Molecular Tracers Research Articles

Dissecting and Visualizing the Functional Diversity of Cardiac Macrophages

Cardiac macrophages represent a functionally diverse population of cells involved in cardiac homeostasis, repair, and remodeling. With recent advancements in single-cell technologies, it is possible to elucidate specific macrophage subsets based on transcriptional signatures and cell surface protein expression to gain a deep understanding of macrophage diversity in the heart. The use of fate-mapping technologies and parabiosis studies have provided insight into the ontogeny and dynamics of macrophages identifying subsets derived from embryonic and adult definitive hematopoietic progenitors that include tissue-resident and bone marrow monocyte-derived macrophages, respectively. Within the heart, these subsets have distinct tissue niches and functional roles in the setting of homeostasis and disease, with cardiac resident macrophages representing a protective cell population while bone marrow monocyte-derived cardiac macrophages have a context-dependent effect, triggering both proinflammatory tissue injury, but also promoting reparative functions. With the increased understanding of the clinical relevance of cardiac macrophage subsets, there has been an increasing need to detect and measure cardiac macrophage compositions in living animals and patients. New molecular tracers compatible with positron emission tomography/computerized tomography and positron emission tomography/ magnetic resonance imaging have enabled investigators to noninvasively and serially visualize cardiac macrophage subsets within the heart to define associations with disease and measure treatment responses. Today, advancements within this thriving field are poised to fuel an era of clinical translation.

Relative alignment between gas structures and magnetic field in Orion A at different scales using different molecular gas tracers

Context. Magnetic fields can play a crucial role in high-mass star formation. Nonetheless, the significance of magnetic fields at various scales and their relationship with gas structures have been largely overlooked. Aims. Our goal is to examine the relationship between the magnetic field and molecular gas structures within the Orion A giant molecular cloud at different scales and density regimes. Methods. We assessed the gas intensity structures and column densities in Orion A using 12CO, 13CO, and C18O from Nobeyama observations. By comparing Nobeyama observations with Planck polarization observations on large scales (~0.6 pc) and JCMT polarization observations on small scales (~0.04 pc), we investigate how the role of magnetic fields changes with scale and density. Results. We find a similar trend from parallel to perpendicular alignment with increasing column density in Orion A at both large and small spatial scales. In addition, when changing from low-density to high-density tracers, the relative orientation preference changes from random to perpendicular. The self-similar results at different scales indicate that magnetic fields are dynamically important in both cloud formation and filament formation. However, magnetic field properties at small scales are relative complicated, and the interplay between magnetic field and star-forming activity needs to be discussed case by case.

On the Flux–Intensity Relation of Molecular Clouds

In this work, we report a study on the relationship between flux and intensity for molecular clouds. Our analysis is established on high-quality CO images from the Milky Way Imaging Scroll Painting project. The new flux–intensity relation characterizes the flux variation of molecular clouds above specific intensity levels. We found that the flux–intensity relation exhibits two prominent features. First, the flux–intensity relation generally follows exponential shapes; second, hierarchical structures of molecular clouds are imprinted on flux–intensity relations. Specifically, 12CO flux–intensity relations are composed of one or more exponential segments, and for molecular clouds with segmented flux–intensity relations, the edge and the flux of the high-temperature component are strikingly consistent with 13CO emission. Further analysis shows that a similar relationship also exists between 13CO flux–intensity relations and C18O emission. The mean brightness temperature of molecular clouds is tightly associated with the decay rate of flux, the break temperature of exponential segments, and, to a certain extent, the flux fraction of the high-temperature component. Broadly, the flux–intensity relation of a molecular tracer, either in optically thick or in optically thin cases, has the capability to outline the silhouette of internal structures of molecular clouds, proving to be a potent tool for probing structures of molecular clouds.

Reporting nanoparticle tracers: Validation of performance in flow-through experiments simulating reservoir conditions

Characterization and monitoring of reservoir properties and conditions are key problems in the exploitation of subsurface aquifers and reservoirs, with tracer tests being an important tool that provides valuable insights into groundwater dynamics. The Reporting Nanoparticle Tracers (RNTs) approach was recently presented with the aim of expanding the scope of measureable parameters and the potential benefits of tracer tests in comparison to tests performed with traditional tracers. However, successful implementation of the concept depends on the ability of the nanoparticle tracers to exhibit a stable dispersion that facilitates sufficiently high recovery rates to allow for meaningful analysis. As a step forward toward the implementation of the approach, we used flow‑through studies with packed-bed quartz sand columns to compare the transport and retention properties of the RNTs with those of prevalent conservative molecular tracers and to show the feasibility of temperature detection. In the main experiments, the RNTs showed recovery rates around 80%, outperformed only by uranine (95 %) and surpassing eosin and sulforhodamine G (15 % and 50 % respectively). Thermally-activated RNTs could also be clearly differentiated from non-activated ones by a signal ratio difference of 50 %. These results validate the feasibility of application, especially considering the modularity of the nanoparticles, which enables adjustment of the RNTs to the hydrochemical conditions prevalent in the tested aquifer.

