The impact of intraocular pressure on optical coherence tomography angiography: A review of current evidence.

A scoping review of 45 peer-reviewed manuscripts involving intraocular pressure (IOP) change and concurrent optical coherence tomography angiography (OCTA) assessments was performed to aggregate knowledge, summarize major findings, and identify gaps in literature and methodology relating to the effect of IOP change on OCTA. Articles were identified through PubMed/Medline, Google Scholar, Cochrane, Web of Science, and article reference lists. A total of 838 results were identified, and 45 articles met the inclusion and exclusion criteria for detailed analysis. OCTA metrics including vessel density (VD), perfusion density, and flow density of the superficial capillary plexus and the radial peripapillary capillaries were analyzed in relation to relative temporal IOP changes. Overall, IOP changes were found to affect superficial vascular plexus (VD) measurements on OCTA, especially when IOP elevated above the physiologic normal range (10-21 mmHg). No significant association was found between diurnal IOP variation and OCTA metrics. Cataract surgery improved the whole-image signal strength and VD regardless of changes in IOP. Beta-blockers were associated with paradoxically reduced vessel density in normal tension glaucoma patients in two studies. Although glaucoma surgical intervention studies were inconsistent and limited by scan quality and low sample sizes, patients requiring glaucoma surgery exhibited attenuated postoperative superficial VD recovery despite significant IOP reductions with surgical intervention. In addition to ensuring near-perfect signal strength with minimal media opacities and controlling for high myopia, central corneal thickness, and the presence of retinopathy, clinicians should consider the statistically significant impact of IOP on OCTA metrics when interpreting results.

Lung Transcriptomics Links Emphysema to Barrier Dysfunction and Macrophage Subpopulations.

RATIONALE: While many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. Finding efficient non-imaging screening methods and disease-modifying therapies has been challenging, but knowledge of the transcriptomic features of emphysema may help in this effort. OBJECTIVES: Our goals were to identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, to determine the lung cell types in which these emphysema-associated pathways are altered, and to detect unique and overlapping transcriptomic signatures in blood and lung samples. METHODS: Using RNA-sequencing data from 446 samples in the Lung Tissue Research Consortium (LTRC) and 3,606 blood samples from the COPDGene study, we examined the transcriptomic features of chest computed tomography-quantified emphysema. We also leveraged publicly available lung single-cell RNA-sequencing data to identify cell types showing COPD-associated differential expression of the emphysema pathways found in the bulk analyses. MEASUREMENTS AND MAIN RESULTS: In the bulk lung RNA-seq analysis, 1,087 differentially expressed genes and 34 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of several genes and increased activity in pluripotency and cell barrier function pathways. Lung tissue and blood samples shared differentially expressed genes and biological pathways. Multiple lung cell types displayed dysregulation of epithelial barrier function pathways, and distinct pathway activities were observed among various macrophage subpopulations. CONCLUSIONS: This study identified emphysema-related changes in gene expression and alternative splicing, cell-type specific dysregulated pathways, and instances of shared pathway dysregulation between blood and lung.

Horizontal Chemistry.

In 1976 Raymond Williams commented, 'Culture is one of the two or three most complicated words in the English language.' Such implied difficulty has not prevented Bloomsbury Academic, since the 2000s, from publishing around forty series of their well-produced and generously illustrated Cultural Histories, with, according to their website, a further fifty in progress. Each series contains six volumes, each book covering, in theory, the same chronological period (antiquity, the Middle Ages, the Renaissance, the Enlightenment, the age of empire and the modern age), though there is some variation depending on precise topic. The idea is that one can use these books not only to read 'horizontally' about a subject across time, but also 'vertically' through different subjects in the same period - a idea made easier by the e-texts of the series on Bloomsbury's website.

An Introduction to the Native and Non-Native Plant-Insect Interactions and Potential Pollinators of Puerto Williams and Yendegaia, Cabo de Hornos, Chile.

The Magellanic sub-Antarctic ecoregion of southern Chile represents one of the last remaining pristine areas on Earth, but there are knowledge gaps concerning the biodiversity and interactions of the regions' flora and fauna. Non-native insect species like Bombus terrestris and Vespula vulgaris are known to have detrimental influence on native populations through competition for resources/nesting habitat, larvae predation, and foreign pathogen introduction. However, their interactions with the native and non-native plants in the region and between introduced species are unknown. This study highlights the importance of further investigations documenting the region's biodiversity, native and non-native species interactions, and local pollinators.

Impact of knockout of dual-specificity protein phosphatase 5 on structural and mechanical properties of rat middle cerebral arteries: implications for vascular aging.

