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Elevated TNF-α levels in serum and broncho-alveolar lavage fluid of acute lung injury patients correlate with mortality rates. We hypothesized that pharmacological plasma membrane potential (Em) hyperpolarization protects against TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells through inhibition of inflammatory Ca2+-dependent MAPK pathways. Since the role of Ca2+ influx in TNF-α-mediated inflammation remains poorly understood, we explored the role of L-type voltage-gated Ca2+ (CaV) channels in TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells. The CaV channel blocker, Nifedipine, decreased both CCL-2 and IL-6 secretion, suggesting that a fraction of CaV channels is open at the significantly depolarized resting Em of human microvascular pulmonary endothelial cells (-6 ± 1.9 mV), as shown by whole-cell patch-clamp measurements. To further explore the role of CaV channels in cytokine secretion, we demonstrated that the beneficial effects of Nifedipine could also be achieved by Em hyperpolarization via the pharmacological activation of large conductance K+ (BK) channels with NS1619, which elicited a similar decrease in CCL-2 but not IL-6 secretion. Using functional gene enrichment analysis tools, we predicted and validated that known Ca2+-dependent kinases, JNK-1/2 and p38, are the most likely pathways to mediate the decrease in CCL-2 secretion.

There are no targeted medical therapies for Acute Lung Injury (ALI) or its most severe form acute respiratory distress syndrome (ARDS). Infections are the most common cause of ALI/ARDS and these disorders present clinically with alveolar inflammation and barrier dysfunction due to the influx of neutrophils and inflammatory mediator secretion. We designed the C6 peptide to inhibit voltage-gated proton channels (Hv1) and demonstrated that it suppressed the release of reactive oxygen species (ROS) and proteases from neutrophils in vitro. We now show that intravenous C6 counteracts bacterial lipopolysaccharide (LPS)-induced ALI in mice, and suppresses the accumulation of neutrophils, ROS, and proinflammatory cytokines in bronchoalveolar lavage fluid. Confirming the salutary effects of C6 are via Hv1, genetic deletion of the channel similarly protects mice from LPS-induced ALI. This report reveals that Hv1 is a key regulator of ALI, that Hv1 is a druggable target, and that C6 is a viable agent to treat ALI/ARDS.

We recently established a role for the stretch-activated two-pore-domain K+ (K2P) channel TREK-1 (K2P2.1) in inflammatory cytokine secretion using models of hyperoxia-, mechanical stretch-, and TNF-α-induced acute lung injury. We have now discovered the expression of large conductance, Ca2+-activated K+ (BK) channels in human pulmonary microvascular endothelial cells and primary human alveolar epithelial cells using semiquantitative real-time PCR, IP and Western blot, and investigated their role in inflammatory cytokine secretion using an LPS-induced acute lung injury model. As expected, LPS induced IL-6 and CCL-2 secretion from pulmonary endothelial and epithelial cells. BK activation with NS1619 decreased LPS-induced CCL-2 but not IL-6 secretion from endothelial cells and had no effect on epithelial cells, although fluorometric assays revealed that BK activation hyperpolarized the plasma membrane potential (Em) of both cell types. Interestingly, BK inhibition (Paxilline) did not alter cytokine secretion or the Em in either cell type. Furthermore, LPS treatment by itself did not affect the Em or intracellular Ca2+ concentrations. Therefore, we propose BK channel activation as a novel targeted approach to counteract LPS-induced CCL-2 secretion from endothelial cells. This protective effect appears to occur via Em hyperpolarization but independent of intracellular Ca2+ concentrations.

No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2P2.1 (TREK-1) K+ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca2+ channels (CaV) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa2+ concentrations. In addition, CCL-2 secretion was decreased after L-type CaV inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.

