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Investigation of novel molecular targets to counteract myocardial remodeling upon pathophysiological stressors
No full textThe heart is a highly adaptable organ that grows through hyperplasia in the embryonic and fetal stages but mainly undergoes hypertrophy in response to increased workload in postnatal and adult life. Hypertrophic remodeling in cardiomyocytes (CMs) is associated with increased protein synthesis (thus requiring tight control over protein quality). In parallel, when CMs enlarge due to hypertrophy, energy expenditure increases to uphold higher protein synthesis while ensuring contractile activity. Thus, an increase in mitochondrial function and number is expected to maintain their energetic homeostasis in the long term. Among different types of hypertrophy, two main forms are conventionally recognised, described as physiological and pathological cardiac hypertrophy. While the former involves long-term potentiation of cardiac function without harmful effects, the latter includes initial adaptive changes followed by molecular and structural changes leading to decreased heart function and eventually heart failure.
During my Ph.D., I focused on these two aspects of cardiac hypertrophy (protein quality control and mitochondrial function) to identify possible targetable mechanisms to counteract pathologic myocardial remodeling.
In the first project I focused on a muscle-specific ubiquitin ligase, MuRF1, which has been shown to participate in cardiac pathological conditions. MuRF1-/- mice do not show cardiac functional defect in the first 6 months, but only later develop diastolic dysfunction, followed by systolic impairment during ageing, accompanied by cellular hypertrophy and a massive interstitial fibrotic remodeling, characterised by increased levels of Collagen VI already in adult animals. Interestingly, these changes occurred in the absence of common markers of maladaptive remodelling (e.g. cell death, fibroblast proliferation, ANF and b-MHC). Our results suggest that the increased collagen expression in fibroblasts is driven by a paracrine CM-to-fibroblast effect, upon MuRF1 ablation.
In the second project, I focused on the Mitochondrial Ca2+ Uniporter (MCU), which was demonstrated to be differentially modulated in patients and mouse models of cardiac hypertrophy. Of note, up- (OE) or down-regulation (KD) of MCU exerted opposite effects in the response of mice to pressure overload. While the KD shows an exacerbated maladaptive phenotype (capillary rarefaction, massive fibrotic deposition), the OE showed a phenotype more similar to a physiological adaptation of the heart (lower fibrosis, preserved vascularisation, lower expression of maladaptive markers) despite a higher hypertrophic growth of CMs. To further assess the mechanism behind the observed cardioprotective role, we exploited an in vitro model, inducing CMs hypertrophy through chronic noradrenaline (NE) treatment. Interestingly, already in basal condition, and further exacerbated after NE stimulation, we observed an increase in the phosphorylation levels of Akt, already linked to beneficial effects on cardiac homeostasis during physiologic hypertrophy of the heart. Our results, obtained both in vitro and in vivo, suggest that upon MCU-OE the increased mitochondrial Ca2+ content impinges on mitochondrial ROS production, which in turn indirectly drives Akt activation.
