Systematic identifiability testing for unambiguous mechanistic modeling – application to JAK-STAT, MAP kinase, and NF-κB signaling pathway models

<p>Abstract</p> <p>Background</p> <p>When creating mechanistic mathematical models for biological signaling processes it is tempting to include as many known biochemical interactions into one large model as possible. For the JAK-STAT, MAP kinase, and NF-<it>κ</it>B pathways a lot of biological insight is available, and as a consequence, large mathematical models have emerged. For large models the question arises whether unknown model parameters can uniquely be determined by parameter estimation from measured data. Systematic approaches to answering this question are indispensable since the uniqueness of model parameter values is essential for predictive mechanistic modeling.</p> <p>Results</p> <p>We propose an eigenvalue based method for efficiently testing identifiability of large ordinary differential models and compare this approach to three existing ones. The methods are benchmarked by applying them to models of the signaling pathways mentioned above. In all cases the eigenvalue method proposed here and the orthogonal method find the largest set of identifiable parameters, thus clearly outperforming the other approaches. The identifiability analysis shows that the pathway models are not identifiable, even under the strong assumption that all system state variables are measurable. We demonstrate how the results of the identifiability analysis can be used for model simplification.</p> <p>Conclusion</p> <p>While it has undoubtedly contributed to recent advances in systems biology, mechanistic modeling by itself does not guarantee unambiguous descriptions of biological processes. We show that some recent signal transduction pathway models have reached a level of detail that is not warranted. Rigorous identifiability tests reveal that even if highly idealized experiments could be carried out to measure all state variables of these signaling pathways, some unknown parameters could still not be estimated. The identifiability tests therefore show that the level of detail of the investigated models is too high <it>in principle</it>, not just because too little experimental information is available. We demonstrate how the proposed method can be combined with biological insight, however, to simplify these models.</p

Impact of organizational politics on employee performance in public sector organizations

The present study seeks to investigate the impact of organizational politics on employee performance in the public sector organizations. The study developed a framework on the basis of an extensive literature review which was then tested to provide an empirical insight about the proposed relationships. The data were collected from the employees of 15 public sector organizations in Pakistan. The data was statistically analyzed using regression analysis. The results revealed that organizational politics have a significant impact on employee performance. The findings of the study reinforce that the management needs to understand the perception of employees about the organizational politics prevailing in their organizations and have to adopt strategies that would minimize the perception of organizational politics and enhance employee performance. The present study has been conducted in a developing economy; therefore, the findings of the present study are partially generalized able to other developing economies as well. The future researchers can also perform the studies in other settings

Silent lupus nephritis: a case report

Systemic lupus erythematosus (SLE) is a multiorgan acquired autoimmune disease. The clinical picture can vary greatly. Lupus nephritis (LN), which affects about 50% of SLE patients, is associated with high morbidity and death. While renal histologic alterations are evident in almost all patients with SLE, clinical renal involvement only affects 40% to 75% of those individuals. Because of this, some patients who have nephritis on their renal biopsy may not actually have clinical kidney disease (silent nephritis). In this article, we discuss a case of silent lupus nephritis (SLN) with respect to clinical presentation, laboratory findings, diagnosis and outcome

Don’t try harder: using customer inoculation to build resistance against service failures

© 2014, Academy of Marketing Science. Capitalizing on a large-scale field experimental dataset involving 1,254 airline customers, this study introduces customer inoculation as a new, proactive strategy for mitigating the negative consequences that service failures have on customer satisfaction. Results confirm that customer inoculation eases the decrease in satisfaction when customers experience a service failure. Additional analyses indicate that customer inoculation does not harm customer satisfaction if no service failure occurs. This finding sets inoculation apart from expectation management and underscores the potential inoculation has for marketing practice. Furthermore, contrary to traditional recovery strategies for addressing service failures, customer inoculation operates in advance of a service failure and thereby circumvents potential drawbacks of traditional strategies. In sum, customer inoculation represents a novel strategy for addressing service failures with respect to existing marketing literature and expands the scope of action for companies when they cannot avoid offering occasionally flawed services

The Mre11 protein interacts with both Rad50 and the HerA bipolar helicase and is recruited to DNA following gamma irradiation in the archaeon Sulfolobus acidocaldarius

Background: The ubiquitous Rad50 and Mre11 proteins play a key role in many processes involved in the maintenance of genome integrity in Bacteria and Eucarya, but their function in the Archaea is presently unknown. We showed previously that in most hyperthermophilic archaea, rad50-mre11 genes are linked to nurA encoding both a single-strand endonuclease and a 5' to 3' exonuclease, and herA, encoding a bipolar DNA helicase which suggests the involvement of the four proteins in common molecular pathway(s). Since genetic tools for hyperthermophilic archaea are just emerging, we utilized immuno-detection approaches to get the first in vivo data on the role(s) of these proteins in the hyperthermophilic crenarchaeon Sulfolobus acidocaldarius. Results: We first showed that S. acidocaldarius can repair DNA damage induced by high doses of gamma rays, and we performed a time course analysis of the total levels and sub-cellular partitioning of Rad50, Mre11, HerA and NurA along with the RadA recombinase in both control and irradiated cells. We found that during the exponential phase, all proteins are synthesized and display constant levels, but that all of them exhibit a different sub-cellular partitioning. Following gamma irradiation, both Mre11 and RadA are immediately recruited to DNA and remain DNA-bound in the course of DNA repair. Furthermore, we show by immuno-precipitation assays that Rad50, Mre11 and the HerA helicase interact altogether. Conclusion: Our analyses strongly support that in Sulfolobus acidocaldarius, the Mre11 protein and the RadA recombinase might play an active role in the repair of DNA damage introduced by gamma rays and/or may act as DNA damage sensors. Moreover, our results demonstrate the functional interaction between Mre11, Rad50 and the HerA helicase and suggest that each protein play different roles when acting on its own or in association with its partners. This report provides the first in vivo evidence supporting the implication of the Mre11 protein in DNA repair processes in the Archaea and showing its interaction with both Rad50 and the HerA bipolar helicase. Further studies on the functional interactions between these proteins, the NurA nuclease and the RadA recombinase, will allow us to define their roles and mechanism of action.Publisher PDFPeer reviewe

Production and Application of CAR T Cells: Current and Future Role of Europe

Rapid developments in the field of CAR T cells offer important new opportunities while at the same time increasing numbers of patients pose major challenges. This review is summarizing on the one hand the state of the art in CAR T cell trials with a unique perspective on the role that Europe is playing. On the other hand, an overview of reproducible processing techniques is presented, from manual or semi-automated up to fully automated manufacturing of clinical-grade CAR T cells. Besides regulatory requirements, an outlook is given in the direction of digitally controlled automated manufacturing in order to lower cost and complexity and to address CAR T cell products for a greater number of patients and a variety of malignant diseases