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Deciphering the role of the mitochondrial chaperonine MCJ in ovarian cancer
Get PDFOvarian cancer (OC) is the most lethal gynecological neoplasm due to its extremely silent invasive capacity, characterized by high mortality frequently caused by therapeutic failure and chemoresistance onset. Recent studies have indicated that the chemotherapy response can be affected by metabolic state and mitochondrial bioenergetic efficiency. Indeed, this latter can finely regulates Wnt/β-catenin pathway which is often involved in OC growth and chemoresistance. Interestingly, the OC therapeutic resistance acquirement has been associated with the silencing of DNAJC15 gene that encodes for the mitochondrial co-chaperonine MCJ, a negative regulator of electron transport chain (ETC) functionality. We therefore hypothesized that MCJ may lead to the re-establishment of pharmacological sensitivity modulating the bioenergetic profile in OC cell models. In this frame, the MCJ overexpression triggers the respiratory capacity and ROS production in OC cells. In addition, we observed an increased cisplatin-sensitivity and lower proliferative and migratory capacities in the MCJ over-expressing chemoresistant cell line. Furthermore, we found that the MCJ over-expression was able to impact on the Wnt/β-catenin signaling pathway, in terms of decreases of β-catenin expression levels accompanied with lower downstream multi-drug resistance and epithelial-mesenchymal transition players in the chemoresistant cells. Based on these data, we speculate that the over-expression of MCJ may modulate the ETC activity and ROS production, inducing β-catenin degradation, which in turn leads to a reduction of both cisplatin-resistance and proliferation of OC chemoresistant cells. The dissection of these mechanisms in which MCJ seems to be involved sets the bases for new insights for this silent killer disease
Reproductive and developmental toxicity study using Sprague-Dawley rats exposed under various calendars to the weedkiller Glyphosate and commercial formulations Glyphosate-based
Get PDFGlyphosate-based herbicides (GBHs) are the most globally used herbicides raising the risk of environmental exposition. Carcinogenic effects are only one component of the multiple adverse health effects of Glyphosate and GBHs that have been reported. Questions related to hazards and corresponding risks identified in relation to endocrine disrupting effects are rising. The present study investigated the possible reproductive/developmental toxicity of GBHs administered to male and female Sprague-Dawley rats under various calendar of treatment. Assessments included maternal and reproductive outcome of F0 and F1 dams exposed to GBHs throughout pregnancy and lactation and developmental landmarks and sexual characteristics of offspring. The study was designed in two stages. In the first stage Glyphosate, or its commercial formulation Roundup Bioflow, was administered to rats at the dose of 1.75 mg/kg bw/day (Glyphosate US Acceptable Daily Intake) from the prenatal period until adulthood. In the second stage, multiple toxicological parameters were simultaneously assessed, including multigeneration reproductive/developmental toxicity of Glyphosate and two GBHs (Roundup Bioflow and Ranger Pro). Man-equivalent doses, beginning from 0.5 mg/kg bw/day (ADI Europe) up to 50 mg/kg bw/day (NOAEL Glyphosate), were administered to male and female rats, covering specific windows of biological susceptibility. The results of stage 1 and preliminary data from stage 2 experiments characterize GBHs as probable endocrine disruptors as suggested by: 1) androgen-like effects of Roundup Bioflow, including a significant increase of anogenital distances in both males and females, delay of first estrous and increased testosterone in females; 2) slight puberty onset anticipation in the high dose of Ranger Pro group, observed in the F1 generation treated from in utero life until adulthood; 3) a delayed balano-preputial separation achievement in the high dose of Ranger Pro-treated males exposed only during the peri-pubertal period, indicating a direct and specific effect of GBHs depending on the timing of exposure
Homoleptic and Heteroleptic Metal Carbonyl Clusters and Nanoclusters
