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- Novel therapeutics often target complex cellular mechanisms. Increasingly, quantitative methods like digital tissue image analysis (tIA) are required to evaluate correspondingly complex biomarkers to elucidate subtle phenotypes that can inform treatment decisions with these targeted therapies. These tIA systems need a gold standard, or reference method, to establish analytical validity. Conventional, subjective histopathologic scores assigned by an experienced pathologist are the gold standard in anatomic pathology and are an attractive reference method. The pathologist's score can establish the ground truth to assess a tIA solution's analytical performance. The paradox of this validation strategy, however, is that tIA is often used to assist pathologists to score complex biomarkers because it is more objective and reproducible than manual evaluation alone by overcoming known biases in a human's visual evaluation of tissue, and because it can generate endpoints that cannot be generated by a human observer. - To discuss common visual and cognitive traps known in traditional pathology-based scoring paradigms that may impact characterization of tIA-assisted scoring accuracy, sensitivity, and specificity. - This manuscript reviews the current literature from the past decades available for traditional subjective pathology scoring paradigms and known cognitive and visual traps relevant to these scoring paradigms. - Awareness of the gold standard paradox is necessary when using traditional pathologist scores to analytically validate a tIA tool because image analysis is used specifically to overcome known sources of bias in visual assessment of tissue sections.

PD-L1 (22C3) checkpoint inhibitor therapy represents a mainstay of modern cancer immunotherapy for non-small cell lung cancer (NSCLC). In vitro diagnostic (IVD) PD-L1 antibody staining is widely used to predict clinical intervention efficacy. However, pathologist interpretation of this assay is cumbersome and variable, resulting in poor positive predictive value concerning patient therapy response. To address this, we developed a digital assay (DA) termed Tissue Insight (TI) 22C3 NSCLC, for the quantification of PD-L1 in NSCLC tissues, including digital recognition of macrophages and lymphocytes. We completed clinical validation of this digital image analysis solution in 66 NSCLC patient samples, followed by concordance studies (comparison of PD-L1 manual and digital scores) in an additional 99 patient samples. We then combined this DA with three distinct immune cell recognition algorithms for detecting tissue macrophages, alveolar macrophages, and lymphocytes to aid in sample interpretation. Our PD-L1 (22C3) DA was successfully validated and had a scoring agreement (digital to manual) higher than the inter-pathologist scoring. Furthermore, the number of algorithm-identified immune cells showed significant correlation when compared with those identified by immunohistochemistry in serial sections stained by double immunofluorescence. Here, we demonstrated that TI 22C3 NSCLC DA yields comparable results to pathologist interpretation while eliminating the intra- and inter-pathologist variability associated with manual scoring while providing characterization of the immune microenvironment, which can aid in clinical treatment decisions.

In this study we present the retrieval of the column-averaged dry air mole fraction of carbon dioxide (XCO2) from the Orbiting Carbon Observatory-2 (OCO-2) satellite observations using the RemoTeC algorithm, previously successfully applied to retrieval of greenhouse gas concentration from the Greenhouse Gases Observing Satellite (GOSAT). The XCO2 product has been validated with collocated ground-based measurements from the Total Carbon Column Observing Network (TCCON) for almost 2 years of OCO-2 data from September 2014 to July 2016. We found that fitting an additive radiometric offset in all three spectral bands of OCO-2 significantly improved the retrieval. Based on a small correlation of the XCO2 error over land with goodness of fit, we applied an a posteriori bias correction to our OCO-2 retrievals. In overpass averaged results, XCO2 retrievals have an SD of  ∼ 1.30 ppm and a station-to-station variability of  ∼ 0.40 ppm among collocated TCCON sites. The seasonal relative accuracy (SRA) has a value of 0.52 ppm. The validation shows relatively larger difference with TCCON over high-latitude areas and some specific regions like Japan.

Retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, significantly contribute to adult blindness. The Royal College of Surgeons (RCS) rat is a well-established disease model for studying these dystrophies; however, molecular investigations remain limited. We conducted a comprehensive analysis of retinal degeneration in RCS rats, including an immunodeficient RCS (iRCS) sub-strain, using ocular coherence tomography, electroretinography, histology, and molecular dissection using transcriptomics and immunofluorescence. No significant differences in retinal degeneration progression were observed between the iRCS and immunocompetent RCS rats, suggesting a minimal role of adaptive immune responses in disease. Transcriptomic alterations were primarily in inflammatory signaling pathways, characterized by the strong upregulation of Tnfa, an inflammatory signaling molecule, and Nox1, a contributor to reactive oxygen species (ROS) generation. Additionally, a notable decrease in Alox15 expression was observed, pointing to a possible reduction in anti-inflammatory and pro-resolving lipid mediators. These findings were corroborated by immunostaining, which demonstrated increased photoreceptor lipid peroxidation (4HNE) and photoreceptor citrullination (CitH3) during retinal degeneration. Our work enhances the understanding of molecular changes associated with retinal degeneration in RCS rats and offers potential therapeutic targets within inflammatory and oxidative stress pathways for confirmatory research and development.

