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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Resistance to oxyimino-cephalosporins conferred by an alternative mechanism of hydrolysis by the Acinetobacter -derived cephalosporinase-33 (ADC-33), a class C β-lactamase present in carbapenem-resistant Acinetobacter baumannii (CR Ab )

ABSTRACT Antimicrobial resistance inAcinetobacter baumanniiis partly mediated by chromosomal class C β-lactamases, theAcinetobacter-derived cephalosporinases (ADCs). Recently, a growing number of emerging variants were described, expanding this threat. Consistent with other β-lactamases, one of the main areas of variance exists in the Ω-loop region near the site of cephalosporin binding. Interestingly, a common alanine duplication (Adup) is found in this region. Herein, we studied specific Adup variants expressed in a uniformEscherichia coligenetic background that demonstrated high-level resistance to multiple oxyimino-cephalosporins. For ceftolozane and ceftazidime, the Adup ADCs significantly increased levels of resistance (minimum inhibitory concentration [MIC] ≥ 512 µg/mL and MIC ≥ 1,024 µg/mL, respectively). These observations were consistent with the increasedk cat /K M for ceftazidime. For cefiderocol, three Adup variants exhibited increased MICs and increasedk cat /K M for this compound. Timed electrospray ionization mass spectrometry demonstrated stable cephalosporin:ADC adducts with ADC-30 (non-Adup), but not with ADC-33 (Adup), consistent with turnover. The X-ray crystal structure of Adup variant ADC-33 in complex with ceftazidime was determined (1.57 Å resolution) and suggests that increased turnover is facilitated by conformational changes (shift in Tyr221 and orientation of the oxyimino portion of the R1 side chain) and repositioning of water in the active site. These changes appear to favor substrate-assisted catalysis as an alternative mechanism to base-assisted catalysis. These studies also provide unprecedented insight into the mechanism underlying oxyimino-cephalosporin hydrolysis by expanded-spectrum ADC β-lactamases and possibly other class C β-lactamases, which is of critical importance to future drug design. IMPORTANCE The characterization of emergingAcinetobacter-derived cephalosporinase (ADC) variants is necessary to understand the increasing resistance to β-lactam antibiotics inAcinetobacterspp. In this study, cefiderocol retains effectiveness against ADC variants with and without an Ω-loop alanine duplication (Adup). However, the presence of the Adup appears to introduce loop flexibility and structural alterations resulting in increased resistance and steady-state turnover of larger cephalosporins. Further characterization provides unprecedented insight into the mechanism of cephalosporin hydrolysis by ADC β-lactamases and supports a concomitant increase in ADC structural flexibility and cephalosporin affinity that leads to more efficient hydrolysis. In addition, the crystal structure of ADC-33 in complex with ceftazidime is consistent with a substrate-assisted catalysis mechanism. The structural differences in the ADC-33 active site leading to ceftazidime catalysis provide a better understanding of β-lactamase Adup variants and open important opportunities for future drug design and development.

Microbiology↗
NASA NTRS2003

Capacitor-Chain Successive-Approximation ADC

A proposed successive-approximation analog-to-digital converter (ADC) would contain a capacitively terminated chain of identical capacitor cells. Like a conventional successive-approximation ADC containing a bank of binary-scaled capacitors, the proposed ADC would store an input voltage on a sample-and-hold capacitor and would digitize the stored input voltage by finding the closest match between this voltage and a capacitively generated sum of binary fractions of a reference voltage (Vref). However, the proposed capacitor-chain ADC would offer two major advantages over a conventional binary-scaled-capacitor ADC: (1) In a conventional ADC that digitizes to n bits, the largest capacitor (representing the most significant bit) must have 2(exp n-1) times as much capacitance, and hence, approximately 2(exp n-1) times as much area as does the smallest capacitor (representing the least significant bit), so that the total capacitor area must be 2(exp n) times that of the smallest capacitor. In the proposed capacitor-chain ADC, there would be three capacitors per cell, each approximately equal to the smallest capacitor in the conventional ADC, and there would be one cell per bit. Therefore, the total capacitor area would be only about 3(exp n) times that of the smallest capacitor. The net result would be that the proposed ADC could be considerably smaller than the conventional ADC. (2) Because of edge effects, parasitic capacitances, and manufacturing tolerances, it is difficult to make capacitor banks in which the values of capacitance are scaled by powers of 2 to the required precision. In contrast, because all the capacitors in the proposed ADC would be identical, the problem of precise binary scaling would not arise.