[68Ga]Ga-NODAGA-TriGalactan, a low molecular weight tracer for the non-invasive imaging of the functional liver reserve

BackgroundDetermination of the functional liver mass is important in a variety of clinical settings including liver surgery and transplantation. [99mTc]Tc-diethylenetriamine-pentaacetic acid galactosyl human serum albumin (99mTc-GSA) is a radiotracer targeting the asialoglycoprotein receptor (ASGR) and is routinely used in Japan for this purpose. Here we describe the development and evaluation of [68Ga]Ga-NODAGA-TriGalactan a low molecular weight PET-tracer targeting this structure.ResultsFor synthesis TRIS as branching unit and NODAGA as chelator for labelling with [68Ga]Ga are included. Three galactose moieties are conjugated via a click chemistry approach resulting in the desired labelling precursor.68Ga-labelling could be accomplished in high radiochemical yield and purity. [68Ga]Ga-NODAGA-TriGalactan is very hydrophilic and revealed high plasma stability and low plasma protein binding. Fluorescence imaging showed binding on ASGR-positive organoids and the IC50-value was in the nanomolar range. Most importantly, both biodistribution as well as animal imaging studies using normal mice demonstrated high liver uptake with rapid elimination from all other organs leading to even higher liver-to-background ratios as found for 99mTc-GSA.Conclusion[68Ga]Ga-NODAGA-TriGalactan shows high in vitro stability and selectively binds to the ASGR allowing imaging of the functional liver mass with high contrast. Thus, our first generation compound resulted already in an alternative to 99mTc-GSA for imaging the functional liver reserve and might allow the broader use of this imaging technique.

Osteochondral fluid transport in an ex vivo system

ObjectiveAlterations to fluid transport from bone-to-cartilage may contribute to the development of osteoarthritis. Larger biological molecules found in bone may transport from bone-to-cartilage (e.g., insulin, 5kDa). However, many questions remain about fluid transport between these tissues. The objectives of this study were to (1) test for diffusion of 3kDa molecular tracers from bone-to-cartilage and (2) assess potential differences in bone-to-cartilage fluid transport between different loading conditions. DesignOsteochondral cores extracted from bovine femurs (N=10 femurs, 10 cores/femur) were subjected to either no-load (i.e., pure diffusion), pre-load only, or cyclic compression (5±2% or 10±2% strain) in a two-chamber transport system. The bone was placed into the bone compartment followed by a 3kDa dextran tracer, and tracer concentrations in the cartilage compartment were measured every 5 minutes for 120 minutes. Tracer concentrations were analyzed for differences in beginning, peak and equilibrium concentrations, loading effects, and time-to-peak tracer concentration. ResultsPeak tracer concentration in the cartilage compartment was significantly higher compared to beginning and equilibrium tracer concentrations indicating fluid transport from bone-to-cartilage. Cartilage-compartment tracer concentration, and maximum fluorescent intensity was influenced by strain magnitude. No time-to-peak relationship was found when comparing strain magnitudes impact on cartilage-compartment tracer concentration. ConclusionThis study shows that osteochondral fluid transport occurs from bone-to-cartilage with 3kDa dextran molecules. These are much larger molecules to move between bone and cartilage than previously reported. Further, these results demonstrate the potential for cyclic compression to impact osteochondral fluid transport. Determining the baseline osteochondral fluid transport in healthy tissues is crucial to elucidating the potential mechanisms of progression and onset of osteoarthritis.

Synthesis, Screening, and Evaluation of Theranostic Molecular CPCR4-Based Probe Targeting CXCR4.