Background: Yttrium‐90 (90Y) positron emission tomography (PET)/computed tomography (CT) imaging is increasingly being used to perform tumor (T) and normal liver (NL) voxel dosimetry after 90Y‐radioembolization (90Y‐RE). Yet, the accuracy of in vivo 90Y‐PET/CT imaging, subject to motion blur and co‐registration inaccuracies, and 90Y‐PET/CT dose quantification, subject to availability of different voxel dosimetry algorithms, are not well understood. Purpose: The purpose of this study was to investigate the accuracy of 90Y‐PET/CT‐based activity estimates following 90Y‐RE and characterize differences between 90Y‐PET/CT‐based voxel dosimetry algorithms. Methods: Thirty‐five patients underwent 90Y‐PET/CT imaging after 90Y‐RE with TheraSphere. The net administered 90Y activity (Aadmin) was determined using a dose calibrator and pre‐ and post‐procedure exposure rate measurements. The summation of image‐based activity (Aimage) was extracted from perfused volume (PV) and 3D‐isotropically 2‐cm expanded PV contour (PV+2 cm). Absorbed doses were calculated using voxel S‐value (VSV), local deposition method (LDM), and LDM with known activity (LDMKA) dosimetry algorithms. Linear regression and Bland‐Altman analysis quantified the relationship between Aimage and Aadmin and between mean dose estimates (DLDM, DVSV, DLDM‐KA) for PV, T, and perfused NL volumes. Results: While Aadmin and Aimage in PV were highly correlated (R2 > 0.95), the mean bias ± standard error (SE) and (95% limits of agreement, LOA) was significantly non‐zero with −22.7 ± 4.7% (± 28.4%). In PV+2 cm, the mean bias ± SE (± LOA) decreased to 1.3 ± 3.4% (± 18.0%) consistent with zero mean error. DLDM and DVSV were highly correlated (R2 > 0.99) for all volumes of interest (VOIs) and the mean bias ± SE (± LOA) was 2.2 ± 0.2% (± 1.0%), 0.7 ± 0.4% (± 2.8%), and 3.2 ± 0.5% (± 2.8%) for PV, T, and NL, respectively. DLDM‐KA and DVSV were correlated with R2 = 0.86, 0.80, and 0.86 for PV, T, and NL, respectively. The mean bias ± SE (± LOA) between DLDM‐KA and DVSV was significantly non‐zero with −19.6 ± 5.1% (± 31.0%), −20.8 ± 4.4% (± 29.0%), and −18.1 ± 5.3% (± 31.1%) for PV, T, and NL, respectively. Conclusions: The summation of Aimage in PV was underestimated relative to Aadmin. Only by accounting for respiratory motion, limited spatial resolution, and PET/CT co‐registration errors through VOI expansion was Aimage, on average, equal to Aadmin. The differences between DLDM and DVSV were not clinically relevant, though DLDM‐KA was approximately 20% greater than DVSV. Given the high quantitative accuracy of dose calibrators and challenges associated with accurate 90Y‐PET/CT quantification, LDMKA is the preferred algorithm for accurate 90Y‐PET/CT‐based dosimetry following 90Y‐RE. [ABSTRACT FROM AUTHOR]

Background: Following yttrium‐90 radioembolization (90Y‐RE), 90Y‐PET/CT and 90Y‐SPECT/CT imaging provide the means to calculate the voxelized absorbed dose distribution. Given the widespread use of the two imaging modalities and lack of well‐established standardized dosimetry protocols for 90Y‐RE, there is a clinical need to systematically investigate and evaluate differences in the performance of voxel‐based dosimetry between 90Y‐PET/CT and 90Y‐SPECT/CT. Purpose: To quantitatively analyze and compare 90Y‐PET/CT and 90Y‐SPECT/CT‐based dosimetry following 90Y‐RE. Methods: 90Y‐PET/CT and 90Y‐SPECT/CT imaging was acquired for 35 patients following 90Y‐RE with TheraSphere for the treatment of unresectable hepatocellular carcinoma. Dosimetry was performed using the local deposition method with known activity and the mean dose (Dmean) was calculated for perfused liver volumes (PV), tumors (T), and perfused normal livers (NL). Additionally, the absorbed dose to x% of the volume (Dx, x ∈$ \in $ [5%, 10%, ..., 90%, 95%]) and the volume receiving y Gy (Vy, y ∈$ \in $ [10 Gy, 20 Gy, ..., 190 Gy, 200 Gy]) were calculated for T and NL, respectively. Dose metrics were compared using linear regression, Bland‐Altman analysis, and statistical testing. Results: Both 90Y‐SPECT/CT and 90Y‐PET/CT‐based tumor Dmean were strongly correlated (R2 ≥ 0.90) with Dx, excluding metrics on the extrema. Intra‐modality comparisons of various Dx and Vy metrics yielded statistically significant differences (ANOVA, p < 0.001) for both90Y‐PET/CT and 90Y‐SPECT/CT. Based on statistical testing, only Dx metrics separated by greater than 20%–30% coverage, and only Vy metrics separated by greater than 40–70 Gy, reported significant differences. For PV, there was a strong correlation (R2 ≥ 0.99) between Dmean derived separately from 90Y‐PET/CT and 90Y‐SPECT/CT imaging. The strength of the correlation was slightly reduced for T and NL with R2 = 0.91 and R2 = 0.95, respectively. For PV, the mean bias ± standard error (SE) and 95% limits of agreement (LOA) between Dmean from the two modalities was effectively zero with ‐0.8 ± 0.4% (± 2.5%). For T and NL, the mean bias ± SE (± LOA) was ‐14.5 ± 3.7% (± 24%) and 9.4 ± 4.7% (± 27%), respectively. Conclusion: The strong correlation between Dmean and Dx suggests information from multiple dose metrics (e.g., D70 and Dmean) is largely redundant when establishing dose‐response relationships in 90Y‐RE. Dmean is highly correlated between 90Y‐PET/CT and 90Y‐SPECT/CT‐based dosimetry, for all liver VOIs. Relative to 90Y‐SPECT/CT, 90Y‐PET/CT, on average, yielded higher Dmean to tumors (14%) and lower Dmean to perfused normal livers (9%). Absorbed dose differences for perfused liver volumes between 90Y‐SPECT/CT and 90Y‐PET/CT were negligible. [ABSTRACT FROM AUTHOR]

