Modeling Regulation of Zinc Uptake via ZIP Transporters in Yeast and Plant Roots

In yeast (Saccharomyces cerevisiae) and plant roots (Arabidopsis thaliana) zinc enters the cells via influx transporters of the ZIP family. Since zinc is both essential for cell function and toxic at high concentrations, tight regulation is essential for cell viability. We provide new insight into the underlying mechanisms, starting from a general model based on ordinary differential equations and adapting it to the specific cases of yeast and plant root cells. In yeast, zinc is transported by the transporters ZRT1 and ZRT2, which are both regulated by the zinc-responsive transcription factor ZAP1. Using biological data, parameters were estimated and analyzed, confirming the different affinities of ZRT1 and ZRT2 reported in the literature. Furthermore, our model suggests that the positive feedback in ZAP1 production has a stabilizing function at high influx rates. In plant roots, various ZIP transporters are involved in zinc uptake. Their regulation is largely unknown, but bZIP transcription factors are thought to be involved. We set up three putative models: activator only, activator with dimerization and activator/inhibitor. These were fitted to measurements and analyzed. Simulations show that the activator/inhibitor model outperforms the other two in providing robust and stable homeostasis at reasonable parameter ranges.Comment: 23 pages including 2 tables and 7 figure

Bildungsstagnation bei abnehmender Erwerbsbevölkerung : Bildungspolitische Herausforderungen durch Geringqualifizierte

Obwohl in einer alternden und schrumpfenden Gesellschaft die Ausbildung des Erwerbspersonenpotenzials immer wichtiger wird, scheint der Bildungsfortschritt in Deutschland in den letzten Jahren zu stagnieren: Der Qualifikationsvorsprung Deutschlands im Vergleich zu anderen OECD-Ländern ist geschrumpft, die Anteile junger Erwachsener mit niedrigen Qualifikationen weisen leicht steigende Tendenz auf, und Studien wie PISA identifizieren deutliche Schwächen deutscher Schüler. Das angesichts des demographischen und technischen Wandels gebotene Mindestziel, die nachfolgenden Generationen mindestens gleich gut oder besser auszubilden als ihre Vorgänger, wird zumindest im Bereich der Niedrigqualifizierten hierzulande nicht erreicht. Erforderlich sind deshalb Maßnahmen, die die Effektivität und Effizienz des Bildungssystems sowie die Bildungsbeteiligung (insbesondere von Zuwanderern) erhöhen. Dabei sollte bereits die vorschulische Bildung intensiviert werden, und Lernschwache sollten in Schule und Berufsausbildung gezielte Förderangebote bekommen. -- Although in an aging and shrinking society the education of the workforce becomes more and more important, in recent years the educational progress in Germany shows signs of stagnation: Germany?s qualification advantage compared to other OECD countries has fallen, the shares of young adults with low qualifications have slightly risen, and studies such as PISA have identified substantial deficits of German pupils. In view of demographic and technical change, the minimum goal should be to qualify the following generations at least as good as or better than their predecessors, but concerning the lowqualified this goal is not reached in Germany. Measures should be implemented which increase the effectiveness and efficiency of the educational system as well as the participation in higher education (in particular of immigrants). In doing so, pre-school education should be intensified, and low performers should get special offers at school and in vocational training.Geringqualifizierte,Bildungspolitik,Demographischer Wandel

