Acute glycogen synthase kinase-3 inhibition modulates human cardiac conduction

Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several diseases, including cancer. However, the role for GSK-3 regulation of human cardiac electrophysiology remains ill-defined. We demonstrate that SB216763, a GSK-3 inhibitor, can acutely reduce conduction velocity in human cardiac slices. Combined computational modeling and experimental approaches provided mechanistic insight into GSK-3 inhibition-mediated changes, revealing that decreased sodium-channel conductance and tissue conductivity may underlie the observed phenotypes. Our study demonstrates that GSK-3 inhibition in human myocardium alters electrophysiology and may predispose to an arrhythmogenic substrate; therefore, monitoring for adverse arrhythmogenic events could be considered

Chern - Simons Gauge Field Theory of Two - Dimensional Ferromagnets

A Chern-Simons gauged Nonlinear Schr\"odinger Equation is derived from the continuous Heisenberg model in 2+1 dimensions. The corresponding planar magnets can be analyzed whithin the anyon theory. Thus, we show that static magnetic vortices correspond to the self-dual Chern - Simons solitons and are described by the Liouville equation. The related magnetic topological charge is associated with the electric charge of anyons. Furthermore, vortex - antivortex configurations are described by the sinh-Gordon equation and its conformally invariant extension. Physical consequences of these results are discussed.Comment: 15 pages, Plain TeX, Lecce, June 199

Human cardiac pericytes are susceptible to SARS-CoV-2 infection

COVID-19 is associated with serious cardiovascular complications, with incompletely understood mechanism(s). Pericytes have key functions in supporting endothelial cells and maintaining vascular integrity. We demonstrate that human cardiac pericytes are permissive to SARS-CoV-2 infection in organotypic slice and primary cell cultures. Viral entry into pericytes is mediated by endosomal proteases, and infection leads to up-regulation of inflammatory markers, vasoactive mediators, and nuclear factor kappa-B-dependent cell death. Furthermore, we present evidence of cardiac pericyte infection in COVID-19 myocarditis patients. These data demonstrate that human cardiac pericytes are susceptible to SARS-CoV-2 infection and suggest a role for pericyte infection in COVID-19

Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1

Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell-intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we demonstrate that mTORC1 activation is sufficient to stimulate specific metabolic pathways, including glycolysis, the oxidative arm of the pentose phosphate pathway, and de novo lipid biosynthesis. This is achieved through the activation of a transcriptional program affecting metabolic gene targets of hypoxia-inducible factor (HIF1α) and sterol regulatory element-binding protein (SREBP1 and SREBP2). We find that SREBP1 and 2 promote proliferation downstream of mTORC1, and the activation of these transcription factors is mediated by S6K1. Therefore, in addition to promoting protein synthesis, mTORC1 activates specific bioenergetic and anabolic cellular processes that are likely to contribute to human physiology and disease

Chamber-specific transcriptional responses in atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, yet the molecular signature of the vulnerable atrial substrate is not well understood. Here, we delineated a distinct transcriptional signature in right versus left atrial cardiomyocytes (CMs) at baseline and identified chamber-specific gene expression changes in patients with a history of AF in the setting of end-stage heart failure (AF+HF) that are not present in heart failure alone (HF). We observed that human left atrial (LA) CMs exhibited Notch pathway activation and increased ploidy in AF+HF but not in HF alone. Transient activation of Notch signaling within adult CMs in a murine genetic model is sufficient to increase ploidy in both atrial chambers. Notch activation within LA CMs generated a transcriptomic fingerprint resembling AF, with dysregulation of transcription factor and ion channel genes, including Pitx2, Tbx5, Kcnh2, Kcnq1, and Kcnip2. Notch activation also produced distinct cellular electrophysiologic responses in LA versus right atrial CMs, prolonging the action potential duration (APD) without altering the upstroke velocity in the left atrium and reducing the maximal upstroke velocity without altering the APD in the right atrium. Our results support a shared human/murine model of increased Notch pathway activity predisposing to AF

Nanoparticles within WWTP sludges have minimal impact on leachate quality and soil microbial community structure and function