Cunningham, Thomas↗
DOE OSTI2023

BeyondPlanck: V. Minimal ADC Corrections for Planck LFI

We describe the correction procedure for Analog-to-Digital Converter (ADC) differential non-linearities (DNL) adopted in the Bayesian end-to-end BEYONDPLANCK analysis framework. This method is nearly identical to that developed for the official Planck Low Frequency Instrument (LFI) Data Processing Center (DPC) analysis, and relies on the binned rms noise profile of each detector data stream. However, rather than building the correction profile directly from the raw rms profile, we first fit a Gaussian to each significant ADC-induced rms decrement, and then derive the corresponding correction model from this smooth model. The main advantage of this approach is that only samples which are significantly affected by ADC DNLs are corrected, as opposed to the DPC approach in which the correction is applied to all samples, filtering out signals not associated with ADC DNLs. The new corrections are only applied to data for which there is a clear detection of the non-linearities, and for which they perform at least comparably with the DPC corrections. Out of a total of 88 LFI data streams (sky and reference load for each of the 44 detectors) we apply the new minimal ADC corrections in 25 cases, and maintain the DPC corrections in 8 cases. All these corrections are applied to 44 or 70 GHz channels, while, as in previous analyses, none of the 30 GHz ADCs show significant evidence of non-linearity. By comparing the BEYONDPLANCK and DPC ADC correction methods, we estimate that the residual ADC uncertainty is about two orders of magnitude below the total noise of both the 44 and 70 GHz channels, and their impact on current cosmological parameter estimation is small. However, we also show that non-idealities in the ADC corrections can generate sharp stripes in the final frequency maps, and these could be important for future joint analyses with the Planck High Frequency Instrument (HFI), Wilkinson Microwave Anisotropy Probe (WMAP), or other datasets. We therefore conclude that, although the existing corrections are adequate for LFI-based cosmological parameter analysis, further work on LFI ADC corrections is still warranted.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2025

A Radiation-Hard 8-Channel 15-Bit 40-MSPS ADC for the ATLAS Liquid Argon Calorimeter Readout

The custom design of a radiation-hardened, 8-channel, 40-MSPS, 15-bit resolution, 14.2-bit dynamic range, 11.4-ENOB ADC data acquisition ASIC fabricated in a commercial 65-nm triple-well CMOS technology is presented. The ADC is developed for and integrates seamlessly into the readout system for the ATLAS liquid argon (LAr) calorimeter in the high-luminosity large hadron collider (HLLHC) upgrade at CERN, which will require a total of 364 936 ADC channels. A three-stage MDAC+SAR pipelined ADC architecture was designed to meet the physics requirements and scientific goals of the ATLAS experiment. The ADC is a fully self-contained data acquisition system that includes foreground calibration, digital data processing, digital control, and supporting circuitry. The measured performance shows the ADC achieves a competitive dynamic range and SNDR, and it meets or exceeds the ATLAS analog requirements. Radiation tolerance and scalability design considerations were implemented at the device-, circuit-, and system-level. Radiation-hardening-by-design techniques used include redundancy for digital circuits, the use of MiM capacitors, and a hybrid RC-DAC for the ADC core. The ADC ASIC was demonstrated to be robust against the effects of the intense radiation expected in the HL-LHC experimental environment.