Modelling of zinc uptake and transport in plant roots

Zinc is an essential micronutrient in green plants, yet toxic at high concentrations. Only specialized hyperaccumulator plants can tolerate high zinc doses and are therefore of special interest for their potential application in phytoremediation and crop development. Zinc ions are taken up from the soil along with water and are transported towards the root’s vascular bundle in two parallel ways: cell wall (apoplast) and cytoplasm (symplast). Cross-membrane transport into and out of the cytoplasm is mediated by ZIP and HMA transporter proteins, respectively. The ZIP transporters responsible for zinc uptake are highly regulated to guarantee an optimal internal zinc concentration under varying external conditions. A dynamical model based on ordinary differential equations is used to study the regulation of ZIP transporters. A data-based model in yeast allows insights into general mechanisms. Simulations of different model variants in plants suggest an activator-inhibitor model as the most likely mechanism, because it provides more robust zinc homeostasis than simpler models without inhibitor. High robustness of the steady state towards external zinc variations, however, leads to instability of the steady state and high-amplitude oscillations. These oscillations form stable periodic solutions and emerge from a supercritical Hopf bifurcation in certain critical values of the external zinc concentration. To study spatial aspects of the zinc distribution in root tissues, the ZIP regulatory model was coupled to a radial transport model. This model accounts for the structure of the root consisting of symplast and apoplast and includes effects of water flow, diffusion, and cross-membrane transport via transporters. It also incorporates the radial geometry and varying porosity of root tissues. We use existing biological data to estimate parameters and analyze the properties of the model in numerical simulations. Experimental results show a pattern of zinc accumulation close to the center of the root, which disappears at high levels of the efflux transporter HMA. Using our model, we study the roles of ZIP regulation, HMA level and water flow velocity in the creation of this radial pattern. In the steady state, the model reproduces the zinc gradient found in experiments as well as its loss at increased levels of HMA. Surprisingly, water flow velocity is found to be also a key parameter for producing this gradient. These results give insight into the uptake and transport of zinc in roots and suggest improved experimental assays. Buffering and vacuolar sequestration are known to play important roles in zinc homeostasis. Regulated vacuolar sequestration in yeast again serves as a databased model for possible mechanisms. In plants, buffering can dampen the oscillations and lead to stability of the steady state. Since experiments do not suggest oscillatory behavior in the cellular zinc concentration, these results indicate the existence of strong zinc buffers

Global Hopf bifurcation in the ZIP regulatory system

Regulation of zinc uptake in roots of Arabidopsis thaliana has recently been modeled by a system of ordinary differential equations based on the uptake of zinc, expression of a transporter protein and the interaction between an activator and inhibitor. For certain parameter choices the steady state of this model becomes unstable upon variation in the external zinc concentration. Numerical results show periodic orbits emerging between two critical values of the external zinc concentration. Here we show the existence of a global Hopf bifurcation with a continuous family of stable periodic orbits between two Hopf bifurcation points. The stability of the orbits in a neighborhood of the bifurcation points is analyzed by deriving the normal form, while the stability of the orbits in the global continuation is shown by calculation of the Floquet multipliers. From a biological point of view, stable periodic orbits lead to potentially toxic zinc peaks in plant cells. Buffering is believed to be an efficient way to deal with strong transient variations in zinc supply. We extend the model by a buffer reaction and analyze the stability of the steady state in dependence of the properties of this reaction. We find that a large enough equilibrium constant of the buffering reaction stabilizes the steady state and prevents the development of oscillations. Hence, our results suggest that buffering has a key role in the dynamics of zinc homeostasis in plant cells.Comment: 22 pages, 5 figures, uses svjour3.cl

Highly branched isoprenoids reveal onset of deglaciation followed by dynamic sea-ice conditions in the western Amundsen Sea, Antarctica

The Amundsen Sea drainage sector of the West Antarctic Ice Sheet (WAIS) is widely regarded as a candidate for triggering potential WAIS collapse. The grounded ice sheet drains into the Amundsen Sea Embayment and is thereby buttressed by its fringing ice shelves, which have thinned at an alarming rate. Satellite-based observations additionally reveal a considerable long-term decrease in sea-ice cover in the Amundsen Sea over the last two decades although the long-term significance of this trend is unclear due to the short instrumental record since the 1970s. In this context, investigations of past sea-ice conditions are crucial for improving our understanding of the influence that sea-ice variability has on the adjacent marine environment as well as any role it plays in modulating ice shelf and ice sheet dynamics. In this study, we apply novel organic geochemical biomarker techniques to a marine sediment core from the western Amundsen Sea shelf in order to provide a valuable long-term perspective on sea-ice conditions and the retreat of the Getz Ice Shelf during the last deglaciation. We analysed a specific biomarker lipid called IPSO25 alongside a phytoplankton biomarker and sedimentological parameters and additionally applied diatom transfer functions for reconstructing palaeo sea-ice coverage. This multi-proxy data set reveals a dynamic behaviour of the Getz Ice Shelf and sea-ice cover during the deglaciation following the last ice age, with potential linkages to inter-hemispheric seesaw climate patterns. We further apply and evaluate the recently proposed PIPSO25 approach for semi-quantitative sea-ice reconstructions and discuss potential limitations

