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A study was conducted to examine the perceived changes in the impressions of others or self on 133 trait dimensions. Attributions to others were reportedly more negative over time whereas attributions to self were more positive over time. Perceived changes in others' traits appear to be guided by basic behavioral inference processes. Trait beliefs about others tend to be revised when the traits are common and disconfirming behavior is infrequent and more diagnostic. Positive trait impressions of others change more frequently because they are more prevalent and because negative behaviors (that disconfirm positive attributions) are less frequent and more diagnostic than positive behaviors. In contrast, revisions of trait impressions of the self appear to be driven heavily by self-evaluation motivations such as the desire to see self-improvement. The favorableness of changes in trait self-concepts were positively correlated with self-esteem. The consequences of the observed patterns of attributional change for interpersonal relations are discussed. [ABSTRACT FROM AUTHOR]

Introduction: The objective was to evaluate the use of a minimally invasive surgical (MIS) approach to perform hemilaminectomies in chondrodystrophic dogs with thoracolumbar intervertebral disc extrusions (IVDE). Additionally, we aimed to evaluate the degree of soft tissue trauma using the endoscopic procedure compared to the standard open approach. Methods: Eight client-owned dogs presented to the Colorado State University Veterinary Teaching Hospital with acute onset thoracolumbar IVDE were included in this study. This was a prospective, randomized case-series. Patients were assigned to undergo an endoscopic (group 1; n = 4) or a standard open approach (group 2; n = 4) for a hemilaminectomy. A post-operative MRI was performed in all cases. Results: Conversion to an open approach was not necessary for any case in group 1. All cases had adequate spinal cord decompression on post-operative MRI. There was no significant difference in soft tissue changes noted on post-operative MRI between the two groups. Discussion: The MIS approach to hemilaminectomies in chondrodystrophic dogs with thoracolumbar IVDE can successfully be performed to decompress the neural tissue and appears to lead to similar clinical outcomes in the early postoperative period compared to the standard open approach. Larger studies are needed to determine the potential advantages of the MIS technique compared to the standard open approach in veterinary medicine. [ABSTRACT FROM AUTHOR]

Patients with sarcoidosis who develop severe clinical phenotypes of pulmonary fibrosis or multiorgan disease experience debilitating symptoms, with fatigue being a common chief complaint. Studies that have investigated this patient-related outcome measure (PROM) have used the Fatigue Assessment Scale (FAS), a self-reported questionnaire that reflects mental and physical domains. Despite extensive work, its cause is unknown and treatment options remain limited. Previously, we showed that the plasma of patients with sarcoidosis with extrapulmonary disease endorsing fatigue was enriched for mitochondrial DNA (mtDNA), a ligand for the innate immune receptor toll-like receptor 9 (TLR9). Through our cross-disciplinary platform, we investigated a relationship between sarcoidosis-induced fatigue and circulating mtDNA. Is there a psychobiologic mechanism that connects sarcoidosis-induced fatigue and mtDNA-mediated TLR9 activation? Using a local cohort of patients at Yale (discovery cohort) and the National Institutes of Health-sponsored Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis study (validation cohort), we scored the FAS and quantified in the plasma, mtDNA concentrations, TLR9 activation, and cytokine levels. Although FAS scores were independent of corticosteroid use and Scadding stage, we observed a robust association between FAS scores, which included mental and physical domains, and multiorgan sarcoidosis. Subsequently, we identified a significant correlation between plasma mtDNA concentrations and all domains of fatigue. Additionally, we found that TLR9 activation is associated with all aspects of the FAS and partially mediates this PROM through mtDNA. Last, we found that TLR9-associated soluble mediators in the plasma are independent of all facets of fatigue. Through our cross-disciplinary translational platform, we identified a previously unrecognized psychobiologic connection between sarcoidosis-induced fatigue and circulating mtDNA concentrations. Mechanistic work that investigates the contribution of mtDNA-mediated innate immune activation in this PROM and clinical studies with prospective cohorts has the potential to catalyze novel therapeutic strategies for this patient population and those with similar conditions. [Display omitted] [ABSTRACT FROM AUTHOR]

Alveolarization ensures sufficient lung surface area for gas exchange, and during bulk alveolarization in mice (postnatal day [P] 4.5-14.5), alpha-smooth muscle actin (SMA)+ myofibroblasts accumulate, secrete elastin, and lay down alveolar septum. Herein, we delineate the dynamics of the lineage of early postnatal SMA+ myofibroblasts during and after bulk alveolarization and in response to lung injury. SMA+ lung myofibroblasts first appear at ~ P2.5 and proliferate robustly. Lineage tracing shows that, at P14.5 and over the next few days, the vast majority of SMA+ myofibroblasts downregulate smooth muscle cell markers and undergo apoptosis. Of note, ~8% of these dedifferentiated cells and another ~1% of SMA+ myofibroblasts persist to adulthood. Single cell RNA sequencing analysis of the persistent SMA-cells and SMA+ myofibroblasts in the adult lung reveals distinct gene expression profiles. For instance, dedifferentiated SMA-cells exhibit higher levels of tissue remodeling genes. Most interestingly, these dedifferentiated early postnatal myofibroblasts re-express SMA upon exposure of the adult lung to hypoxia or the pro-fibrotic drug bleomycin. However, unlike during alveolarization, these cells that re-express SMA do not proliferate with hypoxia. In sum, dedifferentiated early postnatal myofibroblasts are a previously undescribed cell type in the adult lung and redifferentiate in response to injury. [ABSTRACT FROM AUTHOR]

Objective: To determine signalment, injury type, trauma severity score, and outcome of canine trauma patients undergoing surgical (emergency room [ER] or operating room [OR]) and nonsurgical treatment in addition to time to surgery, specialty services involved, and cost in the OR surgery population. Design: Retrospective evaluation of medical record and hospital trauma registry data on canine trauma cases. Setting: University teaching hospital. Animals: One thousand six hundred and thirty dogs presenting for traumatic injury between May 2017 and July 2020. Interventions: None. Measurements and Main Results: Demographics and outcome were compared for canine trauma patients undergoing OR surgery (12.8%, 208/1630), ER surgery (39.1%, 637/1630), or no surgical intervention (48.2%, 785/1630). Among the 2 surgical groups, 98.9% (836/845) survived to discharge compared with 92.2% (724/785) of the nonsurgical group (P < 0.0001). The OR surgical group had significantly higher median Animal Trauma Triage scores (2 vs 1, P < 0.0001) and median days in hospital (2 vs < 1, P < 0.0001) compared with the other groups. For the OR surgical cohort, electronic medical records were reviewed to determine the specialty surgery service involved, time to and duration of anesthesia and surgery, and visit cost. The most common surgery services involved were orthopedics (45.2%, 94/208) and general surgery (26.9%, 56/208). Neurology and general surgery cases required the longest median length of stay in hospital, and ophthalmology and dentistry cases required the shortest. The median cost of visit was highest in neurology ($10,032) and lowest in ophthalmology ($2305) and dentistry ($2404). Conclusions: Surgical intervention in canine trauma patients appears to be associated with higher survival rates, and among the surgery groups, mortality was highest in the ER and general surgery groups. OR surgical intervention, in particular general surgery and neurology, was associated with increased length of hospitalization, increased cost, and higher Animal Trauma Triage scores. [ABSTRACT FROM AUTHOR]

