Multi-Channel Gating Chip in 0.18 µm High-Voltage CMOS for Quantum Applications.

A gating circuit for a photonic quantum simulator is introduced. The gating circuit uses a large excess bias voltage of up to 9.9 V and an integrated single-photon avalanche diode (SPAD). Nine channels are monolithically implemented in an application-specific integrated circuit (ASIC) including nine SPADs using 0.18 µm high-voltage CMOS technology. The gating circuit achieves rise and fall times of 480 ps and 280 ps, respectively, and a minimum full-width-at-half-maximum pulse width of 1.26 ns. Thanks to a fast and sensitive comparator, a detection threshold for avalanche events of less than 100 mV is possible. The power consumption of all nine channels is about 250 mW in total. This gating chip is used to characterize the integrated SPADs. A photon detection probability of around 50% at 9.9 V excess bias and for a wavelength of 635 nm is found.

Area and Bandwidth Enhancement of an n+/p-Well Dot Avalanche Photodiode in 0.35 µm CMOS Technology.

This paper presents a CMOS-integrated dot avalanche photodiode (dot-APD) that features a small central n+/p-well hemispherical cathode/p-well structure circularly surrounded by an anode ring. The dot-APD enables wide hemispherical depletion, charge collection from a large volume, and a small multiplication region. These features result in a large light-sensitive area, high responsivity and bandwidth, and exceptionally low junction capacitance. The active area can be further expanded using a multi-dot structure, which is an array of several cathode/p-well dots with a shared anode. Experimental results show that a 5 × 5 multi-dot APD with an active area of 70 µm × 70 µm achieves a bandwidth of 1.8 GHz, a responsivity of 9.7 A/W, and a capacitance of 27 fF. The structure of the multi-dot APD allows for the design of APDs in various sizes that offer high bandwidth and responsivity as an optical detector for various applications while still maintaining a small capacitance.

Indirect Time-of-Flight with GHz Correlation Frequency and Integrated SPAD Reaching Sub-100 µm Precision in 0.35 µm CMOS.

The purpose of this work is to prove the suitability of integrated single-photon avalanche diode (SPAD)-based indirect time-of-flight (iTOF) for sub-100 µm precision depth sensing using a correlation approach with GHz modulation frequencies. For this purpose, a prototype containing a single pixel consisting of an integrated SPAD, quenching circuit, and two independent correlator circuits was fabricated in a 0.35 µm CMOS process and characterized. It achieved a precision of 70 µm and a nonlinearity of less than 200 µm at a received signal power of less than 100 pW. Sub-mm precision was achieved with a signal power of less than 200 fW. These results and the simplicity of our correlation approach underline the great potential of SPAD-based iTOF for future depth sensing applications.

Photon detection probability enhancement using an anti-reflection coating in CMOS-based SPADs.

This work presents a simulation and experimental study of the photon detection probability (PDP) enhancement in CMOS single-photon avalanche diodes (SPADs) using an anti-reflection coating (ARC) above the sensitive area. It is shown how the ARC layer can improve the PDP, not only by improving the optical transmission, but also by eliminating the penetration of the standing wave into a shallow region close to the silicon surface, where the multiplication region of the SPAD is formed. Furthermore, the appropriate ARC layer thickness corresponding to maximum PDP enhancement at different wavelengths over the visible spectrum is extracted to provide insight regarding the ARC selection if different ARC thicknesses are available within the CMOS process.

Noise and Breakdown Characterization of SPAD Detectors with Time-Gated Photon-Counting Operation.

Being ready-to-detect over a certain portion of time makes the time-gated single-photon avalanche diode (SPAD) an attractive candidate for low-noise photon-counting applications. A careful SPAD noise and performance characterization, however, is critical to avoid time-consuming experimental optimization and redesign iterations for such applications. Here, we present an extensive empirical study of the breakdown voltage, as well as the dark-count and afterpulsing noise mechanisms for a fully integrated time-gated SPAD detector in 0.35-µm CMOS based on experimental data acquired in a dark condition. An "effective" SPAD breakdown voltage is introduced to enable efficient characterization and modeling of the dark-count and afterpulsing probabilities with respect to the excess bias voltage and the gating duration time. The presented breakdown and noise models will allow for accurate modeling and optimization of SPAD-based detector designs, where the SPAD noise can impose severe trade-offs with speed and sensitivity as is shown via an example.

Integrated fiber optical receiver reducing the gap to the quantum limit.

Experimental results of a single-photon avalanche diode (SPAD) based optical fiber receiver integrated in 0.35 µm PIN-photodiode CMOS technology are presented. To cope with the parasitic effects of SPADs an array of four receivers is implemented. The SPADs consist of a multiplication zone and a separate thick absorption zone to achieve a high photon detection probability (PDP). In addition cascoded quenchers allow to use a quenching voltage of twice the usual supply voltage, i.e. 6.6 V instead of 3.3 V, in order to increase the PDP further. Measurements result in sensitivities of -55.7 dBm at a data rate of 50 Mbit/s and -51.6 dBm at 100 Mbit/s for a wavelength of 635 nm and a bit-error ratio of 2 × 10-3, which is sufficient to perform error correction. These sensitivities are better than those of linear-mode APD receivers integrated in the same CMOS technology. These results are a major advance towards direct detection optical receivers working close to the quantum limit.

