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ATHENA has been designed as a general purpose detector capable of delivering the full scientific scope of the Electron-Ion Collider. Careful technology choices provide fine tracking and momentum resolution, high performance electromagnetic and hadronic calorimetry, hadron identification over a wide kinematic range, and near-complete hermeticity. This article describes the detector design and its expected performance in the most relevant physics channels. It includes an evaluation of detector technology choices, the technical challenges to realizing the detector and the R&D required to meet those challenges.

This report describes the physics case, the resulting detector requirements, and the evolving detector concepts for the experimental program at the Electron-Ion Collider (EIC). The EIC will be a powerful new high-luminosity facility in the United States with the capability to collide high-energy electron beams with high-energy proton and ion beams, providing access to those regions in the nucleon and nuclei where their structure is dominated by gluons. Moreover, polarized beams in the EIC will give unprecedented access to the spatial and spin structure of the proton, neutron, and light ions. The studies leading to this document were commissioned and organized by the EIC User Group with the objective of advancing the state and detail of the physics program and developing detector concepts that meet the emerging requirements in preparation for the realization of the EIC. The effort aims to provide the basis for further development of concepts for experimental equipment best suited for the science needs, including the importance of two complementary detectors and interaction regions. This report consists of three volumes. Volume I is an executive summary of our findings and developed concepts. In Volume II we describe studies of a wide range of physics measurements and the emerging requirements on detector acceptance and performance. Volume III discusses general-purpose detector concepts and the underlying technologies to meet the physics requirements. These considerations will form the basis for a world-class experimental program that aims to increase our understanding of the fundamental structure of all visible matter.

Background: Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed., Methods: We applied 1 H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671., Results: 1 H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre + Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre + Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment., Conclusions: BBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials., (© 2022. The Author(s).)

Pediatric patients receiving solid organ transplants may develop lymphoproliferative diseases, including graft-versus-host disease (GvHD) and posttransplant lymphoproliferative diseases (PTLDs). We characterized lesions in 11 clinically ill NOD.Cg- Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice that received pediatric-patient-derived solid tumors (PDXs) and developed immunodeficiency-associated lymphoproliferations comparable to GvHD and PTLDs over a period of 46 to 283 days after implantation. Lymphoproliferations were diffusely positive for human-specific biomarkers, including NUMA1, CD45, and CD43, but lacked immunoreactivity for murine CD45. Human immune cells were CD3-positive, with subsets having immunoreactivity for CD4 and CD8 as well as PAX5, CD79a, and IRF4, resulting from populations of human T and B cells present within the xenotransplants. Tissues and organs infiltrated included mucocutaneous zones (oral cavity and perigenital and perianal regions), haired skin, tongue, esophagus, forestomach, thyroid, salivary glands, lungs, liver, kidneys, spleen, lymph nodes, bone marrow, and brain. In 4 of 5 mice with PTLD, Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) were detected by in situ hybridization in PAX5 + human B cells associated with the PDX ( n = 1/4) or with engrafted human immune cells at other anatomic locations ( n = 4/11). One of the 4 mice had an EBV-associated human large B-cell lymphoma. NSG mice receiving xenotransplants can develop combinations of GvHD, EBV-driven PTLD, and B-cell lymphoma similar to those occurring in human pediatric patients. Therefore, pediatric xenotransplants should undergo histopathologic and immunohistochemical assessment upon collection to ensure that the specimen is not a lymphoma and does not contain lymphoma cells because these neoplasms can morphologically mimic small round blue cell pediatric solid tumors.

Aim: CaCO 3 nanoparticles (nano-CaCO 3 ) can neutralize the acidic pHe of solid tumors, but the lack of intrinsic imaging signal precludes noninvasive monitoring of pH-perturbation in tumor microenvironment. We aim to develop a theranostic version of nano-CaCO 3 to noninvasively monitor pH modulation and subsequent tumor response., Materials & Methods: We synthesized ferromagnetic core coated with CaCO 3 (magnetite CaCO 3 ). Magnetic resonance imaging (MRI) was used to determine the biodistribution and pH modulation using murine fibrosarcoma and breast cancer models., Results: Magnetite CaCO 3 -MRI imaging showed that nano-CaCO 3 rapidly raised tumor pHe, followed by excessive tumor-associated acid production after its clearance. Continuous nano-CaCO 3 infusion could inhibit metastasis., Conclusion: Nano-CaCO 3 exposure induces tumor metabolic reprogramming that could account for the failure of previous intermittent pH-modulation strategies to achieve sustainable therapeutic effect.

