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Single-Photon Avalanche Diodes (SPADs) are p–n junctions operated in Geiger Mode by applying a reverse bias above the breakdown voltage. SPADs have the advantage of featuring single photon sensitivity with timing resolution in the picoseconds range. Nevertheless, their relatively high Dark Count Rate (DCR) is a major issue for charged particle detection, especially when it is much higher than the incoming particle rate. To tackle this issue, we have developed a 3D Silicon Coincidence Avalanche Detector (3D-SiCAD). This novel device implements two vertically aligned SPADs featuring on-chip electronics for the detection of coincident avalanche events occurring on both SPADs. Such a coincidence detection mode allows an efficient discrimination of events related to an incoming charged particle (producing a quasi-simultaneous activation of both SPADs) from dark counts occurring independently on each SPAD. A 3D-SiCAD detector prototype has been fabricated in CMOS technology adopting a 3D flip-chip integration technique, and the main results of its characterization are reported in this work. The particle detection efficiency and noise rejection capability for this novel device have been evaluated by means of a β − strontium-90 radioactive source. Moreover the impact of the main operating parameters (i.e. the hold-off time, the coincidence window duration, the SPAD excess bias voltage) over the particle detection efficiency has been studied. Measurements have been performed with different β − particles rates and show that a 3D-SiCAD device outperforms single SPAD detectors: the former is indeed capable to detect particle rates much lower than the individual DCR observed in a single SPAD-based detectors (i.e. 2 to 3 orders of magnitudes lower).

We propose an application-specified integrated circuit (ASIC)-based vibration damping system implementing a semiactive controlling method called synchronized switch damping on inductor (SSDI). The ASIC integrates high-voltage switches and diodes for an “energy-extracting” passive LC shunt circuit and a controlling part for synchronous voltage inversion on the piezoelectric transducer. The controlling part has two channels, each including a range-adaptive voltage divider with protection and a peak detector with switch-control output. The system has been tested with both cantilever beam and three-side-clamped-plate structures. Cantilever beam testing shows a 15 dB damping in forced harmonic regime and a fivefold damping rate in pulsed-excitation transient response. For the three-side-clamped-plate case, wideband SSDI damping effects are observed. The damping efficiency for each mode depends on the electromechanical coupling factor and the mapping of the piezoelectric-insert damping zones. It also depends on the excitation level, and begins to increase rapidly with vibration magnitude when the piezoelectric transducer's voltage peaks exceed a certain threshold voltage (~ 0.5 V for the system).

A cyclostationarity-based analytical model for noise analysis of charge amplification with correlated double sampling (CDS) is proposed. It is established by signal description and transformation with considerations of input referred noise sources. It predicts that CDS operation has different noise effects: it suppresses reset noise and attenuates 1/f noise from the equivalent input noise voltage, but it has no noise-reduction effect on the input referred noise current. Parametrical analysis can also be performed by using this model. For example, by varying integration duration, the signal-to-noise ratio (SNR) will first be proportional to t int, then to t int ½ , and finally limited by the 1/f noise component becoming predominant. This proposed model is validated by comparison of analysis results with those from temporal noise analysis using SpectreRF of Cadence? CAD tool. Unlike time-hungry temporal noise analysis, this model provides rapid results.

The goal of this paper is to provide some useful design guidelines at the device level regarding the main challenges to be typically faced in the design and integration of Geiger-mode avalanche diodes in a standard CMOS process. Different techniques are found in literature in order to avoid premature edge breakdown with the aim of limiting the electric field at the edges to be weaker than in the multiplication region. In this article, the use of such techniques, the conditions where they can effectively work and above all their limitations are studied by means of TCAD simulations for various diode architectures. Additionally, the noise performance is discussed by focusing on the band-to-band tunneling and shallow trench isolation enhanced dark count rates. Geiger-mode bias techniques as well as a synthesis on the pros and cons of the various avalanche diode architectures are finally presented aiming at facilitating future design choices.

In this paper, a time-integration based passive quenching — active recharge circuit for Geiger-mode avalanche diodes has been proposed with the aim of minimizing the avalanche charge and providing a hold-off time tunable within wide range. These are indeed important features to be taken into account in the design of the avalanche diode quenching — reset electronics. Furthermore a hold-off time tunable within a wide range is typically desirable in every application where a full characterization of the device dark count rate is required. A correct operation of the proposed circuit, designed in a commercial High-Voltage CMOS 0.35um technology, is assessed through circuit simulations as well as Monte Carlo analysis in the Cadence Environment.