An infrastructure for accurate characterization of single-event transients in digital circuits.

We present the architecture and a detailed pre-fabrication analysis of a digital measurement ASIC facilitating long-term irradiation experiments of basic asynchronous circuits, which also demonstrates the suitability of the general approach for obtaining accurate radiation failure models developed in our FATAL project. Our ASIC design combines radiation targets like Muller C-elements and elastic pipelines as well as standard combinational gates and flip-flops with an elaborate on-chip measurement infrastructure. Major architectural challenges result from the fact that the latter must operate reliably under the same radiation conditions the target circuits are exposed to, without wasting precious die area for a rad-hard design. A measurement architecture based on multiple non-rad-hard counters is used, which we show to be resilient against double faults, as well as many triple and even higher-multiplicity faults. The design evaluation is done by means of comprehensive fault injection experiments, which are based on detailed Spice models of the target circuits in conjunction with a standard double-exponential current injection model for single-event transients (SET). To be as accurate as possible, the parameters of this current model have been aligned with results obtained from 3D device simulation models, which have in turn been validated and calibrated using micro-beam radiation experiments at the GSI in Darmstadt, Germany. For the latter, target circuits instrumented with high-speed sense amplifiers have been used for analog SET recording. Together with a probabilistic analysis of the sustainable particle flow rates, based on a detailed area analysis and experimental cross-section data, we can conclude that the proposed architecture will indeed sustain significant target hit rates, without exceeding the resilience bound of the measurement infrastructure.

Clinical significance of genetic aberrations in secondary acute myeloid leukemia.

The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% ± 9.4% vs. 35.4% ± 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.33-5.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms.

Dynamic but not constitutive association of calmodulin with rat TRPV6 channels enables fine tuning of Ca2+-dependent inactivation.

The Ca(2+)-selective TRPV6 as well as the L-type Ca(2+) channel are regulated by the Ca(2+)-binding protein calmodulin (CaM). Here, we investigated the interaction of CaM with rat (r)TRPV6 in response to alterations of intracellular Ca(2+), employing Ca(2+)-imaging and patch-clamp techniques. Additionally, confocal Förster resonance energy transfer (FRET) microscopy on living cells was utilized as a key method to visualize in vivo protein-protein interactions essential for CaM regulation of rTRPV6 activity. The effects of overexpressed CaM or its Ca(2+)-insensitive mutant (CaM(MUT)) was probed on various rTRPV6 mutants and fragments in an attempt to elucidate the molecular mechanism of Ca(2+)/CaM-dependent regulation and to pinpoint the physiologically relevant rTRPV6-CaM interaction site. A significant reduction of rTRPV6 activity, as well as an increase in current inactivation, were observed when CaM was overexpressed in addition to endogenous CaM. The Ca(2+)-insensitive CaM(MUT), however, failed to affect rTRPV6-derived currents. Accordingly, live cell confocal FRET microscopy revealed a robust interaction for CaM but not CaM(MUT) with rTRPV6, suggesting a strict Ca(2+) dependence for their association. Indeed, interaction of rTRPV6 or its C terminus with CaM increased with rising intracellular Ca(2+) levels, as observed by dynamic FRET measurements. An rTRPV6Delta(695-727) mutant with the very C-terminal end deleted, yielded Ca(2+) currents with a markedly reduced inactivation in accordance with a lack of CaM interaction as substantiated by FRET microscopy. These results, in contrast with those for CaM-dependent L-type Ca(2+) channel inactivation, demonstrate a dynamic association of CaM with the very C-terminal end of rTRPV6 (aa 695-727), and this enables acceleration of the rate of rTRPV6 current inactivation with increasing intracellular CaM concentrations.

CaT1 knock-down strategies fail to affect CRAC channels in mucosal-type mast cells.

CaT1, the calcium transport protein 1 encoded by TRPV6, is able to generate a Ca(2+) conductance similar but not identical to the classical CRAC current in mucosal-type mast cells. Here we show that CaT1-derived Ca(2+) entry into HEK293 cells is effectively inhibited either by expression of various dominant negative N-terminal fragments of CaT1 (N(334)-CaT1, N(198)-CaT1 and N(154)-CaT1) or by antisense suppression. By contrast, the endogenous CRAC current of the mast cells was unaffected by CaT1 antisense and siRNA knockdown but markedly suppressed by two (N(334)-CaT1, N(198)-CaT1) of the dominant negative N-CaT1 fragments. Inhibition of CRAC current was not an unspecific, toxic effect, as inward rectifier K(+) and MagNuM currents of the mast cells were not significantly affected by these N-CaT1 fragments. The shortest N(154)-CaT1 fragment inhibited CaT1-derived currents in mast cells, but failed to inhibit CRAC currents. Thus, the structural requirements of rCaT N-terminal fragments for inhibition of rCaT1 and CRAC channels are different. These results together with the lack of CaT1 antisense and siRNA effects on currents render it unlikely that CaT1 is a component of native CRAC channels in mast cells. The data further demonstrate a novel strategy for CRAC current inhibition by an N-terminal structure of CaT1.