Bound star clusters observed in a lensed galaxy 460 Myr after the Big Bang.

The Cosmic Gems arc is among the brightest and highly magnified galaxies observed at redshift z ∼ 10.21. However, it is an intrinsically UV faint galaxy, in the range of those now thought to drive the reionization of the universe2-4. Hitherto the smallest features resolved in a galaxy at a comparable redshift are between a few hundreds and a few tens of parsecs5,6. Here we report JWST observations of the Cosmic Gems. The light of the galaxy is resolved into five star clusters located in a region smaller than 70 parsec. They exhibit minimal dust attenuation and low metallicity, ages younger than 50 Myr and intrinsic masses of ∼ 106 M⊙. Their lensing-corrected sizes are approximately 1 pc, resulting in stellar surface densities near 105 M⊙ /pc2, three orders of magnitude higher than typical young star clusters in the local universe7. Despite the uncertainties inherent to the lensing model, they are consistent with being gravitationally bound stellar systems, i.e., proto-globular clusters (proto-GCs). We conclude that star cluster formation and feedback likely contributed to 3 shape the properties of galaxies during the epoch of reionization.

The nature of an ultra-faint galaxy in the cosmic dark ages seen with JWST.

In the first billion years after the Big Bang, sources of ultraviolet (UV) photons are believed to have ionized intergalactic hydrogen, rendering the Universe transparent to UV radiation. Galaxies brighter than the characteristic luminosity L* (refs. 1,2) do not provide enough ionizing photons to drive this cosmic reionization. Fainter galaxies are thought to dominate the photon budget; however, they are surrounded by neutral gas that prevents the escape of the Lyman-α photons, which has been the dominant way to identify them so far. JD1 was previously identified as a triply-imaged galaxy with a magnification factor of 13 provided by the foreground cluster Abell 2744 (ref. 3), and a photometric redshift of z ≈ 10. Here we report the spectroscopic confirmation of this very low luminosity (≈0.05 L*) galaxy at z = 9.79, observed 480 Myr after the Big Bang, by means of the identification of the Lyman break and redward continuum, as well as multiple ≳4σ emission lines, with the Near-InfraRed Spectrograph (NIRSpec) and Near-InfraRed Camera (NIRCam) instruments. The combination of the James Webb Space Telescope (JWST) and gravitational lensing shows that this ultra-faint galaxy (MUV = -17.35)-with a luminosity typical of the sources responsible for cosmic reionization-has a compact (≈150 pc) and complex morphology, low stellar mass (107.19 M⊙) and subsolar (≈0.6 Z⊙) gas-phase metallicity.

Shock cooling of a red-supergiant supernova at redshift 3 in lensed images.

The core-collapse supernova of a massive star rapidly brightens when a shock, produced following the collapse of its core, reaches the stellar surface. As the shock-heated star subsequently expands and cools, its early-time light curve should have a simple dependence on the size of the progenitor1 and therefore final evolutionary state. Measurements of the radius of the progenitor from early light curves exist for only a small sample of nearby supernovae2-14, and almost all lack constraining ultraviolet observations within a day of explosion. The several-day time delays and magnifying ability of galaxy-scale gravitational lenses, however, should provide a powerful tool for measuring the early light curves of distant supernovae, and thereby studying massive stellar populations at high redshift. Here we analyse individual rest-frame exposures in the ultraviolet to the optical taken with the Hubble Space Telescope, which simultaneously capture, in three separate gravitationally lensed images, the early phases of a supernova at redshift z ≈ 3 beginning within 5.8 ± 3.1 hours of explosion. The supernova, seen at a lookback time of approximately 11.5 billion years, is strongly lensed by an early-type galaxy in the Abell 370 cluster. We constrain the pre-explosion radius to be [Formula: see text] solar radii, consistent with a red supergiant. Highly confined and massive circumstellar material at the same radius can also reproduce the light curve, but because no similar low-redshift examples are known, this is unlikely.

A highly magnified star at redshift 6.2.

Galaxy clusters magnify background objects through strong gravitational lensing. Typical magnifications for lensed galaxies are factors of a few but can also be as high as tens or hundreds, stretching galaxies into giant arcs1,2. Individual stars can attain even higher magnifications given fortuitous alignment with the lensing cluster. Recently, several individual stars at redshifts between approximately 1 and 1.5 have been discovered, magnified by factors of thousands, temporarily boosted by microlensing3-6. Here we report observations of a more distant and persistent magnified star at a redshift of 6.2 ± 0.1, 900 million years after the Big Bang. This star is magnified by a factor of thousands by the foreground galaxy cluster lens WHL0137-08 (redshift 0.566), as estimated by four independent lens models. Unlike previous lensed stars, the magnification and observed brightness (AB magnitude, 27.2) have remained roughly constant over 3.5 years of imaging and follow-up. The delensed absolute UV magnitude, -10 ± 2, is consistent with a star of mass greater than 50 times the mass of the Sun. Confirmation and spectral classification are forthcoming from approved observations with the James Webb Space Telescope.

Ventricular injury in acute left circumflex occlusion: Exploration using precordial bipolar leads and regional vectorcardiograms.

BACKGROUND: Precordial Bipolar Leads (PBLs) provide new electrocardiographic information derived from standard 12­lead ECG recordings. OBJECTIVES: To explore the usefulness of PBLs in patients with acute circumflex coronary artery (CxCA) occlusion. METHODS: Twelve patients undergoing elective percutaneous transluminal coronary angioplasty (PTCA) were studied before and after acute CxCA occlusion and their data were processed with new methods based on PBLs. RESULTS: The findings were: 1. In right PBL V2-V1, a strong systolic current of injury moving in the left-to-right direction coexists with a strong right-to-left current of injury displayed in left standard unipolar precordial leads (V4, V5 and V6). 2. Ischemic changes lead to a significant increase (approximately 10 ms) in the QRS duration in different leads, although changes in the QRS loop rotation and folding were absent. 3. In the transverse, sagittal, and frontal planes, superimposing two PBLs and the corresponding Regional VCG facilitates the location of the J-point. 4. In the Regional VCGs of this group of patients, J-point and ST segment shifts produced an image that reminds the Greek letter omega (Ω). 5. The currents of injury flowing in opposite directions could result in electrical cancellation that minimizes ECG changes in the standard 12­lead recordings. CONCLUSIONS: Computerized processing of digital, standard 12­lead ECG recordings, provides new valuable diagnostic data in patients with acute CxCA occlusion. The loops revealed important information related to systolic currents of injury. Because these methods use routine 12­lead ECG data, the procedure is based only in software applications. CONDENSED ABSTRACT: Twelve patients undergoing PTCA were studied before and after acute CxCA occlusion and their data were processed with the new methods based on Precordial Bipolar Leads (PBLs) to explore their usefulness. The results showed strong systolic currents of injury in different and sometimes opposite directions in the right-to-left axis and ischemic alterations in the time and amplitude of the QRS waves. The superimposition of two-dimensional coordinates planes (x-y, x-z or z-y) helped to locate the J-point and to display the Regional VCG omega sign (Ω) of myocardial injury. In conclusion, computerized processing of digital ECG data provides new diagnostic information in patients with acute CxCA occlusion.

Right ventricle injury in RCA occlusion: Exploration using precordial bipolar leads and surrogate vectorcardiograms.

BACKGROUND: Precordial Bipolar Leads (PBL) provide new electrocardiographic information derived from standard 12­lead ECG recordings. OBJECTIVES: To explore the usefulness of PBL in patients with acute right coronary artery (RCA) occlusion. METHODS: Sixteen patients undergoing elective percutaneous transluminal coronary angioplasty (PTCA) were studied before and after RCA occlusion and their data were processed with new methods based on PBL. RESULTS: The findings were: 1. In PBL V2-V1, strong systolic currents of injury moving in the left to right direction coexist with those directed towards leads II, III and aVF. 2. Changes in the time of the peaks of the QRS waves do not alter the duration of the QRS. 3. The QRS loops of the surrogate VCG generated show that, during ischemia, the time changes in the peak of the QRS waves displayed in one axis are the consequence of an increase in the amplitude of the waves observed in the perpendicular axis. 4. The use of two simultaneous dimensions (transverse and frontal planes) facilitates the location of the J-point. 5. In the surrogate VCGs of this group of patients, J-point and ST segment shifts produced an image that reminded the Greek letter omega (Ω). 6. The QRS wave changes, in time and amplitude, explained the rotational changes and the ischemic distortions of the surrogate VCG loops. CONCLUSIONS: Computerized processing of ECG data appears to provide new and valuable diagnostic data in patients with acute RCA occlusion. The loops revealed important information related to systolic currents of injury. Because these methods use routine 12­lead ECG data, the procedure is based only in software applications.

