The Sec translocon, consisting of a heterotrimeric transmembrane channel (SecYEG) and an associated ATPase (SecA), catalyzes the export of unfolded proteins from the cytosol in bacteria. Kinetically ...resolving protein translocation at high resolution yields mechanistic insight into the process. Translocation is typically followed by measuring the protection of proteins transported into lipid vesicles, which only allows visualization of translocation after it has already been completed and limits time resolution. Here, we describe the implementation of an assay for measuring translocation in real-time. By priming the reconstituted translocon with suitably engineered substrate proteins, the kinetics of the actual translocation process can be resolved at high resolution. To analyze translocation kinetics, we developed a detailed kinetic model of the process that includes on-pathway and off-pathway processes. Together, this experimental protocol and model permit detailed mechanistic analyses of Sec-dependent protein translocation. Graphic abstract: Synchronized real-time measurements, combined with a detailed kinetic model, enable a mechanistic analysis of protein transport.
The majority of proteins in nature are composed of multiple domains connected in a single polypeptide. How these long sequences fold into functional structures without forming toxic misfolds or ...aggregates is poorly understood. Their folding is inextricably linked to protein synthesis and interactions with cellular machinery, making mechanistic studies challenging. Recent progress has revealed critical features of multi-domain protein folding in isolation and in the context of translation by the ribosome. In this review, we discuss challenges and progress in understanding multi-domain protein folding, and highlight how molecular interactions shape folding and misfolding pathways. With the development of new approaches and model systems, the stage is now set for mechanistically exploring the folding of large multi-domain proteins.
The radio luminosity function (RLF) of radio galaxies and radio‐loud quasars is often modelled as a broken power law. The break luminosity is close to the dividing line between the two Fanaroff–Riley ...(FR) morphological classes for the large‐scale radio structure of these objects. We use an analytical model for the luminosity and size evolution of FR type II (FR II) objects together with a simple prescription for FR type I (FR I) sources to construct the RLF. We postulate that all sources start out with a FR II morphology. Weaker jets subsequently disrupt within the quasi‐constant density cores of their host galaxies and develop the turbulent lobes of FR I. With this model, we recover the slopes of the power laws and the break luminosity of the RLF determined from observations. The rate at which active galactic nuclei (AGN) with jets of jet power Q appear in the universe is found to be proportional to Q−1.6. The model also roughly predicts the distribution of the radio lobe sizes for FR II objects, if the radio luminosity of the turbulent jets drops significantly at the point of disruption. We show that our model is consistent with recent ideas of two distinct accretion modes in jet‐producing AGN if radiative efficiency of the accretion process is correlated with jet power.
Single-molecule force spectroscopy has emerged as a powerful tool for studying the folding of biological macromolecules. Mechanical manipulation has revealed a wealth of mechanistic information on ...transient and intermediate states. To date, the majority of state assignment of intermediates has relied on empirical demarcation. However, performing such experiments in the presence of different osmolytes provides an alternative approach that reports on the structural properties of intermediates. Here, we analyze the folding and unfolding of T4 lysozyme with optical tweezers under a chemo-mechanical perturbation by adding osmolytes. We find that two unrelated protective osmolytes, sorbitol and trimethylamine-n-oxide, function by marginally decelerating unfolding rates and specifically modulating early events in the folding process, stabilizing formation of an on-pathway intermediate. The chemo-mechanical perturbation provides access to two independent metrics of the relevant states during folding trajectories, the contour length, and the solvent-accessible surface area. We demonstrate that the dependence of the population of the intermediate in different osmolytes, in conjunction with its measured contour length, provides the ability to discriminate between potential structural models of intermediate states. Our study represents a general strategy that may be employed in the structural modeling of equilibrium intermediate states observed in single-molecule experiments.
Purpose: Biologically-based mechanistic models that are used in combining current understanding of human carcinogenesis with epidemiological studies were reviewed. Assessment was made of how well ...they fit the data, whether they account for non-linear radiobiological low-dose effects, and whether they suggest any implications for the dose response at low doses and dose rates. However, the present paper does not make an attempt to provide a complete review of the existing literature on biologically-based models and their application to epidemiological data.
