Three-tiered kinase modules, such as the Raf-MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase)-ERK (extracellular signal-regulated kinase) mitogen-activated protein ...kinase pathway, are widespread in biology, suggesting that this structure conveys evolutionarily advantageous properties. We show that the three-tiered kinase amplifier module combined with negative feedback recapitulates the design principles of a negative feedback amplifier (NFA), which is used in electronic circuits to confer robustness, output stabilization, and linearization of nonlinear signal amplification. We used mathematical modeling and experimental validation to demonstrate that the ERK pathway has properties of an NFA that (i) converts intrinsic switch-like activation kinetics into graded linear responses, (ii) conveys robustness to changes in rates of reactions within the NFA module, and (iii) stabilizes outputs in response to drug-induced perturbations of the amplifier. These properties determine biological behavior, including activation kinetics and the response to drugs.
The MAPK (mitogen-activated protein kinase) pathway is one of the most important and intensively studied signalling pathways. It is at the heart of a molecular-signalling network that governs the ...growth, proliferation, differentiation and survival of many, if not all, cell types. It is de-regulated in various diseases, ranging from cancer to immunological, inflammatory and degenerative syndromes, and thus represents an important drug target. Over recent years, the computational or mathematical modelling of biological systems has become increasingly valuable, and there is now a wide variety of mathematical models of the MAPK pathway which have led to some novel insights and predictions as to how this system functions. In the present review we give an overview of the processes involved in modelling a biological system using the popular approach of ordinary differential equations. Focusing on the MAPK pathway, we introduce the features and functions of the pathway itself before comparing the available models and describing what new biological insights they have led to.
The role of apoptosis inducing factor (AIF) in promoting cell death versus survival remains controversial. We report that the loss of AIF in fibroblasts led to mitochondrial electron transport chain ...defects and loss of proliferation that could be restored by ectopic expression of the yeast NADH dehydrogenase Ndi1. Aif-deficiency in T cells led to decreased peripheral T cell numbers and defective homeostatic proliferation, but thymic T cell development was unaffected. In contrast, Aif-deficient B cells developed and functioned normally. The difference in the dependency of T cells versus B cells on AIF for function and survival correlated with their metabolic requirements. Ectopic Ndi1 expression rescued homeostatic proliferation of Aif-deficient T cells. Despite its reported roles in cell death, fibroblasts, thymocytes and B cells lacking AIF underwent normal death. These studies suggest that the primary role of AIF relates to complex I function, with differential effects on T and B cells.
Display omitted
•AIF regulates complex I function but not cell death in lymphocytes and MEF•AIF is essential for T cell survival but not for B cell function and development•B cells fulfill their energetic needs via glycolysis and T cells via respiration•Expression of the yeast Ndi1 rescues defects in Aif-deficient T cells and MEF
The role of AIF in cell death versus survival is controversial. Green and colleagues find that Aif deficiency does not affect lymphocyte cell death but instead impairs respiration by reducing complex I levels. Due to differences in their metabolic requirements, Aif deficiency severely reduces T cell survival while B cells remain unaffected.
The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from ...the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway.
We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors.
Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.
We present Herschel photometry and spectroscopy, carried out as part of the Herschel ultraluminous infrared galaxy (ULIRG) survey, and a model for the infrared to submillimetre emission of the ULIRG ...IRAS 08572+3915. This source shows one of the deepest known silicate absorption features and no polycyclic aromatic hydrocarbon emission. The model suggests that this object is powered by an active galactic nucleus (AGN) with a fairly smooth torus viewed almost edge-on and a very young starburst. According to our model, the AGN contributes about 90 per cent of the total luminosity of 1.1 × 1013 L, which is about a factor of 5 higher than previous estimates. The large correction of the luminosity is due to the anisotropy of the emission of the best-fitting torus. Similar corrections may be necessary for other local and high-z analogues. This correction implies that IRAS 08572+3915 at a redshift of 0.058 35 may be the nearest hyperluminous infrared galaxy and probably the most luminous infrared galaxy in the local (z < 0.2) Universe. IRAS 08572+3915 shows a low ratio of C ii to IR luminosity (log L
Cii/L
IR < −3.8) and a O i63 μm to C ii158 μm line ratio of about 1 that supports the model presented in this Letter.