J wave syndromes as a cause of malignant cardiac arrhythmias.

The J wave syndromes, including the Brugada (BrS) and early repolarization (ERS) syndromes, are characterized by the manifestation of prominent J waves in the electrocardiogram appearing as an ST segment elevation and the development of life-threatening cardiac arrhythmias. BrS and ERS differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J wave syndromes. Despite over 25 years of intensive research, risk stratification and the approach to therapy of these two inherited cardiac arrhythmia syndromes are still rapidly evolving. Our objective in this review is to provide an integrated synopsis of the clinical characteristics, risk stratifiers, as well as the molecular, ionic, cellular, and genetic mechanisms underlying these two syndromes that have captured the interest and attention of the cardiology community over the past two decades.

Acute myocardial ischemia: cellular mechanisms underlying ST segment elevation.

The electrocardiogram (ECG) is an essential tool for the diagnosis of acute myocardial ischemia in the emergency department, as well as for that of an evolving acute myocardial infarction (AMI). Changes in the surface ECG in leads whose positive poles face the ischemic region are known to be related to injury currents flowing across the boundaries between the ischemic and the surrounding normal myocardium. Although experimental studies have also shown an endocardium to epicardium differential sensitivity to the effect of acute ischemia, the important contribution of this transmural heterogeneous response to the changes observed in the surface ECG is less appreciated by the clinical cardiologist. This review briefly discusses our current knowledge regarding the electrophysiology of the ischemic myocardium focusing primarily on the electrophysiologic changes underlying the ECG alterations observed at the onset of a transmural AMI.

Effect of Flecainide and Ibutilide Alone and in Combination to Terminate and Prevent Recurrence of Atrial Fibrillation.

BACKGROUND: There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). METHODS: The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary-perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. RESULTS: Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms (P<0.05 for both). Flecainide increased the effective refractory period in atria by 27% (P<0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria (P<0.01) but by only 7% (P<0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and Tpeak-Tend intervals by 25 and 55%, respectively (P<0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects (P<0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. CONCLUSIONS: In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT-mediated ventricular proarrhythmia.

Optical and electrical recordings from isolated coronary-perfused ventricular wedge preparations.

The electrophysiological heterogeneity that exists across the ventricular wall in the mammalian heart has long been recognized, but remains an area that is incompletely understood. Experimental studies of the mechanisms of arrhythmogenesis in the whole heart often examine the epicardial surface in isolation and thereby disregard transmural electrophysiology. Significant heterogeneity exists in the electrophysiological properties of cardiomyocytes isolated from different layers of the ventricular wall, and given that regional heterogeneities of membrane repolarization properties can influence the electrophysiological substrate for re-entry, the diversity of cell types and characteristics spanning the ventricular wall is important in the study of arrhythmogenesis. For these reasons, coronary-perfused left ventricular wedge preparations have been developed to permit the study of transmural electrophysiology in the intact ventricle. Since the first report by Yan and Antzelevitch in 1996, electrical recordings from the transmural surface of canine wedge preparations have provided a wealth of data regarding the cellular basis for the electrocardiogram, the role of transmural heterogeneity in arrhythmogenesis, and differences in the response of the different ventricular layers to drugs and neurohormones. Use of the wedge preparation has since been expanded to other species and more recently it has also been widely used in optical mapping studies. The isolated perfused wedge preparation has become an important tool in cardiac electrophysiology. In this review, we detail the methodology involved in recording both electrical and optical signals from the coronary-perfused wedge preparation and review the advances in cardiac electrophysiology achieved through study of the wedge.