Vascular aging influences hemodynamics, elevating risks for vascular diseases and dementia. We recently demonstrated that knockout (KO) of Dusp5 enhances cerebral and renal hemodynamics and cognitive function. This improvement correlates with elevated pPKC and pERK1/2 levels in the brain and kidneys. Additionally, we observed that Dusp5 KO modulates the passive mechanical properties of cerebral and renal arterioles, associated with increased myogenic tone at low pressure, enhanced distensibility, greater compliance, and reduced stiffness. The present study evaluates the structural and mechanical properties of the middle cerebral artery (MCA) in Dusp5 KO rats. We found that vascular smooth muscle cell layers and the collagen content in the MCA wall are comparable between Dusp5 KO and control rats. The internal elastic lamina in the MCA of Dusp5 KO rats exhibits increased thickness, higher autofluorescence intensity, smaller fenestrae areas, and fewer fenestrations. Despite an enhanced myogenic response and tone of the MCA in Dusp5 KO rats, other passive mechanical properties, such as wall thickness, cross-sectional area, wall-to-lumen ratio, distensibility, incremental elasticity, circumferential wall stress, and elastic modulus, do not significantly differ between strains. These findings suggest that while Dusp5 KO has a limited impact on altering the structural and mechanical properties of MCA, its primary role in ameliorating hemodynamics and cognitive functions is likely attributable to its enzymatic activity on cerebral arterioles. Further research is needed to elucidate the specific enzymatic mechanisms and explore potential clinical applications in the context of vascular aging.

Blood-based Transcriptomic and Proteomic Biomarkers of Emphysema.

Rationale: Emphysema is a chronic obstructive pulmonary disease phenotype with important prognostic implications. Identifying blood-based biomarkers of emphysema will facilitate early diagnosis and development of targeted therapies. Objectives: To discover blood omics biomarkers for chest computed tomography-quantified emphysema and develop predictive biomarker panels. Methods: Emphysema blood biomarker discovery was performed using differential gene expression, alternative splicing, and protein association analyses in a training sample of 2,370 COPDGene participants with available blood RNA sequencing, plasma proteomics, and clinical data. Internal validation was conducted in a COPDGene testing sample (n = 1,016), and external validation was done in the ECLIPSE study (n = 526). Because low body mass index (BMI) and emphysema often co-occur, we performed a mediation analysis to quantify the effect of BMI on gene and protein associations with emphysema. Elastic net models with bootstrapping were also developed in the training sample sequentially using clinical, blood cell proportions, RNA-sequencing, and proteomic biomarkers to predict quantitative emphysema. Model accuracy was assessed by the area under the receiver operating characteristic curves for subjects stratified into tertiles of emphysema severity. Measurements and Main Results: Totals of 3,829 genes, 942 isoforms, 260 exons, and 714 proteins were significantly associated with emphysema (false discovery rate, 5%) and yielded 11 biological pathways. Seventy-four percent of these genes and 62% of these proteins showed mediation by BMI. Our prediction models demonstrated reasonable predictive performance in both COPDGene and ECLIPSE. The highest-performing model used clinical, blood cell, and protein data (area under the receiver operating characteristic curve in COPDGene testing, 0.90; 95% confidence interval, 0.85-0.90). Conclusions: Blood transcriptome and proteome-wide analyses revealed key biological pathways of emphysema and enhanced the prediction of emphysema.

Role of Dusp5 KO on Vascular Properties of Middle Cerebral Artery in Rats.

Vascular aging influences hemodynamics, elevating risks for vascular diseases and dementia. We recently demonstrated that knockout (KO) of Dusp5 enhances cerebral and renal hemodynamics and cognitive function. This improvement correlates with elevated pPKC and pERK1/2 levels in the brain and kidneys. Additionally, we observed that Dusp5 KO modulates the passive mechanical properties of cerebral and renal arterioles, associated with increased myogenic tone at low pressure, enhanced distensibility, greater compliance, and reduced stiffness. The present study evaluates the structural and mechanical properties of the middle cerebral artery (MCA) in Dusp5 KO rats. We found that vascular smooth muscle cell layers and the collagen content in the MCA wall are comparable between Dusp5 KO and control rats. The internal elastic lamina in the MCA of Dusp5 KO rats exhibits increased thickness, higher autofluorescence intensity, smaller fenestrae areas, and fewer fenestrations. Despite an enhanced myogenic response and tone of the MCA in Dusp5 KO rats, other passive mechanical properties, such as wall thickness, cross-sectional area, wall-to-lumen ratio, distensibility, incremental elasticity, circumferential wall stress, and elastic modulus, do not significantly differ between strains. These findings suggest that while Dusp5 KO has a limited impact on altering the structural and mechanical properties of MCA, its primary role in ameliorating hemodynamics and cognitive functions is likely attributable to its enzymatic activity on cerebral arterioles. Further research is needed to elucidate the specific enzymatic mechanisms and explore potential clinical applications in the context of vascular aging.