Chemokines and chemokine receptors are indispensable to play a key role in the development of malignant tumors. As one of the most widely expressed chemokine receptors, chemokine (C-X-C motif) receptor 4 (CXCR4) has been a popular research focus. In most tumors, CXCR4 expression is significantly upregulated. Moreover, integrated nuclide diagnosis and therapy targeting CXCR4 show great potential. [68Ga]Ga-pentixafor, a radioligand targeting CXCR4, exhibits a strong affinity for CXCR4 both in vivo and in vitro. However, [177Lu]Lu-pentixather, the therapeutic companion of [68Ga]Ga-pentixafor, requires significant refinement to mitigate its pronounced hepatic biodistribution. The objective of this study was to synthesize theranostic molecular tracers with superior CXCR4 targeting functions. The Daudi cell line, which highly expressed CXCR4, and the MM.1S cell line, which weakly expressed CXCR4, were used in this study. Based on the pharmacophore cyclo (-d-Tyr-n-me-d-Orn-l-Arg-L-2-NAL-Gly-) (CPCR4) of pentixafor, six tracers were synthesized: [124I]I-1 ([124I]I-CPCR4), [99mTc]Tc-2 ([99mTc]Tc-HYNIC-CPCR4), [124I]I-3 ([124I]I-pentixafor), [18F]AlF-4 ([18F]AlF-NETA-CPCR4), [99mTc]Tc-5 ([99mTc]Tc-MAG3-CPCR4) and [124I]I-6 ([124I]I-pentixafor-Ga) and their radiochemical purities were all higher than 95%. After positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging, the [124I]I-6 group exhibited the best target-nontarget ratio. At the same time, comparing the [68Ga]Ga-pentixafor group with the [124I]I-6 group, we found that the [124I]I-6 group had a better target-nontarget ratio and lower uptake in nontarget organs. Therefore, compound 6 was selected for therapeutic radionuclide (131I) labeling, and the tumor-bearing animal models were treated with [131I]I-6. The volume of the tumor site was significantly reduced in the treatment group compared with the control group, and no significant side effects were found. [124I]I-6 and [131I]I-6 showed excellent affinity for targeting CXCR4, and they showed great potential for the integrated diagnosis and treatment of tumors with high CXCR4 expression.

Benzocarbazole and methylxanthone molecular migration tracers unravel migration routes and filling history of Veslefrikk, Oseberg-East and Brage reservoirs in the Norwegian North Sea

Identification of petroleum migration routes and reservoir filling processes is feasible by applying carbazoles or xanthones as molecular migration tracers. To verify their utility, a well-constrained migration route was chosen for this study: the petroleum migration along the Veslefrikk and Oseberg East fields until reaching the Statfjord Formation compartment within the Brage field in the Norwegian North Sea. This migration route comprises an ideal test case because the oil is sourced from the same kitchen area, yielding very similar oil families in all three fields, and because the maturity remains within the main oil window, below 0.9 Ro % vitrinite reflectance equivalence.Different methodologies applied by two laboratories, from sample preparation to analytical methods, yielded identical results of migration direction and route using the benzocarbazole ratio ([a]/([a]+[c]), thus underlining practicability and robustness of this molecular migration parameter. The benzocarbazole ratio (BCR) in this study was neither affected by source rock facies, and/or biodegradation. A thermal maturity effect on BCR is considered here to be of only subordinate impact whereas it substantially affects benzocarbazole concentrations. The BCR declined from values of 0.68 at onset of migration to 0.42 at end of migration, whereby the absolute concentrations of benzocarbazoles in parallel declined by a factor of 10, from 5000 to 500 ng/g oil. The distribution and concentration of methylxanthones evolved comparable to that of benzocarbazoles. The methylxanthones ratios (MXR) from onset of migration until reaching the Brage field declined from a value of 0.85 to 0.42. The benzocarbazoles and methylxanthones, like other geo/biomarkers, preferentially reflect the first charge of the most polar and least mature oil delivered upon petroleum migration and could help to understand the reservoir filling history.Migrating oils derived from the Sogn Graben kitchen entered the Veslefrikk oil field first and continued until the structure was filled to spill point. Thereafter, migration continued to the Oseberg East oil field and after reaching spill point there it continued to the Brage field and its Statfjord formation compartment. The complex migration route represents a classical fill to spill scenario and benzocarbazole fractionation upon migration delineates the initial filling trends. The maturity values of crude oils are in the mid-oil window and show trends of covariance with the molecular migration indicators, thus proving to be supporting tracers in a classical fill to spill scenario, where maturity values are lowest when migration distances are greatest. This is due to the first expelled oil being of lowest thermal maturity entering the nearest reservoir first and then being displaced into farther reservoirs along the migration route upon arrival of later oil (more mature) charges.

