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Abstract Proliferative diabetic retinopathy (PDR) remains a leading cause of blindness despite progress in screening and treatment. Recently, the Warburg effect, a metabolic alteration affecting amino acid (AA) metabolism in proliferating cells, has drawn attention regarding its role in PDR. This study aimed to investigate the impact of the Warburg effect on AA metabolism in human retinal endothelial cells (HRECs) subjected to PDR-associated risk factors and validate the findings in patients with PDR. In vitro experiments exposed HRECs to high glucose (HG) and/or hypoxia (Hyp), known inducers of the Warburg effect. The HG + Hyp group of HRECs exhibited significant differences in non-essential AAs with aliphatic non-polar side chains, mainly driven by elevated glycine concentrations. Pathway enrichment analysis revealed several glycine metabolism-related pathways significantly altered due to the Warburg effect induced by HG + Hyp. Crucially, vitreous humor samples from PDR patients displayed higher glycine levels compared to non-diabetic and diabetic patients without PDR. The odds ratio for PDR patients with glycine levels above the cut-off of 0.0836 µM was 28 (p = 0.03) compared to non-PDR controls. In conclusion, this study provides mechanistic insights into how a specific Warburg effect subtype contributes to glycine accumulation in PDR and supports glycine's potential as a biomarker for PDR pathogenesis.

Mnomen or wild rice of the genus Zizania is an important part of Native American culture, especially in Michigan for the Ojibwe nation. An oil spill in 2010 along the Kalamazoo River and the subsequent clean-up lead to renewed interest in management of Mnomen within the Kalamazoo watershed. The affected water bodies were surveyed for Zizania species to map existing populations, determine the existing genetic diversity and species present, and to identify potential hybridization. Using Traditional Ecological Knowledge of rice beds and opportunistic sampling of encountered plants, 28 rice beds were sampled. Two species of Zizania were identified Z. palustris and Z. aquatica. Genetic diversity was measured using 11 microsatellite loci and was moderately high for both species (Z. aquatica HE = 0.669, H0 = 0.672, n = 26 and Z. palustris HE = 0.697, H0 = 0.636, n = 57). No evidence of population bottle-necking was found. Z. palustris was found to have k = 3 populations on the landscape, while Z. aquatica was found to be a single panmictic population. Several individual hybrids were confirmed using genotyping and they were all found in areas where the two species co-occurred. Additionally, Z. aquatica was found to have expanded into areas historically with only Z. palustris downstream of the oil spill, potentially due to dredging and sediment relocation as part of the clean-up effort.

We report extreme-ultraviolet high-harmonic generation (HHG) from liquid isopropanol, extending up to 50 eV, when using 1800-nm carrier envelope phase stable pulses of 1.8 cycles with intensities below the laser breakdown threshold. We study the mechanism of the harmonic emission through its dependence on the driving field and find it to be consistent with a strong-field recombination mechanism. We explore the role of scattering from neighboring molecules in simulations using empirical cross-section data. We find that these simulations, within a full propagation calculation, provide good quantitative agreement with the measured intensity-dependent harmonic cutoffs and demonstrate that HHG emission in the liquid phase can be used to corroborate ultrafast electron-scattering processes.

Monoclonal gammopathy of clinical significance (MGCS) represents a new clinical entity referring to a myriad of pathological conditions associated with the monoclonal gammopathy of undetermined significance (MGUS). The establishment of MGCS expands our current understanding of the pathophysiology of a range of diseases, in which the M protein is often found. Aside from the kidney, the three main organ systems most affected by monoclonal gammopathy include the peripheral nervous system, skin, and eye. The optimal management of these MGUS-related conditions is not known yet due to the paucity of clinical data, the rarity of some syndromes, and limited awareness among healthcare professionals. Currently, two main treatment approaches exist. The first one resembles the now-established therapeutic strategy for monoclonal gammopathy of renal significance (MGRS), in which chemotherapy with anti-myeloma agents is used to target clonal lesion that is thought to be the culprit of the complex clinical presentation. The second approach includes various systemic immunomodulatory or immunosuppressive options, including intravenous immunoglobulins, corticosteroids, or biological agents. Although some conditions of the MGCS spectrum can be effectively managed with therapies aiming at the etiology or pathogenesis of the disease, evidence regarding other pathologies is severely limited to individual patient data from case reports or series. Future research should pursue filling the gap in knowledge and finding the optimal treatment for this novel clinical category.