Wheat is used for making many food products due to its diverse quality profile among different wheat classes. Since laboratory analysis of these end-use quality traits is costly and time-consuming, genetic dissection of the traits is preferential. This study used a genome-wide association study (GWAS) of ten end-use quality traits, including kernel protein, flour protein, flour yield, softness equivalence, solvent's retention capacity, cookie diameter, and top-grain, in soft red winter wheat (SRWW) adapted to US southeast. The GWAS included 266 SRWW genotypes that were evaluated in two locations over two years (2020–2022). A total of 27,466 single nucleotide markers were used, and a total of 80 significant marker-trait associations were identified. There were 13 major-effect quantitative trait loci (QTLs) explaining >10% phenotypic variance, out of which, 12 were considered to be novel. Five of the major-effect QTLs were found to be stably expressed across multiple datasets, and four showed associations with multiple traits. Candidate genes were identified for eight of the major-effect QTLs, including genes associated with starch biosynthesis and nutritional homeostasis in plants. These findings increase genetic comprehension of these end-use quality traits and could potentially be used for improving the quality of SRWW. [ABSTRACT FROM AUTHOR]

A new 90Y SIR-Spheres delivery kit (SIROS D-vial and shield) has been introduced with a different physical form from the legacy V-Vial kit. Here, we establish the dose calibrator settings and exposure-rate–to–activity conversion factor to assay 90Y SIR-Spheres activity in the new SIROS kit. Methods: Eight D-vials with initial 90Y activities from 1.2 to 6.6 GBq within acrylic shields were assayed with dose calibrators and exposure-rate meters until activities decayed to approximately 0.1 GBq. The dose calibrator settings resulting in the lowest median activity errors and the best-fit slope of exposure rate versus activity were identified. Results: SIROS D-vial 90Y activity can be accurately and reliably estimated directly using setting 51 × 10 on both the CRC-15R and the CRC-55tR dose calibrators (errors within ±0.5%) and indirectly with an exposure-rate reading at 30 cm using conversion factor 0.664 ± 0.003 GBq/(mR/h) (R2 = 0.985). Conclusion: Dose calibrator settings and exposure-rate–to–activity conversion factor for 90Y activity assays with new SIROS kit should be updated from legacy V-Vial parameters to avoid an approximately 10% underestimation. [ABSTRACT FROM AUTHOR]