Accuracy of ALMA estimates of young disk radii and masses

Context. Protoplanetary disks, which are the natural consequence of the gravitational collapse of the dense molecular cloud cores, host the formation of the known planetary systems in our universe. Substantial efforts have been dedicated to investigating the properties of these disks in the more mature Class II stage, either via numerical simulations of disk evolution from a limited range of initial conditions or observations of their dust continuum and line emission from specific molecular tracers. The results coming from these two standpoints have been used to draw comparisons. However, few studies have investigated the main limitations at work when measuring the embedded Class 0/I disk properties from observations, especially in a statistical fashion. Aims. In this study, we provide a first attempt to compare the accuracy of some critical disk parameters in Class 0/I systems, as derived on real ALMA observational data, with the corresponding physical parameters that can be directly defined by theoreticians and modellers in numerical simulations. The approach we follow here is to provide full post-processing of the numerical simulations and apply it to the synthetic observations the same techniques used by observers to derive the physical parameters. Methods. We performed 3D Monte Carlo radiative transfer and mock interferometric observations of the disk populations formed in a magnetohydrodynamic (MHD) simulation model of disk formation through the collapse of massive clumps with the tools RADMC-3D and CASA, respectively, to obtain their synthetic observations. With these observations, we re-employed the techniques commonly used in disk modelling from their continuum emissions to infer the properties that would most likely be obtained with real interferometers. We then demonstrated how these properties may vary with respect to the gas kinematics analyses and dust continuum modelling. Results. Our modelling procedure, based on a two-component model for the disk and the envelope, shows that the disk sizes can be properly recovered from observations with sufficient angular resolutions, with an uncertainty of a factor ≈1.6–2.2, whereas their masses cannot be accurately measured. Overall, the masses are predominantly underestimated for larger, more massive disks by a median factor of ≈2.5, and even up to 10 in extreme cases, with the conversion from flux to dust mass under the optically thin assumption. We also find that the single Gaussian fittings are not a reliable modelling technique for young, embedded disks characterised by a strong presence of the envelopes. Thus, such an approach is to be used with caution. Conclusions. The radiative transfer post-processing and synthetic observations of MHD simulations offer genuine help in linking important observable properties of young planet-forming disks to their intrinsic values in simulations. Further extended investigations that tackle the caveats of this study, such as the lack of variation in the dust composition and distribution, dust-to-gas ratio, and other shortcomings in the numerical models, would be essential for setting constraints on our understanding of disk and planet formations.

The cold molecular gas in z ≳ 6 quasar host galaxies

Context. Probing the molecular gas reservoirs of z ≳ 6 quasar (QSO) host galaxies is fundamental to understanding the coevolution of star formation and black hole growth in these extreme systems. Yet, there is still an inhomogeneous coverage of molecular gas tracers for z ≳ 6 QSO hosts. Aims. To measure the average excitation and mass of the molecular gas reservoirs in the brightest z > 6.5 QSO hosts, we combined new observations of CO(2–1) emission with existing observations of CO(6–5), CO(7–6), [C I] (2–1), [C II] 158 μm, and dust-continuum emission. Methods. We reduced and analysed observations of CO(2–1), taken with the Karl G. Jansky Very Large Array, in three z = 6.5 − 6.9 QSO hosts – the highest redshift observations of CO(2–1) to date. By combining these with the nine z = 5.7 − 6.4 QSO hosts for which CO(2–1) emission has already been observed, we studied the spread in molecular gas masses and CO excitation of z ≳ 6 QSOs. Results. Two of our three QSOs, P036+03 and J0305–3150, were not detected in CO(2–1), implying more highly excited CO than in the well-studied z = 6.4 QSO J1148+5251. However, we detected CO(2–1) emission at 5.1σ for our highest-redshift target, J2348–3054, yielding a molecular gas mass of (1.2 ± 0.2)×1010 M⊙, assuming αCO = 0.8 (K km s−1 pc2)−1 and r2, 1 = 1. This molecular gas mass is equivalent to the lower limit on the dynamical mass measured previously from resolved [C II] 158 μm observations, implying that there is little mass in stars or neutral gas within the [C II]-emitting region and that a low CO-to-H2 conversion factor is applicable. On average, these z ≳ 6 QSO hosts have far higher CO(6–5)-, CO(7–6)-, and [C II] 158 μm versus CO(2–1) line ratios than the local gas-rich and IR-luminous galaxies that host active galactic nuclei, but with a large range of values, implying some variation in their interstellar medium conditions. We derived a mean CO(6–5)-to-CO(1–0) line luminosity ratio of r6, 1 = 0.9 ± 0.2. Conclusions. Our new CO(2–1) observations show that even at 780 Myr after the Big Bang, QSO host galaxies can already have molecular gas masses of 1010 M⊙, consistent with a picture in which these z ≳ 6 QSOs reside in massive starbursts that are coevolving with the accreting supermassive black holes. Their high gas versus dynamical masses and extremely high line excitation imply the presence of extremely dense and warm molecular gas reservoirs illuminated by strong interstellar radiation fields.

