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Quantum dots in proteomic studies and medical diagnostics

Modern medical diagnostics requires the detection of minor amounts of target proteins at the background of numerous different biological components. With rare exception, these problems cannot be solved by purely physical research methods. In this case, the simplest and efficient approach is concerned with the principles of complementary affine interactions of biopolymers. In this case, high sensitivity of the analysis is achieved by the introduction of labels with certain physical properties in affinity bioreagents. This review is focused on the development of proteomic studies and medical diagnostics with the use of colloidal quantum dots (QDs) as labels in affinity bioreagents. This review is devoted to the description of in vitro proteomic approaches used in the studies and diagnostics, where the problem related to toxicity is not as crucial as in therapy and no restrictions on the types and composition of QDs are imposed. In this case, QDs are considered to be one of the key components of a bioanalytical system. The problems of proteomic medical diagnostics are discussed from the viewpoint of analytical chemistry with the account for the structure and properties of macromolecular analytes and appropriate bioreagents.

60 APPLIED LIFE SCIENCES↗

Diagnostic-free onboard battery health assessment

Diverse usage patterns induce complex and variable aging behaviors in lithiumion batteries, complicating accurate health diagnosis and prognosis. Separate diagnostic cycles are often used to untangle the battery’s current state of health from prior complex aging patterns. However, these same diagnostic cycles alter the battery’s degradation trajectory, are time-intensive, and cannot be practically performed in onboard applications. Here, in this work, we leverage portions of operational measurements in combination with an interpretable machine learning model to enable rapid, onboard battery health diagnostics and prognostics without offline diagnostic testing and the requirement of historical data. We integrate mechanistic constraints within an encoder-decoder architecture to extract electrode states in a physically interpretable latent space and enable improved reconstruction of the degradation path. The health diagnosis model framework can be flexibly applied across diverse application interests with slight fine-tuning.

battery aging reconstruction↗

Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing

Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as 7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of 14C-labeled drug followed by DNA isolation and quantification of drug-DNA adducts via accelerator mass spectrometry. Here, we have shown proof of principle by correlating ARA-C- and DOX-DNA adduct levels with cellular IC50 values of paired sensitive and resistant cancer cell lines and AML cell lines. Moreover, we have completed a pilot retrospective trial of diagnostic microdosing for 10 viably cryopreserved primary AML samples and observed higher ARA-C- and DOX-DNA adducts in the 7 + 3 responders than nonresponders. In conclusion, these initial results suggest that diagnostic microdosing may be a feasible and useful test for predicting patient response to 7 + 3 induction chemotherapy, leading to improved outcomes for AML patients and reduced treatment-related morbidity and mortality.

59 BASIC BIOLOGICAL SCIENCES↗

Harnessing Nanobodies for Precision Targeting of Proteoforms: Opportunities and Challenges in Therapeutics and Diagnostics

Proteoforms are biologically distinct yet structurally similar proteins that play key roles in driving disease progression but are rarely accounted for in the development of therapeutics and diagnostics. Nanobodies (Nbs) have emerged as a therapeutic and diagnostic “silver bullet” as they possess unique structural and functional attributes that offer advantages over traditional antibodies. One of the most profound advantages of Nbs is the heightened sensitivity and ability to distinguish subtle changes in the conformation of a given protein. Thus, Nbs have significant potential as therapeutic and diagnostic agents that can identify and distinguish specific pathological proteoforms that underlie a given disease. However, there remain significant challenges in obtaining sufficient quantities and purities of specific proteoform antigens that are required for engineering proteoform-specific Nbs. Recent advancements in chemical biology tools for precision proteoform synthesis have made this task feasible for the first time. In this perspective, we discuss the advantages and challenges associated with developing proteoform-specific Nbs and how success in this endeavor will significantly advance the fields of therapeutics and diagnostics.