The development of ultra-thin flat liquid sheets capable of running in vacuum has provided an exciting new target for X-ray absorption spectroscopy in the liquid and solution phases. Several methods have become available for delivering in-vacuum sheet jets using different nozzle designs. We compare the sheets produced by two different types of nozzle; a commercially available borosillicate glass chip using microfluidic channels to deliver colliding jets, and an in-house fabricated fan spray nozzle which compresses the liquid on an axis out of a slit to achieve collision conditions. We find in our tests that both nozzles are suitable for use in X-ray absorption spectroscopy with the fan spray nozzle producing thicker but more stable jets than the commercial nozzle. We also provide practical details of how to run these nozzles in vacuum.

Wildlife managers delineate priority areas for species to define critical habitat and to prioritize management efforts. Each method used to identify priority areas involves data that can be unavailable or expensive to obtain. Therefore, it is of interest to compare spatial efficiency between methods used for defining priority areas. We compared priority areas created using different methods and data types. We used resource selection function (RSF) models to predict areas of high use and generated a map depicting ≥ 90% predicted use in three seasons; it was 1,143 km2, encompassed 91% of nests, 68% of summer locations, and 71% of winter locations. We compared the RSF priority area to priority areas developed using two alternative methods: (1) modified conservation buffer, and (2) utilization distribution (UD) models. The modified conservation buffer method was used by South Dakota Game, Fish and Parks in 2014 to delineate a priority area by buffering active lek sites by 6.4 km, including connectivity corridors defined via expert opinion, and known high use areas. The priority area generated by the modified conservation buffer method was 3,977 km2, encompassed 95% of nest locations, 92% of spring/summer locations, and 99% of winter locations. Lastly, we developed a priority area using combined UDs from radio-tracking data gathered during spring/summer, and winter and included a lek buffer encompassing 90% of known nest-sites. This priority area was 3,498 km2, encompassed 99% of nests, 98% of spring/summer locations, and 97% of winter locations. The priority area generated by RSF models was the smallest and encompassed the least number of nests and spring/summer and winter locations but was considered the most spatially efficient; it had the most nests, spring/summer locations, and winter locations per 100 km2. The UD and modified conservation buffer methods created priority areas that were similar in size and spatial efficiency. The modified conservation buffer method encompassed >90% of known sage-grouse locations and nests, indicating that in the absence of detailed movement data and more sophisticated modeling, the method can be sufficient in developing an adequate priority area.

Introduction Chronic obstructive pulmonary disease (COPD) can progress across several domains, complicating the identification of the determinants of disease progression. In our previous work, we applied k-means clustering to spirometric and chest radiological measures to identify four COPD-related subtypes: ‘relatively resistant smokers (RRS)’, ‘mild upper lobe-predominant emphysema (ULE)’, ‘airway-predominant disease (AD)’ and ‘severe emphysema (SE)’. In the current study, we examined the associations of these subtypes to longitudinal COPD-related health measures as well as blood transcriptomic and plasma proteomic biomarkers.Methods We included 8266 non-Hispanic white and African-American smokers from the COPDGene study. We used linear regression to investigate cluster associations to 5-year prospective changes in spirometric and radiological measures and to gene expression and protein levels. We used Cox-proportional hazard test to test for cluster associations to prospective exacerbations, comorbidities and mortality.Results The RRS, ULE, AD and SE clusters represented 39%, 15%, 26% and 20% of the studied cohort at baseline, respectively. The SE cluster had the greatest 5-year FEV1 (forced expiratory volume in 1 s) and emphysema progression, and the highest risks of exacerbations, cardiovascular disease and mortality. The AD cluster had the highest diabetes risk. After adjustments, only the SE cluster had an elevated respiratory mortality risk, while the ULE, AD and SE clusters had elevated all-cause mortality risks. These clusters also demonstrated differential protein and gene expression biomarker associations, mostly related to inflammatory and immune processes.Conclusion COPD k-means subtypes demonstrate varying rates of disease progression, prospective comorbidities, mortality and associations to transcriptomic and proteomic biomarkers. These findings emphasise the clinical and biological relevance of these subtypes, which call for more study for translation into clinical practice.Trail registration number NCT00608764.

