Plastically-driven variation of elastic stiffness in green bodies during powder compaction. Part II: Micromechanical modelling

A micromechanical approach is set-up to analyse the increase in elastic stiffness related to development of plastic deformation (the elastoplastic coupling concept) occurring during the compaction of a ceramic powder. Numerical simulations on cubic (square for 2D) and hexagonal packings of elastoplastic cylinders and spheres validate both the variation of the elastic modulus with the forming pressure and the linear dependence of it on the relative density as experimentally found in Part~I of this study, while the dependence of the Poisson's ratio on the green's density is only qualitatively explained

Inferring metabolic phenotypes from the exometabolome through a thermodynamic variational principle

Networks of biochemical reactions, like cellular metabolic networks, are kept in non-equilibrium steady states by the exchange fluxes connecting them to the environment. In most cases, feasible flux confi gurations can be derived from minimal mass-balance assumptions upon prescribing in- and outtake fluxes. Here we consider the problem of inferring intracellular fl ux patterns from extracellular metabolite levels. Resorting to a thermodynamic out of equilibrium variational principle to describe the network at steady state, we show that the switch from fermentative to oxidative phenotypes in cells can be characterized in terms of the glucose, lactate, oxygen and carbon dioxide concentrations. Results obtained for an exactly solvable toy model are fully recovered for a large scale reconstruction of human catabolism. Finally we argue that, in spite of the many approximations involved in the theory, available data for several human cell types are well described by the predicted phenotypic map of the problem

Quantitative constraint-based computational model of tumor-to-stroma coupling via lactate shuttle

Cancer cells utilize large amounts of ATP to sustain growth, relying primarily on non-oxidative, fermentative pathways for its production. In many types of cancers this leads, even in the presence of oxygen, to the secretion of carbon equivalents (usually in the form of lactate) in the cell's surroundings, a feature known as the Warburg effect. While the molecular basis of this phenomenon are still to be elucidated, it is clear that the spilling of energy resources contributes to creating a peculiar microenvironment for tumors, possibly characterized by a degree of toxicity. This suggests that mechanisms for recycling the fermentation products (e.g. a lactate shuttle) may be active, effectively inducing a mutually beneficial metabolic coupling between aberrant and non-aberrant cells. Here we analyze this scenario through a large-scale in silico metabolic model of interacting human cells. By going beyond the cell-autonomous description, we show that elementary physico-chemical constraints indeed favor the establishment of such a coupling under very broad conditions. The characterization we obtained by tuning the aberrant cell's demand for ATP, amino-acids and fatty acids and/or the imbalance in nutrient partitioning provides quantitative support to the idea that synergistic multi-cell effects play a central role in cancer sustainment

Wave reflection and transmission in multiply stented blood vessels

Closed circulatory systems display an exquisite balance between vascular elasticity and viscous fluid effects, to induce pulse-smoothing and avoid resonance during the cardiac cycle. Stents in the arterial tree alter this balance through stiffening and because a periodic structure is introduced, capable of interacting with the fluid in a complex way. While the former feature has been investigated, the latter received no attention so far. But periodic structures are the building blocks of metamaterials, known for their ‘non-natural’ behaviour. Thus, the investigation of a stent's periodic microstructure dynamical interactions is crucial to assess possible pathological responses. A one-dimensional fluid–structure interaction model, simple enough to allow an analytical solution for situations of interest involving one or two interacting stents, is introduced. It is determined: (i) whether or not frequency bands exist in which reflected blood pulses are highly increased and (ii) if these bands are close to the characteristic frequencies of arteries and finally, (iii) if the internal structure of the stent can sensibly affect arterial blood dynamics. It is shown that, while the periodic structure of an isolated stent can induce anomalous reflection only in pathological conditions, the presence of two interacting stents is more critical, and high reflection can occur at frequencies not far from the physiological values.This work was supported by the ERC advanced grant ERC-2013-ADG-340561-INSTABILITIES (2014– 2019). T.K.P. acknowledges support from the aforementioned programme for the period from 10 May 2016 to 13 September 2016. A.B.M. acknowledges the support from the aforementioned ERC Advanced Grant during his Visiting Professorship at Trento University in 2016

Simulating (electro)hydrodynamic effects in colloidal dispersions: smoothed profile method

Previously, we have proposed a direct simulation scheme for colloidal dispersions in a Newtonian solvent [Phys.Rev.E 71,036707 (2005)]. An improved formulation called the ``Smoothed Profile (SP) method'' is presented here in which simultaneous time-marching is used for the host fluid and colloids. The SP method is a direct numerical simulation of particulate flows and provides a coupling scheme between the continuum fluid dynamics and rigid-body dynamics through utilization of a smoothed profile for the colloidal particles. Moreover, the improved formulation includes an extension to incorporate multi-component fluids, allowing systems such as charged colloids in electrolyte solutions to be studied. The dynamics of the colloidal dispersions are solved with the same computational cost as required for solving non-particulate flows. Numerical results which assess the hydrodynamic interactions of colloidal dispersions are presented to validate the SP method. The SP method is not restricted to particular constitutive models of the host fluids and can hence be applied to colloidal dispersions in complex fluids

Quantitative diffusion and perfusion MRI in the evaluation of endometrial cancer. Validation with histopathological parameters