Antigens↗

Status of the design of the ITER ECE diagnostic

In this study, the baseline design for the ITER electron cyclotron emission (ECE) diagnostic has entered the detailed preliminary design phase. Two plasma views are planned, a radial view and an oblique view that is sensitive to distortions in the electron momentum distribution near the average thermal momentum. Both views provide high spatial resolution electron temperature profiles when the momentum distribution remains Maxwellian. The ECE diagnostic system consists of the front-end optics, including two 1000 K calibration sources, in equatorial port plug EP9, the 70-1000 GHz transmission system from the front-end to the diagnostics hall, and the ECE instrumentation in the diagnostics hall. The baseline ECE instrumentation will include two Michelson interferometers that can simultaneously measure ordinary and extraordinary mode ECE from 70 to 1000 GHz, and two heterodyne radiometer systems, covering 122-230 GHz and 244-355 GHz. Significant design challenges include 1) developing highly-reliable 1000 K calibration sources and the associated shutters/mirrors, 2) providing compliant couplings between the front-end optics and the polarization splitter box that accommodate displacements of the vacuum vessel during plasma operations and bake out, 3) protecting components from damage due to stray ECH radiation and other intense millimeter wave emission and 4) providing the low-loss broadband transmission system.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Design and specifications of the diagnostics for the instrumented calorimeter of Source for the Production of Ions of Deuterium Extracted from Radio frequency plasma

In the development of the neutral beam injector for ITER experiment, the test facility SPIDER is going to be built. To measure the beam parameters, several diagnostics are used. One of them is the Short-Time Retractable Instrumented Kalorimeter Experiment (STRIKE) which measures beam uniformity, beamlet divergence, and stripping losses. This contribution gives an overview of the diagnostics dedicated to these measurements: thermal cameras, thermocouples, current sensors, and electrostatic sensors. The specifications of these diagnostics have been defined according to the results of electrostatic and thermal simulations. A failure modes and effects analysis has been performed during the design. Consequently the project of the STRIKE diagnostics has been optimized to reduce the possible failure risks.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Design of a beam emission spectroscopy diagnostic for negative ions radio frequency source SPIDER

A facility will be built in Padova (Italy) to develop, commission, and optimize the neutral beam injection system for ITER. The full scale prototype negative ion radio frequency source SPIDER, featuring up to 100 kV acceleration voltage, includes a full set of diagnostics, required for safe operation and to measure and optimize the beam performance. Among them, beam emission spectroscopy (BES) will be used to measure the line integrated beam uniformity, divergence, and neutralization losses inside the accelerator (stripping losses). In the absence of the neutralization stage, SPIDER beam is mainly composed by H{sup -} or D{sup -} particles, according to the source filling gas. The capability of a spectroscopic diagnostic of an H{sup -} (D{sup -}) beam relies on the interaction of the beam particles with the background gas particles. The BES diagnostic will be able to acquire the H{sub {alpha}} (D{sub {alpha}}) spectrum from up to 40 lines of sight. The system is capable to resolve stripping losses down to 2 keV and to measure beam divergence with an accuracy of about 10%. The design of this diagnostic is reported, with discussion of the layout and its components, together with simulations of the expected performance.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

A study of beam position diagnostics using beam-excited dipole modes in third harmonic superconducting accelerating cavities at a free-electron laser

We investigate the feasibility of beam position diagnostics using higher order mode (HOM) signals excited by an electron beam in the third harmonic 3.9 GHz superconducting accelerating cavities at FLASH. After careful theoretical and experimental assessment of the HOM spectrum, three modal choices have been narrowed down to fulfill different diagnostics requirements. These are localized dipole beam-pipe modes, trapped cavity modes from the fifth dipole band, and propagating modes from the first two dipole bands. These modes are treated with various data analysis techniques: modal identification, direct linear regression (DLR), and singular value decomposition (SVD). Promising options for beam diagnostics are found from all three modal choices. This constitutes the first prediction, subsequently confirmed by experiments, of trapped HOMs in third harmonic cavities, and also the first direct comparison of DLR and SVD in the analysis of HOM-based beam diagnostics.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Thermal imaging diagnostics of high-current electron beams

The thermal imaging diagnostics of measuring pulsed electron beam energy density is presented. It provides control of the electron energy spectrum and a measure of the density distribution of the electron beam cross section, the spatial distribution of electrons with energies in the selected range, and the total energy of the electron beam. The diagnostics is based on the thermal imager registration of the imaging electron beam thermal print in a material with low bulk density and low thermal conductivity. Testing of the thermal imaging diagnostics has been conducted on a pulsed electron accelerator TEU-500. The energy of the electrons was 300-500 keV, the density of the electron current was 0.1-0.4 kA/cm{sup 2}, the duration of the pulse (at half-height) was 60 ns, and the energy in the pulse was up to 100 J. To register the thermal print, a thermal imager Fluke-Ti10 was used. Testing showed that the sensitivity of a typical thermal imager provides the registration of a pulsed electron beam heat pattern within one pulse with energy density over 0.1 J/cm{sup 2} (or with current density over 10 A/cm{sup 2}, pulse duration of 60 ns and electron energy of 400 keV) with the spatial resolution of 0.9-1 mm. In contrast to the method of using radiosensitive (dosimetric) materials, thermal imaging diagnostics does not require either expensive consumables, or plenty of processing time.

43 PARTICLE ACCELERATORS↗

Langmuir probe diagnostics of plasma in high current electron cyclotron resonance proton ion source

A high current Electron Cyclotron Resonance (ECR) proton ion source has been developed for low energy high intensity proton accelerator at Bhabha Atomic Research Centre. Langmuir probe diagnostics of the plasma generated in this proton ion source is performed using Langmuir probe. The diagnostics of plasma in the ion source is important as it determines beam parameters of the ion source, i.e., beam current, emittance, and available species. The plasma parameter measurement in the ion source is performed in continuously working and pulsed mode using hydrogen as plasma generation gas. The measurement is performed in the ECR zone for operating pressure and microwave power range of 10{sup −4}–10{sup −3} mbar and 400–1000 W. An automated Langmuir probe diagnostics unit with data acquisition system is developed to measure these parameters. The diagnostics studies indicate that the plasma density and plasma electron temperature measured are in the range 5.6 × 10{sup 10} cm{sup −3} to 3.8 × 10{sup 11} cm{sup −3} and 4–14 eV, respectively. Using this plasma, ion beam current of tens of mA is extracted. The variations of plasma parameters with microwave power, gas pressure, and radial location of the probe have been studied.

43 PARTICLE ACCELERATORS↗

Observational constraints of stellar collapse: Diagnostic probes of nature's extreme matter experiment

Supernovae are Nature's high-energy, high density laboratory experiments, reaching densities in excess of nuclear densities and temperatures above 10 MeV. Astronomers have built up a suite of diagnostics to study these supernovae. If we can utilize these diagnostics, and tie them together with a theoretical understanding of supernova physics, we can use these cosmic explosions to study the nature of matter at these extreme densities and temperatures. Capitalizing on these diagnostics will require understanding a wide range of additional physics. Here we review the diagnostics and the physics neeeded to use them to learn about the supernova engine, and ultimate nuclear physics.

79 ASTRONOMY AND ASTROPHYSICS↗

Diagnostics and required R and D for control of DEMO grade plasmas

Even if the diagnostics of ITER performs as expected, installation and operation of the diagnostic systems in Demo device will be much harsher than those of the present ITER device. In order to operate the Demo grade plasmas, which may have a higher beta limit, safely with very limited number of simple diagnostic system, it requires a well defined predictable plasma modelling in conjunction with the reliable control system for burn control and potential harmful instabilities. Development of such modelling in ITER is too risky and the logical choice would be utilization of the present day steady state capable devices such as KSTAR and EAST. In order to fulfill this mission, sophisticated diagnostic systems such as 2D/3D imaging systems can validate the physics in the theoretical modeling and challenge the predictable capability.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

