¹⁴N overtone transition in double rotation solid-state NMR

Solid-state NMR transitions involving outer energy levels of the spin-1 14N nucleus are immune, to first order in perturbation theory, to the broadening caused by the nuclear quadrupole interaction. The corresponding overtone spectra, when acquired in conjunction with magic-angle sample spinning, result in lines, which are just a few kHz wide, permitting the direct detection of nitrogen compounds without the need for labeling. Despite the success of this technique, “overtone” resonances are still broadened due to indirect, second order effects arising from the large quadrupolar interaction. Here we demonstrate that another order of magnitude in spectral resolution may be gained by using double rotation. This brings the width of the 14N solid-state NMR lines much closer to the region commonly associated with high-resolution solid-state NMR spectroscopy of 15N and demonstrates the improvements in resolution that may be possible through the development of pulsed methodologies to suppress these second order effects

Strategies for 1H-Detected Dynamic Nuclear Polarization Magic-Angle Spinning NMR Spectroscopy

© 2020 The Authors. Published by Wiley-VCH GmbH Combining dynamic nuclear polarization with proton detection significantly enhances the sensitivity of magic-angle spinning NMR spectroscopy. Herein, the feasibility of proton-detected experiments with slow (10 kHz) magic angle spinning was demonstrated. The improvement in sensitivity permits the acquisition of indirectly detected 14N NMR spectra allowing biomolecular structures to be characterized without recourse to isotope labelling. This provides a new tool for the structural characterization of environmental and medical samples, in which isotope labelling is frequently intractable

Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

Bicarbonate is involved in a wide range of biological processes, which include respiration, regulation of intracellular pH and fertilization. In this study we use a combination of NMR spectroscopy and ion-selective electrode techniques to show that the natural product prodigiosin, a tripyrrolic molecule produced by microorganisms such as Streptomyces and Serratia, facilitates chloride/bicarbonate exchange (antiport) across liposomal membranes. Higher concentrations of simple synthetic molecules based on a 4,6-dihydroxyisophthalamide core are also shown to facilitate this antiport process. Although it is well known that proteins regulate Cl-/HCO3- exchange in cells, these results suggest that small molecules may also be able to regulate the concentration of these anions in biological systems

Statistical methodology for the evaluation of vaccine efficacy in a phase III multi-centre trial of the RTS,S/AS01 malaria vaccine in African children

BACKGROUND\ud \ud There has been much debate about the appropriate statistical methodology for the evaluation of malaria field studies and the challenges in interpreting data arising from these trials.\ud \ud METHODS\ud \ud The present paper describes, for a pivotal phase III efficacy of the RTS, S/AS01 malaria vaccine, the methods of the statistical analysis and the rationale for their selection. The methods used to estimate efficacy of the primary course of vaccination, and of a booster dose, in preventing clinical episodes of uncomplicated and severe malaria, and to determine the duration of protection, are described. The interpretation of various measures of efficacy in terms of the potential public health impact of the vaccine is discussed.\ud \ud CONCLUSIONS\ud \ud The methodology selected to analyse the clinical trial must be scientifically sound, acceptable to regulatory authorities and meaningful to those responsible for malaria control and public health policy

Worldwide impacts of climate change on energy for heating and cooling

The energy sector is not only a major contributor to greenhouse gases, it is also vulnerable to climate change and will have to adapt to future climate conditions. The objective of this study is to analyze the impacts of changes in future temperatures on the heating and cooling services of buildings and the resulting energy and macro-economic effects at global and regional levels. For this purpose, the techno-economic TIAM-WORLD (TIMES Integrated Assessment Model) and the general equilibrium GEMINI-E3 (General Equilibrium Model of International-National Interactions between Economy, Energy and Environment) models are coupled with a climate model, PLASIM-ENTS (Planet-Simulator - Efficient Numerical Terrestrial Scheme). The key results are as follows. At the global level, the climate feedback induced by adaptation of the energy system to heating and cooling is found to be insignificant, partly because heating and cooling-induced changes compensate and partly because they represent a limited share of total final energy consumption. However, significant changes are observed at regional levels, more particularly in terms of addi- tional power capacity required to satisfy additional cooling services, resulting in increases in electricity prices. In terms of macro-economic impacts, welfare gains and losses are associated more with changes in energy exports and imports than with changes in energy consumption for heating and cooling. The rebound effect appears to be non-negligible. To conclude, the coupling of models of different nature was successful and showed that the energy and economic impacts of climate change on heating and cooling remain small at the global level, but changes in energy needs will be visible at more local scale