Outcome and prognostic factors of multimodal therapy for pulmonary large-cell neuroendocrine carcinomas

Background: There is controversy whether patients diagnosed with large-cell neuroendocrine carcinoma (LCNEC) should be treated according to protocols for non-small cell lung cancers (NSCLC) or small cell lung cancers (SCLC), especially with regard to the administration of prophylactic cranial irradiation (PCI). This study was set up to determine the incidence of brain metastases and to investigate the outcome following multimodal treatment in 70 patients with LCNEC. Methods: Seventy patients with histologically confirmed LCNEC were treated at the University Hospital of Heidelberg between 2001 and 2014. Data were collected retrospectively. Al most all patients received thoracic surgery as initial treatment (94 %). Chemotherapy was administered in 32 patients as part of the initial treatment. Fourteen patients were treated with adjuvant or definitive thoracic radiotherapy according to NSCLC protocols. Cranial radiotherapy due to brain metastases, mostly given as whole brain radiotherapy (WBRT), was received by fourteen patients. Statistical analysis was performed using the long-rank test and the Kaplan–Meier method. Results: Without PCI, the detected rate for brain metastases was 25 % after a median follow-up time of 23.4 months, which is comparable to NSCLC patients in general. Overall (OS), local (LPFS), brain metastases-free survival (BMFS) and extracranial distant progression-free survival (eDPFS) was 43, 50, 63 and 50 % at 5 years, respectively. Patients with incomplete resection showed a survival benefit from adjuvant radiotherapy. The administration of adjuvant chemotherapy improved the general worse prognosis in higher pathologic stages. Conclusion: In LCNEC patients, the administration of radiotherapy according to NSCLC guidelines appears reasonable and contributes to acceptable results of multimodal treatment regimes. The low incidence of spontaneous brain metastases questions a possible role of PCI

Parenchymal and Functional Lung Changes after Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer—Experiences from a Single Institution

IntroductionThis study aimed to evaluate parenchymal and functional lung changes following stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) patients and to correlate radiological and functional findings with patient and treatment characteristics as well as survival.Materials and methodsSeventy patients with early-stage NSCLC treated with SBRT from 2004 to 2015 with more than 1 year of CT follow-up scans were analyzed. Incidence, morphology, severity of acute and late lung abnormalities as well as pulmonary function changes were evaluated and correlated with outcome.ResultsMedian follow-up time was 32.2 months with 2-year overall survival (OS) of 83% and local progression-free survival of 88%, respectively. Regarding parenchymal changes, most patients only developed mild to moderate CT abnormalities. Mean ipsilateral lung dose (MLD) in biological effective dose and planning target volume size were significantly associated with maximum severity score of parenchymal changes (p = 0.014, p < 0.001). Furthermore, both maximum severity score and MLD were significantly connected with OS in univariate analysis (p = 0.043, p = 0.025). For functional lung changes, we detected significantly reduced total lung capacity, forced expiratory volume in 1 s, and forced vital capacity (FVC) parameters after SBRT (p ≤ 0.001). Multivariate analyses revealed SBRT with an MLD ≥ 9.72 Gy and FVC reduction ≥0.54 L as independent prognostic factors for inferior OS (p = 0.029, p = 0.004).ConclusionSBRT was generally tolerated well with only mild toxicity. For evaluating the possible prognostic impact of MLD and FVC reduction on survival detected in this analysis, larger prospective studies are truly needed