DAQ↗
NASA NTRS2013

Minimal Power Latch for Single-Slope ADCs

Column-parallel analog-to-digital converters (ADCs) for imagers involve simultaneous operation of many ADCs. Single-slope ADCs are well adapted to this use because of their simplicity. Each ADC contains a comparator, comparing its input signal level to an increasing reference signal (ramp). When the ramp is equal to the input, the comparator triggers a latch that captures an encoded counter value (code). Knowing the captured code, the ramp value and hence the input signal are determined. In a column-parallel ADC, each column contains only the comparator and the latches; the ramp and code generation are shared. In conventional latch or flip-flop circuits, there is an input stage that tracks the input signal, and this stage consumes switching current every time the input changes. With many columns, many bits, and high code rates, this switching current can be substantial. It will also generate noise that may corrupt the analog signals. A latch was designed that does not track the input, and consumes power only at the instant of latching the data value. The circuit consists of two S-R (set-reset) latches, gated by the comparator. One is set by high data values and the other by low data values. The latches are cross-coupled so that the first one to set blocks the other. In order that the input data not need an inversion, which would consume power, the two latches are made in complementary polarity. This requires complementary gates from the comparator, instead of complementary data values, but the comparator only triggers once per conversion, and usually has complementary outputs to begin with. An efficient CMOS (complementary metal oxide semiconductor) implementation of this circuit is shown in the figure, where C is the comparator output, D is the data (code), and Q0 and Q1 are the outputs indicating the capture of a zero or one value. The latch for Q0 has a negative-true set signal and output, and is implemented using OR-AND-INVERT logic, while the latch for Q1 uses positive- true signals and is implemented using AND-OR-INVERT logic. In this implementation, both latches are cleared when the comparator is reset. Two redundant transistors are removed from the reset side of each latch, making for a compact layout. CMOS imagers with column-parallel ADCs have demonstrated high performance for remote sensing applications. With this latch circuit, the power consumption and noise can be further reduced. This innovation can be used in CMOS imagers and very-low-power electronics

Hancock, Bruce R.↗
NASA NTRS2012

High-Speed, Multi-Channel Serial ADC LVDS Interface for Xilinx Virtex-5 FPGA

Analog-to-digital converters (ADCs) are used in scientific and communications instruments on all spacecraft. As data rates get higher, and as the transition is made from parallel ADC designs to high-speed, serial, low-voltage differential signaling (LVDS) designs, the need will arise to interface these in field programmable gate arrays (FPGAs). As Xilinx has released the radiation-hardened version of the Virtex-5, this will likely be used in future missions. High-speed serial ADCs send data at very high rates. A de-serializer instantiated in the fabric of the FPGA could not keep up with these high data rates. The Virtex-5 contains primitives designed specifically for high-speed, source-synchronous de-serialization, but as supported by Xilinx, can only support bitwidths of 10. Supporting bit-widths of 12 or more requires the use of the primitives in an undocumented configuration, a non-trivial task. A new SystemVerilog design was written that is simpler and uses fewer hardware resources than the reference design described in Xilinx Application Note XAPP866. It has been shown to work in a Xilinx XC5VSX24OT connected to a MAXIM MAX1438 12-bit ADC using a 50-MHz sample clock. The design can be replicated in the FPGA for multiple ADCs (four instantiations were used for a total of 28 channels).

Taylor, Gregory H.↗
DOE OSTI2021

Compact, low power, high resolution ADC per pixel for large area pixel detectors

A compact ADC circuit can include one or more comparators, and a serial DAC (Digital-to-Analog) circuit that provides a signal to the comparator (or comparators). In addition, the ADC circuit can include a serial DAC redistribution sequencer that can provide a plurality of signals as input to the serial DAC circuit and is subject to a redistribution cycle and which receives as input a signal from a data multiplexer whose input connects electronically to an output of the comparator. The circuit can further include an ADC code register that provides an ADC output that connects electronically to the output of the comparator and the input to the data multiplexer. Shared logic circuitry for sharing common logic between pixels can be included, wherein the shared logic circuitry connects electronically to the data multiplexer and the ADC code register, wherein the shared logic circuitry promotes area and power savings for the pixel detector circuit.