International audience; In this paper a preliminary study of coincidence Avalanche Pixel Sensors (APiX) for High Energy Physics (HEP) applications is presented. In this preliminary work, some PEB prevention techniques found in literature have been studied by TCAD simulations adopting 2D Cylindrical geometrical models and 130nm CMOS process technological data.

International audience

For improving sensitivity of nuclear magnetic resonance (NMR) measurements, an in-field preamplifier in a low-cost CMOS process is presented. It is based on a second-generation positive current conveyor (CCII+), with an impedance-matching output stage. The circuit has been designed with optimization of key performances, such as bandwidth, noise, and offset voltage. There have also been precautions taken against potential effect of strong magnetic field under which the circuit should operate. The designed preamplifier has a voltage gain of 15 dB and a bandwidth of 100 MHz. After fabrication of the circuit, we have carried out testing work, including in-field circuit test and characterization of MOS transistors. Under 2-T magnetic field, there have not been substantial changes in overall circuit performances compared to results obtained by post-layout simulations. For an experiment of NMR measurements with and without in-field preamplifier, the circuit is coupled with a receiver micro-coil. The experiment has been to detect protons at 85.13-MHz resonance frequency under 2-T magnetic field with water sample. The obtained results have shown a 14-dB signal-to-noise ratio improvement when the preamplifier is associated with the receiver coil.

An important limitation in the classical energy harvesters based on cantilever beam structure is its monodirectional sensibility. The external excitation must generate an orthogonal acceleration from the beam plane to induced flexural deformation. If the direction of the excitation deviates from this privileged direction, the harvester output power is drastically reduced. This point is obviously very restrictive in the case of an arbitrary excitation direction induced for example by human body movements or vehicles vibrations. In order to overcome this issue of the conventional resonant cantilever configuration with seismic mass, a multidirectional harvester is introduced here by the authors. The multidirectional ability relies on the exploitation of 3 degenerate structural vibration modes where each of them is induced by the corresponding component of the acceleration vector. This specific structure has been already used for 3 axis accelerometers but the approach is here totally revisited because the final functional goal is different. This paper presents the principle and the design considerations of such multidirectional piezoelectric energy harvester. A finite element model has been used for the harvester optimisation. It has been shown that the seismic mass is a relevant parameter for the modes tuning because the resonant frequency of the 1st exploited flexural mode directly depends on the mass whereas the resonance frequency of the 2nd flexural mode depends on its moment of inertia. A simplified centimetric prototype limited to a two orthogonal direction sensibility has permitted to valid the theoretical approach.

Sympathetic neurons undergo programmed cell death (PCD) upon deprivation of nerve growth factor (NGF). PCD of neurons is blocked by inhibitors of the interleukin-1beta converting enzyme (ICE)/Ced-3-like cysteine protease, indicating involvement of this class of proteases in the cell death programme. Here we demonstrate that the proteolytic activities of the proteasome are also essential in PCD of neurons. Nanomolar concentrations of several proteasome inhibitors, including the highly selective inhibitor lactacystin, not only prolonged survival of NGF-deprived neurons but also prevented processing of poly(ADP-ribose) polymerase which is known to be cleaved by an ICE/Ced-3 family member during PCD. These results demonstrate that the proteasome is a key regulator of neuronal PCD and that, within this process, it is involved upstream of proteases of the ICE/Ced-3 family. This order of events was confirmed in macrophages where lactacystin inhibited the proteolytic activation of precursor ICE and the subsequent generation of active interleukin-1beta.

The p53 tumour suppressor gene plays a major role in controlling cell cycle and apoptosis in many different cell types. Here we have examined the status and the potential apoptosis inducing activity of p53 in sympathetic neurons. The p53 protein is expressed in rat sympathetic neurons cultured in the presence of NGF. The protein is not upregulated when these neurons are induced to die upon NGF deprivation. Over-expression of wild-type human p53 in neurons cultured in the presence of NGF does not trigger apoptosis nor does it accelerate apoptosis when the neurons are deprived of NGF. Finally endogenous p53 expression is not necessary for neuronal cell death triggered by NGF deprivation since neurons prepared from p53 knockout mice undergo normal cell death upon NGF deprivation. Our results suggest that p53 may have an unknown function in post-mitotic neurons which is distinct from its well described roles in apoptosis or cell cycle control.

