Direct digital design of PIDF controllers with ComPlex zeros for DC-DC buck converters

This paper presents a new direct digital design method for discrete proportional integral derivative PID + filter (PIDF) controllers employed in DC-DC buck converters. The considered controller structure results in a proper transfer function which has the advantage of being directly implementable by a microcontroller algorithm. Secondly, it can be written as an Infinite Impulse Response (IIR) digital filter. Thirdly, the further degree of freedom introduced by the low pass filter of the transfer function can be used to satisfy additional specifications. A new design procedure is proposed, which consists of the conjunction of the pole-zero cancellation method with an analytical design control methodology based on inversion formulae. These two methods are employed to reduce the negative effects introduced by the complex poles in the transfer function of the buck converter while exactly satisfying steady-state specifications on the tracking error and frequency domain requirements on the phase margin and on the gain crossover frequency. The proposed approach allows the designer to assign a closed-loop bandwidth without constraints imposed by the resonance frequency of the buck converter. The response under step variation of the reference value, and the disturbance rejection capability of the proposed control technique under load variations are also evaluated in real-time implementation by using the Arduino DUE board, and compared with other methods

A Novel MIMO Control for Interleaved Buck Converters in EV DC Fast Charging Applications

This brief proposes a new multiple input multiple output (MIMO) control for off-board electric vehicle (EV) dc fast chargers. The proposed feedback matrix design avoids multiple tuning of controllers in multiple and interconnected loops while improving the performance of interleaved dc buck converters over classical PI/PID controls. The innovative features of the presented strategy are the reference current monotonic tracking from any initial state of charge with an arbitrarily fast settling time and the fast compensation of both load variations and imbalances among the legs. Numerical results validate the performance improvements of the proposed discrete-time MIMO algorithm for interleaved buck converters over classical PI/PID controls. Full-scale hardware-in-the-loop (HIL) and scaled-down prototype experimental results prove the feasibility and effectiveness of the proposal

Model-based adaptive control of modular DAB converter for EV chargers

This paper presents the discrete-time modelling and control of modular input-parallel–output-parallel (IPOP) dual-active-bridge (DAB) converters for electric vehicle (EV) charging. The proposed adaptive control system ensures adequate current-sharing among parallel modules while minimizing DAB current stress by adopting dual phase-shift modulation. Driven by the growing need for fast EV charging options, the paper highlights the importance of achieving top-notch control performance, especially with varying load conditions. Specifically, it introduces a discrete-time model for adjusting controller parameters adaptively, which simplifies the typically cumbersome manual tuning process associated with these systems. The proposed PI formulae are derived to satisfy specifications on the frequency domain as phase margin and the gain crossover frequency of the open loop gain transfer function, ensuring stability and robustness in operation. Moreover, the implementation of these formulae in discrete microcontrollers facilitates seamless PI autotuning for precise current, voltage, or power control. Notably, the proposed control strategy effectively mitigates current overshot issues commonly encountered during module engagement and shedding operations in modular EV chargers. To validate its efficacy, the proposed controller is evaluated through extensive testing and comparisons within the PLECS environment, particularly focusing on a two-module IPOP-DAB converter scenario, and including comparisons with classical offline model-based pole placement methodology. Furthermore, real-time hardware-in-the-loop experiments are conducted to confirm the feasibility and performance of the proposed controller under realistic EV charging profiles

Citrullination: the loss of tolerance and development of autoimmunity in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and pannus formation, which can lead to severe destruction of cartilage and bone. Several self proteins have been suggested to be disease-driving autoantigens. Moreover the presence of autoantibodies to citrullinated proteins in sera of patients with RA enhances the strength of this hypothesis. Proteins are encoded by a limited number of genes in our genome. Post-translational modifications such as phosphorylation, glycosylation and citrullination can increase the morphological and the functional diversity of the proteome

Citrullination: the loss of tolerance and development of autoimmunity in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and pannus formation, which can lead to severe destruction of cartilage and bone. Several self proteins have been suggested to be disease-driving autoantigens. Moreover the presence of autoantibodies to citrullinated proteins in sera of patients with RA enhances the strength of this hypothesis. Proteins are encoded by a limited number of genes in our genome. Post-translational modifications such as phosphorylation, glycosylation and citrullination can increase the morphological and the functional diversity of the proteome