Zimmerman, Tom↗
DOE OSTI2023

Compact, low power, high resolution ADC per pixel for large area pixel detectors

A compact ADC circuit can include one or more comparators, and a serial DAC (Digital-to-Analog) circuit that provides a signal to the comparator (or comparators). In addition, the ADC circuit can include a serial DAC redistribution sequencer that can provide a plurality of signals as input to the serial DAC circuit and is subject to a redistribution cycle and which receives as input a signal from a data multiplexer whose input connects electronically to an output of the comparator. The circuit can further include an ADC code register that provides an ADC output that connects electronically to the output of the comparator and the input to the data multiplexer. Shared logic circuitry for sharing common logic between pixels can be included, wherein the shared logic circuitry connects electronically to the data multiplexer and the ADC code register, wherein the shared logic circuitry promotes area and power savings for the pixel detector circuit.

Fahim, Farah↗
DOE OSTI2025

Evolution of carbapenemase activity in the class C β-lactamase ADC-1

Antibiotic resistance in bacteria poses a significant threat to public health. Among dozens of available antimicrobial agents, carbapenems are used as drugs of choice for the treatment of serious infections caused by pathogens resistant to other antibiotics. However, their usefulness has been severely compromised due to the emergence and wide spread of carbapenem-resistant clinical isolates worldwide. High-level resistance to carbapenems in bacteria is mediated by the production of β-lactamases from three molecular classes, A, B, and D, but not by class C enzymes. In this study, we selected a triple mutant of the intrinsic class C Acinetobacter-derived cephalosporinase ADC-1 (ADC-1 TM ) that confers high-level resistance to the carbapenems meropenem, ertapenem, and doripenem. Kinetic experiments demonstrated that the apparent binding affinity, along with the acylation and deacylation rates, were all improved for the mutant enzyme. X-ray crystallography, molecular docking, and molecular dynamics simulations revealed that the amino acid substitutions in ADC-1 TM produce significant changes in the enzyme active site architecture and binding mode of the carbapenem ertapenem. These changes allow for better positioning of a deacylating water for nucleophilic attack, thus explaining the significantly improved rate of ertapenem deacylation by ADC-1 TM . In this study, we showed for the first time that a class C β-lactamase can produce high-level resistance to carbapenem antibiotics, which underlines the potential for enzymes of this class to evolve such resistance and could further exacerbate the problem of antibiotic resistance in bacteria.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Sulfonamidoboronic Acids as “Cross-Class” Inhibitors of an Expanded-Spectrum Class C Cephalosporinase, ADC-33, and a Class D Carbapenemase, OXA-24/40: Strategic Compound Design to Combat Resistance in Acinetobacter baumannii

Acinetobacter baumannii is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant A. baumannii (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to β-lactams. One of the most important mechanisms is the production of β-lactamase enzymes capable of hydrolyzing β-lactam antibiotics. Co-expression of multiple classes of β-lactamases is present in CRAB; therefore, the design and synthesis of “cross-class” inhibitors is an important strategy to preserve the efficacy of currently available antibiotics. To identify new, nonclassical β-lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid CR167 active against Acinetobacter-derived class C β-lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a K i = 160 nM and proved to be able to decrease MIC values of ceftazidime and cefotaxime in different bacterial strains. Herein, we describe the activity of CR167 against other β-lactamases in A. baumannii: the cefepime-hydrolysing class C extended-spectrum β-lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate CR167 as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of CR167 were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with CR167 and select chiral analogues were obtained. The structure activity relationships (SARs) are highlighted, offering insights into the main determinants for cross-class C/D inhibitors and impetus for novel drug design.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Structural Characterization of Linker Shielding in ADC Site-Specific Conjugates