For positron emission tomography scanners requiring 511 keV two-photon detection, we present a charge-sensitive amplifier (CSA) to be associated with an avalanche photodiode (APD) or photo-multiplier tube (PMT). It is a two-stage structure. The input stage consists of a folded-cascode fully differential circuit and a common-mode feedback (CMFB) circuit. Feedforward technique is implemented to enhance frequency performance. The output stage employs complementary source followers. The amplifier has been designed in a 0.35-μm BiCMOS process with analysis and optimization of noise and speed performances. Testing of fabricated prototypes has given results in good agreement with post-layout simulated ones. The evaluated characteristics of the circuit are: 26 ns peaking time for pulsed stimulus, 2000 electron equivalent input noise charge (ENC) for a detector capacitance up to 80 pF and 136 mW power consumption from a 3.5-V supply.

A new cyclostationarity-based analytical model for noise analysis of a charge amplifier followed by a correlated double sampling (CDS) circuit is proposed. It determines output noise (power spectral density and squared voltage) resulting from input noise voltages and currents. Model validation is performed by comparing the obtained results with those of temporal noise simulations. This model allows analysis of consequences of CDS and integration duration on noise contributions. It predicts that CDS does not suppress or attenuate effect of input current sources. In the case of 1/f input noise current, the SNR can not be improved by increasing the integration duration.

This article deals with the analysis of small sample volume by using a planar microcoil and a micromachined cavity. This microcoil is used as a nuclear magnetic resonance (NMR) radio frequency detection coil in order to perform in vitro NMR analysis of the sample introduced into the microcavity. It is a real challenging task to develop microsystem for NMR spectrum extraction for smaller and smaller sample volume. Moreover, it is advantageous that these microsystems could be integrated in a Micro Total Analysing System (-TAS) as an analysing tool. In this paper, NMR theory, description, fabrication process and electrical characterization of planar microcoils receiver are described. Results obtained on NMR microspectroscopy experiments have been performed on water and ethanol, using a 1 mm diameter planar coil. This microcoil is tuned and matched at 85.13 MHz which is the Larmor frequency of proton in a 2 T magnetic field.

A wideband amplifier design for NMR signal application is described in this paper. The amplifier is based on current-conveyors and benefits from several advantages: large bandwidth, low noise, low offset and low number of discrete components needed for the implementation. In this application, current conveyor is based on the voltage to current conversion using op-amp and current mirror. The amplifier is designed to operate up to 500 MHz using a standard CMOS technology. This paper describes the structure, the principle, the simulation results and practical test of this amplifier.

This paper describes a semi-integrated analog to digital sigma-delta modulator. The very sensitive loop filter front-end is external, but the main part of the converter is integrated in an ASIC. Off-chip, a few high performance operational amplifiers with some passive components are required. Due to design constrains, the loop filter is mixed continuous and discrete time. The design procedure of such modulators is based on a discrete-time prototype.

Structural changes of the male rat aorta were followed from birth to old age in male and female rats. In males, the vessel media width and area progressively increase concomitantly with a decrease of nuclei density during ageing, suggesting an hypertrophy of the smooth muscle cells. These correlations were however not evidenced in females. TUNEL-positive cells were found in media of 4 and 6 months in both sexes, mainly on the luminal side and in the adventitia. When biochemical markers were investigated with immunohistochemistry, media was uniformly stained by the anti-vimentin and anti-alpha-smooth actin at all stages investigated. On the contrary, the surface of media stained with anti-desmin decreased during ageing, especially on the luminal side. As observed with electron microscopy, with ageing the endothelium is replaced by small cells with pseudopodia adhering to the vestigial elastic lamina and infiltrating into the extracellular matrix left after the disappearance of smooth muscle cells. In addition, in the older rats (25-29 months) the elastic laminae are completely disorganised. Hypertrophy of the smooth muscle cells was confirmed by this approach. In parallel to this study, perivascular peptidergic innervation was stained with antibodies against calcitonin gene-related peptide (CGRP), substance P (SP), neuropeptide Y (NPY), and vasoactive intestinal polypeptide (VIP) at different ages during the whole life of rats. These peptides are present in stages younger than 6 months, then gradually disappear. In one year animals and older, the peptidergic innervation has totally disappeared. We discuss the possible role of peptidergic innervation in the control of the vessel wall cellular stability during ageing.