Advances in the Separation and Detection of Secondary Organic Aerosol Produced by Decamethylcyclopentasiloxane (D5) in Laboratory-Generated and Ambient Aerosol.

Decamethylcyclopentasiloxane (D5), a common ingredient in many personal care products (PCPs), undergoes oxidation in the atmosphere, leading to the formation of secondary organic aerosol (SOA). Yet, the specific contributions of D5-derived SOA on ambient fine particulate matter (PM2.5) have not been characterized. This study addresses this knowledge gap by introducing a new analytical method to advance the molecular characterization of oxidized D5 and its detection in ambient aerosol. The newly developed reversed phase liquid chromatography method, in conjunction with high-resolution mass spectrometry, separates and detects D5 oxidation products, enabling new insights into their molecular and isomeric composition. Application of this method to laboratory-generated SOA and urban PM2.5 in New York City expands the number of D5 oxidation products observed in ambient aerosol and informs a list of molecular candidates to track D5-derived SOA in the atmosphere. An oxidation series was observed in which one or more methyl groups in D5 (C10H30O5Si5) is replaced by a hydroxyl group, which indicates the presence of multistep oxidation products in ambient PM2.5. Because of their specificity to PCPs and demonstrated detectability in ambient PM2.5, several oxidation products are proposed as molecular tracers for D5-derived SOA and may prove useful in assessing the impact of PCPs-derived SOA in the atmosphere.

Variable aging and storage of dissolved black carbon in the ocean

During wildfires and fossil fuel combustion, biomass is converted to black carbon (BC) via incomplete combustion. BC enters the ocean by rivers and atmospheric deposition contributing to the marine dissolved organic carbon (DOC) pool. The fate of BC is considered to reside in the marine DOC pool, where the oldest BC 14C ages have been measured (>20,000 14C y), implying long-term storage. DOC is the largest exchangeable pool of organic carbon in the oceans, yet most DOC (>80%) remains molecularly uncharacterized. Here, we report 14C measurements on size-fractionated dissolved BC (DBC) obtained using benzene polycarboxylic acids as molecular tracers to constrain the sources and cycling of DBC and its contributions to refractory DOC (RDOC) in a site in the North Pacific Ocean. Our results reveal that the cycling of DBC is more dynamic and heterogeneous than previously believed though it does not comprise a single, uniformly "old" 14C age. Instead, both semilabile and refractory DBC components are distributed among size fractions of DOC. We report that DBC cycles within DOC as a component of RDOC, exhibiting turnover in the ocean on millennia timescales. DBC within the low-molecular-weight DOC pool is large, environmentally persistent and constitutes the size fraction that is responsible for long-term DBC storage. We speculate that sea surface processes, including bacterial remineralization (via the coupling of photooxidation of surface DBC and bacterial co-metabolism), sorption onto sinking particles and surface photochemical oxidation, modify DBC composition and turnover, ultimately controlling the fate of DBC and RDOC in the ocean.

Porous Membrane Electrical Cell-Substrate Impedance Spectroscopy for Versatile Assessment of Biological Barriers In Vitro.