Multiple myeloma (MM) is a plasma B-cell hematologic cancer that causes significant skeletal morbidity. Despite improvements in survival, heterogeneity in response remains a major challenge in MM. Cluster of differentiation 38 (CD38) is a type II transmembrane glycoprotein overexpressed in myeloma cells and is implicated in MM cell signaling. Daratumumab is a U.S. Food and Drug Administration-approved high-affinity monoclonal antibody targeting CD38 that is clinically benefiting refractory MM patients. Here, we evaluated [ 89 Zr]Zr-desferrioxamine (DFO)-daratumumab PET/CT imaging in MM tumor models. Methods: Daratumumab was conjugated to DFO- p -benzyl-isothiocyanate (DFO-Bz-NCS) for radiolabeling with 89 Zr. Chelator conjugation was confirmed by electrospray ionization-mass spectrometry, and radiolabeling was monitored by instant thin-layer chromatography. Daratumumab was conjugated to Cyanine5 (Cy5) dye for cell microscopy. In vitro and in vivo evaluation of [ 89 Zr]Zr-DFO-daratumumab was performed using CD38 + human myeloma MM1.S- luciferase (MM1.S) cells. Cellular studies determined the affinity, immunoreactivity, and specificity of [ 89 Zr]Zr-DFO-daratumumab. A 5TGM1- luciferase (5TGM1)/KaLwRij MM mouse model served as control for imaging background noise. [ 89 Zr]Zr-DFO-daratumumab PET/CT small-animal imaging was performed in severe combined immunodeficient mice bearing solid and disseminated MM tumors. Tissue biodistribution (7 d after tracer administration, 1.11 MBq/animal, n = 4-6/group) was performed in wild-type and MM1.S tumor-bearing mice. Results: A specific activity of 55.5 MBq/nmol (0.37 MBq/μg) was reproducibly obtained with [ 89 Zr]Zr-daratumumab-DFO. Flow cytometry confirmed CD38 expression (>99%) on the surface of MM1.S cells. Confocal microscopy with daratumumab-Cy5 demonstrated specific cell binding. Dissociation constant, 3.3 nM (±0.58), and receptor density, 10.1 fmol/mg (±0.64), was obtained with a saturation binding assay. [ 89 Zr]Zr-DFO-daratumumab/PET demonstrated specificity and sensitivity for detecting CD38 + myeloma tumors of variable sizes (8.5-128 mm 3 ) with standardized uptake values ranging from 2.1 to 9.3. Discrete medullar lesions, confirmed by bioluminescence images, were efficiently imaged with [ 89 Zr]Zr-DFO-daratumumab/PET. Biodistribution at 7 d after administration of [ 89 Zr]Zr-DFO-daratumumab showed prominent tumor uptake (27.7 ± 7.6 percentage injected dose per gram). In vivo blocking was achieved with a 200-fold excess of unlabeled daratumumab. Conclusion: [ 89 Zr]Zr-DFO- and Cy5-daratumumab demonstrated superb binding to CD38 + human MM cells and significantly low binding to CD38 low cells. Daratumumab bioconjugates are being evaluated for image-guided delivery of therapeutic radionuclides., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: Spatial and temporal coregistration of nuclear and optical images can enable the fusion of the information from these complementary molecular imaging modalities. A critical challenge is in integrating the optical and nuclear imaging hardware. Flexible fiber-based fluorescence-mediated tomography (FMT) systems provide a viable solution. The various bore sizes of small-animal nuclear imaging systems can potentially accommodate the FMT fiber imaging arrays. In addition, FMT imaging facilitates coregistration of the nuclear and optical contrasts in time. Herein, we combine a fiber-based FMT system with a preclinical SPECT/CT platform. Feasibility of in vivo imaging is demonstrated by tracking a monomolecular multimodal imaging agent (MOMIA) during transport from the forepaw to the axillary lymph node region of a rat., Methods: The fiber-based, video-rate FMT imaging system is composed of 12 sources (785- and 830-nm laser diodes) and 13 detectors. To maintain high temporal sampling, the system simultaneously acquires ratio-metric data at each detector. A 3-dimensional finite element model derived from CT projections provides anatomically based light propagation modeling. Injection of a MOMIA intradermally into the forepaw of rats provided spatially and temporally coregistered nuclear and optical contrasts. FMT data were acquired concurrently with SPECT and CT data. The incorporation of SPECT data as a priori information in the reconstruction of FMT data integrated both optical and nuclear contrasts., Results: Accurate depth localization of phantoms with different thicknesses was accomplished with an average center-of-mass error of 4.1 ± 2.1 mm between FMT and SPECT measurements. During in vivo tests, fluorescence and radioactivity from the MOMIA were colocalized in spatially coincident regions with an average center-of-mass error of 2.68 ± 1.0 mm between FMT and SPECT for axillary lymph node localization. Intravital imaging with surgical exposure of the lymph node validated the localization of the optical contrast., Conclusion: The feasibility of integrating a fiber-based, video-rate FMT system with a commercial preclinical SPECT/CT platform was established. These coregistered FMT and SPECT/CT results with MOMIAs may facilitate the development of the next generation of preclinical and clinical multimodal optical-nuclear platforms for a broad array of imaging applications and help elucidate the underlying biologic processes relevant to cancer diagnosis and therapy monitoring.