Get PDFThis Thesis aims at presenting the general results achieved during my PhD, that was focused on the study and characterisation of new homoleptic and heteroleptic metal carbonyl clusters. From a dimensional point of view, the nuclearity of such species ranges from 2 to 44 metal atoms. Lower nuclearity compounds may be viewed as polymetallic complexes, whereas higher nuclearity species can reach the nanocluster size, by resembling to ultrasmall nanoparticles (USNPs). Initially, my research was focused on the investigation of small MCCs stabilised by N-Heterocyclic carbene (NHCs) ligands. At this regard, a general strategy for the synthesis of mono-anionic [Fe(CO)4(MNHC)]− and neutral Fe(CO)4(MNHC)2, Co(CO)4(MNHC) (M = Cu, Ag, Au; NHC = IMes, IPr) species has been developed. Furthermore, during this investigation, neutral trimetallic Fe(CO)4(MNHC)(M’NHC) (M, M’ = Cu, Ag, Au; M ≠ M'; NHC = IPr) and neutral heteroleptic Fe(CO)4(MNHC)(MNHC’) (M = Au; NHC = IMes, IPr) compounds have been isolated. Thermal treatment turned out to be an efficient method for the growth of the dimension of MCCs. Indeed, species of the type [M3Fe3(CO)12]3– and [M4Fe4(CO)16]4– (M = Ag, Au) as well as larger clusters were formed during the thermal treatment of the new Fe-M (M = Ag, Cu, Au) carbonyl compounds. These species inspired the investigation of promising reaction paths for the synthesis of Fe-M (M = Ag, Cu, Au) carbonyl compounds devoid of ancillary ligands and alloy MCCs, such as the heterometallic [MxM’5-xFe4(CO)16]3− (M, M' = Cu, Ag, Au; M ≠ M'; x = 0-5) carbonyl clusters. The second part of this Thesis regards high nuclearity MCCs. In particular, new strategies for the growth of platinum carbonyl clusters involving, for instance, the employment of bidentate phosphines are described, as well as the syntheses and the thermal decomposition of new Ni-M (Pd, Pt) carbonyl clusters
Mesh Morphing Methods for Virtual Prototyping and Mechanical Component Optimization
Get PDFIn this thesis, the coupling of mathematical geometry and its discretization (mesh) is performed using a method that fills the gap between simulation and design. Different modelling strategies are studied, tested and developed to bridge commercial CAD with a new methodology able to perform more accurate simulations without loosing the connection with the geometrical features. The aim of the thesis is to enhance the capabilities of Finite Element Methods (FEM) with the properties of Non-Uniform Radial Basis Functions (NURBS) inherited from CAD models in the design phase leading to a perfect representation of the model's boundary. The parametric space definition of the basis functions is borrowed from standard IGA (Isogeometric Analysis) and the possibility of process CAD models without the need for trivariate NURBS from NEFEM (NURBS Enhanced Finite Element Method). This particular combination yields to a bilinear Lagrangian basis and a new mapping between Cartesian and Parametric spaces for quadrilaterals. Using this new formulation it is possible to track the changes of the geometry and reduce the simulation's error up to 25-50% because of the perfect shape representation when compared to an equivalent FEM system. The problems presented are defined in a 2D space and solved using Matlab. NURBS are the key point to perform parametric morphing and simple optimizations while FEM remains the best way to perform simulations. This new method prevents to remodel B-Rep (Boundary Representation) parts after some simple modification due to the analysis and improves the geometry accuracy of the discretization. The geometrical file is directly imported from commercial software and processed by the method. Accuracy, convergence and seamless integration with commercial CAD packages are demonstrated applied to problems of arbitrary 2D geometry. The main problems treated are thermal analysis and solid mechanics where the better results are achieved
Does Aorto-Iliac Anatomy Affect Endovascular Aortic Aneurysm Repair Durability With The New Generation Endografts?
Get PDFIntroduction:
Endovascular aneurysm repair(EVAR) has become the main treatment for abdominal aortic aneurysm(AAA). Anatomical features of the AAA are pivotal in EVAR success. The aim of this study was to evaluate known anatomical features as risk factors for the freedom from reintervention(FFR) taking into account the new-generation endografts.
Materials and Methods:
This study was a retrospective monocentric study including consecutive patients treated by EVAR from 2012 to 2018 in elective setting. All currently reported anatomic factors including aortic neck and iliac arteries proprieties were examined using the pre-operative AngioCT-imaging. The primary endpoint was to define the anatomical risk factors affecting the FFR.
Results:
A total of 653 patients treated by standard EVAR were included. The mean age was 75.6±8 years. The mean follow-up was 34±11 months. FFR was 98.4%,97.4%,96% and 87.3% at 6,12,24 and 48 months, respectively.