Breast implant anaplastic large cell lymphoma is an entity recently recognized by the World Health Organization. The tumor arises around textured-surface breast implants and is usually confined to the surrounding fibrous capsule. Currently, there are no recommendations for handling and sampling of capsules from patients with suspected breast implant anaplastic large cell lymphoma without a grossly identifiable tumor. We analyzed complete capsulectomies without distinct gross lesions from patients with breast implant anaplastic large cell lymphoma. The gross appearance of the capsules as well as the presence, extent and depth of tumor cells on the luminal side and number of sections involved by lymphoma were determined by review of routine stains and CD30 immunohistochemistry. We then used a mathematical model that included the extent of tumor cells and number of positive sections to calculate the minimum number of sections required to identify 95% of randomly distributed lesions. We identified 50 patients with breast implant anaplastic large cell lymphoma who had complete capsulectomies. The implants were textured in all 32 (100%) cases with available information. Anaplastic large cell lymphoma was found in 44/50 (88%) capsules; no tumor was found in six (12%) patients who had lymphoma cells only in the effusion. The median number of sections reviewed was 20 (range, 2–240), the median percentage of sections involved by tumor was 6% (range, 0–90%), and the median percentage of sections involved by lymphoma was 10% (range, 0–90%). Invasion deep into or through the capsule was identified in 18/50 (36%) patients. In patients with breast implant anaplastic large cell lymphoma without a grossly identifiable tumor we identified a spectrum of involvement and we propose a protocol for handling, sampling and reporting these cases. The number of sections to exclude the presence of lymphoma with more than 95% certainty was supported by a mathematic rationale.

Secondary metabolites are major constituents of plant defense against herbivore attack. Relatively little is known about the cell type—specific formation and antiherbivore activities of secondary compounds in roots despite the substantial impact of root herbivory on plant performance and fitness. Here, we describe the constitutive formation of semivolatile diterpenes called rhizathalenes by the class I terpene synthase (TPS) 08 in roots of Arabidopsis thaliana. The primary enzymatic product of TPS08, rhizathalene A, which is produced from the substrate all-trans geranylgeranyl diphosphate, represents a so far unidentified class of tricyclic diterpene carbon skeletons with an unusual tricyclic spiro-hydrindane structure. Protein targeting and administration of stable isotope precursors indicate that rhizathalenes are biosynthesized in root leucoplasts. TPS08 expression is largely localized to the root stele, suggesting a centric and gradual release of its diterpene products into the peripheral root cell layers. We demonstrate that roots of Arabidopsis tps08 mutant plants, grown aeroponically and in potting substrate, are more susceptible to herbivory by the opportunistic root herbivore fungus gnat (Bradysia spp) and suffer substantial removal of peripheral tissue at larval feeding sites. Our work provides evidence for the in vivo role of semivolatile diterpene metabolites as local antifeedants in belowground direct defense against root-feeding insects.

Herbivores alter plant biodiversity (species richness) in many of the world’s ecosystems, but the magnitude and the direction of herbivore effects on biodiversity vary widely within and among ecosystems. One current theory predicts that herbivores enhance plant biodiversity at high productivity but have the opposite effect at low productivity. Yet, empirical support for the importance of site productivity as a mediator of these herbivore impacts is equivocal. Here, we synthesize data from 252 large-herbivore exclusion studies, spanning a 20-fold range in site productivity, to test an alternative hypothesis—that herbivore-induced changes in the competitive environment determine the response of plant biodiversity to herbivory irrespective of productivity. Under this hypothesis, when herbivores reduce the abundance (biomass, cover) of dominant species (for example, because the dominant plant is palatable), additional resources become available to support new species, thereby increasing biodiversity. By contrast, if herbivores promote high dominance by increasing the abundance of herbivory-resistant, unpalatable species, then resource availability for other species decreases reducing biodiversity. We show that herbivore-induced change in dominance, independent of site productivity or precipitation (a proxy for productivity), is the best predictor of herbivore effects on biodiversity in grassland and savannah sites. Given that most herbaceous ecosystems are dominated by one or a few species, altering the competitive environment via herbivores or by other means may be an effective strategy for conserving biodiversity in grasslands and savannahs globally. Evidence synthesized from 252 large-herbivore exclusion studies suggests that herbivore-induced change in dominance, independent of site productivity or precipitation, best predicts herbivore effects on biodiversity in grassland and savannah sites.