Genetic analysis of two species of Mnomen in the Kalamazoo Watershed reveal panmixia in Z. Aquatica, structure among Z. Palustris, and hybridization in areas of sympatry.

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.

Mechanical Dissociation of Tissues for Single Cell Analysis Using a Motorized Device.

Being able to isolate and prepare single cells for the analysis of tissue samples has rapidly become crucial for new biomedical discoveries and research. Manual protocols for single-cell isolations are highly time-consuming and prone to user variability. Automated mechanical protocols are able to reduce processing time and sample variability but aren't easily accessible or cost-effective in lower-resourced research settings. The device described here was designed for semi-automated tissue dissociation using commercially available materials as a low-cost alternative for academic laboratories. Instructions to fabricate, assemble, and operate the device design have been provided. The dissociation protocol reliably produces single-cell suspensions with comparable cell yields and sample viability to manual preparations across multiple mouse tissues. The protocol provides the ability to process up to 12 tissue samples simultaneously per device, making studies requiring large sample sizes more manageable. The accompanying software also allows for customization of the device protocol to accommodate varying tissues and experimental constraints.

Upper glycolytic components contribute differently in controlling retinal vascular endothelial cellular behavior: Implications for endothelial-related retinal diseases.

BACKGROUND: Retinal degenerative diseases such as diabetic retinopathy and diabetic macular edema are characterized by impaired retinal endothelial cells (RECs) functionality. While the role of glycolysis in glucose homeostasis is well-established, its contributions to REC barrier assembly and cell spreading remain poorly understood. This study aimed to investigate the importance of upper glycolytic components in regulating the behavior of human RECs (HRECs). METHODS: Electric cell-substrate impedance sensing (ECIS) technology was employed to analyze the real-time impact of various upper glycolytic components on maintaining barrier functionality and cell spreading of HRECs by measuring cell resistance and capacitance, respectively. Specific inhibitors were used: WZB117 to inhibit Glut1/3, lonidamine to inhibit hexokinases, PFK158 to inhibit the PFKFB3-PFK axis, and TDZD-8 to inhibit aldolases. Additionally, the viability of HRECs was evaluated using the lactate dehydrogenase (LDH) cytotoxicity assay. RESULTS: The most significant reduction in electrical resistance and increase in capacitance of HRECs resulted from the dose-dependent inhibition of PFKFB3/PFK using PFK158, followed by aldolase inhibition using TDZD-8. LDH level analysis at 24- and 48-hours post-treatment with PFK158 (1 µM) or TDZD-8 (1 and 10 µM) showed no significant difference compared to the control, indicating that the disruption of HRECs functionality was not attributed to cell death. Conversely, inhibiting Glut1/3 with WZB117 had minimal impact on HREC behavior, except at higher concentrations (10 µM) and prolonged exposure. Lastly, inhibiting hexokinase with lonidamine did not noticeably alter HREC cell behavior. CONCLUSION: This study illustrates the unique impacts of components within upper glycolysis on HREC functionality, emphasizing the crucial role of the PFKFB3/PFK axis in regulating HREC behavior. Understanding the specific contributions of each glycolytic component in preserving normal REC functionality will facilitate the development of targeted interventions for treating endothelial cell dysfunction in retinal disorders while minimizing effects on healthy cells.

Outcomes of Activity-Related Lower Extremity Muscle Tears After Application of the British Athletics Muscle Injury Classification: A Systematic Review.

CONTEXT: Muscle injury classification and grading systems have been reported for >100 years; yet it offer limited evidence relating the clinical or radiological qualities of a muscle injury to the pathology or clinical outcome. The British Athletics Muscle Injury Classification (BAMIC) incorporates recent predictive features of muscle injuries and provides a precise radiographic framework for clinical prediction and management. OBJECTIVE: To investigate clinical outcomes, particularly time to return to play (RTP), reinjury rate (RIR), and prognostic value of specific magnetic resonance imaging (MRI) findings, of activity-related muscle injuries (tears) in athletes after application of the BAMIC. DATA SOURCES: A search of PubMed (NLM), EMBASE (Ovid), Web of Science (Clarivate), Cochrane Library (Wiley), and ClinicalTrials.gov from the inception date of each database through August 31, 2022, was conducted. Keywords included the BAMIC. STUDY SELECTION: All English language studies evaluating clinical outcomes of RTP and RIR after activity-related muscle injuries and where BAMIC was applied were included. A total of 136 articles were identified, and 11 studies met inclusion criteria. STUDY DESIGN: Systematic review (PROSPERO: CRD42022353801). LEVEL OF EVIDENCE: Level 2. DATA EXTRACTION: Two reviewers independently screened studies for eligibility and extracted data. Methodological quality of included study was assessed independently by 2 reviewers with the Newcastle-Ottawa Quality Scale (NOS); 11 good quality studies (4 prospective cohort studies, 7 retrospective cohort studies) with 468 athletes (57 female) and 574 muscle injuries were included. RESULTS: All studies reported a statistically significant relationship between BAMIC grade, BAMIC injury site, and/or combined BAMIC grade and injury site with RTP. A statistically significant increased RIR was reported by BAMIC grade and BAMIC injury site in 2 of 4 and 3 of 4 studies, respectively. The prognostic value of individual MRI criteria was limited. CONCLUSION: Consistent evidence suggests that BAMIC offers prognostic and therapeutic guidance for clinical outcomes, particularly RTP and RIR, after activity-related muscle injuries in athletes that may be superior to previous muscle injury classification and grading systems.