Purpose: Mitochondrial dysfunction is central to breaking the barrier integrity of retinal endothelial cells (RECs) in various blinding eye diseases such as diabetic retinopathy and retinopathy of prematurity. Therefore, we aimed to investigate the role of different mitochondrial constituents, specifically those of oxidative phosphorylation (OxPhos), in maintaining the barrier function of RECs. Methods: Electric cell-substrate impedance sensing (ECIS) technology was used to assess in real time the role of different mitochondrial components in the total impedance (Z) of human RECs (HRECs) and its components: capacitance (C) and the total resistance (R). HRECs were treated with specific mitochondrial inhibitors that target different steps in OxPhos: rotenone for complex I, oligomycin for complex V (ATP synthase), and FCCP for uncoupling OxPhos. Furthermore, data were modeled to investigate the effects of these inhibitors on the three parameters that govern the total resistance of cells: Cell–cell interactions (Rb), cell–matrix interactions (α), and cell membrane permeability (Cm). Results: Rotenone (1 µM) produced the greatest reduction in Z, followed by FCCP (1 µM), whereas no reduction in Z was observed after oligomycin (1 µM) treatment. We then further deconvoluted the effects of these inhibitors on the Rb, α, and Cm parameters. Rotenone (1 µM) completely abolished the resistance contribution of Rb, as the Rb became zero immediately after the treatment. Secondly, FCCP (1 µM) eliminated the resistance contribution of Rb only after 2.5 h and increased Cm without a significant effect on α. Lastly, of all the inhibitors used, oligomycin had the lowest impact on Rb, as evidenced by the fact that this value became similar to that of the control group at the end of the experiment without noticeable effects on Cm or α. Conclusion: Our study demonstrates the differential roles of complex I, complex V, and OxPhos coupling in maintaining the barrier functionality of HRECs. We specifically showed that complex I is the most important component in regulating HREC barrier integrity. These observed differences are significant since they could serve as the basis for future pharmacological and gene expression studies aiming to improve the activity of complex I and thereby provide avenues for therapeutic modalities in endothelial-associated retinal diseases.

Chronic obstructive pulmonary disease (COPD) is a disease with marked metabolic disturbance. Previous studies have shown the association between single metabolites and lung function for COPD, but whether a combination of metabolites could predict phenotype is unknown. We developed metabolomic severity scores using plasma metabolomics from the Metabolon platform from two US cohorts of ever-smokers: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) (n = 648; training/testing cohort; 72% non-Hispanic, white; average age 63 years) and the COPDGene Study (n = 1120; validation cohort; 92% non-Hispanic, white; average age 67 years). Separate adaptive LASSO (adaLASSO) models were used to model forced expiratory volume at one second (FEV1) and MESA-adjusted lung density using 762 metabolites common between studies. Metabolite coefficients selected by the adaLASSO procedure were used to create a metabolomic severity score (metSS) for each outcome. A total of 132 metabolites were selected to create a metSS for FEV1. The metSS-only models explained 64.8% and 31.7% of the variability in FEV1 in the training and validation cohorts, respectively. For MESA-adjusted lung density, 129 metabolites were selected, and metSS-only models explained 59.0% of the variability in the training cohort and 17.4% in the validation cohort. Regression models including both clinical covariates and the metSS explained more variability than either the clinical covariate or metSS-only models (53.4% vs. 46.4% and 31.6%) in the validation dataset. The metabolomic pathways for arginine biosynthesis; aminoacyl-tRNA biosynthesis; and glycine, serine, and threonine pathway were enriched by adaLASSO metabolites for FEV1. This is the first demonstration of a respiratory metabolomic severity score, which shows how a metSS can add explanation of variance to clinical predictors of FEV1 and MESA-adjusted lung density. The advantage of a comprehensive metSS is that it explains more disease than individual metabolites and can account for substantial collinearity among classes of metabolites. Future studies should be performed to determine whether metSSs are similar in younger, and more racially and ethnically diverse populations as well as whether a metabolomic severity score can predict disease development in individuals who do not yet have COPD.

Z-cut single-crystal quartz and vitreous silica (silica glass or fused silica) were evaluated for use as reference materials for terahertz and microwave measurements of complex permittivity, with Z-cut quartz confirmed as being suitable. Measurements of refractive indices and absorption coefficients for o-ray and e-ray in quartz and for vitreous silica are reported at frequencies between 0.2 and 6 THz and at 36 and 144 GHz, and compared with data reported in the literature. A previously unreported broad band was seen in the extraordinary absorption of quartz. The Boson peak in silica glass absorption was examined, and for the first time, two negative relationships have been observed: between the refractive index and the Boson peak frequency, and between the Boson peak height and its frequency.