As a side project, I contributed to the optimisation of a culture condition to promote the structural and functional maturation of neonatal CMs in vitro. Exploiting morphological, morphometrical and live imaging analyses, our results show that, upon culture with a Low-Glucose-No-Serum (LGNS) medium, neonatal CMs are morphologically and functionally closer to the adult phenotype. In addition, we also tested this novel condition in CMs and sympathetic neuron co-cultures, obtaining functional connections between these cells, allowing the in vitro study of the dynamics occurring at the neuro-cardiac junction
Tuning-Less Model Predictive Torque Control for Synchronous Motor Drives With Maximum Torque-Per-Ampere Criterion Including Transients
No full textThis article presents a torque control strategy for permanent magnet synchronous motors based on a continuous control-set model predictive control with maximum torque-per-current operations capability. The voltage references are generated by solving the optimization problem without any control weights, thus smoothing the way for an easy implementation. A distinctive feature of this control method is its ability to guarantee the maximum torque-per-current criterion under all operating conditions, including during torque transients. This capability is generally unattainable by traditional torque control techniques. The performances of the proposed algorithm are guaranteed, thanks to the novel design of the optimization problem and constraints formulation. The only requirement of the proposed technique is the accurate knowledge of the motor model. Experimental results are provided using an interior permanent magnet motor, where various operating conditions were tested to validate the effectiveness of the proposed control method
Defining puberty and spectrum of hypogonadism in Alström Syndrome
No full textBackground: Alström syndrome (AS), has been extensively studied for its multi-system organ manifestations. Primary gonadal failure is well described in humans, but little is known about the intricacies of puberty and true incidence of hypogonadism within this population. Hypothesis: We aimed to define the onset and progression of puberty and the incidence of hypogonadism in male patients with AS. Methodology: A retrospective, observational cohort study was conducted on patients with AS across the UK and Italy national services. Additionally, the findings were correlated with Alms1 S701X mouse model as part of the current study. Results: We enrolled 28 paediatric patients (age 14.8 ±2.3) and 41 adult patients (age 34 ±12). All paediatric patients entered puberty at an appropriate age, but the highest testicular volume achieved by patients with AS was 9 ± 3ml in age group of 14-15-year-old boys. Among adults, 95% (39/41) had hypogonadism with primary gonadal failure. Testicular analysis of Alms1 S701X mouse model shows testicular atrophy with no evidence of fibrosis. Moreover, Alms1 S701X mice exhibit reduced sperm count and sperm motility compared to controls (29.03*106/ml vs 110.6*106/ml, 34.77% vs 70.18%). Conclusion: Our study sheds light on the reproductive aspects of AS across paediatric and adult populations with particular emphasis on testicular and pubertal development, and hypogonadism in adult life. Although, all the paediatric AS patients have age-appropriate onset of puberty, almost all exhibit hypogonadism with primary gonadal failure as adults. This mirrors the Alms1 S701X mouse model
Future precipitation extremes: Differential changes from point to catchment scale revealed by a convection-permitting model ensemble
No full textUnderstanding spatial scale-dependent changes in extreme precipitation is crucial for flood risk adaptation in a warming climate. This study investigates how future changes in sub-daily to daily extreme precipitation can be transferred from point to catchment scales. We use the areal reduction factor (ARF) concept to quantify the impact of climate change on extremes at multiple scales from point (individual model grid cell) to catchment scales up to 3,751 km2 in the upper Adige River basin, eastern Italian Alps. We apply the Simplified Metastatistical Extreme Value (SMEV) framework to estimate extreme precipitation return levels (1–24 h durations, up to 100-year return periods) at multiple spatial scales using an ensemble of nine convection-permitting models from FPS-CORDEX. Models provide hourly precipitation data (remapped to 3 km grid) for historical (1996–2005) and future (2090–2099) periods under the RCP8.5 scenario. Our results show that ARFs derived by the models in the historical period align well with ARFs values obtained from observations. Under future scenarios, changes in ARFs cannot be in general deemed statistically significant, due to the important inter-model variability. ARFs slightly increase for short durations (1–3 h) and low-to-medium return periods (2–20 years) over small basins (<100km2), suggesting more spatially uniform extremes at these scales. Conversely, ARFs decrease for longer durations, larger basins and high return periods, implying that corresponding areal design precipitation will increase less than point precipitation under the same conditions. Our results highlight the need for high-resolution ensemble modeling to capture inter-model variability in extreme precipitation projections
Gestione Innovativa dei Progetti di Bonifica delle Discariche con il Raggiungimento della Qualità dello Stoccaggio Finale
No full textThis research, co-financed by the PON REACT-EU program, explores sustainable waste management strategies for landfill remediation to achieve Final Storage Quality. Using the Villadose landfill in Rovigo, Italy, as a case study, the investigation analysed the management of old and fresh waste fractions through landfill mining and subsequent waste disposal practices. Laboratory-scale experiments characterised waste emissions under anaerobic conditions and assessed the impact of flushing and aeration on the removal of key contaminants such as organic carbon, ammonia, and chlorides.