Mast-cell expressed membrane protein-1 (MCEMP1) is higher in patients with idiopathic pulmonary fibrosis (IPF) with an increased risk of death. Here we aimed to establish the mechanistic role of MCEMP1 in pulmonary fibrosis. We identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared with controls. MCEMP1 is upregulated by transforming growth factor beta (TGFβ) at the mRNA and protein levels in monocytic leukemia THP-1 cells. TGFβ-mediated MCEMP1 upregulation results from the cooperation of SMAD3 and SP1 via concomitant binding to SMAD3/SP1 cis-regulatory elements within the MCEMP1 promoter. We also found that MCEMP1 regulates TGFb-mediated monocyte chemotaxis, adhesion, and migration. Our results suggest that MCEMP1 may regulate the migration and transition of monocytes to monocyte-derived alveolar macrophages during pulmonary fibrosis development and progression. [ABSTRACT FROM AUTHOR]

Case: A 13-year-old healthy, nearly skeletally mature, female patient presented to an outpatient clinic after sustaining a bimalleolar ankle fracture-dislocation, which was subsequently treated with open reduction and internal fixation and casting. Postoperatively, the patient had significant limitations to ankle range of motion. Imaging revealed posterior tibiotalar impingement. The patient underwent arthroscopic debridement and osteoplasty, and she was able to return to previous levels of activity. Conclusions: Complications from pediatric ankle fractures are rare, so further diagnostic workup is warranted for patients with persistent pain and limitations. [ABSTRACT FROM AUTHOR]

Background: Single-cell RNA sequencing (scRNA-seq) technology has enabled assessment of transcriptome-wide changes at single-cell resolution. Due to the heterogeneity in environmental exposure and genetic background across subjects, subject effect contributes to the major source of variation in scRNA-seq data with multiple subjects, which severely confounds cell type specific differential expression (DE) analysis. Moreover, dropout events are prevalent in scRNA-seq data, leading to excessive number of zeroes in the data, which further aggravates the challenge in DE analysis. Results: We developed iDESC to detect cell type specific DE genes between two groups of subjects in scRNA-seq data. iDESC uses a zero-inflated negative binomial mixed model to consider both subject effect and dropouts. The prevalence of dropout events (dropout rate) was demonstrated to be dependent on gene expression level, which is modeled by pooling information across genes. Subject effect is modeled as a random effect in the log-mean of the negative binomial component. We evaluated and compared the performance of iDESC with eleven existing DE analysis methods. Using simulated data, we demonstrated that iDESC had well-controlled type I error and higher power compared to the existing methods. Applications of those methods with well-controlled type I error to three real scRNA-seq datasets from the same tissue and disease showed that the results of iDESC achieved the best consistency between datasets and the best disease relevance. Conclusions: iDESC was able to achieve more accurate and robust DE analysis results by separating subject effect from disease effect with consideration of dropouts to identify DE genes, suggesting the importance of considering subject effect and dropouts in the DE analysis of scRNA-seq data with multiple subjects. [ABSTRACT FROM AUTHOR]

VISTA (V domain immunoglobulin suppressor of T cell activation, also called PD-1H [programmed death-1 homolog]), a novel immune regulator expressed on myeloid and T lymphocyte lineages, is upregulated in mouse and human idiopathic pulmonary fibrosis (IPF). However, the significance of VISTA and its therapeutic potential in regulating IPF has yet to be defined. To determine the role of VISTA and its therapeutic potential in IPF, the expression profile of VISTA was evaluated from human single-cell RNA sequencing data (IPF Cell Atlas). Inflammatory response and lung fibrosis were assessed in bleomycin-induced experimental pulmonary fibrosis models in VISTA-deficient mice compared with wild-type littermates. In addition, these outcomes were evaluated after VISTA agonistic antibody treatment in the wild-type pulmonary fibrosis mice. VISTA expression was increased in lung tissue-infiltrating monocytes of patients with IPF. VISTA was induced in the myeloid population, mainly circulating monocyte-derived macrophages, during bleomycin-induced pulmonary fibrosis. Genetic ablation of VISTA drastically promoted pulmonary fibrosis, and bleomycin-induced fibroblast activation was dependent on the interaction between VISTA-expressing myeloid cells and fibroblasts. Treatment with VISTA agonistic antibody reduced fibrotic phenotypes accompanied by the suppression of lung innate immune and fibrotic mediators. In conclusion, these results suggest that VISTA upregulation in pulmonary fibrosis may be a compensatory mechanism to limit inflammation and fibrosis, and stimulation of VISTA signaling using VISTA agonists effectively limits the fibrotic innate immune landscape and consequent tissue fibrosis. Further studies are warranted to test VISTA as a novel therapeutic target for the IPF treatment. [ABSTRACT FROM AUTHOR]

We use a multi‐year record of Pandora‐derived NO2 total column abundance in Boston to examine the influence of atmospheric transport on column NO2 and its surface concentrations during the warm season in a coastal urban environment. We derive tropospheric NO2 estimates from the total column with a measurement‐model fusion approach using near‐real‐time estimates of stratospheric NO2 from NASA's Goddard Earth Observing System Composition Forecast model system and find the average influence of stratospheric NO2 at this urban site can be 30%–70% depending on season and time of day. Sea breeze days tend to exhibit rapid temporal variability in the column that which can go in the opposite direction of changes in surface NO2 concentrations. By comparing tropospheric NO2 with surface concentrations, we constrain the role of boundary layer entrainment processes in the evolution of surface NO2 concentrations, while highlighting the value of column measurements in identifying sea breeze frontal dynamics. We estimate an apparent equal mixing layer height of NO2 and infer that surface NOx emissions remain concentrated near the surface regardless of atmospheric stability regime. When comparing the Pandora‐ to TROPOMI‐derived column NO2 measurements, we find that sea breeze days present a unique challenge likely due to higher spatial heterogeneity in NO2 and the meteorology involved that is not well represented in retrieval inputs. Our observations provide new insights into column and surface variability of NO2 which will be relevant to interpreting geostationary observations, especially in coastal urban locations. Plain Language Summary: Relating satellite‐derived observations of nitrogen dioxide (NO2) to ground‐level air quality has long been an area of research with important applications to human and environmental welfare. Here, we use new remote sensing observations from ground‐ and satellite‐based instruments, along with ground‐level air quality monitoring and meteorological observations, to gain new insight into the relationship of NO2 total column abundance and surface concentrations in a costal urban environment. We show how the total columns (the NO2 between the surface and top of the atmosphere) derived from remote sensing are sensitive to different processes than surface concentrations (the amount of NO2 at a point near the surface), which complicate the interpretation of surface air quality from satellite observations. We also find evidence that the mixing of surface emissions in our urban environment is slow relative to the NOx lifetime even under conditions when the boundary layer is expected to be well‐mixed. We find that sea breeze systems common to coastal environments present particularly challenging circumstances, due to higher spatial and temporal variability in pollutant concentrations. Our results should provide some insights into the interpretation of new geostationary air quality observations. Key Points: Tropospheric NO2 column measurements capture rapid changes in horizontal advection of pollutionCollocated column and in situ measurements constrain the dominant role of vertical entrainment in NO2 surface concentrationsSea breezes pose a challenge to satellite retrievals of NO2 due to heterogeneity in NO2 and meteorology [ABSTRACT FROM AUTHOR]