Ecological corridors are one of the best, and possibly only viable, management tools to maintain biodiversity at large scales and to allow species, and ecological processes, to track climate change. This document has been assembled as a summary of the best available information about managing these systems. Our aim with this paper is to provide managers with a convenient guidance document and tool to assist in applying scientific management principles to management of corridors. We do not cover issues related to corridor design or political buy in, but focus on how a corridor should be managed once it has been established. The first part of our paper outlines the history and value of ecological corridors. We next describe our methodologies for developing this guidance document. We then summarize the information about the impacts of linear features on corridors and strategies for dealing with them—specifically, we focus on the effects of roads, canals, security fences, and transmission lines. Following the description of effects, we provide a summary of the best practices for managing the impacts of linear barriers. Globally, many corridors are established in the flood plains of stream and rivers and occur in riparian areas associated with surface waters. Therefore, we next provide guidance on how to manage corridors that occur in riparian areas. We then segue into corridors and the urban/suburban environment, and summarize strategies for dealing with urban development within corridors. The final major anthropic land use that may affect corridor management is cultivation and grazing agriculture. We end this review by identifying gaps in knowledge pertaining to how best to manage corridors.

A major challenge for biogeographers and conservation planners is to identify where to best locate or distribute high-priority areas for conservation and to explore whether these areas are well represented by conservation actions such as protected areas (PAs). We aimed to identify high-priority areas for conservation, expressed as hotpots of rarity-weighted richness (HRR)-sites that efficiently represent species-for birds across EU countries, and to explore whether HRR are well represented by the Natura 2000 network. Natura 2000 is an evolving network of PAs that seeks to conserve biodiversity through the persistence of the most patrimonial species and habitats across Europe. This network includes Sites of Community Importance (SCI) and Special Areas of Conservation (SAC), where the latter regulated the designation of Special Protected Areas (SPA). Distribution maps for 416 bird species and complementarity-based approaches were used to map geographical patterns of rarity-weighted richness (RWR) and HRR for birds. We used species accumulation index to evaluate whether RWR was efficient surrogates to identify HRRs for birds. The results of our analysis support the proposition that prioritizing sites in order of RWR is a reliable way to identify sites that efficiently represent birds. HRRs were concentrated in the Mediterranean Basin and alpine and boreal biogeographical regions of northern Europe. The cells with high RWR values did not correspond to cells where Natura 2000 was present. We suggest that patterns of RWR could become a focus for conservation biogeography. Our analysis demonstrates that identifying HRR is a robust approach for prioritizing management actions, and reveals the need for more conservation actions, especially on HRR.

Unmanned aerial vehicles (UAV) are increasingly used for spatiotemporal monitoring of invasive plants in coastal wetlands. Early identification of invasive species is necessary in planning, restoring, and managing wetlands. This study assessed the effectiveness of UAV technology to identify invasive Phragmites australis in the Old Woman Creek (OWC) estuary using machine learning (ML) algorithms: Neural network (NN), support vector machine (SVM), and k-nearest neighbor (kNN). The ML algorithms were compared with the parametric maximum likelihood classifier (MLC) using pixel- and object-based methods. Pixel-based NN was identified as the best classifier with an overall accuracy of 94.80% and the lowest error of omission of 1.59%, the outcome desirable for effective eradication of Phragmites. The results were reached combining Sequoia multispectral imagery (green, red, red edge, and near-infrared bands) combined with the canopy height model (CHM) acquired in the mid-growing season and normalized difference vegetation index (NDVI) acquired later in the season. The sensitivity analysis, using various vegetation indices, image texture, CHM, and principal components (PC), demonstrated the impact of various feature layers on the classifiers. The study emphasizes the necessity of a suitable sampling and cross-validation methods, as well as the importance of optimum classification parameters.

Background: Electronic nicotine delivery systems (ENDS) are driving an epidemic of vaping. Identifying biomarkers of vaping and dual use (concurrent vaping and smoking) will facilitate studies of the health effects of vaping. To identify putative biomarkers of vaping and dual use, we performed association analysis in an observational cohort of 3,892 COPDGene study participants with blood transcriptomics and/or plasma proteomics data and self-reported current vaping and smoking behavior. Methods: Biomarkers of vaping and dual use were identified through differential expression analysis and related to prospective health events over six years of follow-up. To assess the predictive accuracy of multi-biomarker panels, we constructed predictive models for vaping and smoking categories and prospective health outcomes. Results: We identified three transcriptomic and three proteomic associations with vaping, and 90 transcriptomic and 100 proteomic associations to dual use. Many of these vaping or dual use biomarkers were significantly associated with prospective health outcomes, such as FEV1 decline (three transcripts and 62 proteins), overall mortality (18 transcripts and 73 proteins), respiratory mortality (two transcripts and 23 proteins), respiratory exacerbations (13 proteins) and incident cardiovascular disease (24 proteins). Multimarker models showed good performance discriminating between vaping and smoking behavior and produced informative, modestly powerful predictions of future FEV1 decline, mortality, and respiratory exacerbations. Conclusions: In summary, vaping and dual use are associated with RNA and protein blood-based biomarkers that are also associated with adverse health outcomes.