Strategies for Improved pDNA Loading and Protection Using Cationic and Neutral LNPs with Industrial Scalability Potential Using Microfluidic Technology

Purpose: In recent years, microfluidic technologies have become mainstream in producing gene therapy nanomedicines (NMeds) following the Covid-19 vaccine; however, extensive optimizations are needed for each NMed type and genetic material. This article strives to improve LNPs for pDNA loading, protection, and delivery, while minimizing toxicity. Methods: The microfluidic technique was optimized to form cationic or neutral LNPs to load pDNA. Classical “post-formulation” DNA addition vs “pre” addition in the aqueous phase were compared. All formulations were characterized (size, homogeneity, zeta potential, morphology, weight yield, and stability), then tested for loading efficiency, nuclease protection, toxicity, and cell uptake. Results: Optimized LNPs formulated with DPPC: Chol:DOTAP 1:1:0.1 molar ratio and 10 μg of DOPE-Rhod, had a size of 160 nm and good homogeneity. The chemico-physical characteristics of cationic LNPs worsened when adding 15 μg/mL of pDNA with the “post” method, while maintaining their characteristics up to 100 μg/mL of pDNA with the “pre” addition remaining stable for 30 days. Interestingly, neutral LNPs formulated with the same method loaded up to 50% of the DNA. Both particles could protect the DNA from nucleases even after one month of storage, and low cell toxicity was found up to 40 μg/mL LNPs. Cell uptake occurred within 2 hours for both formulations with the DNA intact in the cytoplasm, outside of the lysosomes. Conclusion: In this study, the upcoming microfluidic technique was applied to two strategies to generate pDNA-LNPs. Cationic LNPs could load 10x the amount of DNA as the classical approach, while neutral LNPs, which also loaded and protected DNA, showed lower toxicity and good DNA protection. This is a big step forward at minimizing doses and toxicity of LNP-based gene therapy

Dysregulation of NF–Y splicing drives metabolic rewiring and aggressiveness in colon cancer

NF-Y is an evolutionarily conserved transcription factor that binds specifically to the CCAAT elements of eukaryotic genes, most of which frequently deregulated in cancer. NF-YA, the regulatory subunit of the NF-Y complex, has two isoforms generated by alternative splicing, NF-YAl and NF-YAs, which differ in the transactivation domain. Transcriptomic data from The Cancer Genome Atlas (TCGA) database highlighted a significant increase in the expression of NF-YAs at the expense of NF-YAl in colorectal cancer (CRC), compared to healthy tissues. Despite this, high NF-YAl levels predict lower patients’ survival and distinguish the mesenchymal molecular subtype CMS4, which is characterized by the worst prognosis. Through the analysis of 3D cellular models, we demonstrated that altered expression of genes related to extracellular matrix and epithelial-mesenchymal transition sustains enhanced migratory and invasive behavior of NF-YAl-transduced cells. Moreover, the integration of metabolomics, bioenergetics and transcriptional analyses demonstrated a direct role for NFYAl in metabolic flexibility of cancer cells that adjust their metabolism in response to environmental changes to potentiate migration. The zebrafish xenograft model confirmed the metastatic potential triggered by NF-YAl in CRC cells. Altogether, our data highlight the transcriptional role of NF-YAl in CRC aggressiveness and suggest splice-switching strategies to hinder NF-YAl-induced metastatic dissemination

Airway deposition of extrafine inhaled triple therapy in patients with copd: A model approach based on functional respiratory imaging computer simulations

Introduction: There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways. Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and nonextrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC). This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting β2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs. Materials and Methods: Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients’ high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition. Results: HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 19.3% to 66.0% predicted. For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component. Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/ VI/UMEC. Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were <1, indicating greater peripheral than central deposition (0.48 ±0.13, 0.48±0.13 and 0.49±0.13 for BDP, FF and GB, respectively; 1.96±0.84, 0.97±0.34 and 1.20±0.48 for FluF, VI and UMEC, respectively). Conclusions: Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD. This is consistent with the extrafine formulation of BDP/FF/GB

Patent ductus arteriosus (also non-hemodynamically significant) correlates with poor outcomes in very low birth weight infants. A multicenter cohort study