Differential Trends in the Codon Usage Patterns in HIV-1 Genes

Host-pathogen interactions underlie one of the most complex evolutionary phenomena resulting in continual adaptive genetic changes, where pathogens exploit the host's molecular resources for growth and survival, while hosts try to eliminate the pathogen. Deciphering the molecular basis of host–pathogen interactions is useful in understanding the factors governing pathogen evolution and disease propagation. In host-pathogen context, a balance between mutation, selection, and genetic drift is known to maintain codon bias in both organisms. Studies revealing determinants of the bias and its dynamics are central to the understanding of host-pathogen evolution. We considered the Human Immunodeficiency Virus (HIV) type 1 and its human host to search for evolutionary signatures in the viral genome. Positive selection is known to dominate intra-host evolution of HIV-1, whereas high genetic variability underlies the belief that neutral processes drive inter-host differences. In this study, we analyze the codon usage patterns of HIV-1 genomes across all subtypes and clades sequenced over a period of 23 years. We show presence of unique temporal correlations in the codon bias of three HIV-1 genes illustrating differential adaptation of the HIV-1 genes towards the host preferred codons. Our results point towards gene-specific translational selection to be an important force driving the evolution of HIV-1 at the population level

Using Classical Population Genetics Tools with Heterochroneous Data: Time Matters!

BACKGROUND:New polymorphism datasets from heterochroneous data have arisen thanks to recent advances in experimental and microbial molecular evolution, and the sequencing of ancient DNA (aDNA). However, classical tools for population genetics analyses do not take into account heterochrony between subsets, despite potential bias on neutrality and population structure tests. Here, we characterize the extent of such possible biases using serial coalescent simulations. METHODOLOGY/PRINCIPAL FINDINGS:We first use a coalescent framework to generate datasets assuming no or different levels of heterochrony and contrast most classical population genetic statistics. We show that even weak levels of heterochrony ( approximately 10% of the average depth of a standard population tree) affect the distribution of polymorphism substantially, leading to overestimate the level of polymorphism theta, to star like trees, with an excess of rare mutations and a deficit of linkage disequilibrium, which are the hallmark of e.g. population expansion (possibly after a drastic bottleneck). Substantial departures of the tests are detected in the opposite direction for more heterochroneous and equilibrated datasets, with balanced trees mimicking in particular population contraction, balancing selection, and population differentiation. We therefore introduce simple corrections to classical estimators of polymorphism and of the genetic distance between populations, in order to remove heterochrony-driven bias. Finally, we show that these effects do occur on real aDNA datasets, taking advantage of the currently available sequence data for Cave Bears (Ursus spelaeus), for which large mtDNA haplotypes have been reported over a substantial time period (22-130 thousand years ago (KYA)). CONCLUSIONS/SIGNIFICANCE:Considering serial sampling changed the conclusion of several tests, indicating that neglecting heterochrony could provide significant support for false past history of populations and inappropriate conservation decisions. We therefore argue for systematically considering heterochroneous models when analyzing heterochroneous samples covering a large time scale

Effect of Virulence Factors on the Photodynamic Inactivation of Cryptococcus neoformans

Opportunistic fungal pathogens may cause an array of superficial infections or serious invasive infections, especially in immunocompromised patients. Cryptococcus neoformans is a pathogen causing cryptococcosis in HIV/AIDS patients, but treatment is limited due to the relative lack of potent antifungal agents. Photodynamic inactivation (PDI) uses the combination of non-toxic dyes called photosensitizers and harmless visible light, which produces singlet oxygen and other reactive oxygen species that produce cell inactivation and death. We report the use of five structurally unrelated photosensitizers (methylene blue, Rose Bengal, selenium derivative of a Nile blue dye, a cationic fullerene and a conjugate between poly-L-lysine and chlorin(e6)) combined with appropriate wavelengths of light to inactivate C. neoformans. Mutants lacking capsule and laccase, and culture conditions that favoured melanin production were used to probe the mechanisms of PDI and the effect of virulence factors. The presence of cell wall, laccase and melanin tended to protect against PDI, but the choice of the appropriate photosensitizers and dosimetry was able to overcome this resistance.Fundação de Amparo à Pesquisa do Estado de São Paulo (2010/13313–9

The role of war in deep transitions: exploring mechanisms, imprints and rules in sociotechnical systems

This paper explores in what ways the two world wars influenced the development of sociotechnical systems underpinning the culmination of the first deep transition. The role of war is an underexplored aspect in both the Techno-Economic Paradigms (TEP) approach and the Multi-level perspective (MLP) which form the two key conceptual building blocks of the Deep Transitions (DT) framework. Thus, we develop a conceptual approach tailored to this particular topic which integrates accounts of total war and mechanisms of war from historical studies and imprinting from organisational studies with the DT framework’s attention towards rules and meta-rules. We explore in what ways the three sociotechnical systems of energy, food, and transport were affected by the emergence of new demand pressures and logistical challenges during conditions of total war; how war impacted the directionality of sociotechnical systems; the extent to which new national and international policy capacities emerged during wartime in the energy, food, and transport systems; and the extent to which these systems were influenced by cooperation and shared sacrifice under wartime conditions. We then explore what lasting changes were influenced by the two wars in the energy, food, and transport systems across the transatlantic zone. This paper seeks to open up a hitherto neglected area in analysis on sociotechnical transitions and we discuss the importance of further research that is attentive towards entanglements of warfare and the military particularly in the field of sustainability transitions