The phosphate potential maintained by mitochondria in State 4 is proportional to the proton-motive force

AbstractEvidence is presented for a proportional relationship between the extramitochondrial phosphate potential (ΔGexp) and the proton-motive force (Δ\̃gmH+) across the mitochondrial membrane in rat-liver mitochondria oxidising succinate in State 4, when Δ\̃gmH+ is varied by addition of uncouplers or malonate. This relationship was found when precautions were taken to minimise interference with the determination of ΔGpex and Δ\̃gmH+ by intramitochondrial nucleotides, adenylate kinase activity, the quenching method, and Δ\̃gmH+-dependent changes in matrix volume. A non-proportional ΔGpex/Δ\̃gmH+ relationship was obtained when these precautions were omitted. Our results do not support mosaic protonic coupling, but are not necessarily in conflict with other localised coupling schemes

Precipitable water column retrieval from GOME data

We investigate the retrieval of terrestrial precipitable water columns using a new spectral fitting method applied to Global Ozone Monitoring Experiment (GOME) data. The method is an optical absorption spectroscopy technique and employs a new approach to the opacity sampling of absorption line spectra which we apply to a little-studied visible band between 585 and 600 nm. The GOME-retrieved columns are compared with data from the European Center for Medium-Range Weather Forecasts for different orbits and show good agreement. The new retrieval algorithm is sensitive to the temperature and pressure dependence of absorption lines in general and may be easily applied to spectra of trace gases other than water vapor

Adaptation to high ethanol reveals complex evolutionary pathways

Tolerance to high levels of ethanol is an ecologically and industrially relevant phenotype of microbes, but the molecular mechanisms underlying this complex trait remain largely unknown. Here, we use long-term experimental evolution of isogenic yeast populations of different initial ploidy to study adaptation to increasing levels of ethanol. Whole-genome sequencing of more than 30 evolved populations and over 100 adapted clones isolated throughout this two-year evolution experiment revealed how a complex interplay of de novo single nucleotide mutations, copy number variation, ploidy changes, mutator phenotypes, and clonal interference led to a significant increase in ethanol tolerance. Although the specific mutations differ between different evolved lineages, application of a novel computational pipeline, PheNetic, revealed that many mutations target functional modules involved in stress response, cell cycle regulation, DNA repair and respiration. Measuring the fitness effects of selected mutations introduced in non-evolved ethanol-sensitive cells revealed several adaptive mutations that had previously not been implicated in ethanol tolerance, including mutations in PRT1, VPS70 and MEX67. Interestingly, variation in VPS70 was recently identified as a QTL for ethanol tolerance in an industrial bio-ethanol strain. Taken together, our results show how, in contrast to adaptation to some other stresses, adaptation to a continuous complex and severe stress involves interplay of different evolutionary mechanisms. In addition, our study reveals functional modules involved in ethanol resistance and identifies several mutations that could help to improve the ethanol tolerance of industrial yeasts

The significance of the amorphous potential energy landscape for dictating glassy dynamics and driving solid-state crystallisation.

The fundamental origins surrounding the dynamics of disordered solids near their characteristic glass transitions continue to be fiercely debated, even though a vast number of materials can form amorphous solids, including small-molecule organic, inorganic, covalent, metallic, and even large biological systems. The glass-transition temperature, Tg, can be readily detected by a diverse set of techniques, but given that these measurement modalities probe vastly different processes, there has been significant debate regarding the question of why Tg can be detected across all of them. Here we show clear experimental and computational evidence in support of a theory that proposes that the shape and structure of the potential-energy surface (PES) is the fundamental factor underlying the glass-transition processes, regardless of the frequency that experimental methods probe. Whilst this has been proposed previously, we demonstrate, using ab initio molecular-dynamics (AIMD) simulations, that it is of critical importance to carefully consider the complete PES - both the intra-molecular and inter-molecular features - in order to fully understand the entire range of atomic-dynamical processes in disordered solids. Finally, we show that it is possible to utilise this dependence to directly manipulate and harness amorphous dynamics in order to control the behaviour of such solids by using high-powered terahertz pulses to induce crystallisation and preferential crystal-polymorph growth in glasses. Combined, these findings provide compelling evidence that the PES landscape, and the corresponding energy barriers, are the ultimate controlling feature behind the atomic and molecular dynamics of disordered solids, regardless of the frequency at which they occur

Distal chromatin structure influences local nucleosome positions and gene expression

The positions of nucleosomes across the genome influence several cellular processes, including gene transcription. However, our understanding of the factors dictating where nucleosomes are located and how this affects gene regulation is still limited. Here, we perform an extensive in vivo study to investigate the influence of the neighboring chromatin structure on local nucleosome positioning and gene expression. Using truncated versions of the Saccharomyces cerevisiae URA3 gene, we show that nucleosome positions in the URA3 promoter are at least partly determined by the local DNA sequence, with so-called ‘antinucleosomal elements’ like poly(dA:dT) tracts being key determinants of nucleosome positions. In addition, we show that changes in the nucleosome positions in the URA3 promoter strongly affect the promoter activity. Most interestingly, in addition to demonstrating the effect of the local DNA sequence, our study provides novel in vivo evidence that nucleosome positions are also affected by the position of neighboring nucleosomes. Nucleosome structure may therefore be an important selective force for conservation of gene order on a chromosome, because relocating a gene to another genomic position (where the positions of neighboring nucleosomes are different from the original locus) can have dramatic consequences for the gene's nucleosome structure and thus its expression

Onderzoek in de lucht

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Highly excited states of gerade symmetry in molecular nitrogen

The highly excited states of gerade symmetry in molecular nitrogen were investigated in a resonance enhanced XUV+Vis transition scheme. A two photon laser excitation study, with subsequent photo-ionization by a third laser pulse was reported. Tunable XUV laser light was generated by frequency doubling the output of a pulsed dye laser into ultraviolet in a KDP crystal, and subsequently frequency tripling the output ion xenon gas jet. Nineteen bands were observed and level energies were determine with an accuracy of ≈ 0.20 c

Radium-223 Treatment of Patients with Metastatic Castration Resistant Prostate Cancer: Biomarkers for Stratification and Response Evaluation

Radium-223 dichloride ([223Ra]RaCl2; Ra-223) is a targeted alpha-emitting radiopharmaceutical which results in an overall survival and health related quality of life (HRQoL) benefit in symptomatic patients with metastatic castration resistant prostate cancer (mCRPC) and predominantly bone metastasis. Although effective, options to select patients who will derive treatment benefit and to monitor and predict treatment outcomes are limited. PSA response and radiographic evaluation are commonly used in mCRPC treatment assessment but are not informative in Ra-223 treated patients. Consequently, there is a clear need for predictive and prognostic tools. In this review, we discuss the physiology of bone metastases and the mechanism of action and efficacy of Ra-223 treatment, as well as offering an outline of current innovative prognostic and predictive biomarkers