Conclusion: In most studies the two-stage clonal expansion (TSCE) model of carcinogenesis was used. The model provided robust estimates of identifiable parameters and radiation risk. While relatively simple, it is flexible, so that more stages can easily be added, and tests made of various types of radiation action. In general, the model performed similarly or better than descriptive excess absolute and excess relative risk models, in terms of quality of fit and number of parameters. Only very rarely the shape of dose-response predicted by the models was investigated. For some tumors, when more detailed biological information was known, additional pathways were included in the model. The future development of these models will benefit from growing knowledge on carcinogenesis processes, and in particular from use of biobank tissue samples and advances in omics technologies. Their use appears a promising approach to investigate the radiation risk at low doses and low dose rates. However, the uncertainties involved are still considerable, and the models provide only a simplified description of the underlying complexity of carcinogenesis. Current assumptions in radiation protection including the linear-non-threshold (LNT) model are not in contradiction to what is presently known on the process of cancer development.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hot, X-ray-emitting plasma permeates clusters of galaxies. The X-ray surface brightness often shows a peak near the centre of the cluster that is coincident with a drop in the entropy of the gas. ...This has been taken as evidence for a 'cooling flow', where the gas cools by radiating away its energy, and then falls to the centre. Searches for this cool gas have revealed significantly less than predicted, indicating that the mass deposition rate is much lower than expected. Most clusters with cooling flows, however, also host an active galactic nucleus at their centres. These active galactic nuclei can inflate large bubbles of hot plasma that subsequently rise through the cluster 'atmosphere', thus stirring the cooling gas and adding energy. Here we report highly resolved hydrodynamic simulations which show that buoyant bubbles increase the cooling time in the inner regions of clusters and significantly reduce the deposition of cold gas.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Menschennatur in Zeiten des Umbruchs Mariacarla Gadebusch-Bondio, Christian Kaiser, Manuel Förg / Mariacarla Gadebusch-Bondio, Christian Kaiser, Manuel Förg
2020, 2020-08-10
eBook
Die gesellschaftliche Dimension ärztlichen Wirkens wurde schon in der vormodernen Medizin reflektiert, als sich in der Frühen Neuzeit ein Idealbild des politischen Arztes etablierte. Die Beiträge ...beleuchten seine Entstehung, die Konzepte von 'Menschennatur' sowie die politischen Maßnahmen zur Qualitätssicherung medizinischen Handelns. Besonderes Augenmerk gilt den Strategien von Ärzten, die selbst marginalisierten sozialen Gruppen angehörten.
The way in which atoms and molecules are ionized by the impact of charged particles has important consequences for the behaviour of many physical systems, from gas lasers to astrophysical plasmas. ...Much of our understanding of this process has come from ionization measurements of the energy and angular distribution of electrons ejected in the same plane as the trajectory of the incident ionizing beam. Such studies suggest that the mechanisms governing the ionization of atoms and molecules are essentially the same. But by measuring the electrons ejected from a gas in a plane perpendicular to the incident beam, we show this is not always the case. Experiments and quantum mechanical calculations enable us to construct a remarkably accurate classical picture of the physics of charged-particle ionization. This model predicts that the differences in ionization behaviour arise in molecules that do not have nuclei at their centres of mass. PUBLICATION ABSTRACT
•Ionizing radiation causes adverse circulatory and metabolic effects at high doses.•Low-dose radiation is causally associated with circulatory disease.•Impact of low-dose radiation is modulated by ...inflammatory, stress, and immune responses.
Risks to health are the prime consideration in all human situations of ionizing radiation exposure and therefore of relevance to radiation protection in all occupational, medical, and public exposure situations. Over the past few decades, advances in therapeutic strategies have led to significant improvements in cancer survival rates. However, a wide range of long-term complications have been reported in cancer survivors, in particular circulatory diseases and their major risk factors, metabolic diseases. However, at lower levels of exposure, the evidence is less clear. Under real-life exposure scenarios, including radiotherapy, radiation effects in the whole organism will be determined mainly by the response of normal tissues receiving relatively low doses, and will be mediated and moderated by systemic effects. Therefore, there is an urgent need for further research on the impact of low-dose radiation. In this article, we review radiation-associated risks of circulatory and metabolic diseases in clinical, occupational or environmental exposure situations, addressing epidemiological, biological, risk modelling, and systems biology aspects, highlight the gaps in knowledge and discuss future directions to address these gaps.
Abstract
Mathematical models are able to reflect biological processes and to capture epidemiologic data. Thus, they may help elucidate roles of risk factors in disease progression. We propose to ...account for smoking, hypertension, and dyslipidemia in a previously published process-oriented model that describes the development of atherosclerotic lesions resulting in myocardial infarction (MI). The model is sex-specific and incorporates individual heterogeneity. It was applied to population-based individual risk factors and MI rates (Cooperative Health Research in the Region of Augsburg (KORA) study) together with subclinical atherosclerotic lesion data (Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study). Different model variants were evaluated, testing the association of risk factors with different disease processes. Best fits were obtained for smoking affecting a late-stage disease process, suggesting a thrombogenic role. Hypertension was mainly related to complicated, vulnerable lesions. Dyslipidemia was consistent with increasing the number of initial lesions. By accounting for heterogeneity, individual hazard ratios differ from the population average. The mean individual hazard ratio for smoking was twice the population-based hazard ratio for men and even more for women. Atherosclerotic lesion progression and MI incidence data can be related in a mathematical model to illuminate how risk factors affect different phases of this pathological process.
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