Coastal urban environments face unique challenges associated with air quality‐meteorology interactions. In this study, high resolution chemical transport modeling over the Greater Boston area was performed to improve our understanding of sea breezes impacts on the spatiotemporal variability of primary and secondary pollutants. We perform WRF‐Chem simulations at 3 km resolution over June 22 to 10 July 2019 (a period that included 10 sea breeze occurrences), and use Pandora tropospheric NO2 column, surface air quality monitoring, and vertical meteorological aircraft profiles for evaluation. The model generally reproduces observed spatiotemporal variability of air pollution during sea breezes well. Tropospheric columns of NO2 predicted by the model and observed by the Pandora instrument show that sea breezes are associated with rapid increases and steep gradients in tropospheric NO2 and confirm accumulation of local primary emissions. Spatial heterogeneity in tropospheric NO2 is strongly governed by inland penetration lengths of the sea breeze front. Process diagnostics show that three sea‐breeze days where O3 observations recorded hourly concentrations >70 ppb have both efficient net chemical O3 production in the boundary layer (>10 ppb/hr) and rapid O3 convergence in the near‐surface convergence zone (>20 ppb/hr). During sea breezes, interactions between photochemistry, the convergence zone inland penetration, and urban NOx titration effects, contribute to strong heterogeneity and high O3 inland that is not captured by the current monitoring network. We discuss monitoring needs and model applications for the sea breeze scenarios, with broad implications for air quality monitoring in coastal urban environments. Plain Language Summary: The sea breeze is a local meteorological system that brings air from the sea over the land during the day. In areas that usually experience offshore winds, this means the system can recirculate early morning pollutant emissions back onshore later in the day. Understanding the behavior of air pollutants in coastal urban environments is essential for air quality management, but land‐sea breeze circulations are characterized by fine scale features and rapid changes in pollution levels that pose challenges for traditional monitoring and satellite retrievals. In the Greater Boston area, we use highly resolved information from a regional chemical transport model combined with observational assets to examine pollutant behavior and model performance. We find new evidence of underestimated regional ozone pollution and nitrogen dioxide column spatial variability associated with sea breezes. This variability is governed by how far the sea breeze penetrates inland, but is also affected by interactions between chemistry and atmospheric dynamic that are not well captured by current monitoring and coarse resolution models. Our results provide valuable insights for future ground‐based and satellite remote sensing monitoring, highlighting that customized strategies for monitoring coastal urban air quality are required from high‐resolution models constrained by carefully allocated observations. Key Points: High resolution WRF‐Chem modeling reproduces observed spatiotemporal variability of NO2 and O3 during sea breezes in the Greater Boston areaModel results suggest high O3 pollution and NO2 column spatial variability associated with sea breezes is not captured by current monitoringMonitoring coastal urban air quality requires customized strategies with high‐resolution modeling and well‐allocated observations [ABSTRACT FROM AUTHOR]

Introduction: Maternal feeding practices may be linked to infant obesogenic outcomes, but research to date has focused primarily on infant growth as an outcome of maternal feeding practices rather than exploring additional obesogenic outcomes like infant appetite and diet. Therefore, the current study examined the association between maternal feeding practices and beliefs and infant growth, diet, and appetite simultaneously at a critical timepoint for obesity risk development (i.e., 3-months-old). Methods: Thirty-two 3-month-old infants and their mothers participated in this cross-sectional study. Infant anthropometrics were collected by trained staff and mothers completed questionnaires regarding maternal feeding practices and beliefs and infant diet and appetite. The data were analyzed by Spearman correlations. Results: Statistically significant correlations were identified between maternal feeding practices (e.g., using food to calm, concern about infant weight) and infant satiety, appetite, food responsiveness, slow eating, and kilocalories consumed. Infant weight-for-length was related to maternal concern about infant underweight and mother-infant social interaction during feeding. Discussion: These findings highlight the importance of the mother-infant feeding relationship and how these associations may influence responsive feeding practices and infant weight-related outcomes. Significance: What is already known on the subject? Growth trajectories in infancy predict subsequent obesity, and maternal feeding practices and beliefs play a significant role in infant growth. What this study adds? The current study adds to the field by identifying that maternal beliefs (e.g., concern about infant weight) and behaviors (e.g., using food to calm) were uniquely associated with infant obesogenic outcomes (e.g., satiety, appetite) at a critical timepoint in future obesity risk (i.e., 3-months-old). These findings highlight the need of maternal psychoeducation on responsive feeding to increase awareness of child cues, thereby potentially lowering child obesity risk. [ABSTRACT FROM AUTHOR]

Objective: To determine signalment, injury type, trauma severity score, and outcome of feline trauma patients undergoing surgical (emergency room [ER] and operating room [OR]) and nonsurgical treatments in addition to time to surgery, specialty services involved, and cost in the OR surgery population. Design: Retrospective evaluation of medical record and hospital trauma registry data on feline trauma cases. Setting: University teaching hospital. Animals: Two hundred and fifty‐one cats presenting for traumatic injury between May 2017 and July 2020. Interventions: None. Measurements and Main Results: Demographics and outcomes were compared for cats undergoing surgical intervention in an OR (12%, 31/251) or an ER (23%, 58/251) setting and feline trauma patients without surgical intervention (65%, 162/251). Between the 2 surgical groups, 99% survived to discharge compared to 73.5% of the nonsurgical group (P < 0.0001). For the OR surgical cohort, electronic medical records were reviewed to determine the specialty surgery service involved, time to and duration of anesthesia and surgery, and visit cost. The most common surgery services involved were orthopedics (41%, 12/29) and dentistry (38%, 11/29), and the most common surgeries performed were mandibular fracture stabilization (8/29) and internal fixation for long bone fractures (8/29). The ER surgical group had a significantly lower Animal Trauma Triage score than the OR group (P < 0.0001), but a significant difference was not found between OR surgical and nonsurgical groups (P = 0.0553). No difference in modified Glasgow Coma Scale score was found between any groups. Conclusions: Surgical intervention in feline trauma patients appears to be associated with higher survival rates, but no difference in mortality was found across surgery services. OR surgical intervention, in particular, orthopedic surgery, was associated with increased length of hospitalization, increased cost, and increased use of blood products. [ABSTRACT FROM AUTHOR]

Engineered whole lungs may one day expand therapeutic options for patients with end-stage lung disease. However, the feasibility of ex vivo lung regeneration remains limited by the inability to recapitulate mature, functional alveolar epithelium. Here, we modulate multimodal components of the alveolar epithelial type 2 cell (AEC2) niche in decellularized lung scaffolds in order to guide AEC2 behavior for epithelial regeneration. First, endothelial cells coordinate with fibroblasts, in the presence of soluble growth and maturation factors, to promote alveolar scaffold population with surfactant-secreting AEC2s. Subsequent withdrawal of Wnt and FGF agonism synergizes with tidal-magnitude mechanical strain to induce the differentiation of AEC2s to squamous type 1 AECs (AEC1s) in cultured alveoli, in situ. These results outline a rational strategy to engineer an epithelium of AEC2s and AEC1s contained within epithelial-mesenchymal-endothelial alveolar-like units, and highlight the critical interplay amongst cellular, biochemical, and mechanical niche cues within the reconstituting alveolus. [ABSTRACT FROM AUTHOR]

The human lung cellular portfolio, traditionally characterized by cellular morphology and individual markers, is highly diverse, with over 40 cell types and a complex branching structure highly adapted for agile airflow and gas exchange. While constant during adulthood, lung cellular content changes in response to exposure, injury, and infection. Some changes are temporary, but others are persistent, leading to structural changes and progressive lung disease. The recent advance of single-cell profiling technologies allows an unprecedented level of detail and scale to cellular measurements, leading to the rise of comprehensive cell atlas styles of reporting. In this review, we chronical the rise of cell atlases and explore their contributions to human lung biology in health and disease. [ABSTRACT FROM AUTHOR]