Cell culture models of endothelial and epithelial barriers typically use porous membrane inserts (e.g., Transwell inserts) as a permeable substrate on which barrier cells are grown, often in coculture with other cell types on the opposite side of the membrane. Current methods to characterize barrier function in porous membrane inserts can disrupt the barrier or provide bulk measurements that cannot isolate barrier cell resistance alone. Electrical cell-substrate impedance sensing (ECIS) addresses these limitations, but its implementation on porous membrane inserts has been limited by costly manufacturing, low sensitivity, and lack of validation for barrier assessment. Here, we present porous membrane ECIS (PM-ECIS), a cost-effective method to adapt ECIS technology to porous substrate-based in vitro models. We demonstrate high fidelity patterning of electrodes on porous membranes that can be incorporated into well plates of a variety of sizes with excellent cell biocompatibility with mono- and coculture set ups. PM-ECIS provided sensitive, real-time measurement of isolated changes in endothelial cell barrier impedance with cell growth and barrier disruption. Barrier function characterized by PM-ECIS resistance correlated well with permeability coefficients obtained from simultaneous molecular tracer permeability assays performed on the same cultures, validating the device. Integration of ECIS into conventional porous cell culture inserts provides a versatile, sensitive, and automated alternative to current methods to measure barrier function in vitro, including molecular tracer assays and transepithelial/endothelial electrical resistance.

Visual afferents from an eye in the terrestrial slug Limax valentianus.

Terrestrial gastropods have a lens-bearing eye on the tip of their tentacles. There are two morphologically distinct photoreceptors, called Type-I and Type-II photoreceptors, in the retina. Type-I photoreceptors are equipped with highly developed photoreceptive microvilli in their outer rhabdomeric segment, whereas Type-II photoreceptors have short and fewer microvilli. Although both types of photoreceptors send afferent projections directly to the brain, their destinations in the brain, called optic neuropiles, have not been sufficiently investigated. Our recent studies revealed that there are commissural fibers in the cerebral ganglia that transmit photic information acquired by bilateral eyes. Moreover, some of the retinal photoreceptors are connected by gap junctions to the photosensitive brain neurons, suggesting the functional interaction of the photic information between the eye and brain photoreceptors, as well as between bilateral eyes. However, it has not been clarified which type of retinal photoreceptors send commissural projections to the contralateral hemiganglion nor interact with the brain photoreceptors. In the present study, we demonstrated by molecular histological analyses and tracer injections that (1) Type-I and Type-II photoreceptors send glutamatergic afferent projections to the medial and lateral lobes of the ipsilateral optic neuropile, respectively, (2) direct synaptic interaction between bilateral optic nerves occurs in the medial lobe of the optic neuropile, and (3) brain photosensory neurons form gap junctions with the medial lobe of the contralateral optic neuropile. These results reveal an ordered pattern of afferent projections from the retina and provide insight into the different functional roles of retinal photoreceptors.

Recent preclinical and clinical advances in radioimmunotherapy for non-Hodgkin's lymphoma.

Radioimmunotherapy (RIT) is a therapy that combines a radioactive nucleotide with a monoclonal antibody (mAb). RIT enhances the therapeutic effect of mAb and reduces toxicity compared with conventional treatment. The purpose of this review is to summarize the current progress of RIT for treating non-Hodgkin's lymphoma (NHL) based on recent preclinical and clinical studies. The efficacy of RIT targeting the B-lymphocyte antigen cluster of differentiation 20 (CD20) has been demonstrated in clinical trials. Two radioimmunoconjugates targeting CD20, yttrium-90 (90Y)-ibritumomab-tiuxetan (Zevalin) and iodine-131 (131I)-tositumomab (Bexxar), have been approved in the USA Food and Drug Administration (FDA) for treating relapsed/refractory indolent or transformed NHL in 2002 and 2003, respectively. Although these two radioimmunoconjugates are effective and least toxic, they have not achieved popularity due to increasing access to novel therapies and the complexity of their delivery process. RIT is constantly evolving with the identification of novel targets and novel therapeutic strategies using newer radionuclides such as alpha-particle isotopes. Alpha-particles show very short path lengths and high linear energy transfer. These characteristics provide increased tumor cell-killing activities and reduced non-specific bystander responses on normal tissue. This review also discusses reviewed pre-targeted RIT (PRIT) and immuno-positron emission tomography (PET). PRIT potentially increases the dose of radionuclide delivered to tumors while toxicities to normal tissues are limited. Immuno-PET is a molecular imaging tracer that combines the high sensitivity of PET with the specific targeting capability of mAb. Immuno-PET strategies targeting CD20 and other antigens are currently being developed. The theragnostic approach by immuno-PET will be useful in monitoring the treatment response.

Synthesis and Preclinical Evaluation of Novel 99mTc-Labeled FAPI-46 Derivatives with Significant Tumor Uptake and Improved Tumor-to-Nontarget Ratios.