Results revealed that mixing old and fresh waste accelerated stabilisation, with aeration enhancing organic carbon degradation and reducing ammonia levels. Chlorides were removed solely through flushing. Aeration was shown to remove 7–8% of initial organic carbon within 163 days, significantly reducing emissions compared to traditional anaerobic conditions. Intermittent aeration proved sufficient to optimise degradation, supporting the use of hybrid bioreactor landfills.
The study highlights landfill mining as a strategy to create additional disposal space and enhance the degradation of fresh waste, potentially reducing aftercare durations. Flushing, coupled with aeration, emerged as essential for inorganic contaminant removal, while tailored in situ treatments based on biodegradation progress optimise landfill sustainability. A proposed passive aftercare phase incorporating natural flushing and low-energy treatments could further mitigate environmental risks, advancing progress toward Final Storage Quality
Investigating condensation heat transfer and flow pattern of R1233zd(E) in hyper-, micro- and normal gravity conditions
Get PDFfor developing more reliable and efficient thermal control systems (TCS). In fact, TCS are aimed at supporting life
in shuttles and planetary bases and ensuring the proper operation of instrumentation for experiments. Consequently,
their study is of high interest, particularly as TCS are required to reduce their weight and volume. This
latter requirement has led to the introduction of two-phase heat transfer systems in place of traditional singlephase
ones. As a result, two-phase heat transfer processes need to be thoroughly studied under reduced gravity
conditions to ensure the adequate design of thermal control systems for space applications.
In this work, the condensation heat transfer of R1233zd(E) was studied during the 84th ESA Parabolic Flight
Campaign using a 3.38 mm inner diameter channel. Experiments were conducted under hyper-, micro- and
normal gravity conditions at saturation temperature equal to 40 ◦C and mass fluxes equal to 30 kg m-2 s-1 and
40 kg m- 2 s-1. The results reveal a significant reduction in heat transfer coefficients under microgravity conditions,
with annular flow patterns being predominantly observed. Notably, this study presents experimental
condensation data under hyper-gravity conditions for the first time. Comparisons with HFE-7000 data (tested
during a previous Parabolic Flight Campaign) and evaluations against existing correlations are presented,
highlighting the need for accurate predictive models for condensation heat transfer in microgravity and hypergravity
A Book of One’s Own: Private Records and Accountability through a Gendered Perspective in Late Medieval Florence
No full textEthanol dimethyl ammonium functionalized poly[ethylene pyrrole/ethylene ketone/propylene ketone] anion exchange membranes for alkaline electrochemical devices
Get PDFThis study reports the synthesis of new anion exchange membranes (AEMs) based on poly[N-{N′-(2′-hydroxyethyl)-N′,N′-dimethylammoniumethyl}-ethylenepyrrole(X)/(ethyleneketone)/ (propyleneketone)] (E-FPKKf(X)g) with X = I− or OH−, obtained by modulating the degree of functionalization (f). The synthesis of these AEMs involves the reaction of poly[ethylene ketone/propylene ketone] with 2-(2-aminoethylamino)ethanol using a Paal-Knorr chemistry. The physical-chemical characteristics of these membranes are extensively analyzed by elemental analysis (CHNS/O), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), high resolution thermogravimetric analysis (HR-TGA) and modulated differential scanning calorimetry (MDSC). The electrical behavior is examined using broadband electric spectroscopy (BES), demonstrating conductivities of 1.66 and 0.084 mS cm−1 30 °C for the membranes in the hydroxide and iodide form, respectively. Additionally, the stability tests conducted by immersing the membranes in 1 M KOH solution at ambient temperature for 336 h reveal promising chemical resistance in alkaline conditions for the membranes in hydroxide form
A simple experiment to trace stemflow infiltration: Advantages and challenges of using stable isotopes of hydrogen and oxygen and electrical resistivity tomography
Get PDFPrima di San Giovanni. Le fasi precedenti alla costruzione della chiesa (Castelseprio, Va). Scavi 2024
No full textSi descrivono le caratteristiche dell'edificio rinvenuto all'interno della basilica longobarda di San Giovanni e si propone una atazione di V-VI secolo grazie ai reperti rinvenuti all'interno di una serie di fosse in rapporto alla costruzione