A Characterization of Scale Invariant Responses in Enzymatic Networks

An ubiquitous property of biological sensory systems is adaptation: a step increase in stimulus triggers an initial change in a biochemical or physiological response, followed by a more gradual relaxation toward a basal, pre-stimulus level. Adaptation helps maintain essential variables within acceptable bounds and allows organisms to readjust themselves to an optimum and non-saturating sensitivity range when faced with a prolonged change in their environment. Recently, it was shown theoretically and experimentally that many adapting systems, both at the organism and single-cell level, enjoy a remarkable additional feature: scale invariance, meaning that the initial, transient behavior remains (approximately) the same even when the background signal level is scaled. In this work, we set out to investigate under what conditions a broadly used model of biochemical enzymatic networks will exhibit scale-invariant behavior. An exhaustive computational study led us to discover a new property of surprising simplicity and generality, uniform linearizations with fast output (ULFO), whose validity we show is both necessary and sufficient for scale invariance of enzymatic networks. Based on this study, we go on to develop a mathematical explanation of how ULFO results in scale invariance. Our work provides a surprisingly consistent, simple, and general framework for understanding this phenomenon, and results in concrete experimental predictions

Understanding constraint expressions in large conceptual schemas by automatic filtering

Human understanding of constraint expressions (also called schema rules) in large conceptual schemas is very di cult. This is due to the fact that the elements (entity types, attributes, relationship types) involved in an expression are de ned in di fferent places in the schema, which may be very distant from each other and embedded in an intricate web of irrelevant elements. The problem is insignifi cant when the conceptual schema is small, but very signi cant when it is large. In this paper we describe a novel method that, given a set of constraint expressions and a large conceptual schema, automatically filters the conceptual schema, obtaining a smaller one that contains the elements of interest for the understanding of the expressions. We also show the application of the method to the important case of understanding the specication of event types, whose constraint expressions consists of a set of pre and postconditions. We have evaluated the method by means of its application to a set of large conceptual schemas. The results show that the method is eff ective and e cient. We deal with conceptual schemas in UML/OCL, but the method can be adapted to other languages.Peer ReviewedPreprin

Study of cosolvent-induced α-chymotrypsin fibrillogenesis: Does protein surface hydrophobicity trigger early stages of aggregation reaction?

The misfolding of specific proteins is often associated with their assembly into fibrillar aggregates, commonly termed amyloid fibrils. Despite the many efforts expended to characterize amyloid formation in vitro, there is no deep knowledge about the environment (in which aggregation occurs) as well as mechanism of this type of protein aggregation. Alpha-chymotrypsin was recently driven toward amyloid aggregation by the addition of intermediate concentrations of trifluoroethanol. In the present study, approaches such as turbidimetric, thermodynamic, intrinsic fluorescence and quenching studies as well as chemical modification have been successfully used to elucidate the underlying role of hydrophobic interactions (involved in early stages of amyloid formation) in α-chymotrypsin-based experimental system. © 2009 Springer Science+Business Media, LLC

Head-mounted Sensory Augmentation Device: Comparing Haptic and Audio Modality

This paper investigates and compares the effectiveness of haptic and audio modality for navigation in low visibility environment using a sensory augmentation device. A second generation head-mounted vibrotactile interface as a sensory augmentation prototype was developed to help users to navigate in such environments. In our experiment, a subject navigates along a wall relying on the haptic or audio feedbacks as navigation commands. Haptic/audio feedback is presented to the subjects according to the information measured from the walls to a set of 12 ultrasound sensors placed around a helmet and a classification algorithm by using multilayer perceptron neural network. Results showed the haptic modality leads to significantly lower route deviation in navigation compared to auditory feedback. Furthermore, the NASA TLX questionnaire showed that subjects reported lower cognitive workload with haptic modality although both modalities were able to navigate the users along the wall

New Modularity of DAP-Kinases: Alternative Splicing of the DRP-1 Gene Produces a ZIPk-Like Isoform

DRP-1 and ZIPk are two members of the Death Associated Protein Ser/Thr Kinase (DAP-kinase) family, which function in different settings of cell death including autophagy. DAP kinases are very similar in their catalytic domains but differ substantially in their extra-catalytic domains. This difference is crucial for the significantly different modes of regulation and function among DAP kinases. Here we report the identification of a novel alternatively spliced kinase isoform of the DRP-1 gene, termed DRP-1β. The alternative splicing event replaces the whole extra catalytic domain of DRP-1 with a single coding exon that is closely related to the sequence of the extra catalytic domain of ZIPk. As a consequence, DRP-1β lacks the calmodulin regulatory domain of DRP-1, and instead contains a leucine zipper-like motif similar to the protein binding region of ZIPk. Several functional assays proved that this new isoform retained the biochemical and cellular properties that are common to DRP-1 and ZIPk, including myosin light chain phosphorylation, and activation of membrane blebbing and autophagy. In addition, DRP-1β also acquired binding to the ATF4 transcription factor, a feature characteristic of ZIPk but not DRP-1. Thus, a splicing event of the DRP-1 produces a ZIPk like isoform. DRP-1β is highly conserved in evolution, present in all known vertebrate DRP-1 loci. We detected the corresponding mRNA and protein in embryonic mouse brains and in human embryonic stem cells thus confirming the in vivo utilization of this isoform. The discovery of module conservation within the DAPk family members illustrates a parsimonious way to increase the functional complexity within protein families. It also provides crucial data for modeling the expansion and evolution of DAP kinase proteins within vertebrates, suggesting that DRP-1 and ZIPk most likely evolved from their ancient ancestor gene DAPk by two gene duplication events that occurred close to the emergence of vertebrates