One of the main pathways by which engineered nanoparticles (ENPs) enter the environment is through land application of waste water treatment plant (WWTP) sewage sludges. WWTP sludges, enriched with Ag and ZnO ENPs or their corresponding soluble metal salts during anaerobic digestion and subsequently mixed with soil (targeting a final concentration of 1400 and 140 mg/kg for Zn and Ag, respectively), were subjected to 6 months of ageing and leaching in lysimeter columns outdoors. Amounts of Zn and Ag leached were very low, accounting for <0.3% and <1.4% of the total Zn and Ag, respectively. No differences in total leaching rates were observed between treatments of Zn or Ag originally input to WWTP as ENP or salt forms. Phospholipid fatty acid profiling indicated a reduction in the fungal component of the soil microbial community upon metal exposure. However, overall, the leachate composition and response of the soil microbial community following addition of sewage sludge enriched either with ENPs or metal salts was very similar

The peak-flux of GRB 221009A measured with GRBAlpha

The brightest gamma-ray burst ever observed, long-duration GRB 221009A, was detected by GRBAlpha nano-satellite without saturation. We present light curves of the prompt emission in 13 energy bands, from 80 keV to 950 keV, and perform a spectral analysis to calculate the peak flux and peak isotropic-equivalent luminosity. Since the satellite's attitude information is not available for the time of this GRB, more than 200 incident directions were probed in order to find the median luminosity and its systematic uncertainty. We found that the peak flux in the $80-800$ keV range (observer frame) was $F_{\rm{ph}}^{\rm{p}}=1300_{-200}^{+1200}$ ph cm$^{-2}$s$^{-1}$ or $F_{\rm{erg}}^{\rm{p}}=5.7_{-0.7}^{+3.7}\times10^{-4}$ erg cm$^{-2}$s$^{-1}$ and the fluence in the same energy range of the first GRB episode lasting 300 s, which was observable by GRBAlpha, was $S=2.2_{-0.3}^{+1.4}\times10^{-2}$ erg cm$^{-2}$ or $S^{\rm{bol}}=4.9_{-0.5}^{+0.8}\times10^{-2}$ erg cm$^{-2}$ for the extrapolated range of $0.9-8,690$ keV. We infer the isotropic-equivalent released energy of the first GRB episode to be $E_{\rm{iso}}^{\rm{bol}}=2.8_{-0.5}^{+0.8}\times10^{54}$ erg in the $1-10,000$ keV band (rest frame at $z=0.15$). The peak isotropic-equivalent luminosity in the $92-920$ keV range (rest frame) was $L_{\rm{iso}}^{\rm{p}}=3.7_{-0.5}^{+2.5}\times10^{52}$ erg s$^{-1}$ and the bolometric peak isotropic-equivalent luminosity was $L_{\rm{iso}}^{\rm{p,bol}}=8.4_{-1.5}^{+2.5}\times10^{52}$ erg s$^{-1}$ (4 s scale) in the $1-10,000$ keV range (rest frame). The peak emitted energy is $E_p^\ast=E_p(1+z)=1120\pm470$ keV. Our measurement of $L_{\rm{iso}}^{\rm{p,bol}}$ is consistent with the Yonetoku relation. It is possible that, due to the spectral evolution of this GRB and orientation of GRBAlpha at the peak time, the true values of peak flux, fluence, $L_{\rm{iso}}$, and $E_{\rm{iso}}$ are even higher. [abridged]Comment: 7 pages, 7 figures, 1 table, accepted for publication in Astronomy & Astrophysic

A rockslide-generated tsunami in a Greenland fjord rang Earth for 9 days

Climate change is increasingly predisposing polar regions to large landslides. Tsunamigenic landslides have occurred recently in Greenland (Kalaallit Nunaat), but none have been reported from the eastern fjords. In September 2023, we detected the start of a 9-day-long, global 10.88-millihertz (92-second) monochromatic very-long-period (VLP) seismic signal, originating from East Greenland. In this study, we demonstrate how this event started with a glacial thinning–induced rock-ice avalanche of 25 × 106 cubic meters plunging into Dickson Fjord, triggering a 200-meter-high tsunami. Simulations show that the tsunami stabilized into a 7-meter-high long-duration seiche with a frequency (11.45 millihertz) and slow amplitude decay that were nearly identical to the seismic signal. An oscillating, fjord-transverse single force with a maximum amplitude of 5 × 1011 newtons reproduced the seismic amplitudes and their radiation pattern relative to the fjord, demonstrating how a seiche directly caused the 9-day-long seismic signal. Our findings highlight how climate change is causing cascading, hazardous feedbacks between the cryosphere, hydrosphere, and lithosphere.acceptedVersio

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines