Neural precursor cells tune striatal connectivity through the release of IGFBPL1

The adult brain retains over life endogenous neural stem/precursor cells (eNPCs) within the subventricular zone (SVZ). Whether or not these cells exert physiological functions is still unclear. In the present work, we provide evidence that SVZ-eNPCs tune structural, electrophysiological, and behavioural aspects of striatal function via secretion of insulin-like growth factor binding protein-like 1 (IGFBPL1). In mice, selective ablation of SVZ-eNPCs or selective abrogation of IGFBPL1 determined an impairment of striatal medium spiny neuron morphology, a higher failure rate in GABAergic transmission mediated by fast-spiking interneurons, and striatum-related behavioural dysfunctions. We also found IGFBPL1 expression in the human SVZ, foetal and induced-pluripotent stem cell-derived NPCs. Finally, we found a significant correlation between SVZ damage, reduction of striatum volume, and impairment of information processing speed in neurological patients. Our results highlight the physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Enhanced-performance integrated Resonant Switched-Capacitor and Buck DC-DC converters for application in extreme radiation and magnetic field environments

DC-DC converters based on Application Specific Integrated Circuits (ASICs) have been developed in this doctoral work for the High-Luminosity Large Hadron Collider (HL-LHC) experiments at CERN. They step down the voltage from a 2.5 V line and supply a load current up to 3 A. The main focus has been the miniaturization of the converters while maintaining high efficiency, together with the improvement of the dynamic performance and the minimization of the impact of substrate parasitic devices. These are challenges that industry and research are facing to power modern microprocessors, with the aim of minimizing the system volume, cost and power consumption, while guaranteeing good regulation performance. Miniaturization is a key requirement for application in the HL-LHC experiments, since any added material is detrimental for the physics performance. In addition, the converters must be tolerant to a high magnetic field (up to 4 T) and to ultra-high levels of radiation. Tolerance to the magnetic field is achieved by employing air-core inductors (which are the bulkiest components on the board), while radiation-hard ASICs have been designed in this work in a commercial 130 nm CMOS technology by extensively applying hardening by design techniques. Converters using two different architectures have been designed: a buck converter, which had been identified in a previous work as a good option to achieve high efficiency and low mass, and a Resonant Switched-Capacitor (ReSC) converter, which can further increase the power density while keeping high efficiency. A novel dual-edge pulse width modulator for the buck converter that has improved dynamic performance compared to conventional solutions has been designed and implemented. Its small-signal response has been modeled, and the model has been validated by measurements. In addition, this thesis proposes an integrated system that monitors in real-time the voltage stress experienced by the devices of the buck converter and adjusts its operation accordingly, in order to guarantee the required reliability, while maximizing the efficiency. The main building block of this system has been designed and has proved to be fully functional. A substrate-currents-aware characterization method that allows the evaluation of the impact of substrate parasitic devices on the circuit performance and reliability has been also devised, and it has been applied to select the best floor-plan for the buck converter. A novel control scheme that optimizes the efficiency of the ReSC converter for the whole load current range by adopting different operation modes has been proposed and implemented. This thesis reports the steady-state analysis of each mode and a small-signal model for one of them. The buck converter uses a 100 nH inductor, and the last prototype shows a peak efficiency of 88.4% for the 2.5 V-to-1.2 V conversion. It complies with the radiation specifications, and mass production will soon start. The designed prototype ReSC converter employs a 12 nH inductor, and its area occupancy and thickness are respectively 20% and 55% lower than the buck. Its efficiency is larger than that of the buck converter in a range of conversion ratios and load currents, reaching a peak efficiency of 91.4% for the 2.5 V-to-1.2 V conversion. Radiation tests have highlighted that the converter complies with Total Ionizing Dose specifications. By introducing a few improvements, a future prototype could be close to production readiness

Knowledge Representation in Virtual Teams: A Perspective Approach for Synthetic Worlds, in Collaborative Networks for a Sustainable

Abstract. Thanks to ICT, new organizational forms are emerging that keep the pace of an increasingly demanding competitive environment. Among them, Virtual Enterprises (VEs) and Virtual Teams (VTs) represent two challenging organizational forms from the point of view of effective management. An open issue in VEs/VTs is the social and economical sustainability of knowledge sharing in virtual environments, which is often underestimated. We address it from the point of view of "virtual worlds" and developed a prototypal solution that facilitates the cooperative building/sharing of knowledge representation

Regulated Resonant Switched-Capacitor Point-of-Load Converter Architecture and Modeling

This article presents a novel control system for a regulated resonant switched-capacitor point-of-load converter, together with its steady-state and small-signal analyses. The output voltage is regulated through a combined frequency/phase shift on-chip controller that operates, thanks to a zero-crossing detector for the tank current. By using such a control technique, voltage regulation can be achieved for a wide range of conversion ratios. Different operation modes are adopted to maximize the efficiency at every load condition. A prototype based on an ASIC developed in a 130-nm CMOS technology has been designed, which achieves the 2.5 to 0.8-1.35 V conversion and supplies up to 3 A. The external resonant tank is composed of a 12 nH air-core inductor and a 4.7 μF capacitor in a 0805 package, achieving high power density. The converter efficiency is demonstrated to be similar to that of an integrated buck converter designed for the same application, whereas the inductor size is reduced by a factor of eight

The bPOL12V DCDC converter for HL-LHC trackers: towards production readiness

We present the electrical and radiation characterisation of the most recent prototype of the bPOL12V DCDC converter, a stacked assembly of two ASICs inside a QFN32 package. The use of a reference voltage generator chip in 130nm CMOS on top of the ASIC integrating the control system and power train enables improved radiation tolerance and the trimming of the output voltage during the production phase. Prototype samples have been exposed to X-rays, proton and neutron irradiations, as well as subject to long-term electrical stress to evaluate their reliability in the application. The results confirm that only a few minor modifications are required to achieve production readiness

Substrate-currents-aware characterization of an integrated buck DC/DC converter for floor-plan optimization

The performance of integrated DC/DC converters is affected by substrate parasitic devices, such as bipolar transistors and thyristors: these devices cause enhanced substrate noise that can lead to the malfunctioning of the control circuitry, they degrade the efficiency, and thyristors can even cause the failure of the converter by latch-up. Due to the lack of software tools for the evaluation of the effects of such parasitic devices in the design phase, often only qualitative counter-measures are taken. This can lead to sub-optimal floor-plans in terms of substrate noise immunity of the control circuitry, power efficiency and area consumption. Being the effects of the substrate parasitic devices often overlooked in the characterization phase, in this work we propose a systematic approach to evaluate such effects in a buck converter. Such method can be used to determine the best floor-plan among several options. Finally, we apply the method to compare two different floor-plans of an integrated buck converter designed in a 130 nm technology

A Reliability and Efficiency Optimization System for Hard-Switching DC/DC Converters

The Large Hadron Collider experiments at CERN will use power distribution schemes relying on integrated buck DCIDC converters. Due to the radiation-hardness requirements, the devices used for the development of such converters will have a voltage rating which is close to the converters' input voltage. The voltage spikes generated during the hard-switching operation can affect the reliability of such low-voltage MOSFETs. A fixed and sufficiently small gate driver current for the high-side switch could be used to guarantee the reliable operation even in the worst-case conditions in terms of input voltage, output current, temperature and process variations. Nevertheless, this would result in a suboptimal efficiency in all the other working conditions. This work presents an integrated system than monitors in real-time the voltage stress, and adjusts the gate driver current to achieve maximum efficiency in all conditions, while ensuring compliance with the reliability specifications. A buck converter including the voltage peak detector and an adjustable gate driver current has been designed in a 130 nm technology, demonstrating the functionality of the voltage stress monitoring system

bPOL48V, a rad-hard 48V DC/DC Converter for Space and HEP Applications

A radiation-hard DC/DC converter has been developed at CERN, which tolerates a higher input voltage (up to 48 V) and provides a larger output power than existing solutions. It is called bPOL48V, and it employs a commercial Gallium Nitride power device and a CERN-developed control ASIC (GaN_Controller). bPOL48V can provide 10 A of output current at efficiencies higher than 95%, it features a radiation tolerance for space and high energy physics (HEP) requirements, being able to withstand 228 MRad for TID, LET =88.8 MeV·cm2/mg for SEE, 2.23. 1014p/cm2for protons irradiation, and 4. 1014n/cm2neutrons irradiation