EFFETTI DINAMICI DELL’INNALZAMENTO DEL CARICO PER ASSE DI ROTABILI FERROVIARI PER TRASPORTO MERCI

Lo sviluppo di un sistema di trasporto ferroviario merci richiede di minimizzare i tempi di percorrenza e massimizzare la capacità di carico dei convogli. Questo obiettivo può essere raggiunto mediante tre diverse strategie, che possono essere adottate separatamente o in modo congiunto. Le strategie consistono sostanzialmente nell’aumento della capacità di carico del singolo carro, nell’aumento della lunghezza del convoglio e nell’aumento della velocità del veicolo. La possibilità di attuare simultaneamente le tre strategie è possibile solo disponendo di infrastrutture dedicate e utilizzando una progettazione specifica della linea e dei veicoli. Il lavoro illustra gli effetti di un innalzamento del carico per asse, oltre al limite attualmente consentito in Italia, sui principali indicatori utilizzati dalla norma UIC per l’omologazione del materiale rotabile. Le valutazioni sono state effettuate utilizzando un tracciato reale di buona qualità ed un modello numerico di un veicolo di tipo Y25

The fate of Galilean relativity in minimal-length theories

A number of arguments at the interplay of general relativity and quantum theory suggest an operational limit to spatial resolution, conventionally modelled as a generalized uncertainty principle (GUP). Recently, it has been demonstrated that the dynamics postulated as a part of these models are only loosely related to the existence of the minimal-length scale. In this paper, we intend to make a more informed choice on the Hamiltonian by demanding, among other properties, that the model be invariant under (possibly) deformed Galilean transformations in one dimension. In this vein, we study a two-particle system with general interaction potential under the condition that the composition as well as the action of Galilean boosts on wave numbers be deformed so as to comply with the cut-off. We find that the customary GUP-Hamiltonian does not allow for invariance under (any kind of) generalised Galilean transformations. Those Hamiltonians which allow for a deformed relativity principle have to be related to the ordinary Galilean ones by virtue of a momentum-space diffeomorphism, i.e. a canonical transformation. Far from being trivial, the resulting dynamics is deformed, as we show at the example of the harmonic interaction.Comment: 21 pages, 2 figures, 1 appendi

30 years in: Quo vadis generalized uncertainty principle?

According to a number of arguments in quantum gravity, both model-dependent and model-independent, Heisenberg's uncertainty principle is modified when approaching the Planck scale. This deformation is attributed to the existence of a minimal length. The ensuing models have found entry into the literature under the term Generalized Uncertainty Principle (GUP). In this work, we discuss several conceptual shortcomings of the underlying framework and critically review recent developments in the field. In particular, we touch upon the issues of relativistic and field theoretical generalizations, the classical limit and the application to composite systems. Furthermore, we comment on subtleties involving the use of heuristic arguments instead of explicit calculations. Finally, we present an extensive list of constraints on the model parameter $\beta$, classifying them on the basis of the degree of rigour in their derivation and reconsidering the ones subject to problems associated with composites.Comment: 38 pages. Accepted for publication in Classical and Quantum Gravity, "Special Issue: Focus on Quantum Gravity Phenomenology in the Multi-Messenger Era: Challenges and Perspectives

A role for Separase in telomere protection

Drosophila telomeres are elongated by transposition of specialized retroelements rather than telomerase activity and are assembled independently of the sequence. Fly telomeres are protected by the terminin complex that localizes and functions exclusively at telomeres and by non-terminin proteins that do not serve telomere-specific functions. We show that mutations in the Drosophila Separase encoding gene Sse lead not only to endoreduplication but also telomeric fusions (TFs), suggesting a role for Sse in telomere capping. We demonstrate that Separase binds terminin proteins and HP1, and that it is enriched at telomeres. Furthermore, we show that loss of Sse strongly reduces HP1 levels, and that HP1 overexpression in Sse mutants suppresses TFs, suggesting that TFs are caused by a HP1 diminution. Finally, we find that siRNA-induced depletion of ESPL1, the Sse human orthologue, causes telomere dysfunction and HP1 level reduction in primary fibroblasts, highlighting a conserved role of Separase in telomere protection

Characterization of the Channel Constriction Allowing the Access of the Substrate to the Active Site of Yeast Oxidosqualene Cyclase

In oxidosqualene cyclases (OSCs), an enzyme which has been extensively studied as a target for hypocholesterolemic or antifungal drugs, a lipophilic channel connects the surface of the protein with the active site cavity. Active site and channel are separated by a narrow constriction operating as a mobile gate for the substrate passage. In Saccharomyces cerevisiae OSC, two aminoacidic residues of the channel/constriction apparatus, Ala525 and Glu526, were previously showed as critical for maintaining the enzyme functionality. In this work sixteen novel mutants, each bearing a substitution at or around the channel constrictions, were tested for their enzymatic activity. Modelling studies showed that the most functionality-lowering substitutions deeply alter the H-bond network involving the channel/constriction apparatus. A rotation of Tyr239 is proposed as part of the mechanism permitting the access of the substrate to the active site. The inhibition of OSC by squalene was used as a tool for understanding whether the residues under study are involved in a pre-catalytic selection and docking of the substrate oxidosqualene