Context.--Distinguishing the different types of amyloid is clinically important because treatments and outcomes are different. Mass spectrometry is the new gold standard for amyloid typing, but it is costly and not widely available. Therefore, immunolabeling remains the first step in identifying the most common types of amyloidosis. In amyloid subtyping, direct immunofluorescence works well when applied to frozen sections, but immunohistochemistry on formalin-fixed, paraffin-embedded material often yields poor results, particularly for light chain amyloidosis. Recently, paraffin immunofluorescence has been described as a valuable salvage technique in renal pathology when frozen sections are not available but it has not been evaluated for extra-renal diseases. Objectives.--To evaluate the use of paraffin immunofluorescence for light-chain detection in extra-renal amyloidosis and other light-chain-associated diseases. Design.--First, we compared the staining intensity of both light chains between paraffin immunofluorescence and immunohistochemistry on a retrospective cohort of 28 cases of amyloidosis that have been previously typed. Then, we studied the role of paraffin immunofluorescence as an addition to our classical immunohistochemistry panel for amyloidosis typing. Results.--In the retrospective cohort, we found that paraffin immunofluorescence outperformed immunohistochemistry for light-chain detection. Then, in the prospective part of the study, we showed that the proportion of correctly classified cases increased from 50% to 71.9% with the adjunction of second-intention paraffin immunofluorescence to the immunohistochemistry procedure. Conclusions.--We therefore view paraffin immunofluorescence as a significant addition to the routine workflow for detection of light-chain-related diseases. (Arch Pathol Lab Med. 2021;145:343-351; doi: 10.5858/arpa.2020-0124-OA), Amyloidosis is a group or disorders associated with the presence of extracellular amyloid deposits constituted by fibrillar aggregates of misfolded protein. More than 35 protein types have been identified as [...]

BACKGROUND: Dengue is a major public health problem worldwide. Assessment of adaptive immunity is important to understanding immunopathology and to define correlates of protection against dengue virus (DENV). To enable global assessment of CD4+ T cell responses, we mapped HLA-DRB1-restricted DENV-specific CD4+ T cell epitopes in individuals previously exposed to DENV in the general population of the dengue-endemic region of Managua, Nicaragua. METHODS: HLA class II epitopes in the population of Managua were identified by an in vitro IFNγ ELISPOT assay. CD4+ T cells purified by magnetic bead negative selection were stimulated with HLA-matched epitope pools in the presence of autologous antigen-presenting cells, followed by pool deconvolution to identify specific epitopes. The epitopes identified in this study were combined with those previously identified in the DENV endemic region of Sri Lanka, to generate a megapool (MP) consisting of 180 peptides specifically designed to achieve balanced HLA and DENV serotype coverage. The DENV CD4MP180 was validated by intracellular cytokine staining assays. RESULTS: We detected responses directed against a total of 431 epitopes, representing all 4 DENV serotypes, restricted by 15 different HLA-DRB1 alleles. The responses were associated with a similar pattern of protein immunodominance, overall higher magnitude of responses, as compared to what was observed previously in the Sri Lanka region. Based on these epitope mapping studies, we designed a DENV CD4 MP180 with higher and more consistent coverage, which allowed the detection of CD4+ T cell DENV responses ex vivo in various cohorts of DENV exposed donors worldwide, including donors from Nicaragua, Brazil, Singapore, Sri Lanka, and U.S. domestic flavivirus-naïve subjects immunized with Tetravalent Dengue Live-Attenuated Vaccine (TV005). This broad reactivity reflects that the 21 HLA-DRB1 alleles analyzed in this and previous studies account for more than 80% of alleles present with a phenotypic frequency ≥5% worldwide, corresponding to 92% phenotypic coverage of the general population (i.e., 92% of individuals express at least one of these alleles). CONCLUSION: The DENV CD4 MP180 can be utilized to measure ex vivo responses to DENV irrespective of geographical location.

This qualitative study investigated the lived experiences of six community college dance students. The theoretical framework of social cognitive career theory was used but was modified to include only the tenets most frequently cited in the literature that directly influenced the career identity of dancers particularly in relation to their motivation to academically persist and graduate. The research provides insight into the individual experiences of the participants in their dance journey. The goal was to obtain current data on the student experience so that dance programs can further enhance the student experience. The phenomenological analysis produced an early thematic matrix of 18 codes that were reduced to six major themes. Of those six themes, this study will focus on academic commitment, dance identification, and challenges.