Background/Objectives: Antibody–Drug Conjugates (ADCs) have rapidly evolved from early, rudimentary conjugates to highly targeted and precisely engineered molecules. Despite notable clinical successes, ADCs continue to face significant challenges, including aggregation and high hydrophobicity driven by high drug-to-antibody ratios (DARs), premature payload release, dose-limiting toxicities, and suboptimal pharmacokinetics. While site-specific linker–payload conjugation has improved ADC homogeneity and stability, the structural basis of antibody–linker interactions at specific sites remains underexplored. Methods: In this work, we present the crystal structures of trastuzumab Fab and Fc domains site-specifically conjugated with a cleavable linker–payload. Results: Our findings suggest that pockets within both Fab and Fc regions may interact with and shield the linker portion of the conjugate. Conclusions: These insights highlight the previously underappreciated potential of structure-based design to drive the optimization of ADC linker chemistry and facilitate the co-design of bespoke linker–payloads tailored to individual antibody conjugation sites.

Jaime-Garza, Maru [Discovery Chemistry, Merck & Co↗
NASA NTRS2011

Attitude Determination and Control Subsystem (ADCS) Preparations for the EPOXI Flyby of Comet Hartley 2

On November 4, 2010 the former "Deep Impact" spacecraft, renamed "EPOXI" for its extended mission, flew within 700km of comet 103P/Hartley 2. In July 2005, the spacecraft had previously imaged a probe impact of comet Tempel 1. The EPOXI flyby was the fifth close encounter of a spacecraft with a comet nucleus and marked the first time in history that two comet nuclei were imaged at close range with the same suite of onboard science instruments. This challenging objective made the function of the attitude determination and control subsystem (ADCS) critical to the successful execution of the EPOXI flyby.As part of the spacecraft flyby preparations, the ADCS operations team had to perform meticulous sequence reviews, implement complex spacecraft engineering and science activities and perform numerous onboard calibrations. ADCS contributions included design and execution of 10 trajectory correction maneuvers, the science calibration of the two telescopic instruments, an in-flight demonstration of high-rate turns between Earth and comet point, and an ongoing assessment of reaction wheel health. The ADCS team was also responsible for command sequences that included updates to the onboard ephemeris and sun sensor coefficients and implementation of reaction wheel assembly (RWA) de-saturations.

attitude determination and control↗
NASA NTRS2024

COLUTA: Custom 8-Channel 15-bit 40-MSPS ADC for the ATLAS Liquid Argon Calorimeter Readout

The stringent radiation-tolerance, quantization requirements, and the need for seamless integration of the on-detector readout electronics chain require the design of a full-custom analog-to-digital converter (ADC) for the 182,468 channels in the ATLAS Liquid Argon (LAr) calorimeter at the Large Hadron Collider (LHC) at CERN, as part of the High-Luminosity LHC (HL-LHC) upgrade. Each of the 8 channels in the prototype 65 nm CMOS ADC with 15-bit resolution and >68 dB signal-to-noise-and-distortion ratio (SNDR), or equivalently >11 effective number of bits (ENOB), consists of a Multiplying-DAC (MDAC) and a successive-approximation (SAR) ADC. A digital data processing unit (DDPU) calibrates and serially transmits the quantized data. Initial lab characterization of 18 chips shows a minimum SNDR of 69.5 dB at full-scale at about 5 MHz and a maximum power consumption of 1.17 W; differential non-linearity (DNL) measurements show no missing codes. Additional validation of the ADC is ongoing before approximately 70k chips can be mass-produced for the upgrade.

Rui Xu↗
DOE OSTI2024

A Cryogenic readout integrated circuit with analog pile-up and in-Pixel ADC for high frame rate Skipper CCD-in-CMOS Sensors

