Evaluating Mobility Service Providers’ Strategies in an Activity-Based Supernetwork

A Mathematical Problem with Equilibrium Constraints (MPEC) is formulated to capture the relationships between multiple Mobility Service Providers (MSPs) and the users of a multimodal transport network. The network supply structure is represented as a supernetwork where users’ daily activity chains are represented sequentially and their modal choices to reach different destinations are based on the mobility services active in each connection. At the upper level, a profit maximization formulation is introduced to describe MSPs’ behaviour. At the lower level, groups of users choose the routes with the lowest cost, according to Wardrop’s first equilibrium principle. Due to non-separable interactions between supernetwork links, the equilibrium conditions defining users travel behaviour are written as Variational Inequality (VI). Finally, a numerical example is presented in order to show the characteristics of the model when car-sharing, bus and private car are available in the network

A Markov Chain Monte Carlo Approach for Estimating Daily Activity Patterns

Determining the purpose of trips brings is a fundamental information to evaluate travel demand during the day and to predict longer-term impacts on the population’s travel behavior. The concept of tours is the most suited to consider the value of a daily scheduling of individuals and travel interdependencies. However, the meticulous care required for both collecting data of high quality and interpret results of advanced demand models are frequently considered as major drawbacks. The objective of this study is to incorporate into a standard trip-based model some inherent concepts of activity-based models in order to enhance the representation of travel behavior. The main focus of this work is to infer, employing utility theory, the trip purpose of a population, at a zonal level. Making use of Markov Chain Monte Carlo, a set of parameters is estimated in order to retrieve tour-based primitives of the demand. The main advantage of this methodology is the low requirements in terms of data, as no individual information are used, and the good interpretation of the model. Estimated parameters of the priors set a utility-based probability function for departure time, which allows to have a dynamic overview of the demand. In order to account for the tour consistency of travel decisions, a duration constraint is added to the model. The proposed model is applied to the region of Luxembourg city and the results show the potential of the methodologies for dividing an observed demand based on the activity at destination

Hyaluronan Esters Drive Smad Gene Expression and Signaling Enhancing Cardiogenesis in Mouse Embryonic and Human Mesenchymal Stem Cells

BACKGROUND: Development of molecules chemically modifying the expression of crucial orchestrator(s) of stem cell commitment may have significant biomedical impact. We have recently developed hyaluronan mixed esters of butyric and retinoic acids (HBR), turning cardiovascular stem cell fate into a high-yield process. The HBR mechanism(s) remain still largely undefined. METHODOLOGY/PRINCIPAL FINDINGS: We show that in both mouse embryonic stem (ES) cells and human mesenchymal stem cells from fetal membranes of term placenta (FMhMSCs), HBR differentially affected the patterning of Smad proteins, one of the major conductors of stem cell cardiogenesis. Real-time RT-PCR and Western blot analyses revealed that in both cell types HBR enhanced gene and protein expression of Smad1,3, and 4, while down-regulating Smad7. HBR acted at the transcriptional level, as shown by nuclear run-off experiments in isolated nuclei. Immunofluorescence analysis indicated that HBR increased the fluorescent staining for Smad1,3, and 4, confirming that the transcriptional action of HBR encompassed the upregulation of the encoded Smad proteins. Chromatin immune precipitation and transcriptional analyses showed that HBR increased the transcription of the cardiogenic gene Nkx-2.5 through Smad4 binding to its own consensus Smad site. Treatment of mouse ES cells and FMhMSCs with HBR led to the concomitant overexpression of both Smad4 and α-sarcomeric actinin. Smad4 silencing by the aid of lentiviral-mediated Smad4 shRNA confirmed a dominant role of Smad4 in HBR-induced cardiogenesis. CONCLUSIONS/SIGNIFICANCE: The use of HBR may pave the way to novel combinatorial strategies of molecular and stem cell therapy based on fine tuning of targeted Smad transciption and signaling leading to a high-throughput of cardiogenesis without the needs of gene transfer technologies

Next-generation ultra-compact calorimeters based on oriented crystals

Calorimeters based on oriented crystals provide unparalleled compactness and resolution in measuring the energy of electromagnetic particles. Recent experiments performed at CERN and DESY beamlines by the AXIAL/ELIOT experiments demonstrated a significant reduction in the radiation length inside tungsten and PbWO4, the latter being the scintillator used for the CMS ECAL, observed when the incident particle trajectory is aligned with a lattice axis within ∼1∘. This remarkable effect, being observed over the wide energy range from a few GeV to 1 TeV or higher, paves the way for the development of innovative calorimeters based on oriented crystals, featuring a design significantly more compact than currently achievable while rivaling the current state of the art in terms of energy resolution in the range of interest for present and future forward detectors (such as the KLEVER Small Angle Calorimeter at CERN SPS) and source-pointing space-borne γ-ray telescopes

Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients

BACKGROUND: The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. METHODS: CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test. RESULTS: Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. CONCLUSIONS: CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment

The sacral chordoma margin

[Objective]: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. [Background]: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. [Methods]: A multidisciplinary meeting of the “Chordoma Global Consensus Group” was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. [Results]: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. [Conclusion]: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients

Towards a muon collider

A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work