Agro‐morphological traits play a significant role in the adaptation of wheat to diverse agroecosystems. Genetic understanding of these traits is crucial to develop cultivars adapted to specific environments and maximize their productivity. This is a comprehensive genome‐wide association study (GWAS) of 230 diverse lines of soft red winter wheat for identifying quantitative trait loci (QTLs) related to eight key agro‐morphological traits. The diversity panel was evaluated in two locations for three consecutive years (2020–2023). A total of 150 significant marker–trait associations were detected, including 65 for three flag leaf traits, 35 for peduncle length, 33 for plant height, 16 for heading date, and one for plant vigor using 27,466 single nucleotide polymorphism (SNP) markers. Eleven high‐confidence major‐effect QTLs explaining greater than 10% phenotypic variance were detected, of which seven were stable, and one showed an association with plant height and peduncle length. QTLs possibly allelic for important dwarfing (Rht23) and vernalization (Vrn‐B1) genes were identified. Six QTLs, QFlw.uga‐1A, QPdl.uga‐1A, QFlw.uga‐2B.2, QPdl.uga‐5A, QPdl.uga‐7A, and QPht.uga‐7B, are presumed to be novel, and nearby candidate gene(s) were identified for all except QPdl.uga‐1A. The pyramiding of favorable alleles from major‐effect QTLs was found to have significant improvement in peduncle length (shortened by 5 cm), flag leaf width (increased by 0.18 cm), and plant height (shortened by 11 cm). This study has improved our genetic understanding of important agro‐morphological traits. These results, upon further validation, can be used in breeding for desirable plant architecture to improve wheat yield potential. Core Ideas: Genome‐wide association study (GWAS) was conducted using 230 wheat lines evaluated for eight agro‐morphological traits.One hundred fifty significant marker–trait associations were found using 27,466 single nucleotide polymorphism (SNP) markers.Eleven major‐effect quantitative trait loci (QTLs) including seven stable QTLs were identified.Six major‐effect QTLs were presumed to be novel, and candidate genes were identified for five of them.Pyramiding favorable alleles from these QTLs led to significant improvement in traits. [ABSTRACT FROM AUTHOR]

Abstract Background Alveolar septation marks the beginning of the transition from the saccular to alveolar stage of lung development. Inflammation can disrupt this process and permanently impair alveolar formation resulting in alveolar hypoplasia as seen in bronchopulmonary dysplasia in preterm newborns. NF-κB is a transcription factor central to multiple inflammatory and developmental pathways including dorsal-ventral patterning in fruit flies; limb, mammary and submandibular gland development in mice; and branching morphogenesis in chick lungs. We have previously shown that epithelial overexpression of NF-κB accelerates lung maturity using transgenic mice. The purpose of this study was to test our hypothesis that targeted deletion of NF-κB signaling in lung epithelium would impair alveolar formation. Methods We generated double transgenic mice with lung epithelium-specific deletion of IKKβ, a known activating kinase upstream of NF-κB, using a cre-loxP transgenic recombination strategy. Lungs of resulting progeny were analyzed at embryonic and early postnatal stages to determine specific effects on lung histology, and mRNA and protein expression of relevant lung morphoreulatory genes. Lastly, results measuring expression of the angiogenic factor, VEGF, were confirmed in vitro using a siRNA-knockdown strategy in cultured mouse lung epithelial cells. Results Our results showed that IKKβ deletion in the lung epithelium transiently decreased alveolar type I and type II cells and myofibroblasts and delayed alveolar formation. These effects were mediated through increased alveolar type II cell apoptosis and decreased epithelial VEGF expression. Conclusions These results suggest that epithelial NF-κB plays a critical role in early alveolar development possibly through regulation of VEGF.

Because of the importance of potassium efflux in inflammasome activation, we investigated the role of the two-pore potassium (K2P) channel TREK-1 in macrophage inflammasome activity. Using primary alveolar macrophages (AMs) and bone marrow-derived macrophages (BMDMs) from wild-type (wt) and TREK-1–/– mice, we measured responses to inflammasome priming [using lipopolysaccharide (LPS)] and activation (LPS + ATP). We measured IL-1β, caspase-1, and NLRP3 via ELISA and Western blot. A membrane-permeable potassium indicator was used to measure potassium efflux during ATP exposure, and a fluorescencebased assay was used to assess changes in membrane potential. Inflammasome activation induced by LPS + ATP increased IL-1β secretion in wt AMs, whereas activation was significantly reduced in TREK-1–/– AMs. Priming of BMDMs using LPS was not affected by either genetic deficiency or pharmacological inhibition of TREK-1 with Spadin. Cleavage of caspase-1 following LPS + ATP treatment was significantly reduced in TREK-1–/– BMDMs. The intracellular potassium concentration in LPS-primed wt BMDMs was significant[ly lower compared with TREK-1–/– BMDMs or wt BMDMs treated with Spadin. Conversely, activation of TREK-1 with BL1249 caused a decrease in intracellular potassium in wt BMDMs. Treatment of LPS-primed BMDMs with ATP caused a rapid reduction in intracellular potassium levels, with the largest change observed in TREK-1–/– BMDMs. Intracellular K+ changes were associated with changes in the plasma membrane potential (Em), as evidenced by a more depolarized Em in TREK-1–/– BMDMs compared with wt, and Em hyperpolarization upon TREK-1 channel opening with BL1249. These results suggest that TREK-1 is an important regulator of NLRP3 inflammasome activation in macrophages. NEW & NOTEWORTHY Because of the importance of potassium efflux in inflammasome activation, we investigated the role of the two-pore potassium (K2P) channel TREK-1 in macrophage inflammasome activity. Using primary alveolar macrophages and bone marrow-derived macrophages from wild-type and TREK-1–/– mice, we measured responses to inflammasome priming (using LPS) and activation (LPS + ATP). Our results suggest that TREK-1 is an important regulator of NLRP3 inflammasome activation in macrophages. [ABSTRACT FROM AUTHOR]

