Igniting Passion for Science Across a Vast Ocean: Nurturing a New Generation of Pacific Island Scientists

This article introduces the work that was done through the Coordinating Center at the John A. Burns School of Medicine at the University of Hawaii

Endurance exercise training in pulmonary hypertension increases skeletal muscle electron transport chain supercomplex assembly

Pulmonary hypertension is associated with pronounced exercise intolerance (decreased V ċ O2 max) that can significantly impact quality of life. The cause of exercise intolerance in pulmonary hypertension remains unclear. Mitochondrial supercomplexes are large respiratory assemblies of individual electron transport chain complexes which can promote more efficient respiration. In this study, we examined pulmonary hypertension and exercise-induced changes in skeletal muscle electron transport chain protein expression and supercomplex assembly. Pulmonary arterial hypertension was induced in rats with the Sugen/Hypoxia model (10% FiO2, three weeks). Pulmonary arterial hypertension and control rats were assigned to an exercise training protocol group or kept sedentary for one month. Cardiac function and V ċ O2 max were assessed at the beginning and end of exercise training. Red (Type 1—oxidative muscle) and white (Type 2—glycolytic muscle) gastrocnemius were assessed for changes in electron transport chain complex protein expression and supercomplex assembly via SDS- and Blue Native-PAGE. Results showed that pulmonary arterial hypertension caused a significant decrease in V ċ O2 max via treadmill testing that was improved with exercise (P \u3c 0.01). Decreases in cardiac output and pulmonary acceleration time due to pulmonary arterial hypertension were not improved with exercise. Pulmonary arterial hypertension reduced expression in individual electron transport chain complex protein expression (NDUFB8 (CI), SDHB (CII), Cox IV (CIV), but not UQCRC2 (CIII), or ATP5a (CV)) in red gastrocnemius muscle. Both red gastrocnemius and white gastrocnemius electron transport chain expression was unaffected by exercise. However, non-denaturing Blue Native-PAGE analysis of mitochondrial supercomplexes demonstrated increases with exercise training in pulmonary arterial hypertension in the red gastrocnemius but not white gastrocnemius muscle. Pulmonary arterial hypertension-induced exercise intolerance is improved with exercise and is associated with muscle type specific alteration in mitochondrial supercomplex assembly and expression of mitochondrial electron transport chain proteins

The Fire and Smoke Model Evaluation Experiment - A plan for integrated, large fire-atmosphere field campaigns

The Fire and Smoke Model Evaluation Experiment (FASMEE) is designed to collect integrated observations from large wildland fires and provide evaluation datasets for new models and operational systems. Wildland fire, smoke dispersion, and atmospheric chemistry models have become more sophisticated, and next-generation operational models will require evaluation datasets that are coordinated and comprehensive for their evaluation and advancement. Integrated measurements are required, including ground-based observations of fuels and fire behavior, estimates of fire-emitted heat and emissions fluxes, and observations of near-source micrometeorology, plume properties, smoke dispersion, and atmospheric chemistry. To address these requirements the FASMEE campaign design includes a study plan to guide the suite of required measurements in forested sites representative of many prescribed burning programs in the southeastern United States and increasingly common high-intensity fires in the western United States. Here we provide an overview of the proposed experiment and recommendations for key measurements. The FASMEE study provides a template for additional large-scale experimental campaigns to advance fire science and operational fire and smoke models

The Fire and Smoke Model Evaluation Experiment—A Plan for Integrated, Large Fire–Atmosphere Field Campaigns

The Fire and Smoke Model Evaluation Experiment (FASMEE) is designed to collect integrated observations from large wildland fires and provide evaluation datasets for new models and operational systems. Wildland fire, smoke dispersion, and atmospheric chemistry models have become more sophisticated, and next-generation operational models will require evaluation datasets that are coordinated and comprehensive for their evaluation and advancement. Integrated measurements are required, including ground-based observations of fuels and fire behavior, estimates of fire-emitted heat and emissions fluxes, and observations of near-source micrometeorology, plume properties, smoke dispersion, and atmospheric chemistry. To address these requirements the FASMEE campaign design includes a study plan to guide the suite of required measurements in forested sites representative of many prescribed burning programs in the southeastern United States and increasingly common high-intensity fires in the western United States. Here we provide an overview of the proposed experiment and recommendations for key measurements. The FASMEE study provides a template for additional large-scale experimental campaigns to advance fire science and operational fire and smoke models

Citrobacter rodentium Subverts ATP Flux and Cholesterol Homeostasis in Intestinal Epithelial Cells In Vivo.

The intestinal epithelial cells (IECs) that line the gut form a robust line of defense against ingested pathogens. We investigated the impact of infection with the enteric pathogen Citrobacter rodentium on mouse IEC metabolism using global proteomic and targeted metabolomics and lipidomics. The major signatures of the infection were upregulation of the sugar transporter Sglt4, aerobic glycolysis, and production of phosphocreatine, which mobilizes cytosolic energy. In contrast, biogenesis of mitochondrial cardiolipins, essential for ATP production, was inhibited, which coincided with increased levels of mucosal O2 and a reduction in colon-associated anaerobic commensals. In addition, IECs responded to infection by activating Srebp2 and the cholesterol biosynthetic pathway. Unexpectedly, infected IECs also upregulated the cholesterol efflux proteins AbcA1, AbcG8, and ApoA1, resulting in higher levels of fecal cholesterol and a bloom of Proteobacteria. These results suggest that C. rodentium manipulates host metabolism to evade innate immune responses and establish a favorable gut ecosystem