Developmental changes in expression and biophysics of ion channels in the canine ventricle.

BACKGROUND: Developmental changes in the electrical characteristics of the ventricular myocardium are not well defined. This study examines the contribution of inwardly rectifying K(+) current (IK1), transient outward K(+) current (Ito), delayed rectifier K(+) currents (IKr and IKs) and sodium channel current (INa) to repolarization in the canine neonate myocardium. METHODS: Single myocytes isolated from the left ventricle of 2-3week old canine neonate hearts were studied using patch-clamp techniques. RESULTS: Neonate cells were ~6-fold smaller than those of adults (28.8±8.8 vs. 176±6.7pF). IK1 was larger in neonate myocytes and displayed a substantial inward component and an outward component with negative slope conductance, peaking at -60mV (4.13 pA/pF). IKr tail currents (at -40mV), were small (<20pA). IKs could not be detected, even after exposure to isoproterenol (100nM). Ito was also absent in the neonate, consistent with the absence of a phase 1 in the action potential. Peak INa, late INa and ICa were smaller in the neonate compared with adults. KCND3, KCNIP2 and KCNQ1 mRNA expression was half, while KCNH2 was equal and KCNJ2 was greater in the neonate when compared with adults. CONCLUSIONS: Two major repolarizing K(+) currents (IKs and Ito) present in adult ventricular cells are absent in the 2week old neonate. Peak and late INa are significantly smaller in the neonate. Our results suggest that the absence of these two currents in the neonate heart may increase the susceptibility to arrhythmias under certain long QT conditions.

Identification and characterization of a transient outward K+ current in human induced pluripotent stem cell-derived cardiomyocytes.

BACKGROUND: The ability to recapitulate mature adult phenotypes is critical to the development of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) as models of disease. The present study examines the characteristics of the transient outward current (Ito) and its contribution to the hiPSC-CM action potential (AP). METHOD: Embryoid bodies were made from a hiPS cell line reprogrammed with Oct4, Nanog, Lin28 and Sox2. Sharp microelectrodes were used to record APs from beating-clusters (BC) and patch-clamp techniques were used to record Ito in single hiPSC-CM. mRNA levels of Kv1.4, KChIP2 and Kv4.3 were quantified from BCs. RESULTS: BCs exhibited spontaneous beating (60.5±2.6 bpm) and maximum-diastolic-potential (MDP) of 67.8±0.8 mV (n=155). A small 4-aminopyridine-sensitive phase-1-repolarization was observed in only 6/155 BCs. A robust Ito was recorded in the majority of cells (13.7±1.9 pA/pF at +40 mV; n=14). Recovery of Ito from inactivation (at -80 mV) showed slow kinetics (τ1=200±110 ms (12%) and τ2=2380±240 ms (80%)) accounting for its minimal contribution to the AP. Transcript data revealed relatively high expression of Kv1.4 and low expression of KChIP2 compared to human native ventricular tissues. Mathematical modeling predicted that restoration of IK1 to normal levels would result in a more negative MDP and a prominent phase-1-repolarization. CONCLUSION: The slow recovery kinetics of Ito coupled with a depolarized MDP account for the lack of an AP notch in the majority of hiPSC-CM. These characteristics reveal a deficiency for the development of in vitro models of inherited cardiac arrhythmia syndromes in which Ito-induced AP notch is central to the disease phenotype.

Mechanisms underlying the antiarrhythmic effect of ARumenamide-787 in experimental models of the J wave syndromes and hypothermia.