Sympatric species with similar ecological requirements and differences in body size would be expected to partition resources to facilitate coexistence. For sexually dimorphic species, we may expect resource partitioning by gender as well as by species identity. However, it is difficult to document species and sexual resource partitioning in marine ecosystems, given the intractability of these systems and the vagility of many marine animals. Here, we examined differences in the foraging behavior and prey selection of 2 congeneric and coexisting seabird species—masked boobiesSula dactylatraand red-footed boobiesSula sula—on Palmyra Atoll in the equatorial Pacific Ocean. These seabirds exhibit substantial size dimorphism between species and also have reverse sexual dimorphism within species. Pronounced interspecific differences in foraging patterns were observed with high-resolution GPS tracking devices, where smaller red-footed boobies conducted longer foraging trips (in both time and distance). Red-footed boobies also had more frequent landings on the sea surface, slower mean and maximum travel speeds, and more westerly trip azimuths. Stable isotope and diet analyses produced data that complemented returns from electronic tagging. Stable isotope ratios of carbon indicated that masked boobies foraged on prey with a less pelagic δ13C signature compared to red-footed boobies. In contrast, no gender differences were identified in any foraging parameters. The mechanisms for maintenance of these pronounced differences in niche partitioning across species were not explicitly examined, yet the data suggest physiological variation across species may be a more plausible mechanism than competitive interactions.

Community–academic research partnerships aim to build stakeholder trust in order to improve the reach and translation of health research, but there is limited empirical research regarding effective ways to build trust. This multisite study was launched to identify similarities and differences among stakeholders’ perspectives of antecedents to trust in research partnerships. In 2013-2014, we conducted a mixed-methods concept mapping study with participants from three major stakeholder groups who identified and rated the importance of different antecedents of trust on a 5-point Likert-type scale. Study participants were community members (n = 66), health care providers (n = 38), and academic researchers (n = 44). All stakeholder groups rated “authentic communication” and “reciprocal relationships” the highest in importance. Community members rated “communication/methodology to resolve problems” (M = 4.23, SD = 0.58) significantly higher than academic researchers (M = 3.87, SD = 0.67) and health care providers (M = 3.89, SD = 0.62; p <. 01) and had different perspectives regarding the importance of issues related to “sustainability.” The importance of communication and relationships across stakeholders indicates the importance of colearning processes that involve the exchange of knowledge and skills. The differences uncovered suggest specific areas where attention and skill building may be needed to improve trust within partnerships. More research on how partnerships can improve communication specific to problem solving and sustainability is merited.

Atmospheric methane (CH4) concentrations have more than doubled since the beginning of the industrial age, making CH4 the second most important anthropogenic greenhouse gas after carbon dioxide (CO2). The oil and gas sector represents one of the major anthropogenic CH4 emitters as it is estimated to account for 22 % of global anthropogenic CH4 emissions. An airborne field campaign was conducted in April–May 2019 to study CH4 emissions from offshore gas facilities in the southern North Sea with the aim of deriving emission estimates using a top-down (measurement-led) approach. We present CH4 fluxes for six UK and five Dutch offshore platforms or platform complexes using the well-established mass balance flux method. We identify specific gas production emissions and emission processes (venting and fugitive or flaring and combustion) using observations of co-emitted ethane (C2H6) and CO2. We compare our top-down estimated fluxes with a ship-based top-down study in the Dutch sector and with bottom-up estimates from a globally gridded annual inventory, UK national annual point-source inventories, and operator-based reporting for individual Dutch facilities. In this study, we find that all the inventories, except for the operator-based facility-level reporting, underestimate measured emissions, with the largest discrepancy observed with the globally gridded inventory. Individual facility reporting, as available for Dutch sites for the specific survey date, shows better agreement with our measurement-based estimates. For all the sampled Dutch installations together, we find that our estimated flux of (122.9 ± 36.8) kg h−1 deviates by a factor of 0.64 (0.33–12) from reported values (192.8 kg h−1). Comparisons with aircraft observations in two other offshore regions (the Norwegian Sea and the Gulf of Mexico) show that measured, absolute facility-level emission rates agree with the general distribution found in other offshore basins despite different production types (oil, gas) and gas production rates, which vary by 2 orders of magnitude. Therefore, mitigation is warranted equally across geographies.