Oscillatory stimuli differentiate adapting circuit topologies

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.Biology emerges from interactions between molecules, which are challenging to elucidate with current techniques. An orthogonal approach is to probe for 'response signatures' that identify specific circuit motifs. For example, bistability, hysteresis, or irreversibility are used to detect positive feedback loops. For adapting systems, such signatures are not known. Only two circuit motifs generate adaptation: negative feedback loops (NFLs) and incoherent feed-forward loops (IFFLs). On the basis of computational testing and mathematical proofs, we propose differential signatures: in response to oscillatory stimulation, NFLs but not IFFLs show refractory-period stabilization (robustness to changes in stimulus duration) or period skipping. Applying this approach to yeast, we identified the circuit dominating cell cycle timing. In Caenorhabditis elegans AWA neurons, which are crucial for chemotaxis, we uncovered a Ca2+ NFL leading to adaptation that would be difficult to find by other means. These response signatures allow direct access to the outlines of the wiring diagrams of adapting systems.The work was supported by US National Institutes of Health grant 5RO1-GM078153-07 (F.R.C.), NRSA Training Grant CA009673-36A1 (S.J.R.), a Merck Postdoctoral Fellowship at The Rockefeller University (S.J.R.), and the Simons Foundation (S.J.R.). J.L. was supported by a fellowship from the Boehringer Ingelheim Fonds. E.D.S. was partially supported by the US Office of Naval Research (ONR N00014-13-1-0074) and the US Air Force Office of Scientific Research (AFOSR FA9550-14-1-0060)

Tourism Destination Management: A Collaborative Approach

Collaboration is a key factor of sustainable growth across territories and industrial sectors. Tourism, one of the largest industries in the world, has been subject to strongest innovation in the last years. Main reasons of this reside both in the availability of new ICTs - Information and Communication Technologies - and organizational models, which directly connect tourists among them and with service providers, and in the always more personalized supply of tourism experience. Tourism destinations can benefit of such innovations if they are able to reorganize the territorial tourism offer around different pattern of collaboration in order to give 2.0 tourists opportunities to live an augmented tourism experience. This paper deals with the possible forms of collaborative networks that can rise within a destination with a focus on relationships between services delivered by the Tourism Destination and the requests of services at the different phases of the tourist 2.0 lifecycle

Smart Tourism Destinations: Can the Destination Management Organizations Exploit Benefits of the ICTs? Evidences from a Multiple Case Study

Recent developments of ICTs enable new ways to experience tourism and conducted to the concept of smart tourism. The adoption of cutting-edge technologies and its combination with innovative organizational models fosters cooperation, knowledge sharing, and open innovation among service providers in tourism destination. Moreover, it offers innovative services to visitors. In few words, they become smart tourism destinations. In this paper, we report first results of the SMARTCAL project aimed at conceiving a digital platform assisting Destination Management Organizations (DMOs) in providing smart tourism services. A DMO is the organization charged with managing the tourism offer of a collaborative network, made up of service providers acting in a destination. In this paper, we adopted a multiple case studies approach to analyze five Italian DMOs. Our aims were to investigate (1) if, and how, successful DMOs were able to offer smart tourism services to visitors; (2) if the ICTs adoption level was related to the collaboration level among DMO partners. First results highlighted that use of smart technologies was still in an embryonic stage of development, and it did not depend from collaboration levels

Serum amyloid A (SAA): a novel biomarker for uterine serous papillary cancer

BACKGROUND: Uterine serous papillary carcinoma (USPC) is a biologically aggressive variant of endometrial cancer. We investigated the expression of Serum Amyloid A (SAA) and evaluated its potential as a serum biomarker in USPC patients. METHODS: SAA gene and protein expression levels were evaluated in USPC and normal endometrial tissues (NEC) by real-time PCR, immunohistochemistry (IHC), flow cytometry and by a sensitive bead-based immunoassay. SAA concentration in 123 serum samples from 51 healthy women, 42 women with benign diseases, and 30 USPC patients were also studied. RESULTS: SAA gene expression levels were significantly higher in USPC when compared with NEC (mean copy number by RT\u2013PCR\ubc162 vs 2.21; P\ubc0.0002). IHC revealed diffuse cytoplasmic SAA protein staining in USPC tissues. High intracellular levels of SAA were identified in primary USPC cell lines evaluated by flow cytometry and SAA was found to be actively secreted in vitro. SAA concentrations (mgml 1) had a median (95% CIs) of 6.0 (4.0\u20138.9) in normal healthy females and 6.0 (4.2\u20138.1) in patients with benign disease (P\ubc0.92). In contrast, SAA values in the serum of USPC patients had a median (95% CI) of 15.6 (9.2\u201356.2), significantly higher than those in the healthy group (P\ubc0.0005) and benign group (P\ubc0.0006). Receiver operating characteristics (ROC) analysis of serum SAA to classify advanced- and early-stage USPC yielded an area under the ROC curve of 0.837 (P\ubc0.0024). CONCLUSION: SAA is not only a liver-secreted protein but is also a USPC cell product. SAA may represent a novel biomarker for USPC to assist in staging patients preoperatively, and to monitor early-disease recurrence and response to therapy