Background: The calculation of the net administered activity (Aadmin) in patients undergoing 90Y‐radioembolization is essential for dosimetry and radiation safety, yet current methods for measuring residual 90Y activity are often associated with high uncertainty. Therefore, an accurate, robust, and clinically viable method for the determination of Aadmin across approved 90Y microsphere devices is desirable. Purpose: We report on a novel method to determine Aadmin by leveraging the quantitative capabilities of SPECT/CT to measure 90Y‐emission in vivo from patients following 90Y‐radioembolization with glass or resin microspheres. Methods: 90Y‐SPECT/CT attenuation‐corrected count data from 147 sequential 90Y‐radioembolization patients was used for this analysis. Aadmin was calculated as part of routine clinical practice via the exposure rate differences between the initial 90Y‐vial and the 90Y‐residual jar. This served as our gold standard measure of Aadmin. Patient data for each microsphere device were separated into training and testing cohorts to first develop regression models and then to independently assess model performance. The training cohorts were divided into four groups: first, based on the microsphere device (glass or resin), and second, based on the SPECT volume used to calculate counts (the full SPECT field of view (FOV) or liver only (VOIliver)). Univariate linear regression models were generated for each group to predict Aadmin based on 90Y‐SPECT data from the training cohorts. Leave‐one‐out cross validation was implemented to estimate variability in model parameters. To assess performance, linear models derived from the training cohort were applied to 90Y‐SPECT data from the testing cohort. A comparison of the models between microspheres devices was also performed. Results: Linear models derived from the glass and resin training cohorts demonstrated a strong, positive correlation between 90Y‐SPECT image counts and Aadmin for VOIliver and FOV with R2 > 0.98 in all cases. In the glass training cohort, model accuracy (100%—absolute mean prediction error) and precision (95% prediction intervals of mean prediction error) were 99.0% and 15.4% for the VOIliver and 99.7% and 17.5% for the FOV models, respectively. In the resin training cohort, the corresponding values were 98.6% and 16.7% for VOIliver and > 99.9% and 11.4% for the FOV models, respectively. The application of these linear models to 90Y‐SPECT data from the testing cohort showed Aadmin prediction errors to have high accuracy and precision for both microsphere devices. For the glass testing cohort, accuracy (precision) was 96.9% (19.6%) and 98.8% (21.1%) for the VOIliver and FOV models, respectively. The corresponding values for the resin training cohort were 97.3% (26.2%) and 98.5% (25.7%) for the VOIliver and FOV models, respectively. The slope of the linear models between the two microsphere devices was observed to be significantly different with resin microspheres generating 48%–49% more SPECT counts for equivalent 90Y activity based on each device manufacturer's activity calibration process. Conclusion: 90Y‐SPECT image counts can reliably predict (accuracy > 95% and precision < 18%) Aadmin after 90Y‐radioembolization, with performance characteristics essentially equivalent for both glass and resin microspheres. There is a clear indication that activity calibrations are fundamentally different between the two microsphere devices. [ABSTRACT FROM AUTHOR]

The Hessian fly (HF) is an invasive insect that has caused millions of dollars in yield losses to southeastern US wheat farms. Genetic resistance is the most sustainable solution to control HF. However, emerging biotypes are quickly overcoming resistance genes in the southeast; therefore, identifying novel sources of resistance is critical. The resistant line "UGA 111729" and susceptible variety "AGS 2038" were crossbred to generate a population of 225 recombinant inbred lines. This population was phenotyped in the growth chamber (GC) during 2019 and 2021 and in field (F) trials in Georgia during the 2021–2022 growing seasons. Visual scoring was utilized in GC studies. The percentage of infested tillers and number of pupae/larvae per tiller, and infested tiller per sample were measured in studies from 2021 to 2022. Averaging across all traits, a major QTL on chromosome 3D explained 42.27% (GC) and 10.43% (F) phenotypic variance within 9.86 centimorgans (cM). SNP marker IWB65911 was associated with the quantitative trait locus (QTL) peak with logarithm of odds (LOD) values of 14.98 (F) and 62.22 (GC). IWB65911 colocalized with resistance gene H32. KASP marker validation verified that UGA 111729 and KS89WGRC06 express H32. IWB65911 may be used for marker-assisted selection. [ABSTRACT FROM AUTHOR]