The Skipper CCD-in-CMOS Parallel Read-Out Circuit V2 (SPROCKET2) is designed to enable high frame rate readout of Skipper CCD-in-CMOS image sensors. The SPROCKET2 pixel is fabricated in a 65 nm CMOS process and occupies a 60$\mu$m $\times$ 60$\mu$m footprint. SPROCKET2 is intended to be heterogeneously integrated with a pixelated Skipper CCD-in-CMOS sensor, such that one readout pixel is connected to a multiplexed array of 16 active image sensor pixels, to match their spatial geometry. Our design benefits from the Skipper CCD-in-CMOS sensor's non-destructive readout capability to achieve exceptionally low noise through multi-sampling and averaging while optimizing for total power consumption. The pixel readout utilizes correlated double sampling to minimize 1/f noise and includes "pile-up" of ten successive samples in the analog domain before digitizing at a rate of 66.7 ksps. Measurement results of in-pixel serial SAR ADC show DNL and INL of ~0. 44 LSB and 0.58 LBS respectively. A large area array of 20,000 SPROCKET2 ADC pixels (multiplexed 1:16 to 320,000 sensor pixels) is currently under test. By reading out data over a 10 Gbps optical link, this pixel design enables a frame rate of $\sim$ 4 kfps for large sensing areas with minimal sensing deadtime. In the highest gain mode, the pixelated ADC has an input-referred resolution of 10$\mu$V with a simulated power consumption of 50$\mu$W. The pixel operates with constant current draw to minimize power-rail crosstalk.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
NASA NTRS2002

Chandra and XMM Observations of the ADC Source 0921-630

We analyze observations of the low mass X-ray binary 2S0921-63 obtained with the gratings and CCDs on Chandra and XMM. This object is a high inclination system showing evidence for an accretion disk corona (ADC). Such a corona has the potential to constrain the properties of the heated accretion disk in this system, and other LMXBs by extension. We find evidence for line emission which is generally consistent with that found by previous experiments, although we are able to detect more lines. For the first time in this source, we find that the iron K line has multiple components. We set limits on the line widths and velocity offsets, and we fit the spectra to photoionization models and discuss the implications for accretion disk corona models. For the first time in any ADC source we use these fits, together with density constraints based on the O VII line ratio, in order to constrain the flux in the medium-ionization region of the ADC. Under various assumptions about the source luminosity this constrains the location of the emitting region. These estimates, together with estimates for the emission measure, favor a scenario in which the intrinsic luminosity of the source is comparable to what we observe.

Kallman, T. R.↗
NASA NTRS1996

Recent Progress in On-Focal-Plane ADC

Two 8 bit successive approximation analog-to-digital converters (ADC) and a 12 bit current mode incremental sigma delta ADC have been designed, fabricated, and tested.

analog-to-digital converters adc↗
NASA NTRS1992

An 18 bit 50 kHz ADC for low earth orbit

A fourth order incremental analog to digital converter (ADC) is proposed which performs 18 bit conversions at a 50 kHz rate on sampled and held data. A new self calibration scheme is presented which eases the matching requirements of capacitors, and the performance of the operational amplifiers in the ADC by changing coefficients in the digital postprocessing.

Thelen, Donald C.↗
NASA NTRS2011

Attitude Determination and Control Subsystem (ADCS) Preparations for the EPOXI Flyby of Comet Haley 2

On November 4, 2010 the already "in-flight" Deep Impact spacecraft flew within 700km of comet 103P/Hartley 2 as part of its extended mission EPOXI, the 5th time to date any spacecraft visited a comet. In 2005, the spacecraft had previously imaged a probe impact comet Tempel 1. The EPOXI flyby marked the first time in history that two comets were explored with the same instruments on a re-used spacecraft-with hardware and software originally designed and optimized for a different mission. This made the function of the attitude determination and control subsystem (ADCS) critical to the successful execution of the EPOXI flyby. As part of the spacecraft team preparations, the ADCS team had to perform thorough sequence reviews, key spacecraft activities and onboard calibrations. These activities included: review of background sequences for the initial conditions vector, sun sensor coefficients, and reaction wheel assembly (RWA) de-saturations; design and execution of 10 trajectory correction maneuvers; science calibration of the two telescope instruments; a flight demonstration of the fastest turns conducted by the spacecraft between Earth and comet point; and assessment of RWA health (given RWA problems on other spacecraft).

Harley↗