Although counterproductive work behavior (CWB) has long been established as a broad domain of job behaviors, little agreement exists about its internal structure. The present research addressed ...alternative models of broadly defined CWB according to which specific behaviors can be grouped into (a) one general factor, or into (b) two, (c) five, or (d) eleven narrower facets, and a number of possible integrations of these models. First, conceptual differences between these models (including the nature of overall CWB as implying a reflective or formative model, boundaries of the domain, and relations among specific facets) are reviewed with regard to theoretical and practical implications. In Study 1, structural meta-analysis was then used to test whether a reflective higher-order factor underlies meta-analytically constructed correlation matrices of five CWB facets. Analyses supported a general factor model. For Study 2, a primary data set (N = 1,237 employees) was collected in order to test alternative structural models and possible integrations of these models. Confirmatory factor analyses revealed that the best fit was for a bimodal (nonhierarchical) model in which individual CWBs simultaneously load on one of the eleven facets describing their content (e.g., theft, absenteeism) and on one of three factors describing the target primarily harmed (organization, other persons, self). Less support was found for hierarchical models and for models involving fewer content factors. These findings suggest that CWB is best described by a reflective higher-order factor at the general level and by a complex set of bimodal facets at the more specific level.
We study the evolution of the dust temperature of galaxies in the SFR− M∗ plane up to z ~ 2 using far-infrared and submillimetre observations from the Herschel Space Observatory taken as part of the ...PACS Evolutionary Probe (PEP) and Herschel Multi-tiered Extragalactic Survey (HerMES) guaranteed time key programmes. Starting from a sample of galaxies with reliable star-formation rates (SFRs), stellar masses (M∗) and redshift estimates, we grid the SFR− M∗parameter space in several redshift ranges and estimate the mean dust temperature (Tdust) of each SFR–M∗ − z bin. Dust temperatures are inferred using the stacked far-infrared flux densities (100–500 μm) of our SFR–M∗ − z bins. At all redshifts, the dust temperature of galaxies smoothly increases with rest-frame infrared luminosities (LIR), specific SFRs (SSFR; i.e., SFR/M∗), and distances with respect to the main sequence (MS) of the SFR− M∗ plane (i.e., Δlog (SSFR)MS = log SSFR(galaxy)/SSFRMS(M∗,z)). The Tdust − SSFR and Tdust − Δlog (SSFR)MS correlations are statistically much more significant than the Tdust − LIR one. While the slopes of these three correlations are redshift-independent, their normalisations evolve smoothly from z = 0 and z ~ 2. We convert these results into a recipe to derive Tdust from SFR, M∗ and z, valid out to z ~ 2 and for the stellar mass and SFR range covered by our stacking analysis. The existence of a strong Tdust − Δlog (SSFR)MS correlation provides us with several pieces of information on the dust and gas content of galaxies. Firstly, the slope of the Tdust − Δlog (SSFR)MS correlation can be explained by the increase in the star-formation efficiency (SFE; SFR/Mgas) with Δlog (SSFR)MS as found locally by molecular gas studies. Secondly, at fixed Δlog (SSFR)MS, the constant dust temperature observed in galaxies probing wide ranges in SFR and M∗ can be explained by an increase or decrease in the number of star-forming regions with comparable SFE enclosed in them. And thirdly, at high redshift, the normalisation towards hotter dust temperature of the Tdust − Δlog (SSFR)MS correlation can be explained by the decrease in the metallicities of galaxies or by the increase in the SFE of MS galaxies. All these results support the hypothesis that the conditions prevailing in the star-forming regions of MS and far-above-MS galaxies are different. MS galaxies have star-forming regions with low SFEs and thus cold dust, while galaxies situated far above the MS seem to be in a starbursting phase characterised by star-forming regions with high SFEs and thus hot dust.
In this study, partial least square (PLS) regression models were developed to predict moisture content (MC) (model 1), CIELAB color (model 2) or all four parameters (model 3) of beef slices during ...drying. Model development was based on data from two measurement campaigns of MC (%), CIELAB L*, a* and b*values and hyperspectral data in the range of 500–1009 nm. To increase the robustness of the models, the beef samples varied dependent on cattle breed, cut and pre-treatment. With low-cost, non-invasive continuous monitoring systems in mind, the models were simplified by wavelengths selection. The Deming and Passing-Bablok regression and the Bland-Altman plot revealed high model performances. Mean differences (full/reduced model) of −0.64/-0.64 for MC, −0.14/-0.15 for CIELAB L*, 0.05/0.04 for a* and 0.08/0.06 for b* values were achieved for model 3, which shows the high potential for simple real-time monitoring applications combining all investigated factors and parameters.
•Robust models for spectral measurements of moisture and color during drying of beef.•High accordance between spectral and laboratory measurements.•Simplified high performance models by selection of maximum ten wavelengths.•High potential of simple non-invasive spectral monitoring systems for beef drying.