The Warburg effect alters amino acid homeostasis in human retinal endothelial cells: implication for proliferative diabetic retinopathy.

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.

Bruton's tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination.

Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1ß, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.

Be here now: Perceptions of uncertainty enhance savoring.

Savoring-an emotion-regulation strategy that involves deliberately upregulating positive affect-has many benefits, but what enhances savoring in the present moment? Drawing from life-history theory, affective and developmental science, and social-psychological frameworks, we examined the idea that perceptions of uncertainty--perceiving the world as random and unpredictable-enhance subsequent savoring. In a large experience-sampling study (Study 1, N = 6,680), we found that individuals who perceived more uncertainty showed increases in subsequent savoring in their daily lives. In a preregistered experiment (Study 2, N = 397), individuals who watched a film that induced uncertainty (vs. order or a control condition) subsequently reported higher savoring intentions. Finally, in a field experiment on a busy urban street (Study 3, N = 201), we found that passersby who received fliers that induced uncertainty (vs. order) subsequently engaged in more savoring behavior by stopping to smell a bouquet of roses. These findings from three studies with diverse samples and methodologies underscore an upside to the specter of uncertainty: it can cause people to savor the positives of the present. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The moralization of effort.

People believe that effort is valuable, but what kind of value does it confer? We find that displays of effort signal moral character. Eight studies (N = 5,502) demonstrate the nature of these effects in the domains of paid employment, personal fitness, and charitable fundraising. The exertion of effort is deemed morally admirable (Studies 1-6) and is monetarily rewarded (Studies 2-6), even in situations where effort does not directly generate additional product, quality, or economic value. Convergent patterns of results emerged in South Korean and French cross-cultural replications (Studies 2b and 2c). We contend that the seeming irrationality of valuing effort for its own sake, such as in situations where one's efforts do not directly increase economic output (Studies 3-6), reveals a "deeply rational" social heuristic for evaluating potential cooperation partners. Specifically, effort cues engender broad moral trait ascriptions, and this moralization of effort influences donation behaviors (Study 5) and cooperative partner choice decision-making (Studies 4 and 6). In situating our account of effort moralization into past research and theorizing, we also consider the implications of these effects for social welfare policy and the future of work. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Delivery of stable ultra-thin liquid sheets in vacuum for biochemical spectroscopy.

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.

Monoclonal gammopathies of clinical significance (MGCS): In pursuit of optimal treatment.

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.

Relative Importance of Different Elements of Mitochondrial Oxidative Phosphorylation in Maintaining the Barrier Integrity of Retinal Endothelial Cells: Implications for Vascular-Associated Retinal Diseases.

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.

Habitat amount or landscape configuration: Emerging HotSpot analysis reveals the importance of habitat amount for a grassland bird in South Dakota.

Habitat loss and fragmentation are two important drivers of biodiversity decline. Understanding how species respond to landscape composition and configuration in dynamic landscapes is of great importance for informing the conservation and management of grassland species. With limited conservation resources, prescribed management targeted at the appropriate landscape process is necessary for the effective management of species. We used pheasants (Phasianus colchicus) across South Dakota, USA as a model species to identify environmental factors driving spatiotemporal variation in population productivity. Using an emerging Hotspot analysis, we analyzed annual count data from 105 fixed pheasant brood routes over a 24-year period to identify high (HotSpot) and low (ColdSpot) pheasant population productivity areas. We then applied classification and regression tree modeling to evaluate landscape attributes associated with pheasant productivity among spatial scales (500 m and 1000 m). We found that the amount of grassland at a local spatial scale was the primary factor influencing an area being a HotSpot. Our results also demonstrated non-significant or weak effects of fragmentation per se on pheasant populations. These findings are in accordance with the habitat amount hypothesis highlighting the importance of habitat amount in the landscape for maintaining and increasing the pheasant population. We, therefore, recommend that managers should focus on increasing the total habitat area in the landscape and restoring degraded habitats. Our method of identifying areas of high productivity across the landscape can be applied to other species with count data.

Clustering-based COPD subtypes have distinct longitudinal outcomes and multi-omics biomarkers.

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.