Fluorescence microscopy offers high sensitivity for disease diagnosis. However, little structural information is revealed by this method, requiring another technique to localize the source of fluorescence. We developed a complementary fluorescence-polarization microscope. We used a division-of-focal-plane charge coupled device polarization sensor to enable real-time video rate polarization imaging without any moving parts. The polarization information provided by the microscope enabled detection of structural element and complements the fluorescence information. Application of this multimodal system for cancer imaging using a tumor selective molecular probe revealed the association of diminished structural integrity of tumor tissue with high fluorescence of the imaging agent compared to surrounding normal tissue. This study demonstrates a new paradigm to improve cancer detection and diagnosis.

We have developed a fiber-based, video-rate fluorescence diffuse optical tomography (DOT) system for noninvasive in vivo sentinel lymph node (SLN) mapping. Concurrent acquisition of fluorescence and reference signals allowed the efficient generation of ratio-metric data for 3D image reconstruction. Accurate depth localization and high sensitivity to fluorescent targets were established in to depths of >10 mm. In vivo accumulation of indocyanine green (ICG) dye was imaged in the region of the SLN following intradermal injection into the forepaw of rats. These results suggest that video-rate fluorescence DOT has significant potential as a clinical tool for noninvasive mapping of SLN.

We report what we believe to be the first near-infrared pH-sensitive fluorescence lifetime molecular probe suitable for biological applications in physiological range. Specifically, we modified a known fluorophore skeleton, hexamethylindotricarbocyanine, with a tertiary amine functionality that was electronically coupled to the fluorophore, to generate a pH-sensitive probe. The pK(a) of the probe depended critically on the location of the amine. Peripheral substitution at the 5-position of the indole ring resulted in a compound with pK(a) ∼ 4.9 as determined by emission spectroscopy. In contrast, substitution at the meso-position shifted the pK(a) to 5.5. The resulting compound, LS482, demonstrated steady-state and fluorescence-lifetime pH-sensitivity. This sensitivity stemmed from distinct lifetimes for protonated (∼1.16 ns in acidic DMSO) and deprotonated (∼1.4 ns in basic DMSO) components. The suitability of the fluorescent dyes for biological applications was demonstrated with a fluorescence-lifetime tomography system. The ability to interrogate cellular processes and subsequently translate the findings in living organisms further augments the potential of these lifetime-based pH probes., (Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Local molecular and physiological processes can be imaged in vivo through perturbations in the fluorescence lifetime (FLT) of optical imaging agents. In addition to providing functional information, FLT methods can quantify specific molecular events and multiplex diagnostic and prognostic information. We have developed a fluorescence lifetime diffuse optical tomography (DOT) system for in vivo preclinical imaging. Data is captured using a time-resolved intensified charge coupled device (ICCD) system to measure fluorescence excitation and emission in the time domain. Data is then converted to the frequency domain, and we simultaneously reconstruct images of yield and lifetime using an extension to the normalized Born approach. By using differential phase measurements, we demonstrate DOT imaging of short lifetimes (from 350 ps) with high precision (+/-5 ps). Furthermore, this system retains the efficiency, speed, and flexibility of transmission geometry DOT. We demonstrate feasibility of FLT-DOT through a progressive series of experiments. Lifetime range and repeatability are first measured in phantoms. Imaging of subcutaneous implants then verifies the FLT-DOT approach in vivo in the presence of inhomogeneous optical properties. Use in a common research scenario is ultimately demonstrated by imaging accumulation of a targeted near-infrared (NIR) fluorescent-labeled peptide probe (cypate-RGD) in a mouse with a subcutaneous tumor.

