HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium

Background: While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection. Methods and Findings: To examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions—an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of 13C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A. Conclusions: These studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation

Interactive Effects of Racial Identity and Repetitive Head Impacts on Cognitive Function, Structural MRI-Derived Volumetric Measures, and Cerebrospinal Fluid Tau and A beta

Background: Factors of increased prevalence among individuals with Black racial identity (e.g., cardiovascular disease, CVD) may influence the association between exposure to repetitive head impacts (RHI) from American football and later-life neurological outcomes. Here, we tested the interaction between racial identity and RHI on neurobehavioral outcomes, brain volumetric measures, and cerebrospinal fluid (CSF) total tau (t-tau), phosphorylated tau (p-tau181), and Aβ1–42 in symptomatic former National Football League (NFL) players. Methods: 68 symptomatic male former NFL players (ages 40–69; n = 27 Black, n = 41 White) underwent neuropsychological testing, structural MRI, and lumbar puncture. FreeSurfer derived estimated intracranial volume (eICV), gray matter volume (GMV), white matter volume (WMV), subcortical GMV, hippocampal volume, and white matter (WM) hypointensities. Multivariate generalized linear models examined the main effects of racial identity and its interaction with a cumulative head impact index (CHII) on all outcomes. Age, years of education, Wide Range Achievement Test, Fourth Edition (WRAT-4) scores, CVD risk factors, and APOEε4 were included as covariates; eICV was included for MRI models. P-values were false discovery rate adjusted. Results: Compared to White former NFL players, Black participants were 4 years younger (p = 0.04), had lower WRAT-4 scores (mean difference = 8.03, p = 0.002), and a higher BMI (mean difference = 3.09, p = 0.01) and systolic blood pressure (mean difference = 8.15, p = 0.03). With regards to group differences on the basis of racial identity, compared to White former NFL players, Black participants had lower GMV (mean adjusted difference = 45649.00, p = 0.001), lower right hippocampal volume (mean adjusted difference = 271.96, p = 0.02), and higher p-tau181/t-tau ratio (mean adjusted difference = −0.25, p = 0.01). There was not a statistically significant association between the CHII with GMV, right hippocampal volume, or p-tau181/t-tau ratio. However, there was a statistically significant Race x CHII interaction for GMV (b = 2206.29, p = 0.001), right hippocampal volume (b = 12.07, p = 0.04), and p-tau181/t-tau ratio concentrations (b = −0.01, p = 0.004). Conclusion: Continued research on racial neurological disparities could provide insight into risk factors for long-term neurological disorders associated with American football play

A possible role for river restoration enhancing biodiversity through interaction with wildfire

BackgroundHistorically, wildfire regimes produced important landscape-scale disturbances in many regions globally. The “pyrodiversity begets biodiversity” hypothesis suggests that wildfires that generate temporally and spatially heterogeneous mosaics of wildfire severity and post-burn recovery enhance biodiversity at landscape scales. However, river management has often led to channel incision that disconnects rivers from their floodplains, desiccating floodplain habitats and depleting groundwater. In conjunction with predicted increases in frequency, intensity and extent of wildfires under climate change, this increases the likelihood of deep, uniform burns that reduce biodiversity.Predicted synergy of river restoration and biodiversity increaseRecent focus on floodplain re-wetting and restoration of successional floodplain habitat mosaics, developed for river management and flood prevention, could reduce wildfire intensity in restored floodplains and make the burns less uniform, increasing climate-change resilience; an important synergy. According to theory, this would also enhance biodiversity. However, this possibility is yet to be tested empirically. We suggest potential research avenues.Illustration and future directionsWe illustrate the interaction between wildfire and river restoration using a restoration project in Oregon, USA. A project to reconnect the South Fork McKenzie River and its floodplain suffered a major burn (“Holiday Farm” wildfire, 2020), offering a rare opportunity to study the interaction between this type of river restoration and wildfire; specifically, the predicted increases in pyrodiversity and biodiversity. Given the importance of river and wetland ecosystems for biodiversity globally, a research priority should be to increase our understanding of potential mechanisms for a “triple win” of flood reduction, wildfire alleviation and biodiversity promotion

White matter signal abnormalities in former National Football League players

Introduction: Later-life brain alterations in former tackle football players are poorly understood, particularly regarding their relationship with repetitive head impacts (RHIs) and clinical function. We examined white matter signal abnormalities (WMSAs) and their association with RHIs and clinical function in former National Football League (NFL) players. Methods: Eighty-six clinically symptomatic former NFL players and 23 same-age reportedly asymptomatic controls without head trauma exposure underwent magnetic resonance imaging and neuropsychological testing. FreeSurfer calculated WMSAs. A cumulative head impact index quantified RHIs. Results: In former NFL players, increased volume of WMSAs was associated with higher cumulative head impact index scores (P = .043) and worse psychomotor speed and executive function (P = .015). Although former NFL players had greater WMSA volume than controls (P = .046), these findings are inconclusive due to recruitment of controls based on lack of clinical symptoms and head trauma exposure. Discussion In former NFL players, WMSAs may reflect long-term microvascular and nonmicrovascular pathologies from RHIs that negatively impact cognition

Cellular Proteins in Influenza Virus Particles

Virions are thought to contain all the essential proteins that govern virus egress from the host cell and initiation of replication in the target cell. It has been known for some time that influenza virions contain nine viral proteins; however, analyses of other enveloped viruses have revealed that proteins from the host cell can also be detected in virions. To address whether the same is true for influenza virus, we used two complementary mass spectrometry approaches to perform a comprehensive proteomic analysis of purified influenza virus particles. In addition to the aforementioned nine virus-encoded proteins, we detected the presence of 36 host-encoded proteins. These include both cytoplasmic and membrane-bound proteins that can be grouped into several functional categories, such as cytoskeletal proteins, annexins, glycolytic enzymes, and tetraspanins. Interestingly, a significant number of these have also been reported to be present in virions of other virus families. Protease treatment of virions combined with immunoblot analysis was used to verify the presence of the cellular protein and also to determine whether it is located in the core of the influenza virus particle. Immunogold labeling confirmed the presence of membrane-bound host proteins on the influenza virus envelope. The identification of cellular constituents of influenza virions has important implications for understanding the interactions of influenza virus with its host and brings us a step closer to defining the cellular requirements for influenza virus replication. While not all of the host proteins are necessarily incorporated specifically, those that are and are found to have an essential role represent novel targets for antiviral drugs and for attenuation of viruses for vaccine purposes

The Impact of a 5-Week Shoulder Strengthening Program on Division I Swimmers

Poor shoulder strength in swimming may lead to shoulder injury in swimmers. The objective of this study was to determine the impact of a five-week shoulder strengthening program on division I collegiate swimmers. Eighteen participants from the University men\u27s and women\u27s swimming teams participated in a control group (n=8) and experimental group (n=10). Both groups were evaluated pre-exercise program using a shoulder strength dynamometer designed to measure the strength of shoulder extension and internal rotation. The experimental group was given five exercises to perform three days per week for five weeks. Both groups were evaluated again post-exercise program. All exercises performed by the experimental group were done on the pool deck. Data is still in collection process

A Possible Role for River Restoration Enhancing Biodiversity through Interaction with Wildfire

Background Historically, wildfire regimes produced important landscape-scale disturbances in many regions globally. The “pyrodiversity begets biodiversity” hypothesis suggests that wildfires that generate temporally and spatially heterogeneous mosaics of wildfire severity and post-burn recovery enhance biodiversity at landscape scales. However, river management has often led to channel incision that disconnects rivers from their floodplains, desiccating floodplain habitats and depleting groundwater. In conjunction with predicted increases in frequency, intensity and extent of wildfires under climate change, this increases the likelihood of deep, uniform burns that reduce biodiversity. Predicted synergy of river restoration and biodiversity increase Recent focus on floodplain re-wetting and restoration of successional floodplain habitat mosaics, developed for river management and flood prevention, could reduce wildfire intensity in restored floodplains and make the burns less uniform, increasing climate-change resilience; an important synergy. According to theory, this would also enhance biodiversity. However, this possibility is yet to be tested empirically. We suggest potential research avenues. Illustration and future directions We illustrate the interaction between wildfire and river restoration using a restoration project in Oregon, USA. A project to reconnect the South Fork McKenzie River and its floodplain suffered a major burn (“Holiday Farm” wildfire, 2020), offering a rare opportunity to study the interaction between this type of river restoration and wildfire; specifically, the predicted increases in pyrodiversity and biodiversity. Given the importance of river and wetland ecosystems for biodiversity globally, a research priority should be to increase our understanding of potential mechanisms for a “triple win” of flood reduction, wildfire alleviation and biodiversity promotion