Fibroblast activation protein (FAP), which is expressed on the cell membranes of fibroblasts in most solid tumors, has become an important target for tumor diagnosis and treatment. However, previously reported 99mTc-labeled FAPI-04 complexes have high blood uptake, limiting their use in the clinic. In this work, six 99mTc-labeled FAPI-46 derivatives with different linkers (different amino acids, peptides, or polyethylene glycol) were prepared and evaluated. They had good in vitro stability, hydrophilicity, and good specificity for FAP. The biodistribution and MicroSPECT images revealed that they all had high specific tumor uptake for FAP, and their blood uptake was significantly decreased. Among them, [99mTc]Tc-6-1 exhibited the highest target-to-nontarget ratios (tumor/blood: 6.06 ± 1.19; tumor/muscle: 10.26 ± 0.44) and good tumor uptake (16.15 ± 0.83%ID/g), which also had significantly high affinity for FAP, good in vivo stability, and safety. Therefore, [99mTc]Tc-6-1 holds great potential as a promising molecular tracer for FAP tumor imaging.

RadioLabeling of the Mutant form of Anti-PlGF Nanobody by 99mTc-Tricarbonyl.

Molecular imaging is a highly effective method for diagnosing cancer and evaluating treatment. A molecular tracer often consists of two segments: A targeting segment, which can be antibodies, antibody fragments, or VHH (nanobody), and a detection segment, such as radioisotopes. The small size of VHH allows for excellent tissue penetration and fast clearance, resulting in minimal nonspecific background, which makes them appealing for use as imaging agents. 99m-technetium (99mTc), one of the well-known radioisotopes, is particularly useful in routine clinical imaging. This study aims to construct 99mTc-anti-placenta growth factor (PlGF) nanobody and assess its radiochemical purity (RCP). The mutant form of anti-PlGF nanobody was expressed in E. coli TG1 and purified using Ni-NTA column affinity chromatography. The purified nanobodies were confirmed by SDS-PAGE and western blotting. A 99mTc-tricarbonyl solution was added to phosphate-buffered saline (PBS) containing the mutant nanobody for labeling, and the mixture was purified using a PD-10 column. The RCP of 99mTc-tricarbonyl is > 98%. After the addition of radioisotopes to the mixture of nanobodies, purity reached 70% in 2 hours and remained constant during incubation. After purifying the labeled nanobody, activity was measured, and the highest amount of labeled nanobodies was collected in the second part. The stability of the labeled nanobody in PBS and in competition with histidine for 4 hours was checked by thin-layer chromatography (TLC). The findings of this study reveal that the RCP of the labeled nanobody was above 95% after 4 hours, indicating the labeled antibody's stability. These results are promising and could be utilized in future in vitro and in vivo studies.

Short-term source apportionment of fine particulate matter with time-dependent profiles using SoFi Pro: exploring the reliability of rolling positive matrix factorization (PMF) applied to bihourly molecular and elemental tracer data

Abstract. Positive matrix factorization (PMF) has been widely used to apportion the sources of fine particulate matter (PM2.5) by utilizing PM chemical speciation data measured at the receptor site(s). Traditional PMF, which typically relies on long-term observational datasets of daily or lower time resolution to meet the required sample size, has its reliability undermined by changes in source profiles; thus, it is inherently ill-suited for apportioning sporadic sources or ephemeral pollution events. In this study, we explored short-term source apportionment of PM2.5 using a set of bihourly chemical speciation data over a period of 37 d in the winter of 2019–2020. PMF run with campaign-wide data as input (PMFref) was initially conducted to obtain reference profiles for the primary source factors. Subsequently, short-term PMF analysis was performed using the Source Finder Professional (SoFi Pro). The analysis sets a window length of 18 d and constrained the primary source profiles using the a-value approach embedded in SoFi Pro software. Rolling PMF was then conducted with a fixed window length of 18 d and a step of 1 d using the remaining dataset. By applying the a-value constraints to the primary sources, the rolling PMF effectively reproduced the individual primary sources, as evidenced by the slope values close to unity (i.e., 0.9–1.0). However, the estimation for the firework emission factor in the rolling PMF was lower compared with PMFref (slope: 0.8). These results suggest the unique advantage of short-term PMF analysis in accurately apportioning sporadic sources. Although the total secondary sources were well modeled (slope: 1.0), larger biases were observed for individual secondary sources. The variation in source profiles indicated higher variabilities for the secondary sources, with average relative differences ranging from 42 % to 173 %, while the primary source profiles exhibited much smaller variabilities (relative differences of 8 %–26 %). This study suggests that short-term PMF analysis with the a-value constraints in SoFi Pro can be utilized to apportion primary sources accurately, while future efforts are needed to improve the prediction of individual secondary sources. Additionally, future rapid source apportionment analysis can benefit from utilizing a library of source profiles derived from existing measurement data, thereby significantly reducing the time lag associated with receptor modeling source apportionment techniques.