Larger aortic neck diameter was significant risk factor for FFR(P=0.001). Aortic neck severe angulation >60° was correlated to the need for reintervention(P=0.001). Larger aneurysm diameter was associated with higher incidence of reinterventions(P<0.001). Infrarenal aortic length(IRAL) measured as distance between renal artery and aortic bifurcation level, was associated with lower FFR(P=0.002). Similarly, the mean aorto-iliac length(MAIL) measured as the sum of distance between the most distal renal artery and iliac bifurcation in both sides divided by two, resulted a negative factor for FFR (P=0.002). At the multivariate analysis of anatomical features, aortic neck diameter (HR1.18;CI:1.02-1.37,P=0.03) and MAIL (HR1.02;CI:1.01-1.04,P=0.01) were confirmed as significant risk factors for FFR.
Conclusion:
This 7-years real-world study focused on the analysis of anatomic risk factors predisposing for graft-related reinterventions at mid-term. Patient survival and FFR are satisfactory and compatible with other studies results. Aortic neck diameter and MAIL resulted the main risk factors for FFR. IRAL and MAIL resulting significant factors are not described before and need further investigations
Mining the genome of livestock species to identify markers associated with economically relevant morphological traits and breed-specific features
Get PDFMorphological traits in livestock breeding especially the ones that are associated with production or reproduction efficiency are of great importance since they could affect in some aspects the profitability of farm animals. With regard to the economic values of the Reggiana cattle, we have conducted different genome-wide association studies (GWAS) for different morphological traits. GWASs for stature showed a significant peak on Bos taurus chromosome (BTA) 6, with the single nucleotide polymorphisms (SNPs) located on LCORL-NCAPG genes and another suggestively significant SNP on BTA14 and PLAG1 gene which is in a cluster with CHCHD7. For muzzle colour including all possible comparisons between pink, grey and black muzzle, GWASs highlighted significant SNPs on BTA18, in a genome region harbouring the MC1R gene. Considering genome scan for presence or absence of supernumerary nipples, results showed two peaks on BTA17 including TBX3 and TBX5 genes as the known genes associated with this phenotype and BTA10 with MCC gene. GWAS for horn shape identified only a suggestive significant marker on BTA19. Considering the importance of the number of teats in pigs, we carried out GWASs for the total number of teats and other 12 related parameters. For four investigated parameters (total number of teats, number of teats of the left and right lines, and maximum number of teats comparing the two sides), significant markers were identified on SSC7, in the region of the vertnin (VRTN) gene. Significant markers for the number of posterior teats and absolute difference between anterior and posterior teat numbers were consistently identified on SSC6 with the most significant SNP that was an intron variant in TOX high mobility group box family member 3 (TOX3) gene. The GWASs highlighted genomic regions potentially affecting biological mechanisms controlling the developmental programme of morphological features in Reggiana cattle and Italian Large White pig populations
Body composition in 65+ European population: a focus on inflammatory and metabolic markers in healthy and frail
Get PDFObjectives: The aims of this PhD work were: 1. provide a profile of Body Composition (BC) in healthy elderly from five European countries and investigate country- and sex-related differences; 2. explore the relationship between BC markers for adipose and lean tissue and bone mass, and inflammatory and adipose-related markers in healthy elderly Europeans; 3. detect differences of BC and health markers that characterize pre-frail or frail individuals trying to define a “frailty signature”.
Methods: Data from whole-body dual-energy X-ray absorptiometry (DXA) scan, markers of inflammation as well as clinical dataset were available for 1,121 healthy (65-79 years) non-frail and pre-frail women and men from five European countries participating to the “NU-AGE" EU project (NCT01754012) and 23 frail women and men participating to the “ProAGE” Project (DUND-100373). The presence of frailty was assessed using the standardized phenotype scale proposed by Fried et al. Advanced statistical methods such as hierarchical cluster analysis were applied in order to answer the above-mentioned research questions.
Results: BC characteristics were different in elderly women and men, and more favorable BC markers were associated with a better adipose-related inflammatory profile, with the exception of skeletal muscle mass index. Moreover, five BC profiles in women and six in men have been identified by a hierarchical cluster analysis based on BC parameters. Furthermore, frail subjects have significantly higher fat mass and lower lean mass markers compared with non-frail and pre-frail subjects and the amount of subcutaneous adipose tissue (SAT) seems to be a valid predictor of frailty in elderly female.