Vegetative filter strip characteristics such as perenniality drive hydrology and subsequent ecosystem services. However, the extent and the potential for forage–biomass crops to improve water quality, provide fodder, and optimize nutrient cycling in multifunctional systems is unknown. We evaluated (a) how species, perenniality, and plant community composition are linked to water quality; and (b) the multiuse forage–biomass potential of filter strips. Whole plots were species [eastern gamagrass (Tripsacum dactyloides), Kernza [or intermediate wheatgrass (Thinopyrum intermedium)], silphium (Silphium integrifolium), switchgrass (Panicum virgatum), and winter wheat (Triticum aestivum)], with split‐plots receiving 0 or 5.6 Mg ha−1 broiler litter. Rainfall simulations were conducted at 5 cm h−1 (until 30 min of continuous runoff) in summer and fall of 2019 and 2021 with dual forage and biomass harvests occurring 2019–2021. Kernza and silphium had the lowest biomass regrowth after forage harvests relative to native grasses, suggesting they would not be ideal multifunctional forage–bioenergy crops. Among all soil–plant–water variables, canonical correlations indicate poultry litter (.97), and soil phosphorus saturation (.77) were the most influential variables for water quality. Water quality score, FWQ, which is inversely related to runoff water quality, was lowest for switchgrass (0.03) and greatest (P ≥.05) for eastern gamagrass and wheat (1.77 and 3.33, respectively), but not different from Kernza (0.98) and silphium (0.31). Therefore, switchgrass resulted in the best water quality scores and highest forage–biomass yields, with Kernza and silphium also showing promise for reducing sediment and nutrient loads following poultry litter applications in multifunctional filter strip systems. Core Ideas: Filter strip characteristics drive surface hydrology and subsequent ecosystem services. Greatest multiuse (forage–biomass filter strip) yields occurred for switchgrass. Poultry litter applications and soil P saturation were most correlated with water quality. Perennial crops (excluding eastern gamagrass) improved water quality. Switchgrass had the highest water quality and biomass yields, indicating greatest multiuse filter strip potential. [ABSTRACT FROM AUTHOR]

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration--approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Objectives: Using an in silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. Methods: We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: 1) in vitro in normal human lung fibroblasts; 2) in vivo in bleomycin and recombinant Ad-TGF-b (adenovirus transforming growth factor-b) murine models of pulmonary fibrosis; and 3) ex vivo in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. Measurements and Main Results: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-b--stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial--mesenchymal transition, TGF-b, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial--mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment. [ABSTRACT FROM AUTHOR]

Terminal lakes throughout the American West provide important amenity and environmental values, but many are shrinking due to reduced inflows and warming temperatures. In California's Imperial Valley, agricultural water use reductions diminish inflows supporting the Salton Sea, a terminal desert lake and important environmental amenity for both the region and the state as a whole. The costs of these reduced inflows are difficult to monetize yet complicate management decisions. We assess the costs of potential future drought‐induced transfers by linking novel hydrologic scenarios to an economic framework for quantifying local and regional damages based on existing estimates of non‐market environmental values from the literature. The costs of lost wetland ecosystems, increases in particulate matter from exposed playa, and other local disamenities are substantial. For the scenarios considered, they range between approximately $500 million and $1 billion in present value (2019 USD). Estimated damages per acre‐foot (or thousand m3) of reallocated water exceed several thousand dollars. The majority arise from loss of wetland habitat; incremental particulate matter damages are relatively modest in our modeling but exacerbate salient air quality issues in the region. Interest in reallocating water from Imperial Valley, the largest user of Colorado River water, to other applications will increase over time. Our work highlights the importance of evaluating the impacts of such efforts. [ABSTRACT FROM AUTHOR]

306 Background: Health related social needs (HRSN) impact cancer outcomes and patient experience, but their integration into routine cancer care is highly variable. To expand the implementation-centered evidence base for effective HRSN assessments, we studied a scalable HRSN screening tool to identify distress and complex symptom burden in patients with cancer. Methods: We prospectively tracked HRSN screenings (using the National Comprehensive Cancer Network [NCCN] Distress Thermometer [DT]) of patients at varying points during their cancer care between 07/2023-12/2023 at seven multi-site community oncology practices within the US Oncology Network. DT responses were used to evaluate the positive finding rate, types of distress reported, and correlations between distress areas and concerns reported. Results: Overall, 219,720 unique patients with cancer received 269,666 HRSN screenings using the NCCN DT; 27% had a distress score ≥1 and 38.5% reported a concern (of whom, 58.2% reported >1). Co-occurring concerns that were most correlated (Pearson correlation coefficient) were emotional & practical concerns in 49% of screenings, physical & practical 44%, emotional & social 37% and social & practical concerns 36%. Emotional symptoms most frequently reported together were sadness/depression + worry/anxiety 47%, loss of interest + sadness/depression 44%, and loneliness & sadness/depression 38.5%. Regarding complex symptom burden, the physical and psychosocial symptoms that were most correlated were fatigue & sleep 43%, pain & fatigue 40%, pain & sleep 38%, anxiety/worry & fatigue 37%, anxiety/worry & sleep 36%. Fatigue and pain, the two most frequently reported concerns were strongly correlated with emotional and practical concerns like sleep, worry or anxiety, memory or concentration, loss or change of physical abilities, sadness or depression, loss of interest or enjoyment, changes in eating, ability to take care of self, feelings of worthlessness or being a burden, etc. Concerns with the strongest correlations are reported in the table. Conclusions: Distress and its components impact multiple cancer outcomes making their rapid identification and consequent action key to high-quality cancer care. The findings highlight the NCCN DT as a scalable approach to integrate HRSN screening and to identify complex symptom burden in the real-world practice. Co-occurring physical and psychosocial concerns. Concern 1 Concern 2 Correlation r Sadness or depression Worry or anxiety 47.3% 0.5 Loss of interest or enjoyment Sadness or depression 44.3% 0.4 Fatigue Sleep 42.5% 0.4 Pain Fatigue 40.0% 0.4 Loneliness Sadness or depression 38.5% 0.4 Pain Sleep 37.8% 0.4 Worry or anxiety Fatigue 36.7% 0.4 Worry or anxiety Sleep 36.1% 0.4 Taking care of myself Taking care of others 35.9% 0.4 [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. In this study, we focus on the properties of airway basal cells (ABC) obtained from patients with IPF (IPF-ABC). Single cell RNA sequencing (scRNAseq) of bronchial brushes revealed extensive reprogramming of IPF-ABC towards a KRT17high PTENlow dedifferentiated cell type. In the 3D organoid model, compared to ABC obtained from healthy volunteers, IPF-ABC give rise to more bronchospheres, de novo bronchial structures resembling lung developmental processes, induce fibroblast proliferation and extracellular matrix deposition in co-culture. Intratracheal application of IPF-ABC into minimally injured lungs of Rag2−/− or NRG mice causes severe fibrosis, remodeling of the alveolar compartment, and formation of honeycomb cyst-like structures. Connectivity MAP analysis of scRNAseq of bronchial brushings suggested that gene expression changes in IPF-ABC can be reversed by SRC inhibition. After demonstrating enhanced SRC expression and activity in these cells, and in IPF lungs, we tested the effects of saracatinib, a potent SRC inhibitor previously studied in humans. We demonstrate that saracatinib modified in-vitro and in-vivo the profibrotic changes observed in our 3D culture system and novel mouse xenograft model. The functional role of airway basal cells has not been comprehensively studied in idiopathic pulmonary fibrosis (IPF). Here, the authors show that airway basal cells of IPF patients display a distinct phenotype, are profibrotic if transplanted to mice and that fibrosis can be ameliorated by Src iinhibitors. [ABSTRACT FROM AUTHOR]

