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Despite effective antiretroviral therapy (ART), people living with HIV (PLWH) still present persistent chronic immune activation and inflammation. This condition is the result of several factors including thymic dysfunction, persistent antigen stimulation due to low residual viremia, microbial translocation and dysbiosis, caused by the disruption of the gut mucosa, co-infections, and cumulative ART toxicity. All of these factors can create a vicious cycle that does not allow the full control of immune activation and inflammation, leading to an increased risk of developing non-AIDS co-morbidities such as metabolic syndrome and cardiovascular diseases. This review aims to provide an overview of the most recent data about HIV-associated inflammation and chronic immune exhaustion in PLWH under effective ART. Furthermore, we discuss new therapy approaches that are currently being tested to reduce the risk of developing inflammation, ART toxicity, and non-AIDS co-morbidities.

Anti-CD20 therapy is effective in idiopathic nephrotic syndrome (INS). However, transient or sustained hypogammaglobulinemia predisposing to an increased risk of infectious diseases can follow treatment in some patients. We analyzed the long-term effects of anti-CD20 therapy on immunological memory in 27 frequently-relapsing/steroid-dependent INS pediatric patients after more than 4 years from the first and at least 2 years from the last anti-CD20 infusion. Twenty-one INS children, never treated with anti-CD20 and under an intense oral immunosuppression with prednisone, mycophenolate mofetil, and calcineurin inhibitors were also included as control group. Levels of circulating B-cell subpopulations, total serum immunoglobulins and IgG and memory B cells directed against hepatitis B virus (HBV) and tetanus were determined and correlated with clinical characteristics. Nine patients never relapsed after more than 2 years from the last anti-CD20 administration (5 after the first, 3 after the second, and 1 after the fifth infusion). At last follow-up, most patients showed a complete recovery and normalization of total (27/27), transitional (27/27), and mature-naïve B cells (25/27). However, a sustained and significant reduction of total memory (20/27) and switched memory (21/27) B cells was found in most patients. 11/27 patients showed hypogammaglobulinemia at last follow-up and, among these, four presented with a severe hypogammaglobulinemia (IgG < 160 mg/dl). In contrast, no patient in the control group developed a severe hypogammaglobulinemia. Age at the time of first anti-CD20 administration was positively associated with IgG levels at last follow-up ( = 0.008); accordingly, younger patients had an increased risk of hypogammaglobulinemia ( = 0.006). Furthermore, severe hypogammaglobulinemia and delayed switched memory B-cell reconstitution were more frequent in non-relapsing patients. Reduced IgG levels against HBV and tetanus were observed at baseline and further declined at last follow-up. Antigen-specific memory B-cells were induced by re-immunization, but specific IgG titers remained low. In conclusion, anti-CD20 therapy can be disease-modifying in some INS patients. However, a prolonged impairment of immunological memory occurs frequently, independently from the number of anti-CD20 infusions, particularly in younger patients. Re-immunization may be necessary in these patients.

Routine vaccination is among the most effective clinical interventions to prevent diseases as it is estimated to save over 3 million lives every year. However, the full potential of global immunization programs is not realised because population coverage is still suboptimal. This is also due to the inadequate immune response and paucity of informative correlates of protection upon immunization of vulnerable individuals such as newborns, preterm infants, pregnant women, and elderly individuals as well as those patients affected by chronic and immune compromising medical conditions. In addition, these groups are undervaccinated for a number of reasons, including lack of awareness of vaccine-preventable diseases and uncertainty or misconceptions about the safety and efficacy of vaccination by parents and healthcare providers. The presence of these nonresponders/undervaccinated individuals represents a major health and economic burden to society, which will become particularly difficult to address in settings with limited public resources. This review describes innovative and experimental approaches that can help identify specific genomic profiles defining nonresponder individuals for whom specific interventions might be needed. We will provide examples that show how such information can be useful to identify novel biomarkers of safety and immunogenicity for future vaccine trials. Finally, we will discuss how system biology “OMICs” data can be used to design bioinformatic tools to predict the vaccination outcome providing genetic and molecular “signatures” of protective immune response. This strategy may soon enable identification of signatures highly predictive of vaccine safety, immunogenicity, and efficacy/protection thereby informing personalized vaccine interventions in vulnerable populations.

Safety and reliability of electrical actuators are essential for success of all electric and more electric aircrafts (MEA). Torque limiters improve the reliability of electromechanical actuators (EMA) by restricting the amount of force experienced by the actuator drive train components. If transmitted torque in the shaft exceeds a limit, it gives way in a controlled manner. This protects the actuator from potential failure and jamming. In this paper, different types of existing torque limiters are investigated for their suitability in aerospace EMA application and further integration within the electric motor. They classified based on the torque transmission mechanism and each type is described in detail. Operating principle and basic characteristics are reported. Comparative evaluation of commercially available devices is presented. It is found that those based on friction based and permanent magnet are most suitable due to their good torque density, reliability and high speed capability. Further, based on the characteristics, integration of torque limiter within the actuator motor is investigated in this paper. An example actuator motor is considered for integration. Different integration options suitable for the different types of torque limiting devices are described. Reduction in overall volume is shown for the integration options. Such integration can lead to improved reliability as well as higher power density resulting in next-generation actuator electrical drives for MEA.