Feasibility study of a diesel-powered hybrid DMU

Nowadays the interest in hybrid vehicles is constantly increasing, not only in the automotive sector, but also in other transportation systems, to reduce pollution and emissions and to improve the overall efficiency of the vehicles. Although railway vehicles are typically the most eco-friendly transportation system, since commonly their primary energy source is electricity, they can still gain benefits from hybrid technologies, as many lines worldwide are not electrified. In fact, hybrid solutions allow ICE-powered railway vehicles, such as diesel multiple units (DMU), to operate in full-electric mode even when the track lacks electrification. The possibility to switch to full electric mode is of paramount importance when the vehicle runs on urban or underground track sections, where low or zero emission levels are required. The paper describes the feasibility study of hybridization of an existing DMU vehicle, designed by Blue Engineering S.r.l., running on the Aosta-Torino Italian railway line, which includes a non-electrified urban track section and an electrified underground section. The hybridization is obtained by replacing one of the diesel generators installed on the original vehicle with a battery pack, which ensures the vehicle to operate in full-electric mode to complete its mission profile. The hybridization is also exploited to implement a regenerative braking strategy, which allows an increase in the energetical efficiency of the vehicle up to 18%. The paper shows the sizing of the battery pack based on dynamic simulations performed on the Turin underground track section, and the results demonstrate the feasibility of the hybridization process

Consequences of telomere dysfunction in fibroblasts, club and basal cells for lung fibrosis development.

TRF1 is an essential component of the telomeric protective complex or shelterin. We previously showed that dysfunctional telomeres in alveolar type II (ATII) cells lead to interstitial lung fibrosis. Here, we study the lung pathologies upon telomere dysfunction in fibroblasts, club and basal cells. TRF1 deficiency in lung fibroblasts, club and basal cells induced telomeric damage, proliferative defects, cell cycle arrest and apoptosis. While Trf1 deletion in fibroblasts does not spontaneously lead to lung pathologies, upon bleomycin challenge exacerbates lung fibrosis. Unlike in females, Trf1 deletion in club and basal cells from male mice resulted in lung inflammation and airway remodeling. Here, we show that depletion of TRF1 in fibroblasts, Club and basal cells does not lead to interstitial lung fibrosis, underscoring ATII cells as the relevant cell type for the origin of interstitial fibrosis. Our findings contribute to a better understanding of proper telomere protection in lung tissue homeostasis.We are grateful to Dr. J. Xu from the Baylor College of Medicine for providing p63-CreERT2 mouse sperm for the generation of the p63 mutant mouse line. Research in the Blasco Lab is funded by AstraZeneca; Fundacion Botin and Banco Santander (Spain); Agencia Estatal de Investigacion (AEI/MCI/10.13039/501100011033) with the project RETOS SAF2017-82623-R, cofunded by European Regional Development Fund (ERDF), "A way of making Europe"; Comunidad de Madrid with the Synergy Project COVIDPREclinicalMODels-CM and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 882385) through the project ERC-AvG SHELTERINS. The CNIO, certified since 2011 as Severo Ochoa Centre of Excellence by AEI/MCI/10.13039/501100011033, is supported by the Spanish Government through the Instituto de Salud Carlos III (ISCIII).S

Multiple cancer pathways regulate telomere protection

Telomeres are considered as universal anti-cancer targets, as telomere maintenance is essential to sustain indefinite cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are among the most frequently found in cancer. In addition, mutations in components of the telomere protective complex, or shelterin, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition; however, recent studies suggest that direct targeting of the shelterin complex could represent a more effective strategy. In particular, we recently showed that genetic deletion of the TRF1 essential shelterin protein impairs tumor growth in aggressive lung cancer and glioblastoma (GBM) mouse models by direct induction of telomere damage independently of telomere length. Here, we screen for TRF1 inhibitory drugs using a collection of FDA-approved drugs and drugs in clinical trials, which cover the majority of pathways included in the Reactome database. Among other targets, we find that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulates the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. We further show that both bRAF and ERK2 kinases phosphorylate TRF1 in vitro and that these modifications are essential for TRF1 location to telomeres in vivo Finally, we use these new TRF1 regulatory pathways as the basis to discover novel drug combinations based on TRF1 inhibition, with the goal of effectively blocking potential resistance to individual drugs in patient-derived glioblastoma xenograft models.We thank the Confocal Microscopy, Protein Engineering, Mass Spectrometry,Comparative Pathology, and Mouse Facility Units at CNIO. MAB laboratory is funded by SAF 2013-45111-R from MINECO,Fundación Botín and Banco Santander, Worldwide Cancer Research 16-1177. LB is a fellow of the La Caixa-Severo Ochoa International PhD Programme.S

The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review

Introduction: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC. Areas covered: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development. Expert opinion: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC