven European countries were randomized to either a control group (nonpersonalized advice, Level 0, L0) or to one of three personalized groups receiving personalized advice via the Internet based on current PA plus diet (Level 1, L1), PA plus diet and phenotype (Level 2, L2), or PA plus diet, phenotype, and genotype (Level 3, L3). PA was measured for 6 months using triaxial accelerometers, and self-reported using the Baecke questionnaire. Outcomes were objective and self-reported PA after 3 and 6 months. Results: While 1270 participants (85.81% of 1480 actual starters) completed the 6-month trial, 1233 (83.31%) self-reported PA at both baseline and month 6, but only 730 (49.32%) had sufficient objective PA data at both time points. For the total cohort after 6 months, a greater improvement in self-reported total PA (P=.02) and PA during leisure (nonsport) (P=.03) was observed in personalized groups compared with the control group. For individuals advised to increase PA, we also observed greater improvements in those two self-reported indices (P=.006 and P=.008, respectively) with increased personalization of the advice (L2 and L3 vs L1). However, there were no significant differences in accelerometer results between personalized and control groups, and no significant effect of adding phenotypic or genotypic information to the tailored feedback at month 3 or 6. After 6 months, there were small but significant improvements in the objectively measured physical activity level (P<.05), moderate PA (P<.01), and sedentary time (P<.001) for individuals advised to increase PA, but these changes were similar across all groups. Conclusions: Different levels of personalization produced similar small changes in objective PA. We found no evidence that personalized advice is more effective than conventional “one size fits all” guidelines to promote changes in PA in our Web-based intervention when PA was measured objectively. Based on self-reports, PA increased to a greater extent with more personalized advice. Thus, it is crucial to measure PA objectively in any PA intervention study.

Objectively measured physical activity in European adults: cross-sectional findings from the Food4Me study

Background Comparisons of objectively measured physical activity (PA) between residents of European countries measured concurrently with the same protocol are lacking. We aimed to compare PA between the seven European countries involved in the Food4Me Study, using accelerometer data collected remotely via the Internet. Methods Of the 1607 participants recruited, 1287 (539 men and 748 women) provided at least 3 weekdays and 2 weekend days of valid accelerometer data (TracmorD) at baseline and were included in the present analyses. Results Men were significantly more active than women (physical activity level = 1.74 vs. 1.70, p < 0.001). Time spent in light PA and moderate PA differed significantly between countries but only for women. Adherence to the World Health Organization recommendation to accumulate at least 150 min of moderate-equivalent PA weekly was similar between countries for men (range: 54–65%) but differed significantly between countries for women (range: 26–49%). Prevalence estimates decreased substantially for men and women in all seven countries when PA guidelines were defined as achieving 30 min of moderate and vigorous PA per day. Conclusions We were able to obtain valid accelerometer data in real time via the Internet from 80% of participants. Although our estimates are higher compared with data from Sweden, Norway, Portugal and the US, there is room for improvement in PA for all countries involved in the Food4Me Study.