Role of the Mitochondrion in Programmed Necrosis

In contrast to the “programmed” nature of apoptosis and autophagy, necrotic cell death has always been believed to be a random, uncontrolled process that leads to the “accidental” death of the cell. This dogma, however, is being challenged and the concept of necrosis also being “programmed” is gaining ground. In particular, mitochondria appear to play a pivotal role in the mediation of programmed necrosis. The purpose of this review, therefore, is to appraise the current concepts regarding the signaling mechanisms of programmed necrosis, with specific attention to the contribution of mitochondria to this process

Ruling Out Possible Secondary Stars to Exoplanet Host Stars Using the CHARA Array

Of the over 450 exoplanets known to date, more than 420 of them have been discovered using radial velocity studies, a method that tells nothing about the inclination of the planet's orbit. Because it is more likely that the companion is a planetary-mass object in a moderate- to high-inclination orbit than a low-mass stellar object in a nearly face-on orbit, the secondary bodies are presumed to be planets. Interferometric observations allow us to inspect the angular diameter fit residuals to calibrated visibilities in order to rule out the possibility of a low-mass stellar companion in a very low-inclination orbit. We used the Center for High Angular Resolution Astronomy (CHARA) Array interferometer to observe 20 exoplanet host stars and considered five potential secondary spectral types: G5 V, K0 V, K5 V, M0 V, and M5 V. If a secondary star is present and is sufficiently bright, the effects of the added light will appear in interferometric observations where the planet will not. All secondary types could be eliminated from consideration for 7 host stars and no secondary stars of any spectral type could be ruled out for 7 more. The remaining 6 host stars showed a range of possible secondary types.Comment: Accepted for publication in the Astronomical Journa

Optical mapping and optogenetics in cardiac electrophysiology research and therapy:a state-of-the-art review

State-of-the-art innovations in optical cardiac electrophysiology are significantly enhancing cardiac research. A potential leap into patient care is now on the horizon. Optical mapping, using fluorescent probes and high-speed cameras, offers detailed insights into cardiac activity and arrhythmias by analysing electrical signals, calcium dynamics, and metabolism. Optogenetics utilizes light-sensitive ion channels and pumps to realize contactless, cell-selective cardiac actuation for modelling arrhythmia, restoring sinus rhythm, and probing complex cell–cell interactions. The merging of optogenetics and optical mapping techniques for ‘all-optical’ electrophysiology marks a significant step forward. This combination allows for the contactless actuation and sensing of cardiac electrophysiology, offering unprecedented spatial–temporal resolution and control. Recent studies have performed all-optical imaging ex vivo and achieved reliable optogenetic pacing in vivo, narrowing the gap for clinical use. Progress in optical electrophysiology continues at pace. Advances in motion tracking methods are removing the necessity of motion uncoupling, a key limitation of optical mapping. Innovations in optoelectronics, including miniaturized, biocompatible illumination and circuitry, are enabling the creation of implantable cardiac pacemakers and defibrillators with optoelectrical closed-loop systems. Computational modelling and machine learning are emerging as pivotal tools in enhancing optical techniques, offering new avenues for analysing complex data and optimizing therapeutic strategies. However, key challenges remain including opsin delivery, real-time data processing, longevity, and chronic effects of optoelectronic devices. This review provides a comprehensive overview of recent advances in optical mapping and optogenetics and outlines the promising future of optics in reshaping cardiac electrophysiology and therapeutic strategies

Impact of Obesity on Atrial Fibrillation Pathogenesis and Treatment Options

Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF increases the risk of stroke, heart failure, dementia, and hospitalization. Obesity significantly increases AF risk, both directly and indirectly, through related conditions, like hypertension, diabetes, and heart failure. Obesity-driven structural and electrical remodeling contribute to AF via several reported mechanisms, including adiposity, inflammation, fibrosis, oxidative stress, ion channel alterations, and autonomic dysfunction. In particular, expanding epicardial adipose tissue during obesity has been suggested as a key driver of AF via paracrine signaling and direct infiltration. Weight loss has been shown to reverse these changes and reduce AF risk and recurrence after ablation. However, studies on how obesity affects pharmacologic or interventional AF treatments are limited. In this review, we discuss mechanisms by which obesity mediates AF and treatment outcomes, aiming to provide insight into obesity-drug interactions and guide personalized treatment for this patient subgroup.</p