Miscellany

Art Writinghttps://digitalcommons.georgiasouthern.edu/miscell/1000/thumbnail.jp

Functional Role of Kallikrein 6 in Regulating Immune Cell Survival

Kallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. Notably, KLK6 is also elevated in the serum of multiple sclerosis (MS) patients however its potential roles in immune function are unknown. Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur.Using murine whole splenocyte preparations and the human Jurkat T cell line we demonstrate that KLK6 robustly supports cell survival across a range of cell death paradigms. Recombinant KLK6 was shown to significantly reduce cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Moreover, KLK6-over expression in Jurkat T cells was shown to generate parallel pro-survival effects. In mixed splenocyte populations the vigorous immune cell survival promoting effects of KLK6 were shown to include both T and B lymphocytes, to occur with as little as 5 minutes of treatment, and to involve up regulation of the pro-survival protein B-cell lymphoma-extra large (Bcl-XL), and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim). The ability of KLK6 to promote survival of splenic T cells was also shown to be absent in cell preparations derived from PAR1 deficient mice.KLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of PAR1. These findings point to a novel molecular mechanism regulating lymphocyte survival that is likely to have relevance to a range of immunological responses that depend on apoptosis for immune clearance and maintenance of homeostasis

Too Big to Fail — U.S. Banks’ Regulatory Alchemy: Converting an Obscure Agency Footnote into an “At Will” Nullification of Dodd-Frank’s Regulation of the Multi-Trillion Dollar Financial Swaps Market

The multi-trillion-dollar market for, what was at that time wholly unregulated, over-the-counter derivatives (“swaps”) is widely viewed as a principal cause of the 2008 worldwide financial meltdown. The Dodd-Frank Act, signed into law on July 21, 2010, was expressly considered by Congress to be a remedy for this troublesome deregulatory problem. The legislation required the swaps market to comply with a host of business conduct and anti-competitive protections, including that the swaps market be fully transparent to U.S. financial regulators, collateralized, and capitalized. The statute also expressly provides that it would cover foreign subsidiaries of big U.S. financial institutions if their swaps trading could adversely impact the U.S. economy or represent the use of extraterritorial trades as an attempt to “evade” Dodd-Frank. In July 2013, the CFTC promulgated an 80-page, triple-columned, and single-spaced “guidance” implementing Dodd-Frank’s extraterritorial reach, i.e., that manner in which Dodd-Frank would apply to swaps transactions executed outside the United States. The key point of that guidance was that swaps trading within the “guaranteed” foreign subsidiaries of U.S. bank holding company swaps dealers were subject to all of Dodd-Frank’s swaps regulations wherever in the world those subsidiaries’ swaps were executed. At that time, the standardized industry swaps agreement contemplated that, inter alia, U.S. bank holding company swaps dealers’ foreign subsidiaries would be “guaranteed” by their corporate parent, as was true since 1992. In August 2013, without notifying the CFTC, the principal U.S. bank holding company swaps dealer trade association privately circulated to its members standard contractual language that would, for the first time, “deguarantee” their foreign subsidiaries. By relying only on the obscure footnote 563 of the CFTC guidance’s 662 footnotes, the trade association assured its swaps dealer members that the newly deguaranteed foreign subsidiaries could (if they so chose) no longer be subject to Dodd-Frank. As a result, it has been reported (and it also has been understood by many experts within the swaps industry) that a substantial portion of the U.S. swaps market has shifted from the large U.S. bank holding companies swaps dealers and their U.S. affiliates to their newly deguaranteed “foreign” subsidiaries, with the attendant claim by these huge big U.S. bank swaps dealers that Dodd-Frank swaps regulation would not apply to these transactions. The CFTC also soon discovered that these huge U.S. bank holding company swaps dealers were “arranging, negotiating, and executing” (“ANE”) these swaps in the United States with U.S. bank personnel and, only after execution in the U.S., were these swaps formally “assigned” to the U.S. banks’ newly “deguaranteed” foreign subsidiaries with the accompanying claim that these swaps, even though executed in the U.S., were not covered by Dodd-Frank. In October 2016, the CFTC proposed a rule that would have closed the “deguarantee” and “ANE” loopholes completely. However, because it usually takes at least a year to finalize a “proposed” rule, this proposed rule closing the loopholes in question was not finalized prior to the inauguration of President Trump. All indications are that it will never be finalized during a Trump Administration. Thus, in the shadow of the recent tenth anniversary of the Lehman failure, there is an understanding among many market regulators and swaps trading experts that large portions of the swaps market have moved from U.S. bank holding company swaps dealers and their U.S. affiliates to their newly deguaranteed foreign affiliates where Dodd- Frank swaps regulation is not being followed. However, what has not moved abroad is the very real obligation of the lender of last resort to rescue these U.S. swaps dealer bank holding companies if they fail because of poorly regulated swaps in their deguaranteed foreign subsidiaries, i.e., the U.S. taxpayer. While relief is unlikely to be forthcoming from the Trump Administration or the Republican-controlled Senate, some other means will have to be found to avert another multi-trillion-dollar bank bailout and/or a financial calamity caused by poorly regulated swaps on the books of big U.S. banks. This paper notes that the relevant statutory framework affords state attorneys general and state financial regulators the right to bring so-called “parens patriae” actions in federal district court to enforce, inter alia, Dodd- Frank on behalf of a state’s citizens. That kind of litigation to enforce the statute’s extraterritorial provisions is now badly needed

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223