Studies comparing single cell RNA-Seq (scRNA-Seq) data between conditions mainly focus on differences in the proportion of cell types or on differentially expressed genes. In many cases these differences are driven by changes in cell interactions which are challenging to infer without spatial information. To determine cell-cell interactions that differ between conditions we developed the Cell Interaction Network Inference (CINS) pipeline. CINS combines Bayesian network analysis with regression-based modeling to identify differential cell type interactions and the proteins that underlie them. We tested CINS on a disease case control and on an aging mouse dataset. In both cases CINS correctly identifies cell type interactions and the ligands involved in these interactions improving on prior methods suggested for cell interaction predictions. We performed additional mouse aging scRNA-Seq experiments which further support the interactions identified by CINS. Author summary: Single cell transcriptomics has emerged as a leading technology for studying the composition of organs and tissues in the human body, development and several other biological processes. More recent studies, including studies of various diseases (such as cancer), treatment—response studies and aging studies aim at comparing samples at the single cell level. To date, such analysis mainly focused on the differences in expression of genes in the different cell types. However, in addition to differences in expression such studies also provide information on the differences of cell type proportions between the conditions. To use such information for inferring cell interactions we developed a new computational framework termed CINS. CINS combines Bayesian network learning (which is used to infer cell type–cell type interactions) with constrained regression analysis (used to infer the specific proteins involved in such interactions). We applied CINS to a number of different case-control scRNA-Seq datasets including a lung disease and an aging study. By analyzing public data and profiling new scRNA-Seq data we show that CINS is able to correctly identify several proteins as playing a significant role in interactions controlling disease progression and aging, improving on prior methods suggested for this task. [ABSTRACT FROM AUTHOR]

Rationale: A prevailing paradigm recognizes idiopathic pulmonary fibrosis (IPF) originating from various alveolar epithelial cell (AEC) injuries, and there is a growing appreciation of AEC aging as a key driver of the pathogenesis. Despite this progress, it is incompletely understood what main factor(s) contribute to the worsened alveolar epithelial aging in lung fibrosis. It remains a challenge how to dampen AEC aging and thereby mitigate the disease progression. Objectives: To determine the role of AEC CD38 (cluster of differentiation 38) in promoting cellular aging and lung fibrosis. Methods: We used single-cell RNA sequencing, real-time PCR, flow cytometry, and Western blotting. Measurements and Main Results: We discovered a pivotal role of CD38, a cardinal nicotinamide adenine dinucleotide (NAD) hydrolase, in AEC aging and its promotion of lung fibrosis. We found increased CD38 expression in IPF lungs that inversely correlated with the lung functions of patients. CD38 was primarily located in the AECs of human lung parenchyma and was markedly induced in IPF AECs. Similarly, CD38 expression was elevated in the AECs of fibrotic lungs of young mice and further augmented in those of old mice, which was in accordance with a worsened AEC aging phenotype and an aggravated lung fibrosis in the old animals. Mechanistically, we found that CD38 elevation downregulated intracellular NAD, which likely led to the aging promoting impairment of the NAD-dependent cellular and molecular activities. Furthermore, we demonstrated that genetic and pharmacological inactivation of CD38 improved these NAD dependent events and ameliorated bleomycin-induced lung fibrosis. Conclusions: Our study suggests targeting alveolar CD38 as a novel and effective therapeutic strategy to treat this pathology. [ABSTRACT FROM AUTHOR]

Animal tissues comprise diverse cell types. However, the mechanisms controlling the number of each cell type within tissue compartments remain poorly understood. Here, we report that different cell types utilize distinct strategies to control population numbers. Proliferation of fibroblasts, stromal cells important for tissue integrity, is limited by space availability. In contrast, proliferation of macrophages, innate immune cells involved in defense, repair, and homeostasis, is constrained by growth factor availability. Examination of density-dependent gene expression in fibroblasts revealed that Hippo and TGF-ß target genes are both regulated by cell density. We found YAP1, the transcriptional coactivator of the Hippo signaling pathway, directly regulates expression of Csf1, the lineage-specific growth factor for macrophages, through an enhancer of Csf1 that is specifically active in fibroblasts. Activation of YAP1 in fibroblasts elevates Csf1 expression and is sufficient to increase the number of macrophages at steady state. Our data also suggest that expression programs in fibroblasts that change with density may result from sensing of mechanical force through actin-dependent mechanisms. Altogether, we demonstrate that two different modes of population control are connected and coordinated to regulate cell numbers of distinct cell types. Sensing of the tissue environment may serve as a general strategy to control tissue composition. [ABSTRACT FROM AUTHOR]

Groundwater modeling can be made more accessible to stakeholders and water managers through interface tools that prepare model inputs and create graphical outputs. An application of this improved modeling technique is presented here, where a model interface tool, called the Groundwater Management Tool (GMT) was developed for the widely used MODFLOW model. The GMT facilitates the evaluation of various water use scenarios for those who have limited time for and/or experience in modifying groundwater model inputs and outputs, yet who need the complexity of a three‐dimensional numerical groundwater model to adequately represent the hydrologic system of interest. The impacts of new pumping wells and altered pumping regimes in existing wells are easily explored through the current version of this interface tool. The modeling technique employed by the GMT provides water managers with the ability to efficiently leverage the decision‐support power and confidence provided by a calibrated groundwater model without the time‐consuming processing of model input and output files, and thereby increases the value and utility provided by the model in supporting water resource management decisions. The purpose of this Technical Note is to highlight an improved modeling approach by combining the power of FloPy with the widely used Microsoft Excel software, to quickly utilize the power of an existing MODFLOW model. Research Impact Statement: Interfaces that provide specified, selectable, input parameters for groundwater models facilitate rapid generation of outputs thereby streamlining the decision‐making process for water managers. [ABSTRACT FROM AUTHOR]

Poultry litter is generated in large quantities throughout the southeastern United States and is an excellent nutrient source for increasing crop yields. However, surface applications result in nutrient losses to air, soil, and water. Subsurface banding poultry litter is a promising technology for reducing nutrient losses to surface and groundwater, but information is needed on optimum crop seeding distance from bands. This study evaluated edamame [Glycine max (L.) Merr. 'Edamame'] yield (residue, pod, and total plant), crop quality, and leaf greenness. Subsurface banded poultry litter and crop row distances (13, 25, and 38 cm) were compared with surface‐applied poultry litter (all received 168 kg ha−1 total N) under irrigated and nonirrigated conditions from 2019 to 2020. Both chlorophyll and edamame total yields were greatest (P ≤.05) under subsurface banding litter, relative to surface applications, regardless of distance. Overall, greatest total crop yields were observed for 13‐ and 25‐cm banding distances under irrigation and the 38‐cm distance, irrespective of irrigation, relative to surface applications. Residue nutritive value for the 13‐cm distance was greater under irrigation than dryland. Both systems provided high levels of nutritive residual mass, thus edamame could be used as a vegetable crop and a forage following harvest. Overall, subsurface banding poultry litter in conservation tillage systems is a viable replacement to surface applications for edamame production (vegetable and fodder), particularly in organic systems. Results can be used to develop nutrient management plans for organic edamame and other specialty crop production systems in the Mid‐South. Core Ideas: Subsurface banding resulted in greater leaf greenness and yield compared with surface litter.Edamame can serve as a multifunctional crop for use as an organic vegetable and fodder.Subsurface banding litter at all distances were optimum for organic total edamame yields. [ABSTRACT FROM AUTHOR]