A Totally Enclosed Fan-Cooled (TEFC) low voltage induction motor has been extensively investigated by means of Computational Fluid Dynamics (CFD) in order to look at detailed airflow and heat transfer modelling of such machines. The typical structure of this machine design, where the heat removal is dependent on both the internal and external features, provides a significant modelling challenge as the internal and external flows and heat transfer must be analysed jointly, creating a complex scenario with multiple dependencies. Local fluid flow and thermal investigations of the most critical regions of the internal and external domains respectively allowed the identification of the best modelling approach and optimal mesh settings in terms of solution accuracy and computational cost. A new modelling approach for more realistic end windings representation, which potentially can be applied to different kinds of machines, was developed in order to achieve more accurate predictions of complex fluid flow and heat transfer phenomena compared to a simplified representation commonly used. The developed methodology allowed different levels of end windings porosity to be investigated with results showing a significant impact on overall fluid flow and thermal predictions. A full thermal CFD 3D model of the selected TEFC motor which includes all internal/external fluid and solid domains, in conjunction with electrical/thermal losses distributed across the whole machine, was then developed. The thermal and airflow analysis performed with the CFD conjugate model allowed an accurate understanding and prediction of the overall machine temperature distribution. Experimental tests were carried out to validate the CFD model developed: temperatures, heat fluxes and torque were measured throughout the tests and data collected were compared to quantities predicted analytically and numerically showing a good agreement with predictions. The validation of the developed CFD model allowed also to identify opportunities to improve the machine performance; enhanced cooling can lead to significant improvements in terms of reduction of temperature dependent losses and materials lifetime. Alternative design improvements were therefore proposed to enhance the overall TEFC machine performance and they were investigated with the numerical model developed. Geometrical modifications of the internal original cooling design, consisting of shaft mounted stirrers in the machine's end region, were considered. The more realistic and detailed end windings representation developed in this work allowed to investigate the impact of higher level of porosity/cavities of the end windings on the overall machine thermal perfomance; results showed how a more accurate and detailed control of the porosity of the end windings can lead to sensible cooling improvements. An alternative external cooling design consisting of a new fan and fan cover was also considered and the impact on the overall machine efficiency was numerically investigated; a 3D printed version of the proposed cooling fan was also manufactured and used for further experimental investigation. The methodology presented in this thesis highlights the capability of CFD to model and simulate very complex geometries and fluid flows, with a high degree of detail and flexibility, allowing accurate predictions of temperature distribution within the electrical machine to be achieved.

The efficacy and safety of aztreonam in the prophylaxis of urinary tract infection following transurethral resection of the prostate (TURP) in patients with preoperatively sterile urine were studied in a multicenter trial including 300 patients at six Italian urology centers. The present report describes the first 192 patients enrolled in the protocol. Aztreonam or placebo was administered to each patient in three doses, which were given at the induction of anesthesia and 8 and 16 hours later. The development of bacteriuria was monitored by cultures of urine obtained before surgery, 3 days later, at removal of the bladder catheter, at discharge from the hospital, and at a follow-up visit 39-46 days after surgery. A febrile peak was observed for 6% of aztreonamtreated patients and for 20.9% of the placebo group (P < .005), while bacteriuria was reported in 17.9% and 59.3% of these groups, respectively (P < .001). From our data, TURP appears to be a clean-contaminated procedure requiring antibiotic prophylaxis, and aztreonam appears to reduce significantly the incidence of postoperative bacteriuria after this surgical procedure.

The metabolic requirements of T cells vary according to their functional state. Matarese and colleagues show that the most functionally active human regulatory T cells are highly glycolytic and that this directly controls expression of a distinct splice variant of the transcription factor Foxp3. Human regulatory T cells (T reg cells) that develop from conventional T cells (T conv cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced T reg cells (iT reg cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iT reg cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2–related suppressive activity of iT reg cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of T reg cells in health and in autoimmunity.

The bulk of RNA produced from the genome of complex organisms consists of a very large number of transcripts lacking protein translational potential and collectively known as noncoding RNAs (ncRNAs). Initially thought to be mere products of spurious transcriptional noise, ncRNAs are now universally recognized as pivotal players in cell regulatory networks across a broad spectrum of biological processes. Owing to their critical regulatory roles, ncRNA dysfunction is closely associated with the etiopathogenesis of various human malignancies, including cancer. As such, ncRNAs represent valuable diagnostic biomarkers as well as potential targets for innovative therapeutic intervention. In this review, we focus on microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), the two most extensively studied classes in the field of ncRNA biology. After outlining key concepts of miRNA and lncRNA biogenesis pathways, we examine their multiple roles in mediating epigenetic regulation of gene expression and chromatin organization. Finally, by providing numerous examples of specific miRNAs and lncRNAs, we discuss how dysregulation of these mechanisms contributes to the onset and/or progression of various human diseases.

Peyronie’s disease (PD) is characterized with formation of fibrous plaques which result in penile deformity, pain, and erectile dysfunction. The aim of this study was to investigate the activation of the intrinsic apoptotic pathway in plaques from PD patients. Tunica albuginea from either PD or control patients was assessed for the expression of bax, bcl-2 and caspases 9 and 3 using immunohistochemistry and by measurement of apoptotic cells using TUNEL assay. Bax overexpression was observed in metaplastic bone tissue, in fibroblasts, and in myofibroblast of plaques from PD patients. Little or no bcl-2 immunostaining was detected in samples from either patients or controls. Caspase 3 immunostaining was very strong in fibrous tissue, in metaplasic bone osteocytes, and in primary ossification center osteoblasts. Moderate caspase 9 immunostaining was seen in fibrous cells plaques and in osteocytes and osteoblasts of primary ossification centers from PD patients. Control samples were negative for caspase 9 immunostaining. In PD patients the TUNEL immunoassay showed intense immunostaining of fibroblasts and myofibroblasts, the absence of apoptotic cells in metaplasic bone tissue and on the border between fibrous and metaplastic bone tissue. Apoptosis occurs in stabilized PD plaques and is partly induced by the intrinsic pathway.