Background: Current molecular breast imaging (MBI) images are limited to qualitative evaluation, not absolute measurement, of 99mTc uptake in benign and malignant breast tissues. Purpose: This work assesses the accuracy of previously‐published and newly‐proposed tumor and normal breast tissue 99mTc uptake MBI measurements using simulations of a commercial dual‐headed planar MBI system under typical clinical and acquisition protocols. Methods: Quantification techniques were tested in over 4000 simulated acquisitions of spherical and ellipsoid tumors with clinically relevant uptake conditions using a validated Monte Carlo application of the GE Discovery NM750b system. The evaluated techniques consisted of four tumor total activity methodologies (two single‐detector‐based and two geometric‐mean‐based), two tumor MBI volume methodologies (diameter‐based and ROI‐based), and two normal tissue activity concentration methodologies (single‐detector‐based and geometric‐mean‐based). The most accurate of these techniques were then used to estimate tumor activity concentrations and tumor to normal tissue relative activity concentrations (RC). Results: Single‐detector techniques for tumor total activity quantification achieved mean (standard deviation) relative errors of 0.2% (4.3%) and 1.6% (4.4%) when using the near and far detector images, respectively and were more accurate and precise than the measured 8.1% (5.8%) errors of a previously published geometric‐mean technique. Using these activity estimates and the true tumor volumes resulted in tumor activity concentration and RC errors within 10% of simulated values. The precision of tumor activity concentration and RC when using only MBI measurements were largely driven by the errors in estimating tumor MBI volume using planar images (± 30% inter‐quartile range). Conclusions: Planar MBI images were shown to accurately and reliably be used to estimate tumor total activities and normal tissue activity concentrations in this simulation study. However, volumetric tumor uptake measurements (i.e., absolute and relative concentrations) are limited by inaccuracies in MBI volume estimation using two‐dimensional images, highlighting the need for either tomographic MBI acquisitions or anatomical volume estimates for accurate three‐dimensional tumor uptake estimates. [ABSTRACT FROM AUTHOR]

Background: Yttrium-90 (90Y) radioembolization is increasingly being utilized with curative intent. While single-compartment doses with respect to the perfused volume for the complete pathologic necrosis (CPN) of tumors have been reported, the actual doses delivered to the tumor and at-risk margins that leads to CPN have hitherto not been estimated. We present an ablative dosimetry model that calculates the dose distribution for tumors and at-risk margins based on numerical mm-scale dose modeling and the available clinical CPN evidence and report on the necessary dose metrics needed to achieve CPN following 90Y-radioembolization. Methods: Three-dimensional (3D) activity distributions (MBq/voxel) simulating spherical tumors were modeled with a 121 × 121 × 121 mm3 soft tissue volume (1 mm3 voxels). Then, 3D dose distributions (Gy/voxel) were estimated by convolving 3D activity distributions with a 90Y 3D dose kernel (Gy/MBq) sized 61 × 61 × 61 mm3 (1 mm3 voxels). Based on the published data on single-compartment segmental doses for the resected liver samples of HCC tumors showing CPN after radiation segmentectomy, the nominal voxel-based mean tumor dose ( D m e a n C P N ), point dose at tumor rim ( D r i m C P N ), and point dose 2 mm beyond the tumor boundary ( D 2 m m C P N ), which are necessary to achieve CPN, were calculated. The single-compartment dose prescriptions to required achieve CPN were then analytically modeled for more general cases of tumors with diameters d t = 2, 3, 4, 5, 6, and 7 cm and with tumor-to-normal-liver uptake ratios T : N = 1:1, 2:1, 3:1, 4:1, and 5:1. Results: The nominal case defined to estimate the doses needed for CPN, based on the previously published clinical data, was a single hyperperfused tumor with a diameter of 2.5 cm and T : N = 3:1, treated with a single-compartment segmental dose of 400 Gy. The voxel-level doses necessary to achieve CPN were 1053 Gy for the mean tumor dose, 860 Gy for the point dose at the tumor boundary, and 561 Gy for the point dose at 2 mm beyond the tumor edge. The single-compartment segmental doses necessary to satisfy the criteria for CPN in terms of the mean tumor dose, point dose at the tumor boundary, and the point dose at 2 mm beyond the tumor edge were tabulated for a range of tumor diameters and tumor-to-normal-liver uptake ratios. Conclusions: The analytical functions that describe the relevant dose metrics for CPN and, more importantly, the single-compartment dose prescriptions for the perfused volume needed to achieve CPN are reported for a large range of conditions in terms of tumor diameters (1–7 cm) and T : N uptake ratios (2:1–5:1). [ABSTRACT FROM AUTHOR]