Single-cell RNA-sequencing data has revolutionized our ability to understand of the patterns of cell–cell and ligand–receptor connectivity that influence the function of tissues and organs. However, the quantification and visualization of these patterns in a way that informs tissue biology are major computational and epistemological challenges. Here, we present Connectome, a software package for R which facilitates rapid calculation and interactive exploration of cell–cell signaling network topologies contained in single-cell RNA-sequencing data. Connectome can be used with any reference set of known ligand–receptor mechanisms. It has built-in functionality to facilitate differential and comparative connectomics, in which signaling networks are compared between tissue systems. Connectome focuses on computational and graphical tools designed to analyze and explore cell–cell connectivity patterns across disparate single-cell datasets and reveal biologic insight. We present approaches to quantify focused network topologies and discuss some of the biologic theory leading to their design. [ABSTRACT FROM AUTHOR]

Systems-level studies aimed at determining how soil properties are linked to plant production and ultimately animal response spatially are lacking. This study aims to identify if grazing pressure is linked to soil properties, terrain attributes, and above-ground plant accumulation and nutritive value in a silvopastoral (or integrated tree-livestock) system. Overall, cattle prefer grazing native grasses (2.81 vs. 1.24 h ha−1 AU−1) and udic (dry) landscape positions compared to aquic (wet) areas (2.07 vs. 1.60 h ha−1 AU−1). Greater grazing frequency occurs in udic soils with greater phosphorus and potassium contents and with accumulated forage with less lignin (P ≤ 0.05), which correspond to reduced elevation and greater tree height and diameter (shade) during summer mob grazing. Combining spatial monitoring technologies (both soil and animal) with forage allowance can optimize grazing systems management and sustainability spatially and temporally. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD. Using transcriptomic network analyses, we predict capillary endothelial cells are inflamed in COPD, particularly through increased CXCL-motif chemokine signaling. Finally, we detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD. Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD. Chronic obstructive pulmonary disease is a leading cause of death worldwide, while our understanding of cell-specific mechanisms underlying its pathobiology remains incomplete. Here the authors perform scRNA-seq of human lung tissue to identify transcriptional changes in alveolar niche cells associated with the disease. [ABSTRACT FROM AUTHOR]

During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate excess myofibroblasts and extracellular matrix; herein, we focus on signaling in the mesenchyme. Our studies indicate that platelet-derived growth factor receptor (PDGFR)-β+ cells are the predominant source of myofibroblasts and Kruppel-like factor (KLF) 4 is upregulated in PDGFR-β+ cells, inducing TGFβ pathway signaling and fibrosis. In fibrotic lung patches, KLF4 is down-regulated, suggesting KLF4 levels decrease as PDGFR-β+ cells transition into myofibroblasts. In contrast to PDGFR-β+ cells, KLF4 reduction in α-smooth muscle actin (SMA)+ cells non-cell autonomously exacerbates lung fibrosis by inducing macrophage accumulation and pro-fibrotic effects of PDGFR-β+ cells via a Forkhead box M1 to C-C chemokine ligand 2—receptor 2 pathway. Taken together, in the context of lung fibrosis, our results indicate that KLF4 plays opposing roles in PDGFR-β+ cells and SMA+ cells and highlight the importance of further studies of interactions between distinct mesenchymal cell types. The pluripotency factor KLF4 has been described as pro-fibrotic or anti-fibrotic in various diseases. Herein, the authors show that during lung fibrosis, these distinct effects can be attributed to mesenchymal cell-type specific functions of KLF4. [ABSTRACT FROM AUTHOR]

Background: Recent development of single cell sequencing technologies has made it possible to identify genes with different expression (DE) levels at the cell type level between different groups of samples. In this article, we propose to borrow information through known biological networks to increase statistical power to identify differentially expressed genes (DEGs). Results: We develop MRFscRNAseq, which is based on a Markov random field (MRF) model to appropriately accommodate gene network information as well as dependencies among cell types to identify cell-type specific DEGs. We implement an Expectation-Maximization (EM) algorithm with mean field-like approximation to estimate model parameters and a Gibbs sampler to infer DE status. Simulation study shows that our method has better power to detect cell-type specific DEGs than conventional methods while appropriately controlling type I error rate. The usefulness of our method is demonstrated through its application to study the pathogenesis and biological processes of idiopathic pulmonary fibrosis (IPF) using a single-cell RNA-sequencing (scRNA-seq) data set, which contains 18,150 protein-coding genes across 38 cell types on lung tissues from 32 IPF patients and 28 normal controls. Conclusions: The proposed MRF model is implemented in the R package MRFscRNAseq available on GitHub. By utilizing gene-gene and cell-cell networks, our method increases statistical power to detect differentially expressed genes from scRNA-seq data. [ABSTRACT FROM AUTHOR]

Grass root production and decomposition is a major source of C entering soils, although rates are largely unknown based on edaphic and management factors. Therefore, study objectives were to evaluate four explanatory variables including forage species (native and nonnative), fertility (poultry litter and a control), soil moisture (udic and aquic), and pasture management (grazed and an ungrazed control) in order to evaluate driving factors for root turnover and subsequent soil organic matter formation in silvopastoral systems using the root litter bag technique. Native grass root decomposition was accelerated relative to the nonnative forage based on root mass balance, as well as the exponential decay function, likely owing to greater five‐ and six‐C sugars and more digestible root tissues of native grasses. These physiochemical results suggest more favorable microbial food sources, which culminate in faster decomposition and greater microbially derived organic matter. Overall, there was greater root sloughing and subsequent soil organic matter formation potential with native grass species and poultry litter applications, with soil moisture affecting decomposition to a lesser extent. This study contributes to the understanding of complex interactions of grass species, soil moisture, nutrients, and grazing, which controls primary productivity, as well as nutrient cycling and C sequestration in silvopastures. Core Ideas: Root decomposition is a major source of C entering soils in grasslands.Native grass roots decomposed quicker than roots from the nonnative forage.Poultry litter increased root decay, with soil moisture affecting rates to a lesser extent.Root chemical composition and management were driving factors for decomposition.This work contributes to understanding factors affecting root decomposition. [ABSTRACT FROM AUTHOR]

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observe a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response. Additionally, we identify basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection. Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients. [ABSTRACT FROM AUTHOR]