We study a sample of 61submillimetre galaxies (SMGs) selected from ground-based surveys, with known spectroscopic redshifts and observed with the Herschel Space Observatory as part of the PACS ...Evolutionary Probe (PEP) and the Herschel Multi-tiered Extragalactic Survey (HerMES) guaranteed time key programmes. Our study makes use of the broad far-infrared and submillimetre wavelength coverage (100−600 μm) only made possible by the combination of observations from the PACS and SPIRE instruments aboard the Herschel Space Observatory. Using a power-law temperature distribution model to derive infrared luminosities and dust temperatures, we measure a dust emissivity spectral index for SMGs of β = 2.0 ± 0.2. Our results unambiguously unveil the diversity of the SMG population. Some SMGs exhibit extreme infrared luminosities of s10\hbox{$^{13} {L_{\odot}}$}L⊙13 and relatively warm dust components, while others are fainter (a few times 1012 L⊙) and are biased towards cold dust temperatures. Although at zs2 classical SMGs (>5 mJy at 850 μm) have large infrared luminosities (s1013 L⊙), objects only selected on their submm flux densities (without any redshift informations) probe a large range in dust temperatures and infrared luminosities. The extreme infrared luminosities of some SMGs (LIR ≳ 1012.7 L⊙, 26/61 systems) imply star formation rates (SFRs) of >500 M⊙ yr-1 (assuming a Chabrier IMF and no dominant AGN contribution to the FIR luminosity). Such high SFRs are difficult to reconcile with a secular mode of star formation, and may instead correspond to a merger-driven stage in the evolution of these galaxies. Another observational argument in favour of this scenario is the presence of dust temperatures warmer than that of SMGs of lower luminosities (s40 K as opposed to s25 K), consistent with observations of local ultra-luminous infrared galaxies triggered by major mergers and with results from hydrodynamic simulations of major mergers combined with radiative transfer calculations. Moreover, we find that luminous SMGs are systematically offset from normal star-forming galaxies in the stellar mass-SFR plane, suggesting that they are undergoing starburst events with short duty cycles, compatible with the major merger scenario. On the other hand, a significant fraction of the low infrared luminosity SMGs have cold dust temperatures, are located close to the main sequence of star formation, and therefore might be evolving through a secular mode of star formation. However, the properties of this latter population, especially their dust temperature, should be treated with caution because at these luminosities SMGs are not a representative sample of the entire star-forming galaxy population.
Approximately 30,000 people are affected by severe injuries in Germany each year. Continuous progress in prehospital and hospital care has significantly reduced the mortality of polytrauma patients. ...With increasing survival rates, the functional outcome, health-related quality (hrQoL) of life and ability to work are now gaining importance. Aim of the study is, the presentation of the response behavior of seriously injured patients on the one hand and the examination of the factors influencing the quality of life and ability to work 12 months after major trauma on the other hand. Building on these initial results, a standard outcome tool shall be integrated in the established TraumaRegister DGUR in the future. In 2018, patients Injury Severity Score (ISS) greater than or equal to 16; age:18-75 years underwent multicenter one-year posttraumatic follow-up in six study hospitals. In addition to assessing hrQoL by using the Short-Form Health Survey (SF-12), five additional questions (treatment satisfaction; ability to work; trauma-related medical treatment; relevant physical disability, hrQoL as compared with the prior to injury status) were applied. Of the 1,162 patients contacted, 594 responded and were included in the analysis. The post-injury hrQoL does not show statistically significant differences between the sexes. Regarding age, however, the younger the patient at injury, the better the SF-12 physical sum score. Furthermore, the physically perceived quality of life decreases statistically significantly in relation to the severity of the trauma as measured by the ISS, whereas the mentally perceived quality of life shows no differences in terms of injury severity. A large proportion of severely injured patients were very satisfied (42.2%) or satisfied (39.9%) with the treatment outcome. It should be emphasized that patients with a high injury severity (ISS > 50) were on average more often very satisfied with the treatment outcome (46.7%). A total of 429 patients provided information on their ability to work 12 months post-injury. Here, 194 (45.2%) patients had a full employment, and 58 (13.5%) patients were had a restricted employment. The present results show the importance of a structured assessment of the postinjury hrQoL and the ability to work after polytrauma. Further studies on the detection of influenceable risk factors on hrQoL and ability to work in the intersectoral course of treatment should follow to enable the best possible outcome of polytrauma survivors.
PDF