Background: Molecular breast imaging (MBI) of 99mTc‐sestamibi is an emerging adjunct qualitative tool in the detection and diagnosis of breast cancer. Purpose: This work outlines the development and performance evaluation of a methodology to absolutely quantify tumor 99mTc activity uptake using a commercially available dual‐headed MBI system by implementing corrections for background, scatter, attenuation, and detector characteristics. Methods: A validated Monte Carlo application of a commercial MBI system was used to simulate over 7000 unique acquisitions of spherical and ellipsoidal tumors in breast tissue. Tumor absolute activity was calculated following background, scatter, and attenuation corrections of tumor region of interest counts. The methodology was first optimized using a set of high‐uptake spherical tumors, and its accuracy and precision was then assessed in a set of spherical tumors with clinical uptake conditions. Finally, the performance of the activity methodology was evaluated under various bias and uncertainty conditions to better characterize the technique under expected clinical measurement conditions. Results: In a test set of images with clinically relevant contrast and noise conditions, the mean ± standard deviation relative error in total tumor activity was 0.5% ± 6.5% (n = 2363) under ideal measurement conditions. Allowing for variability in tumor and background contours and in estimated tumor depths, the expected accuracy of the methodology in clinical practice was 0.5% ± 11.1% (n = 2363), with minimal loss of accuracy for ellipsoidal tumors. Conclusions: Planar MBI photopeak images acquired with standard‐of‐care protocols can be used to accurately quantify absolute tumor 99mTc activity with an accuracy and precision of 0.5% ± 11.1%. The reported precision was based on a comprehensive evaluation of random errors and systematic biases. [ABSTRACT FROM AUTHOR]

Influenza-A virus (IAV) infects yearly an estimated one billion people worldwide, resulting in 300,000-650,000 deaths. Preventive vaccination programs and antiviral medications represent the mainstay of therapy, but with unacceptably high morbidity and mortality rates, new targeted therapeutic approaches are urgently needed. Since inflammatory processes are commonly associated with measurable changes in the cell membrane potential (Em), we investigated whether Em hyperpolarization via TREK-1 (K2P2.1) K+ channel activation can protect against influenza-A virus (IAV)-induced pneumonia. We infected mice with IAV, which after 5 days caused 10-15% weight loss and a decrease in spontaneous activity, representing a clinically relevant infection. We then started a 3-day intratracheal treatment course with the novel TREK-1 activating compounds BL1249 or ML335. We confirmed TREK-1 activation with both compounds in untreated and IAV-infected primary human alveolar epithelial cells (HAECs) using high-throughput fluorescent imaging plate reader (FLIPR) assays. In mice, TREK-1 activation with BL1249 and ML335 counteracted IAV-induced histological lung injury and decrease in lung compliance and improved BAL fluid total protein levels, cell counts, and inflammatory IL-6, IP-10/CXCL-10, MIP-1α, and TNF-α levels. To determine whether these anti-inflammatory effects were mediated by activation of alveolar epithelial TREK-1 channels, we studied the effects of BL1249 and ML335 in IAV-infected HAEC, and found that TREK-1 activation decreased IAV-induced inflammatory IL-6, IP-10/CXCL10, and CCL-2 secretion. Dissection of TREK-1 downstream signaling pathways and construction of protein-protein interaction (PPI) networks revealed NF-κB1 and retinoic acid-inducible gene-1 (RIG-1) cascades as the most likely targets for TREK-1 protection. Therefore, TREK-1 activation may represent a novel therapeutic approach against IAV-induced lung injury. [ABSTRACT FROM AUTHOR]