Conclusions: BC parameters measured by DXA are different among healthy male and female elderly across Europe and also among frail and non-frail subjects and are specifically associated with health and inflammatory markers. BC represents a key factor in the aging process and in the prevention of age-related pathologies
Erythropoietin reduces pathogenic humoral immunity by inhibiting T Follicular Helper cell differentiation and function
Get PDFA large fraction of organ transplant recipients develop anti-donor antibodies (DSA), with accelerated graft loss and increased mortality. We tested the hypothesis that erythropoietin (EPO) reduces DSA formation by inhibiting T follicular helper (TFH) cells.
We measured DSA levels, splenic TFH, TFR cells, germinal center (GC), and class switched B cells, in murine models of allogeneic sensitization, allogeneic transplantation and in parent-to-F1 models of graft versus host disease (GVHD).
We quantified the same cell subsets and specific antibodies, upon EPO or vehicle treatment, in wild type mice and animals lacking EPO receptor selectively on T or B cells, immunized with T-independent or T-dependent stimuli.
In vitro, we tested the EPO effect on TFH induction. We isolated TFH and TFR cells to perform in vitro assay and clarify their role.
EPO reduced DSA levels, GC, class switched B cells, and increased the TFR/TFH ratio in the heart transplanted mice and in two GVHD models.
EPO did also reduce TFH and GC B cells in SRBC-immunized mice, while had no effect in TNP-AECM-FICOLL-immunized animals, indicating that EPO inhibits GC B cells by targeting TFH cells. EPO effects were absent in T cells EPOR conditional KO mice, confirming that EPO affects TFH in vivo through EPOR.
In vitro, EPO affected TFH induction through an EPO-EPOR-STAT5-dependent pathway.
Suppression assay demonstrated that the reduction of IgG antibodies was dependent on TFH cells, sustaining the central role of the subset in this EPO-mediated mechanism.
In conclusion, EPO prevents DSA formation in mice through a direct suppression of TFH. Development of DSA is associated with high risk of graft rejection, giving our data a strong rationale for studies testing the hypothesis that EPO administration prevents their formation in organ transplant recipients. Our findings provide a foundation for testing EPO as a treatment of antibody mediated disease processes
Employment of Real-Time/FPGA Architectures for Test and Control of Automotive Engines
Get PDFNowadays the production of increasingly complex and electrified vehicles requires the implementation of new control and monitoring systems. This reason, together with the tendency of moving rapidly from the test bench to the vehicle, leads to a landscape that requires the development of embedded hardware and software to face the application effectively and efficiently. The development of application-based software on real-time/FPGA hardware could be a good answer for these challenges: FPGA grants parallel low-level and high-speed calculation/timing, while the Real-Time processor can handle high-level calculation layers, logging and communication functions with determinism. Thanks to the software flexibility and small dimensions, these architectures can find a perfect collocation as engine RCP (Rapid Control Prototyping) units and as smart data logger/analyser, both for test bench and on vehicle application. Efforts have been done for building a base architecture with common functionalities capable of easily hosting application-specific control code. Several case studies originating in this scenario will be shown; dedicated solutions for protype applications have been developed exploiting a real-time/FPGA architecture as ECU (Engine Control Unit) and custom RCP functionalities, such as water injection and testing hydraulic brake control
The parametrix method for SPDEs and conditional transition densities
Get PDFWe extend the classic parametrix method in the context of evolution SPDEs.
Our method is based on a It\^o-Wentzell reduction of the SPDE to a PDE with random coefficients to which we apply a revised parametrix technique to construct a fundamental solution. This approach avoids the use of the Duhamel's principle for SPDEs and the related measurability issues that appear in the stochastic framework.
We first apply our method to a parabolic SPDE with random and measurable coefficients; then we expand our study to a class degenerate SPDEs of Kolmogorov type, we discuss the filtering problem for the associated partially observable degenerate diffusion and show existence, regularity and Gaussian-type estimates of a conditional transition density.
In the second part of the work, we consider non degenerate Brownian SDEs with H\"older continuous in space diffusion coefficient and unbounded drift with linear growth. We derive two sided bounds for the associated density and pointwise controls of its derivatives up to order two under some additional spatial H\"older continuity assumptions on the drift. Importantly, the estimates reflect the transport of the initial condition by the unbounded drift through an auxiliary, possibly regularized, flow