Functional consequences of alveolar HIF1A deletion during ALI.

<p>(A–J) <i>Hif1a^f/f</i> SurfactantCre+ mice or age, gender, and weight-matched littermate controls (SurfactantCre+) were exposed to ventilator-induced lung injury (VILI; pressure-controlled mechanical ventilation at an inspiratory pressure of 45 mbar with an inspired oxygen concentration of 100%, exposure time 180 min). (A) Isolation of alveolar epithelial cells from <i>Hif1a^f/f</i> SurfactantCre+ or control mice after VILI exposure. Frozen cells were lysed and proteins resolved by SDS-PAGE. Resultant Western blots were probed with anti-Hif1a antibody. A representative blot of three is displayed. (B) Pulmonary neutrophil accumulation was quantified using myeloperoxidase (MPO) ELISA. (C–E) IL-6, KC, or TNF-α, levels were evaluated in lung tissue homogenates using a mouse-enzyme-linked immunosorbent assay (ELISA). Results are presented as mean ± s.d. (<i>n</i> = 6). (F) For quantification of histological tissue damage by ventilator-induced lung injury following 180 min ventilation, VILI scores were assessed in <i>Hif1a^f/f</i> SurfactantCre+ or corresponding littermate control mice (SurfactantCre+). Results are displayed as median and range (<i>n</i> = 4). (G) One of four representative photomicrographs (×200) stained with hematoxylin/eosin is displayed. (H–J) <i>Hif1a^f/f</i> SurfactantCre+ or matched controls (Surfactant Cre+) were treated with the pharmacologic HIF activator dimethyl-oxaloylglycine DMOG (1 mg/mouse i.p. 4 h period to VILI) and subsequently exposed to VILI. (H) Albumin concentration in the bronchoalveolar fluid by enzyme-linked immunosorbent assay (ELISA), (I) pulmonary gas exchange by the ratio of the arterial partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2), and (J) MPO activity by using a murine ELISA from lung tissue (mean ± s.d.; <i>n</i> = 6).</p

Functional consequences of HIF1A inhibition during ALI.

<p>(A–E) HIF1A inhibition by Echinomycin during VILI: BL6C57 mice were treated with 30 µg Echinomycin i.p. or vehicle control 1 h prior to the experimental procedure. (A) Mechanical ventilation was instituted and mice were ventilated for 0 or 180 min using pressure-controlled settings (pressure-controlled mechanical ventilation at an inspiratory pressure of 45 mbar with an inspired oxygen concentration of 100%, exposure time 180 min). Albumin concentration in the bronchoalveolar fluid (BAL) was determined by enzyme linked immunosorbent assay (<i>n</i> = 6). (B and C) Pulmonary neutrophil sequestration was quantified using a myeloperoxidase (MPO) assay. MPO activity was assessed using a murine ELISA from lung tissue (B) or BAL (C) (<i>n</i> = 6). Results are presented as mean ± s.d. and derived from six animals in each condition. (D) To assess pulmonary gas exchange, blood gas analyses were performed by obtaining arterial blood via cardiac puncture. Analysis was performed immediately and the ratio of the arterial partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2) was determined (mean ± s.d., <i>n</i> = 6). (E) Mechanical ventilation was instituted and mice were ventilated using pressure-controlled settings (inspiratory pressure of 35 mbar, 100% inspired oxygen concentration) until a cardiac standstill was observed in the surface electrocardiogram (<i>n</i> = 6).</p