X-ray diagnostic developments in the perspective of DEMO

Soft X-ray diagnostics at present are not adequate for a burning plasma experiment, neither in term of hardware nor as diagnostic conception. Detectors have to be radiation tolerant, easily shielded, with low sensitivity to neutrons and gammas and with energy discrimination. Layout and viewing capability should be more flexible, thanks to the use also of optical devices, going toward a configuration intermediate between discrete tomography and pure imaging. The general conception of these diagnostics should therefore evolve in the direction of pattern recognition for a real time feedback. This work is focused on the diagnostic developments undertaken at the ENEA- Frascati X-ray Laboratory, following in particular three directions: gas detector for fast and advanced high density tomography, C-MOS solid state imaging detectors for slow control and X-ray polycapillary optics. GEM gas detectors in photon counting mode (noise free) were developed in the range 1-30 keV having high efficiency, high time resolution (up to microseconds), energy discrimination in bands and optical flexibility. Discrimination of X-rays, neutrons and gammas has been demonstrated, thanks to the combination of intrinsic gain and discrimination thresholds, at neutron fluxes (10{sup 7} n/s*cm{sup 2}) comparable with the expected ones at the ports of ITER. GEM detectors are also extremely flexible in the design, allowing optimization of the measurements and solutions for shielding or minimization of the effect of background radiation. Two solid state C-MOS imagers working in photon counting mode, one based on Si semiconductor (Medipix-2, range 5-30 keV) and the other one having a CdTe sensor (Pixirad, range 2-100 keV) have been characterized in laboratory. C-MOS imagers have features and performances thoroughly complementary to the GEM detector and, thanks to their higher pixel density, could be used as remote imaging detectors coupled to optics. X-ray polycapillary lenses have been therefore studied in the laboratory both as imaging optical device (full lens) or to define a line of sight (cylinder lens); the preliminary results are encouraging toward the goal of using these lenses to transport X-ray radiation far from the reactor. Reflective or diffractive X-ray optics can be also an option for tomography. A GEM detector has been installed at KSTAR and in the next future hopefully the other approaches will be tested there: once their feasibility will be demonstrated, the issue of the improvement of the radiation tolerance will be faced and the development of algorithms for data analysis as well.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

A new B-dot probe-based diagnostic for amplitude, polarization, and wavenumber measurements of ion cyclotron range-of frequency fields on ASDEX Upgrade

A new B-dot probe-based diagnostic has been installed on an ASDEX Upgrade tokamak to characterize ion cyclotron range-of frequency (ICRF) wave generation and interaction with magnetized plasma. The diagnostic consists of a field-aligned array of B-dot probes, oriented to measure fast and slow ICRF wave fields and their field-aligned wavenumber (k{sub //}) spectrum on the low field side of ASDEX Upgrade. A thorough description of the diagnostic and the supporting electronics is provided. In order to compare the measured dominant wavenumber of the local ICRF fields with the expected spectrum of the launched ICRF waves, in-air near-field measurements were performed on the newly installed 3-strap ICRF antenna to reconstruct the dominant launched toroidal wavenumbers (k{sub tor}). Measurements during a strap current phasing scan in tokamak discharges reveal an upshift in k{sub //} as strap phasing is moved away from the dipole configuration. This result is the opposite of the k{sub tor} trend expected from in-air near-field measurements; however, the near-field based reconstruction routine does not account for the effect of induced radiofrequency (RF) currents in the passive antenna structures. The measured exponential increase in the local ICRF wave field amplitude is in agreement with the upshifted k{sub //}, as strap phasing moves away from the dipole configuration. An examination of discharges heated with two ICRF antennas simultaneously reveals the existence of beat waves at 1 kHz, as expected from the difference of the two antennas’ operating frequencies. Beats are observed on both the fast and the slow wave probes suggesting that the two waves are coupled outside the active antennas. Although the new diagnostic shows consistent trends between the amplitude and the phase measurements in response to changes applied by the ICRF antennas, the disagreement with the in-air near-field measurements remains. An electromagnetic model is currently under development to address this issue.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

High density plasmas and new diagnostics: An overview (invited)