The CHARA Array Angular Diameter of HR 8799 Favors Planetary Masses for Its Imaged Companions

HR 8799 is an hF0 mA5 gamma Doradus, lambda Bootis, Vega-type star best known for hosting four directly imaged candidate planetary companions. Using the CHARA Array interferometer, we measure HR 8799's limb-darkened angular diameter to be 0.342 +/- 0.008 mas; this is the smallest interferometrically measured stellar diameter to date, with an error of only 2%. By combining our measurement with the star's parallax and photometry from the literature, we greatly improve upon previous estimates of its fundamental parameters, including stellar radius (1.44 +/- 0.06 R_Sun), effective temperature (7193 +/- 87 K, consistent with F0), luminosity (5.05 +/- 0.29 L_Sun), and the extent of the habitable zone (1.62 AU to 3.32 AU). These improved stellar properties permit much more precise comparisons with stellar evolutionary models, from which a mass and age can be determined, once the metallicity of the star is known. Considering the observational properties of other lambda Bootis stars and the indirect evidence for youth of HR 8799, we argue that the internal abundance, and what we refer to as the effective abundance, is most likely near-solar. Finally, using the Yonsei-Yale evolutionary models with uniformly scaled solar-like abundances, we estimate HR 8799's mass and age considering two possibilities: 1.516 +0.038/-0.024 M_Sun and 33 +7/-13 Myr if the star is contracting toward the zero age main-sequence or 1.513 +0.023/-0.024 M_Sun and 90 +381/-50 Myr if it is expanding from it. This improved estimate of HR 8799's age with realistic uncertainties provides the best constraints to date on the masses of its orbiting companions, and strongly suggests they are indeed planets. They nevertheless all appear to orbit well outside the habitable zone of this young star.Comment: Accepted for publication in ApJ; 37 pages, 6 tables, 13 figure

Angular Diameters and Effective Temperatures of Twenty-five K Giant Stars from the CHARA Array

Using Georgia State University's CHARA Array interferometer, we measured angular diameters for 25 giant stars, six of which host exoplanets. The combination of these measurements and Hipparcos parallaxes produce physical linear radii for the sample. Except for two outliers, our values match angular diameters and physical radii estimated using photometric methods to within the associated errors with the advantage that our uncertainties are significantly lower. We also calculated the effective temperatures for the stars using the newly-measured diameters. Our values do not match those derived from spectroscopic observations as well, perhaps due to the inherent properties of the methods used or because of a missing source of extinction in the stellar models that would affect the spectroscopic temperatures

Western Diet-Fed, Aortic-Banded Ossabaw Swine: A Preclinical Model of Cardio-Metabolic Heart Failure.

The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF

Elevated Paracellular Glucose Flux across Cystic Fibrosis Airway Epithelial Monolayers Is an Important Factor for Pseudomonas aeruginosa Growth.

