Advanced GN&C Technologies for TAEM: Flight Test Results of the Italian Unmanned Space Vehicle

This paper describes the guidance, navigation and control challenges posed by the Unmanned Space Vehicles Program. Within the framework of this program the Italian Aerospace Research Center has conceived several advanced GN&C technologies useful in the Terminal Area Energy Management phase of a re-entry flight pattern. These technologies were flight tested during the first two dropped transonic flight tests (DTFT1 and DTFT2) of the program. More specifically, this paper will present the design of the adaptive guidance algorithms developed to accomplish the mission objectives of the DTFT2 flight test. Flight results will be shown in order to state the performance of the guidance strategy putting in evidence, where possible, its most promising aspects for future TAEM applications

GNC Post Flight Analysis of the Italian Dropped Transonic Flight Tests

The Italian Aerospace Research Centre (CIRA), in the framework of the Unmanned Space Vehicles (USV) Program, has developed several advanced Guidance, Navigation and Control technologies for the Terminal Area Energy Management (TAEM) phase of a re-entry ight. These technologies were in-flight tested during the first two dropped transonic flight tests (DTFT1 and DTFT2) of the program. These missions allowed CIRA to investigate critical technological aspects related to the autonomous execution of a typical TAEM phase of a re-entry flight, from a velocity of about Mach 2 down to the typical Approach/Landing Interface speed of Mach 0.5 and below. This paper presents flight tests results and post flight data analysis of these missions. How technological innovations in the Guidance, Navigation and Control domain can contribute to a more autonomous, more safe and less costly future generation of reusable launch vehicles is well stated in open literature. In the USV program, focus was given to adaptive guidance with on-line trajectory re-planning capabilities and to robust and fault tolerant control, as key enabling technologies for atmospheric re-entry and hypersonic flight. Obviously, the complexity of such missions also required dedicated research on advanced methodologies in the field of robustness analysis, design and verification of GNC systems for highly uncertain and non-linear systems. Methodologies for vehicle model identification from flight data have been also included in this technological road map to maximize the scientific return from the flight tests. Model identification methodologies for processing flight data are frequently used to validate and improve a pre-flight aerodynamic data-base and, specifically, to reduce the associated uncertainties. However in this field conventional techniques need to be improved because the USV flight tests have a non-stationary trajectory and specific identification manoeuvres should be avoided being hazardous for the mission. More specifically, the problem of the identification of the aerodynamic model of the Italian Unmanned Space Vehicle was solved through a multi-step approach, where the aerodynamic coefficients are identified first and, in a following phase, a set of model parameters are updated. The methodology was applied to actual flight data, acquired during the two dropped transonic flight tests

Integrative organelle-based functional proteomics: in silico prediction of impaired functional annotations in SACS KO cell model

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disease characterized by early-onset spasticity in the lower limbs, axonal-demyelinating sensorimotor peripheral neuropathy, and cerebellar ataxia. Our understanding of ARSACS (genetic basis, protein function, and disease mechanisms) remains partial. The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure. Our integrated results strengthen the evidence for disease-specific defects related to bioenergetics and protein quality control systems and reinforce the role of dysregulated cytoskeletal organization in the pathogenesis of ARSACS

Growing in the darkness: predation ability and cannibalism in cave-born larvae of fire salamander, Salamandra salamandra (Linnaeus, 1758)

Crescere al buio: abilit\ue0 predatoria e cannibalismo in larve di salamandra pezzata, Salamandra salamandra nate in grotta. La salamandra pezzata in diverse aree carsiche del proprio areale pu\uf2 deporre le larve anche in ambienti ipogei come grotte naturali e artificiali. Lo scopo di questo studio \ue8 valutare se le popolazioni che utilizzano tali, inusuali, siti riproduttivi, abbiano sviluppato degli adattamenti specifici. Per tale scopo abbiamo effettuato alcuni esperimenti comportamentali sulla capacit\ue0 di predazione e sul cannibalismo. Da 20 grotte e da 20 ruscelli adiacenti abbiamo raccolto delle larve che abbiamo allevato in due differenti condizioni: in ambiente ipogeo ed in ambiente epigeo. Sia le larve da grotta che da ruscello sono state in grado di catturare prede in condizioni di buio totale. Le larve nate in grotta hanno per\uf2 mostrato una maggiore efficienza. Per quanto riguarda il cannibalismo esso \ue8 ridotto alla nascita e molto pi\uf9 accentuato dopo un mese di vita delle larve. Il grado di digiuno e la taglia delle larve influenzano l\u2019aggressivit\ue0. Non sono per\uf2 risultati evidenti effetti della provenienza delle larve o delle condizioni di allevamento

PTEN deficiency and mutant p53 confer glucose-addiction to thyroid cancer cells: impact of glucose depletion on cell proliferation, cell survival, autophagy and cell migration.