Carbon cycling is a highly complex yet critical process, especially in silvopastures, which have multiple pools with the ability to store large amounts of C. However, it is largely unknown how site‐specific variables, including edaphic factors, vegetation type, topography, and management, affect soil CO2 flux in silvopastures. Therefore, this study aimed to evaluate CO2 fluxes in a silvopastoral system as affected by soil moisture (udic and aquic), forage species (C4; native grass mix and orchardgrass [C3; Dactylis glomerata L.]), fertilization (poultry litter and a control), and grazing pressure (grazed and ungrazed). Temperature and volumetric water content (VWC) were measured simultaneous with flux measurements during summer grazing in 2018 and 2019. Averaged across years, fluxes were at least 20% greater (P ≤.05) in the native mix fertilized with poultry litter than in the unfertilized native mix and fertilized or unfertilized orchardgrass, likely owing to increased microbial diversity activity in the rhizosphere of poultry litter‐amended native grass species. Across years, CO2 flux was 7% greater (P ≤.05) in the fertilized ungrazed areas and 7% lower (P ≤.05) in the unfertilized ungrazed areas, respectively, compared with both fertilized grazed and unfertilized grazed areas. Carbon dioxide flux was correlated (P ≤.05) with sampling date, soil temperature, and VWC. Study results improve the understanding of C dynamics in complex silvopasture systems and may assist producers in their selection of forage species and nutrient sources when designing silvopastoral systems for enhanced regional sustainability.Core Ideas: Studies of soil CO2 flux in silvopastoral systems are limited.Fluxes were greatest in a native grass mix fertilized with poultry litter.Carbon dioxide flux was correlated to sampling date, soil temperature, and soil water content. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. The mechanisms promoting disease pathogenesis and progression are unknown, although interleukin-15 (IL-15) has been associated with the immune-mediated inflammation of sarcoidosis. Because the identification of a mechanistically based, clinically relevant biomarker for sarcoidosis remains elusive, we hypothesized this role for IL-15. Pulmonary sarcoidosis granuloma formation was modeled using trehalose 6,60-dimicolate (TDM), which was administered into wild-type and three lineages of mice: those overexpressing IL-15, deficient in IL-15, and deficient in IL-15 receptor α. The number of granulomas per lung was counted and normalized to the wild type. IL-15 concentrations were measured in the bronchoalveolar lavage (BAL) from healthy controls and subjects with sarcoidosis in our cohort, where associations between IL-15 levels and clinical manifestations were sought. Findings were validated in another independent sarcoidosis cohort. TDM administration resulted in similar granuloma numbers across all lineages of mice. IL-15 concentrations were elevated in the BAL of both human cohorts, irrespective of disease phenotypes. In exploratory analysis, an association with obesity was observed, and various other soluble mediators were identified in the BAL of both cohorts. Although IL-15 is enriched in the sarcoidosis lung, it was independent of disease pathogenesis or clinical manifestations in our mouse model and human cohorts of sarcoidosis. An association with obesity perhaps reflects the ongoing inflammatory processes of these comorbid conditions. Our findings showed that IL-15 is redundant for disease pathogenesis and clinical progression of sarcoidosis. [ABSTRACT FROM AUTHOR]

Background: Asthma has been associated with impaired interferon response. Multiple cell types have been implicated in such response impairment and may be responsible for asthma immunopathology. However, existing models to study the immune response in asthma are limited by bulk profiling of cells. Our objective was to Characterize a model of peripheral blood mononuclear cells (PBMCs) of patients with severe asthma (SA) and its response to the TLR3 agonist Poly I:C using two single-cell methods.Methods: Two complementary single-cell methods, DropSeq for single-cell RNA sequencing (scRNA-Seq) and mass cytometry (CyTOF), were used to profile PBMCs of SA patients and healthy controls (HC). Poly I:C-stimulated and unstimulated cells were analyzed in this study.Results: PBMCs (n = 9414) from five SA (n = 6099) and three HC (n = 3315) were profiled using scRNA-Seq. Six main cell subsets, namely CD4 + T cells, CD8 + T cells, natural killer (NK) cells, B cells, dendritic cells (DCs), and monocytes, were identified. CD4 + T cells were the main cell type in SA and demonstrated a pro-inflammatory profile characterized by increased JAK1 expression. Following Poly I:C stimulation, PBMCs from SA had a robust induction of interferon pathways compared with HC. CyTOF profiling of Poly I:C stimulated and unstimulated PBMCs (n = 160,000) from the same individuals (SA = 5; HC = 3) demonstrated higher CD8 + and CD8 + effector T cells in SA at baseline, followed by a decrease of CD8 + effector T cells after poly I:C stimulation.Conclusions: Single-cell profiling of an in vitro model using PBMCs in patients with SA identified activation of pro-inflammatory pathways at baseline and strong response to Poly I:C, as well as quantitative changes in CD8 + effector cells. Thus, transcriptomic and cell quantitative changes are associated with immune cell heterogeneity in this model to evaluate interferon responses in severe asthma. [ABSTRACT FROM AUTHOR]

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals.Methods: We performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects' clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay.Result: We observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns.Conclusions: We successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals' genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity. [ABSTRACT FROM AUTHOR]

Long‐noncoding RNAs (lncRNAs) have numerous biological functions controlling cell differentiation and tissue development. The knowledge about the role of lncRNAs in human lungs remains limited. Here we found the regulatory role of the terminal differentiation‐induced lncRNA (TINCR) in bronchial cell differentiation. RNA in situ hybridization revealed that TINCR was mainly expressed in bronchial epithelial cells in normal human lung. We performed RNA sequencing analysis of normal human bronchial epithelial cells (NHBECs) with or without TINCR inhibition and found the differential expression of 603 genes, which were enriched for cell adhesion and migration, wound healing, extracellular matrix organization, tissue development and differentiation. To investigate the role of TINCR in the differentiation of NHBECs, we employed air–liquid interface culture and 3D organoid formation assay. TINCR was upregulated during differentiation, loss of TINCR significantly induced an early basal‐like cell phenotype (TP63) and a ciliated cell differentiation (FOXJ1) in late phase and TINCR overexpression suppressed basal cell phenotype and the differentiation toward to ciliated cells. Critical regulators of differentiation such as SOX2 and NOTCH genes (NOTCH1, HES1, and JAG1) were significantly upregulated by TINCR inhibition and downregulated by TINCR overexpression. RNA immunoprecipitation assay revealed that TINCR was required for the direct bindings of Staufen1 protein to SOX2, HES1, and JAG1 mRNA. Loss of Staufen1 induced TP63, SOX2, NOTCH1, HES1, and JAG1 mRNA expressions, which TINCR overexpression suppressed partially. In conclusion, TINCR is a novel regular of bronchial cell differentiation, affecting downstream regulators such as SOX2 and NOTCH genes, potentially in coordination with Staufen1. [ABSTRACT FROM AUTHOR]

Reference 1 Liu Y. iDESC: identifying differential expression in single-cell RNA sequencing data with multiple subjects. Correction: iDESC: identifying differential expression in single-cell RNA sequencing data with multiple subjects. [Extracted from the article]

Rationale: Cystic fibrosis (CF) is a life-shortening, multisystem hereditary disease caused by abnormal chloride transport. CF lung disease is driven by innate immune dysfunction and exaggerated inflammatory responses that contribute to tissue injury. To define the transcriptional profile of this airway immune dysfunction, we performed the first single-cell transcriptome characterization of CF sputum.Objectives: To define the transcriptional profile of sputum cells and its implication in the pathogenesis of immune function and the development of CF lung disease.Methods: We performed single-cell RNA sequencing of sputum cells from nine subjects with CF and five healthy control subjects. We applied novel computational approaches to define expression-based cell function and maturity profiles, herein called transcriptional archetypes.Measurements and Main Results: The airway immune cell repertoire shifted from alveolar macrophages in healthy control subjects to a predominance of recruited monocytes and neutrophils in CF. Recruited lung mononuclear phagocytes were abundant in CF and were separated into the following three archetypes: activated monocytes, monocyte-derived macrophages, and heat shock-activated monocytes. Neutrophils were the most prevalent in CF, with a dominant immature proinflammatory archetype. Although CF monocytes exhibited proinflammatory features, both monocytes and neutrophils showed transcriptional evidence of abnormal phagocytic and cell-survival programs.Conclusions: Our findings offer an opportunity to understand subject-specific immune dysfunction and its contribution to divergent clinical courses in CF. As we progress toward personalized applications of therapeutic and genomic developments, we hope this inflammation-profiling approach will enable further discoveries that change the natural history of CF lung disease. [ABSTRACT FROM AUTHOR]

Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis. Collagen production by lung cells is critical to maintain organ architecture but can also drive pathological scarring. Here the authors perform single cell RNA sequencing of collagen-producing lung cells identifying a subset of pathologic fibroblasts characterized by Cthrc1 expression which are concentrated within fibroblastic foci in fibrotic lungs and show a pro-fibrotic phenotype. [ABSTRACT FROM AUTHOR]

State yield contests offer a unique opportunity to examine the high end of crop productivity. Yield-contest-entered and average-yielding areas on the same or a similar soil can provide large yield and soil property variations to better examine the relationships among various near-surface soil properties and soybean (Glycine maxL. [Merr.]) yield. The objective of this study was to evaluate the relationships among a suite of near-surface soil properties and soybean yield across average- and high-yield areas using state yield-contest sites. Multiple regression analyses were conducted to evaluate best-fit relationships among various soil physical, chemical, and biological properties and yield separately for average- and high-yielding areas and for data combined across yield areas. Soybean yield variation was most explained for the high-yield-area dataset (R2 = 73%) and less explained for the average-yield-area (R2 = 51%) and the combined (R2 = 50%) datasets. Extractable soil Ca and S explained the largest proportion of yield variation (37% and 31% of total sum of squares) in the high-yield setting and both were inversely related to yield. A better understanding of the soil environment may be a key component of more frequent attainment of the 6270 kg ha−1(100 bu acre−1) soybean yield mark. Additional soil properties, beyond those evaluated in this study, may need to be included for a more complete understanding of the soil environment that is associated with high-yield soybean production. [ABSTRACT FROM PUBLISHER]

Most cell types in multicellular organisms can perform multiple functions. However, not all functions can be optimally performed simultaneously by the same cells. Functions incompatible at the level of individual cells can be performed at the cell population level, where cells divide labor and specialize in different functions. Division of labor can arise due to instruction by tissue environment or through self-organization. Here, we develop a computational framework to investigate the contribution of these mechanisms to division of labor within a cell-type population. By optimizing collective cellular task performance under trade-offs, we find that distinguishable expression patterns can emerge from cell-cell interactions versus instructive signals. We propose a method to construct ligand-receptor networks between specialist cells and use it to infer division-of-labor mechanisms from single-cell RNA sequencing (RNA-seq) and spatial transcriptomics data of stromal, epithelial, and immune cells. Our framework can be used to characterize the complexity of cell interactions within tissues. [Display omitted] • Division of labor theory predicts distinct, mechanism-dependent spatial patterns • Spatial proximity of specialist cells suggests involvement of cell interactions • Archetype crosstalk networks reveal patterns of interactions between specialist cells • Enterocytes and fibroblasts exemplify distinct division of labor strategies Two of the mechanisms that can drive division of labor in tissues are external signaling gradients and cell-cell interactions. Theory for optimal task allocation explains how to distinguish between the two strategies in single-cell and spatial omics data. This is demonstrated for colon fibroblasts, intestinal enterocytes, lung fibroblasts, and macrophages. [ABSTRACT FROM AUTHOR]

Since soybean (Glycine max L. (Merr.)) yields greater than 6719 kg ha-1 have only recently and infrequently been achieved, little is known about the soil microbiological environment related to high-yield soybean production. Soil microbiological properties are often overlooked when assessing agronomic practices for optimal production. Therefore, a greater understanding is needed regarding how soil biological properties may differ between high- and average-yielding areas within fields. The objectives of this study were to (i) evaluate the effects of region on soil microbial carbon substrate utilization differences between high- (HY) and average-yield (AY) areas and (ii) assess the effect of yield area on selected microbiological property differences. Replicate soil samples were collected from the 0-10 cm depth from yield-contest-entered fields in close proximity that had both a HY and an AY area. Samples were collected immediately prior to or just after soybean harvest in 2014 and 2015 from each of seven geographic regions within Arkansas. Averaged across yield area, community-level carbon substrate utilization and Shannon's and Simpson's functional diversity and evenness were greater (p < 0.05) in Region 7 than all other regions. Averaged across regions, Shannon's functional diversity and evenness were greater (p < 0.05) in HY than in AY areas. Principal component analysis demonstrated that a greater variety of carbon substrates were used in HY than AY areas. These results may help producers understand the soil microbiological environment in their own fields that contribute to or hinder achieving high-yielding soybeans; however, additional parameters may need to be assessed for a more comprehensive understanding of the soil environment that is associated with high-yielding soybean. [ABSTRACT FROM AUTHOR]

This research investigates the impact of Title IX on women's education in the U.S. and how a comparable policy in India could improve women's education in India. The existing education policies in the U.S. and India were thoroughly reviewed to understand the impact of Title IX on female education over the past 40 years and to recognize gaps in Indian policy. Data from the U.S. Census Bureau, NSF through WebCASPAR and the India Ministry of Human Resource Development was reviewed through descriptive analysis. Different variables from primary, secondary and tertiary education were examined. It was determined that Title IX improved the outcomes for nearly all the markers for female education within the U.S. Thus, the research concluded that despite differences between the educational frameworks of both countries, a form of Title IX policy in India would be beneficial in reducing the gender inequality present in the education system. [ABSTRACT FROM AUTHOR]

The persistence of Conservation Reserve Program (CRP) seed mixtures following planting is crucial for the long-term support of pollinator habitat; however, the role of disturbance regimes and their interactions in supporting this ecosystem service are largely unknown. This study set out to evaluate how ecological disturbances (prescribed burn, light disking, or fallow control) and commercially available diverse species mixtures ('Hamilton', 'Bamert', and 'Holland') affect pollinator habitat and the flowering period of commonly used CRP species mixtures. Specifically, three pollinator species mixtures were assessed for plant stand dynamics (plant density, yield, and dual-use pollinator-lignocellulosic feedstock potential); the resulting soil properties; and the total bloom count during the growing season. Following 5 years after their establishment, the proportions of flowering pollinator species varied by disturbance regime × seed mixture (p < 0.05), with the burned Hamilton and disked Holland plots having the greatest pollinator species percentages. Overall, if the long-term stability of pollinator blooms is a key consideration for management, the Hamilton mixture should be disturbed via prescribed burning, while the Holland mixture should be disked, owing to a species-specific disturbance regime preference. However, post-senescence yield and soil health properties did not vary (p > 0.05) across pollinator mixtures or disturbance regimes. Pollinator mixtures could also be harvested as a lignocellulosic feedstock without damaging pollinator habitat and providing comparable biomass for regional feedstocks; however, seeding mixtures and disturbance regimes should be considered based on desired residue usage for long-term sustainable CRP pollinator habitat. [ABSTRACT FROM AUTHOR]