One of the limiting factors for the full understanding of Electron Cyclotron Resonance Ion Sources (ECRISs) fundamental mechanisms consists of few types of diagnostic tools so far available for such compact machines. Microwave-to-plasma coupling optimisation, new methods of density overboost provided by plasma wave generation, and magnetostatic field tailoring for generating a proper electron energy distribution function, suitable for optimal ion beams formation, require diagnostic tools spanning across the entire electromagnetic spectrum from microwave interferometry to X-ray spectroscopy; these methods are going to be implemented including high resolution and spatially resolved X-ray spectroscopy made by quasi-optical methods (pin-hole cameras). The ion confinement optimisation also requires a complete control of cold electrons displacement, which can be performed by optical emission spectroscopy. Several diagnostic tools have been recently developed at INFN-LNS, including “volume-integrated” X-ray spectroscopy in low energy domain (2-30 keV, by using silicon drift detectors) or high energy regime (>30 keV, by using high purity germanium detectors). For the direct detection of the spatially resolved spectral distribution of X-rays produced by the electronic motion, a “pin-hole camera” has been developed also taking profit from previous experiences in the ECRIS field. The paper will give an overview of INFN-LNS strategy in terms of new microwave-to-plasma coupling schemes and advanced diagnostics supporting the design of new ion sources and for optimizing the performances of the existing ones, with the goal of a microwave-absorption oriented design of future machines.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

First set of gated x-ray imaging diagnostics for the Laser Megajoule facility

The Laser Megajoule (LMJ) facility located at CEA/CESTA started to operate in the early 2014 with two quadruplets (20 kJ at 351 nm) focused on target for the first experimental campaign. We present here the first set of gated x-ray imaging (GXI) diagnostics implemented on LMJ since mid-2014. This set consists of two imaging diagnostics with spatial, temporal, and broadband spectral resolution. These diagnostics will give basic measurements, during the entire life of the facility, such as position, structure, and balance of beams, but they will also be used to characterize gas filled target implosion symmetry and timing, to study x-ray radiography and hydrodynamic instabilities. The design requires a vulnerability approach, because components will operate in a harsh environment induced by neutron fluxes, gamma rays, debris, and shrapnel. Grazing incidence x-ray microscopes are fielded as far as possible away from the target to minimize potential damage and signal noise due to these sources. These imaging diagnostics incorporate microscopes with large source-to-optic distance and large size gated microchannel plate detectors. Microscopes include optics with grazing incidence mirrors, pinholes, and refractive lenses. Spatial, temporal, and spectral performances have been measured on x-ray tubes and UV lasers at CEA-DIF and at Physikalisch-Technische Bundesanstalt BESSY II synchrotron prior to be set on LMJ. GXI-1 and GXI-2 designs, metrology, and first experiments on LMJ are presented here.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Modifications to the synthetic aperture microwave imaging diagnostic

The synthetic aperture microwave imaging diagnostic has been operating on the MAST experiment since 2011. It has provided the first 2D images of B-X-O mode conversion windows and showed the feasibility of conducting 2D Doppler back-scattering experiments. The diagnostic heavily relies on field programmable gate arrays to conduct its work. Recent successes and newly gained experience with the diagnostic have led us to modify it. The enhancements will enable pitch angle profile measurements, O and X mode separation, and the continuous acquisition of 2D DBS data. Finally, the diagnostic has also been installed on the NSTX-U and is acquiring data since May 2016.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Invited Review Article: Gas puff imaging diagnostics of edge plasma turbulence in magnetic fusion devices

Gas puff imaging (GPI) is a diagnostic of plasma turbulence which uses a puff of neutral gas at the plasma edge to increase the local visible light emission for improved space-time resolution of plasma fluctuations. This paper reviews gas puff imaging diagnostics of edge plasma turbulence in magnetic fusion research, with a focus on the instrumentation, diagnostic cross-checks, and interpretation issues. The gas puff imaging hardware, optics, and detectors are described for about 10 GPI systems implemented over the past similar to 15 years. Comparison of GPI results with other edge turbulence diagnostic results is described, and many common features are observed. Here, several issues in the interpretation of GPI measurements are discussed, and potential improvements in hardware and modeling are suggested.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