Today's medical imaging technologies are expected to furnish anatomic, physiologic, molecular, and genomic information for accurate disease diagnosis, prediction of treatment response, and development of highly specific and sensitive drugs and imaging agents. However, none of the current imaging methods used in humans provides comprehensive medical imaging. To harness the strengths of different imaging methods, multimodality imaging has become an attractive strategy for in vivo studies. Beyond small-animal imaging, a less frequently used multimodality imaging strategy is the fusion of radionuclear and optical methods. This less frequent use is probably attributable to some misconceptions, technical difficulties, or a lack of appreciation for the benefits of the 2 methods in patient care. This minireview addresses some of these concerns, with emphasis on the potential applications of multimodality optical and SPECT/PET systems.

The polarity of biological mediums controls a host of physiological processes such as digestion, signaling, transportation, metabolism, and excretion. With the recent widespread use of near-infrared (NIR) fluorescent dyes for biological imaging of cells and living organisms, reporting medium polarity with these dyes would provide invaluable functional information in addition to conventional optical imaging parameters. Here, we report a new approach to determine polarities of macro- and microsystems for in vitro and potential in vivo applications using NIR polymethine molecular probes. Unlike the poor solvatochromic response of NIR dyes in solvents with diverse polarity, their fluorescence lifetimes are highly sensitive, increasing by a factor of up to 8 on moving from polar to nonpolar mediums. We also established a correlation between fluorescence lifetime and solvent orientation polarizability and developed a lifetime polarity index for determining the polarity of complex systems, including micelles and albumin binding sites. Because of the importance of medium polarity in molecular, cellular, and biochemical processes and the significance of reduced autofluorescence and deep tissue penetration of light in the NIR region, the findings reported herein represent an important advance toward using NIR molecular probes to measure the polarity of complex biological systems in vitro and in vivo.

The biodistribution of two near-infrared fluorescent agents was assessed in vivo by time-resolved diffuse optical imaging. Bacteriochlorophyll a (BC) and cypate-glysine-arginine-aspartic acid-serine-proline-lysine-OH (Cyp-GRD) were administered separately or combined to mice with subcutaneous xenografts of human breast adenocarcinoma and slow-release estradiol pellets for improved tumor growth. The same excitation (780 nm) and emission (830 nm) wavelengths were used to image the distinct fluorescence lifetime distribution of the fluorescent molecular probes in the mouse cancer model. Fluorescence intensity and lifetime maps were reconstructed after raster-scanning whole-body regions of interest by time-correlated single-photon counting. Each captured temporal point-spread function (TPSF) was deconvolved using both a single and a multiexponental decay model to best determine the measured fluorescence lifetimes. The relative signal from each fluorophore was estimated for any region of interest included in the scanned area. Deconvolution of the individual TPSFs from whole-body fluorescence intensity scans provided corresponding lifetime images for comparing individual component biodistribution. In vivo fluorescence lifetimes were determined to be 0.8 ns (Cyp-GRD) and 2 ns (BC). This study demonstrates that the relative biodistribution of individual fluorophores with similar spectral characteristics can be compartmentalized by using the time-domain fluorescence lifetime gating method.