People with cystic fibrosis (CF) who develop related diabetes (CFRD) have accelerated pulmonary decline, increased infection with antibiotic-resistant Pseudomonas aeruginosa and increased pulmonary exacerbations. We have previously shown that glucose concentrations are elevated in airway surface liquid (ASL) of people with CF, particularly in those with CFRD. We therefore explored the hypotheses that glucose homeostasis is altered in CF airway epithelia and that elevation of glucose flux into ASL drives increased bacterial growth, with an effect over and above other cystic fibrosis transmembrane conductance regulator (CFTR)-related ASL abnormalities. The aim of this study was to compare the mechanisms governing airway glucose homeostasis in CF and non-CF primary human bronchial epithelial (HBE) monolayers, under normal conditions and in the presence of Ps. aeruginosa filtrate. HBE-bacterial co-cultures were performed in the presence of 5 mM or 15 mM basolateral glucose to investigate how changes in blood glucose, such as those seen in CFRD, affects luminal Ps. aeruginosa growth. Calu-3 cell monolayers were used to evaluate the potential importance of glucose on Ps. aeruginosa growth, in comparison to other hallmarks of the CF ASL, namely mucus hyperviscosity and impaired CFTR-dependent fluid secretions. We show that elevation of basolateral glucose promotes the apical growth of Ps. aeruginosa on CF airway epithelial monolayers more than non-CF monolayers. Ps. aeruginosa secretions elicited more glucose flux across CF airway epithelial monolayers compared to non-CF monolayers which we propose increases glucose availability in ASL for bacterial growth. In addition, elevating basolateral glucose increased Ps. aeruginosa growth over and above any CFTR-dependent effects and the presence or absence of mucus in Calu-3 airway epithelia-bacteria co-cultures. Together these studies highlight the importance of glucose as an additional factor in promoting Ps. aeruginosa growth and respiratory infection in CF disease

Validation of the Exoplanet Kepler-21b using PAVO/CHARA Long-Baseline Interferometry

We present long-baseline interferometry of the Kepler exoplanet host star HD179070 (Kepler-21) using the PAVO beam combiner at the CHARA Array. The visibility data are consistent with a single star and exclude stellar companions at separations ~1-1000 mas (~ 0.1-113 AU) and contrasts < 3.5 magnitudes. This result supports the validation of the 1.6 R_{earth} exoplanet Kepler-21b by Howell et al. (2012) and complements the constraints set by adaptive optics imaging, speckle interferometry, and radial velocity observations to rule out false-positives due to stellar companions. We conclude that long-baseline interferometry has strong potential to validate transiting extrasolar planets, particularly for future projects aimed at brighter stars and for host stars where radial velocity follow-up is not available.Comment: 5 pages, 3 figures, accepted for publication in MNRAS Letters; v2: minor changes added in proo

Co-circulation of Multidrug-resistant Shigella Among Men Who Have Sex With Men in Australia.

BACKGROUND: In urban Australia, the burden of shigellosis is either in returning travelers from shigellosis-endemic regions or in men who have sex with men (MSM). Here, we combine genomic data with comprehensive epidemiological data on sexual exposure and travel to describe the spread of multidrug-resistant Shigella lineages. METHODS: A population-level study of all cultured Shigella isolates in the state of Victoria, Australia, was undertaken from 1 January 2016 through 31 March 2018. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatic analyses of 545 Shigella isolates were performed at the Microbiological Diagnostic Unit Public Health Laboratory. Risk factor data on travel and sexual exposure were collected through enhanced surveillance forms or by interviews. RESULTS: Rates of antimicrobial resistance were high, with 17.6% (95/541) and 50.6% (274/541) resistance to ciprofloxacin and azithromycin, respectively. There were strong associations between antimicrobial resistance, phylogeny, and epidemiology. Specifically, 2 major MSM-associated lineages were identified: a Shigellasonnei lineage (n = 159) and a Shigella flexneri 2a lineage (n = 105). Of concern, 147/159 (92.4%) of isolates within the S. sonnei MSM-associated lineage harbored mutations associated with reduced susceptibility to recommended oral antimicrobials: namely, azithromycin, trimethoprim-sulfamethoxazole, and ciprofloxacin. Long-read sequencing demonstrated global dissemination of multidrug-resistant plasmids across Shigella species and lineages, but predominantly associated with MSM isolates. CONCLUSIONS: Our contemporary data highlight the ongoing public health threat posed by resistant Shigella, both in Australia and globally. Urgent multidisciplinary public health measures are required to interrupt transmission and prevent infection