Objectives To standardize the diagnosis of patent ductus arteriosus (PDA) and report its association with adverse neonatal outcomes in very low birth weight infants (VLBW, birth weight < 1500 g). Study design A multicenter prospective observational study was conducted in Emilia Romagna from March 2018 to October 2019. The association between ultrasound grading of PDA and adverse neonatal outcomes was evaluated after correction for gestational age. A diagnosis of hemodynamically significant PDA (hsPDA) was established when the PDA diameter was ≥ 1.6 mm at the pulmonary end with growing or pulsatile flow pattern, and at least 2 of 3 indexes of pulmonary overcirculation and/or systemic hypoperfusion were present. Results 218 VLBW infants were included. Among infants treated for PDA closure in the first postnatal week, up to 40% did not have hsPDA on ultrasound, but experienced clinical worsening. The risk of death was 15 times higher among neonates with non-hemodynamically significant PDA (non-hsPDA) compared to neonates with no PDA. In contrast, the risk of death was similar between neonates with hsPDA and neonates with no PDA. The occurrence of BPD was 6-fold higher among neonates with hsPDA, with no apparent beneficial role of early treatment for PDA closure. The risk of IVH (grade ≥ 3) and ROP (grade ≥ 3) increased by 8.7-fold and 18-fold, respectively, when both systemic hypoperfusion and pulmonary overcirculation were present in hsPDA. Conclusions The increased risk of mortality in neonates with non-hsPDA underscores the potential inadequacy of criteria for defining hsPDA within the first 3 postnatal days (as they may be adversely affected by other clinically severe factors, i.e. persistent pulmonary hypertension and mechanical ventilation). Parameters such as length, diameter, and morphology may serve as more suitable ultrasound indicators during this period, to be combined with clinical data for individualized management. Additionally, BPD, IVH (grade ≥ 3) and ROP (grade ≥ 3) are associated with hsPDA. The existence of an optimal timeframe for closing PDA to minimize these adverse neonatal outcomes remains uncertain

Strategies for Improved pDNA Loading and Protection Using Cationic and Neutral LNPs with Industrial Scalability Potential Using Microfluidic Technology

Ilaria Ottonelli,1,* Elisa Adani,2,* Andrea Bighinati,2 Sabrina Cuoghi,1 Giovanni Tosi,1,3 Maria Angela Vandelli,1 Barbara Ruozi,1 Valeria Marigo,2,3 Jason Thomas Duskey1 1Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; 2Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; 3Center for Neuroscience and Neurotechnology, Modena, Italy*These authors contributed equally to this workCorrespondence: Jason Thomas Duskey, Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, Modena, MO, Italy, 41125, Tel +390592058573, Email [email protected] Valeria Marigo, Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 287, Modena, MO, 41125, Italy, Tel +390592055392, Email [email protected]: In recent years, microfluidic technologies have become mainstream in producing gene therapy nanomedicines (NMeds) following the Covid-19 vaccine; however, extensive optimizations are needed for each NMed type and genetic material. This article strives to improve LNPs for pDNA loading, protection, and delivery, while minimizing toxicity.Methods: The microfluidic technique was optimized to form cationic or neutral LNPs to load pDNA. Classical “post-formulation” DNA addition vs “pre” addition in the aqueous phase were compared. All formulations were characterized (size, homogeneity, zeta potential, morphology, weight yield, and stability), then tested for loading efficiency, nuclease protection, toxicity, and cell uptake.Results: Optimized LNPs formulated with DPPC: Chol:DOTAP 1:1:0.1 molar ratio and 10 μg of DOPE-Rhod, had a size of 160 nm and good homogeneity. The chemico-physical characteristics of cationic LNPs worsened when adding 15 μg/mL of pDNA with the “post” method, while maintaining their characteristics up to 100 μg/mL of pDNA with the “pre” addition remaining stable for 30 days. Interestingly, neutral LNPs formulated with the same method loaded up to 50% of the DNA. Both particles could protect the DNA from nucleases even after one month of storage, and low cell toxicity was found up to 40 μg/mL LNPs. Cell uptake occurred within 2 hours for both formulations with the DNA intact in the cytoplasm, outside of the lysosomes.Conclusion: In this study, the upcoming microfluidic technique was applied to two strategies to generate pDNA-LNPs. Cationic LNPs could load 10x the amount of DNA as the classical approach, while neutral LNPs, which also loaded and protected DNA, showed lower toxicity and good DNA protection. This is a big step forward at minimizing doses and toxicity of LNP-based gene therapy.Keywords: gene therapy, lipid nanoparticles, microfluidics, lipoplexes, DNA deliver