Recent research shows high potential for some p-N,N-dialkylaminobenzylidenecyanoacetates, part of a group known as fluorescent molecular rotors, to serve as fluorescent, non-mechanical viscosity sensors. Of particular interest are molecules compatible with aqueous environments. In this study, we present the synthesis and physical characterization of derivatives from 9-(2-carboxy-2-cyanovinyl)-julolidine and related molecules. All compounds show a power-law relationship of fluorescence emission with the viscosity of the solvent, different mixtures of ethylene glycol and glycerol to modulate viscosity. Compounds with high water solubility exhibit the same behavior in aqueous solutions of dextran, where the dextran concentration was varied to modulate viscosity. In addition, some compounds have been found to have low sensitivity towards changes in the pH in the physiological range. The compounds presented show promise to be used in biofluids, such as blood plasma or lymphatic fluid, to rapidly and non-mechanically determine viscosity.

Angiotensin II and norepinephrine (NE) have been implicated in the neurohumoral response to pressure overload and the development of left ventricular hypertrophy. The purpose of this study was to determine the temporal sequence for activation of the renin-angiotensin and sympathetic nervous systems in the rat after 3-60 days of pressure overload induced by aortic constriction. Initially on pressure overload, there was transient activation of the systemic renin-angiotensin system coinciding with the appearance of left ventricular hypertrophy (day 3). At day 10, there was a marked increase in AT(1) receptor density in the left ventricle, increased plasma NE concentration, and elevated cardiac epinephrine content. Moreover, the inotropic response to isoproterenol was reduced in the isolated, perfused heart at 10 days of pressure overload. The affinity of the beta(2)-adrenergic receptor in the left ventricle was decreased at 60 days. Despite these alterations, there was no decline in resting left ventricular function, beta-adrenergic receptor density, or the relative distribution of beta(1)- and beta(2)-receptor sites in the left ventricle over 60 days of pressure overload. Thus activation of the renin-angiotensin system is an early response to pressure overload and may contribute to the initial development of cardiac hypertrophy and sympathetic activation in the compensated heart.

This study investigated the effect of verapamil metabolites on R- and S-verapamil protein binding in plasma samples collected from subjects prior to rac-verapamil dosing and following single dose and steady state rac-verapamil dosing. In vitro studies of the effects of norverapamil, D617 and D620 on R- and S-verapamil protein binding were also performed. Protein binding of R- and S-verapamil was unchanged following single and multiple doses of rac-verapamil as compared with protein binding in pre-dose samples. In vitro, norverapamil had no effect on R- and S-verapamil protein binding up to 1000 ng ml-1. Norverapamil 5000 ng ml-1 caused a 30% increase in free fraction of both R- and S-verapamil. D617 and D620 concentrations up to 5000 ng ml-1 had no effect on R- and S-verapamil protein binding. We conclude the metabolites of verapamil have no clinically significant effect on R- and S-verapamil protein binding.

Tyrosinamidomethyl dihydrohaloisoxazoles (THX) irreversibly inhibit isolated epidermal transglutaminases and ionophore-induced cell envelope formation in malignant human keratinocytes. In cultured human foreskin keratinocytes cultured in 10(-5) M THX for 5 days, soluble and particulate transglutaminases were inhibited by 90% and 44-51%, respectively. Spontaneous cell envelope formation was inhibited up to 54%. When THX-treated keratinocytes were simultaneously incubated with 10(-5) M retinoic acid (RA), there was enhanced inhibition of cell envelope formation compared to either agent alone. The inhibitors were equally effective in keratinocytes incubated with fetal calf serum or delipidized serum. After THX was applied to normal human thoracic skin in vivo for 9 d, the soluble and particulate transglutaminases isolated from suction blister epidermis were inhibited 30% and 40%, respectively. THX may be effective in inhibiting both soluble and particulate transglutaminase activity in disorders with increased transglutaminase activity.

The theory of fluid flow in compliant tubes developed in a previous paper is applied to a catheter, and the results of various calculations are compared with experiment. When a parabola is used for the unknown velocity profile, the calculated gains are too high. Agreement is slightly improved by using more reasonable profiles. It is shown that there exists a functional relationship between the parameter gamma and the nondimensional parameter alpha(10) which gives reasonable agreements with all the experimental data considered. The theory of Womersley is applied to the catheter, and the calculated gains are larger than those observed experimentally. A form for the frictional force suggested by Lambossy is used in some further calculations.