On the basis of compelling preclinical data in cats and dogs we initiated a clinical gene therapy study in nine patients with advanced solid tumors using xenogeneic fibroblasts secreting human IL-2 (Vero-IL-2 cells). Cohorts of three successive patients with tumors accessible to CT- or ultrasound-guided injection were treated repeatedly with 5 x 10(5), 5 x 10(6), or 5 x 10(7) Vero-IL-2 cells. Endpoints of the study were feasibility, toxicity, and clinical and biological effects of this novel approach to immunotherapy of cancer. Histopathological, immunological and molecular analyses were performed on biopsy specimens of tumors and blood samples from before, during and after treatment. Low levels of serum antibodies to Vero cells developed in 2/9 patients. Analysis of tumor biopsies showed increased expression of CD3 mRNA and enhanced tumor infiltration with varying lymphocyte subpopulations after treatment. In addition, monoclonal alterations of the TCR repertoire of blood and tumor lymphocytes were observed. Treatment was well tolerated and toxicity consisted of transient fever in one patient and short-lived, mild itching and erythema in two others. One patient with soft tissue sarcoma showed a more than 90% and more than 50% reduction of the volume of two distant, non-injected metastases, respectively, lasting for 22+ months. Four other patients showed stabilization of their disease for three to nine months, among whom was a patient with melanoma who developed marked vitiligo. We conclude that repeated injection of up to 5 x 10(7) Vero-IL-2 cells was safe and showed biological and clinical activity in heavily pretreated patients with advanced solid tumors. Further evaluation of intratumoral application of Vero-IL-2 seems warranted.

The presence of one or two apoliprotein E4 (apoE4) alleles constitutes a major risk factor for Alzheimer's disease (AD) and coronary heart disease (CHD). Numerous observations have suggested that misregulation of proteases may be instrumental in both diseases. Tissue-type plasminogen activator (tPA) has been recently demonstrated to play a key role in neuronal plasticity and in experimental neurodegeneration. One receptor for the ApoE protein is the LRP/alpha 2 macroglobulin receptor, which also binds to and endocytoses tPA and plasminogen activator inhibitor I (PAI-1). Here we tested whether the apoE genotype has an influence on the plasma levels of these proteins. We demonstrate that there is no difference in plasma levels of tPA- and PAI-1-antigens between middled-aged individuals with one apoE4 allele and those having none. This suggests that the impact of apoE4 on Alzheimer's disease is not the result of altered clearance of tPA or PAI-1 by the LRP receptor.

The p53 tumour suppressor gene plays a major role in controlling cell cycle and apoptosis in many different cell types. Here we have examined the status and the potential apoptosis inducing activity of p53 in sympathetic neurons. The p53 protein is expressed in rat sympathetic neurons cultured in the presence of NGF. The protein is not upregulated when these neurons are induced to die upon NGF deprivation. Over-expression of wild-type human p53 in neurons cultured in the presence of NGF does not trigger apoptosis nor does it accelerate apoptosis when the neurons are deprived of NGF. Finally endogenous p53 expression is not necessary for neuronal cell death triggered by NGF deprivation since neurons prepared from p53 knockout mice undergo normal cell death upon NGF deprivation. Our results suggest that p53 may have an unknown function in post-mitotic neurons which is distinct from its well described roles in apoptosis or cell cycle control.

Analog to digital converters using the /spl Sigma//spl Delta/ technique have been realized in switched-capacitor form to implement basic low-cost 14 to 16 bit audio data-converters, and resolutions of up to 20 bits can be achieved. Current memory based realizations have so far been disappointing, with most realizations exhibiting performances in the 10 to 12 bit range. Only recently, a 14-bit modulator has been reported. Behavioural simulations with sophisticated model have shown that the main limitations come from the inherent nonlinearity of the current memory cell, and from mismatch errors in some modulator architectures with multiple signal paths. A new architecture for /spl Sigma//spl Delta/ modulators, based on an analog to digital symmetry is presented. 2nd and 3rd order modulators show promising results in terms of signal reduction in the delay cells.