Proliferating cancer cells oxidize glucose through the glycolytic pathway. Since this metabolism is less profitable in terms of ATP production, cancer cells consume large quantity of glucose, and those that experience insufficient blood supply become glucose-addicted. We have analyzed the response to glucose depletion in WRO and FTC133 follicular thyroid cancer cells, which differ in the expression of two key regulators of the glucose metabolism. WRO cells, which express wild type p53 and PTEN, showed a higher rate of cell proliferation and were much less sensitive to glucose-depletion than FTC133 cells, which are PTEN null and express mutant p53. Glucose depletion slowed-down the autophagy flux in FTC133 cells, not in WRO cells. In a wound-healing assay, WRO cells were shown to migrate faster than FTC133 cells. Glucose depletion slowed down the cell migration rate, and these effects were more evident in FTC133 cells. Genetic silencing of either wild-type PTEN or p53 in WRO cells resulted in increased uptake of glucose, whereas the ectopic expression of PTEN in FTC133 cells resulted in diminished glucose uptake. In conclusion, compared to WRO, FTC133 cells were higher glucose up-taker and consumer. These data do not support the general contention that cancer cells lacking PTEN or expressing the mutant p53R273H are more aggressive and prone to better face glucose depletion. We propose that concurrent PTEN deficiency and mutant p53 leads to a glucose-addiction state that renders the cancer cell more sensitive to glucose restriction. The present observation substantiates the view that glucose-restriction may be an adjuvant strategy to combat these tumours

Oestrogen receptor alpha in pulmonary hypertension

Aims Pulmonary arterial hypertension (PAH) occurs more frequently in women with mutations in bone morphogenetic protein receptor type 2 (BMPR2) and dysfunctional BMPR2 signalling underpinning heritable PAH. We have previously shown that serotonin can uncover a pulmonary hypertensive phenotype in BMPR2+/− mice and that oestrogen can increase serotinergic signalling in human pulmonary arterial smooth muscle cells (hPASMCs). Hence, here we wished to characterize the expression of oestrogen receptors (ERs) in male and female human pulmonary arteries and have examined the influence of oestrogen and serotonin on BMPR2 and ERα expression. Methods and results: By immunohistochemistry, we showed that ERα, ERβ, and G-protein-coupled receptors are expressed in human pulmonary arteries localizing mainly to the smooth muscle layer which also expresses the serotonin transporter (SERT). Protein expression of ERα protein was higher in female PAH patient hPASMCs compared with male and serotonin also increased the expression of ERα. 17β-estradiol induced proliferation of hPASMCs via ERα activation and this engaged mitogen-activated protein kinase and Akt signalling. Female mice over-expressing SERT (SERT+ mice) develop PH and the ERα antagonist MPP attenuated the development of PH in normoxic and hypoxic female SERT+ mice. The therapeutic effects of MPP were accompanied by increased expression of BMPR2 in mouse lung. Conclusion: ERα is highly expressed in female hPASMCs from PAH patients and mediates oestrogen-induced proliferation of hPASMCs via mitogen-activated protein kinase and Akt signalling. Serotonin can increase ERα expression in hPASMCs and antagonism of ERα reverses serotonin-dependent PH in the mouse and increases BMPR2 expression.</p

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Loss of expression of the oncosuppressor PTEN in thyroid incidentalomas associates with GLUT1 plasmamembrane expression

AIM: Molecular imaging diagnosis with FDG-PET ((18)F-fluorodeoxyglucose positron emission tomography with computed tomography) can reveal the presence of un-suspected thyroid cancer that are referred to as "incidentaloma" because of the incidental finding. The glucose analogue (18)FDG is internalized in the cells by glucose transporters belonging to the GLUTs family. The surface expression of GLUT is under the control of the PI3k/Akt pathway. PTEN is an oncosuppressor frequently mutated or deleted in thyroid cancers. The lipid phosphatase activity of wild type PTEN switches off the Akt pathway. Here we tested the hypothesis that PTEN expression might affect the surface expression of GLUT1 and therefore influence the possibility of "incidental" detection of thyroid cancer based on FDG-PET. METHODS: The biopsy of 8 patients, who were incidentally diagnosed with PTC by (18)F-fluorodeoxyglucose positron emission tomography with computed tomography, was assayed by immunofluorescence for the co-expression of the PTEN oncosuppressor and of GLUT1. RESULTS: Loss of PTEN expression was detected in the majority of investigated cases (N.=6/8). Strikingly, while the two PTEN positive cases were negative for GLUT1 expression, the PTEN negative cases showed intense expression of GLUT1 at the cell surface. CONCLUSION: The present observations, though made in a limited number of cases, suggest that PTEN negative thyroid cancers have high chances to be revealed as incidentalomas at FDG-PET