Objectives: To investigate the role of quantitative Magnetic Resonance Imaging (MRI) in preoperative assessment of tumour aggressiveness in patients with endometrial cancer, correlating multiple parameters obtained from diffusion and dynamic contrast-enhanced (DCE) MR sequences with conventional histopathological prognostic factors and inflammatory tumour infiltrate.Methods: Forty-four patients with biopsy-proven endometrial cancer underwent preoperative MR imaging at 3T scanner, including DCE imaging, diffusion-weighted imaging (DWI) and intravoxel incoherent motion imaging (IVIM). Images were analysed on dedicated post-processing workstations and quantitative parameters were extracted: K-trans, K-ep, V-e and AUC from the DCE; ADC from DWI; diffusion D, pseudo diffusion D*, perfusion fraction f from IVIM and tumour volume from DWI. The following histopathological data were obtained after surgery: histological type, grading (G), lympho-vascular invasion (LVI), lymph node status, FIGO stage and inflammatory infiltrate.Results: ADC was significantly higher in endometrioid histology, G1-G2 (low grade), and stage IA. Significantly higher D* were found in endometrioid subptype, negative lymph nodes and stage IA. The absence of LVI is associated with higher f values. K-trans and V-e values were significantly higher in low grade. Higher D*, f and AUC occur with the presence of chronic inflammatory cells, D * was also able to distinguish chronic from mixed type of inflammation. Larger volume was significantly correlated with the presence of mixed-type inflammation, LVI, positive lymph nodes and stage >= IB.Conclusions: Quantitative biomarkers obtained from pre-operative DWI, IVIM and DCE-MR examination are an in vivo representation of the physiological and micro-structural characteristics of endometrial carcinoma allowing to obtain the fundamental parameters for stratification into Risk Classes.Advances in knowledge: Quantitative imaging biomarkers obtained from DWI, DCE and IVIM may improve preoperative prognostic stratification in patients with endometrial cancer leading to a more informed therapeutic choice

Tyrosol may prevent obesity by inhibiting adipogenesis in 3T3-L1 preadipocytes

Tyrosol (TR), a major polyphenol found in extra virgin olive oil (EVOO), exerts several antioxidant effects. However, only scarce evidences are present regarding its activity on adipocytes and obesity. This study evaluated the role of TR in adipogenesis. Murine 3T3-L1 preadipocytes were incubated with TR (300 and 500 μM), and TR administration inhibited adipogenesis by downregulation of several adipogenic factors (leptin and aP2) and transcription factors (C/EBPα, PPARγ, SREBP1c, and Glut4) and by modulation of the histone deacetylase sirtuin 1. After complete differentiation, adipocytes treated with 300 and 500 μM TR showed a reduction of 20% and 30% in lipid droplets, respectively. Intracellular triglycerides were significantly reduced after TR treatment (p < 0.05). Mature adipocytes treated with TR at 300 and 500 μM showed a marked decrease in the inflammatory state and oxidative stress as shown by the modulation of specific biomarkers (TNF, IL6, ROS, and SOD2). TR treatment also acted on the early stage of differentiation by reducing cell proliferation (~40%) and inducing cell cycle arrest during Mitotic Expansion Clonal (first 48 h of differentiation), as shown by the increase in both S1 phase and p21 protein expression. We also showed that TR induced lipolysis by activating the AMPK-ATGL-HSL pathway. In conclusion, we provided evidence that TR reduces 3T3-L1 differentiation through downregulation of adipogenic proteins, inflammation, and oxidative stress. Moreover, TR may trigger adipose tissue browning throughout the induction of the AMPK-ATGL-UCP1 pathway and, subsequently, may have promise as a potential therapeutic agent for the treatment and prevention of obesity

Evidenze di un possibile trattamento chirurgico in uno scheletro del sepolcreto di Casal Bertone (Roma, I-III sec. d.C.)

Nel corso dello scavo di Casal Bertone, che ha restituito oltre 200 sepolture è stato rinvenuto un individuo con evidenti alterazioni dei piedi. Le ossa tarsali risultavano fuse, i metatarsali avevano epifisi sfrangiate e cavità pseudocistiche e la tuberosità del calcagno destro era attraversata da un foro di dubbia eziologia. L’ individuo, d’età alla morte compresa tra 50 e 60 anni, di sesso femminile, è di corporatura gracile con una statura pari a 147 cm ca. Al fine di comprendere la patologia che aveva colpito l’individuo e la natura del foro del calcagno, gli elementi dei piedi sono stati sottoposti ad indagine tramite tomografia assiale computerizzata (TAC). Dalle immagini ottenute si osserva che la zona adiacente al foro presenta una radiopacità molto elevata dovuta alla calcificazione dell’osso; tale dettaglio suggerisce che il foro sia stato praticato in vita. L’ipotesi di un possibile intervento chirurgico potrebbe essere avvalorata dal rinvenimento di tracce d’argento all’interno del foro. Le fonti storiche riportano che alcuni strumenti chirurgici e contenitori utilizzati per miscelare i farmaci potevano esserne rivestiti; inoltre in età imperiale è attestato l’utilizzo dell’argento nelle ricette, come componente di farmaci e impiastri per il trattamento di alcune patologie.During the excavation of Casal Bertone an individual was found with evident alterations of the feet. The tarsal bones were fused, the metatarsals had fringed epiphysis and pseudocyst cavities and the tuberosity of the right calcane was crossed by a hole of dubious etiology. The individual, aged between 50 and 60 years old, of a female gender, is of a gracile body with a height of about 147 cm. ..............