Aerosol source apportionment uncertainty linked to the choice of input chemical components

For a Positive Matrix Factorization (PMF) aerosol source apportionment (SA) studies there is no standard procedure to select the most appropriate chemical components to be included in the input dataset for a given site typology, nor specific recommendations in this direction. However, these choices are crucial for the final SA outputs not only in terms of number of sources identified but also, and consequently, in the source contributions estimates. In fact, PMF tends to reproduce most of PM mass measured independently and introduced as a total variable in the input data, regardless of the percentage of PM mass which has been chemically characterized, so that the lack of some specific source tracers (e.g. levoglucosan) can potentially affect the results of the whole source apportionment study. The present study elaborates further on the same concept, evaluating quantitatively the impact of lacking specific sources’ tracers on the whole source apportionment, both in terms of identified sources and source contributions. This work aims to provide first recommendations on the most suitable and critical components to be included in PMF analyses in order to reduce PMF output uncertainty as much as possible, and better represent the most commons PM sources observed in many sites in Western countries. To this aim, we performed three sensitivity analyses on three different datasets across EU, including extended sets of organic tracers, in order to cover different types of urban conditions (Mediterranean, Continental, and Alpine), source types, and PM fractions. Our findings reveal that the vehicle exhaust source resulted to be less sensitive to the choice of analytes, although source contributions estimates can deviate significantly up to 44 %. On the other hand, for the detection of the non-exhaust one is clearly necessary to analyze specific inorganic elements. The choice of not analysing non-polar organics likely causes the loss of separation of exhaust and non-exhaust factors, thus obtaining a unique road traffic source, which provokes a significant bias of total contribution. Levoglucosan was, in most cases, crucial to identify biomass burning contributions in Milan and in Barcelona, in spite of the presence of PAHs in Barcelona, while for the case of Grenoble, even discarding levoglucosan, the presence of PAHs allowed identifying the BB factor. Modifying the rest of analytes provoke a systematic underestimation of biomass burning source contributions. SIA factors resulted to be generally overestimated with respect to the base case analysis, also in the case that ions were not included in the PMF analysis. Trace elements were crucial to identify shipping emissions (V and Ni) and industrial sources (Pb, Ni, Br, Zn, Mn, Cd and As). When changing the rest of input variables, the uncertainty was narrow for shipping but large for industrial processes. Major and trace elements were also crucial to identify the mineral/soil factor at all cities. Biogenic SOA and Anthropogenic SOA factors were sensitive to the presence of their molecular tracers, since the availability of OC alone is unable to separate a SOA factor. Arabitol and sorbitol were crucial to detecting fungal spores while odd number of higher alkanes (C27 to C31) for plant debris.

A pH-Sensitive I-Motif Aptamer Probe for Dual Targeting and Imaging of Pancreatic Cancer Cells via Nucleolin Interactions

This study investigates the targeted imaging and tumor inhibition effects of a “signal-off” imaging-based activatable aptamer probe (I-AAP) for pancreatic cancer. AS1411, contained in the I-AAP probe, targets the nucleolin and i-motifs on the membrane surfaces of pancreatic cancer cells (PANC-1) and has a dual response to pH and an acidic environment. In vitro, a “signal-off” type I-AAP probe was constructed that possesses a fluorescence effect in a phosphate buffer solution at pH 6.0 and 6.5. The probe has no fluorescence effect at pH 7.0 or 7.5; thus, the “signal-off” type I-AAP probe has a targeted acid-sensitive response in pancreatic cancer and a tumor microenvironment imaging effect. After incubation for 30 min, AS1411 was taken up by PANC-1 cells and reached its peak value within 2 h. AS1411 inhibited pancreatic cancer cells in a time-dependent manner. This “signal-off” I-AAP probe is expected to be suitable for a low-background and high-specificity molecular pathologic tracer technique, making use of the presence of nucleolins on the surface of pancreatic cancer cells and the low pH response of the tumor microenvironment.