BACKGROUND: Brugada (BrS) and early repolarization syndromes (ERS), the so-called J wave syndromes (JWS), are associated with life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently limited. In this study, we examine the effects of ARumenamide-787 (AR-787) to suppress the electrocardiographic and arrhythmic manifestations of JWS and hypothermia. METHODS: We studied the effects of AR-787 on INa and IKr in HEK-293 cells stably expressing the α- and ß1-subunits of the cardiac (NaV1.5) sodium channel and hERG channel, respectively. In addition, we studied its effect on Ito, INa and ICa in dissociated canine ventricular myocytes along with action potentials and ECG from coronary-perfused right (RV) and left (LV) ventricular wedge preparations. The Ito agonist, NS5806 (5-10 µM), ICa blocker, verapamil (2.5 µM), and INa blocker, ajmaline (2.5 µM), were used to mimic the genetic defects associated with JWS and to induce the electrocardiographic and arrhythmic manifestations of JWS (prominent J waves/ST segment elevation, phase 2 reentry and polymorphic VT/VF) in canine ventricular wedge preparations. RESULTS: AR-787 (1, 10 and 50 µM) exerted pleiotropic effects on cardiac ion channels. The predominant effect was inhibition of the transient outward current (Ito) and enhancement of the sodium channel current (INa), with lesser effects to inhibit IKr and augment calcium channel current (ICa). AR-787 diminished the electrocardiographic J wave and prevented and/or suppressed all arrhythmic activity in canine RV and LV experimental models of BrS, ERS and hypothermia. CONCLUSIONS: Our findings point to AR-787 as promising candidate for the pharmacologic treatment of JWS and hypothermia.

A magnified compact galaxy at redshift 9.51 with strong nebular emission lines.

Ultraviolet light from early galaxies is thought to have ionized gas in the intergalactic medium. However, there are few observational constraints on this epoch because of the faintness of those galaxies and the redshift of their optical light into the infrared. We report the observation, in JWST imaging, of a distant galaxy that is magnified by gravitational lensing. JWST spectroscopy of the galaxy, at rest-frame optical wavelengths, detects strong nebular emission lines that are attributable to oxygen and hydrogen. The measured redshift is z = 9.51 ± 0.01, corresponding to 510 million years after the Big Bang. The galaxy has a radius of [Formula: see text] parsecs, which is substantially more compact than galaxies with equivalent luminosity at z ~ 6 to 8, leading to a high star formation rate surface density.

Constraints on the Hubble constant from supernova Refsdal's reappearance.

The gravitationally lensed supernova Refsdal appeared in multiple images produced through gravitational lensing by a massive foreground galaxy cluster. After the supernova appeared in 2014, lens models of the galaxy cluster predicted that an additional image of the supernova would appear in 2015, which was subsequently observed. We use the time delays between the images to perform a blinded measurement of the expansion rate of the Universe, quantified by the Hubble constant (H0). Using eight cluster lens models, we infer [Formula: see text]. Using the two models most consistent with the observations, we find [Formula: see text]. The observations are best reproduced by models that assign dark-matter halos to individual galaxies and the overall cluster.

Physiological consequences of transient outward K+ current activation during heart failure in the canine left ventricle.

BACKGROUND: Remodeling of ion channel expression is well established in heart failure (HF). We determined the extent to which I(to) is reduced in tachypacing-induced HF and assessed the ability of an I(to) activator (NS5806) to recover this current. METHOD AND RESULTS: Whole-cell patch clamp was used to record I(to) in epicardial (Epi) ventricular myocytes. Epi- and endocardial action potentials were recorded from left ventricular wedge preparations. Right ventricular tachypacing-induced heart failure reduced I(to) density in Epi myocytes (Control=22.1±1.9pA/pF vs 16.1±1.4 after 2weeks and 10.7±1.4pA/pF after 5 weeks, +50mV). Current decay as well as recovery of I(to) from inactivation progressively slowed with the development of heart failure. Reduction of I(to) density was paralleled by a reduction in phase 1 magnitude, epicardial action potential notch and J wave amplitude recorded from coronary-perfused left ventricular wedge preparations. NS5806 increased I(to) (at +50mV) from 16.1±1.4 to 23.9±2.1pA/pF (p<0.05) at 2weeks and from 10.7±1.4 to 14.4±1.9pA/pF (p<0.05) in 5 weeks tachypaced dogs. NS5806 increased both fast and slow phases of I(to) recovery in 2 and 5-week HF cells and restored the action potential notch and J wave in wedge preparations from HF dogs. CONCLUSIONS: The I(to) agonist NS5806 increases the rate of recovery and density of I(to), thus reversing the HF-induced reduction in these parameters. In wedge preparations from HF dogs, NS5806 restored the spike-and-dome morphology of the Epi action potential providing proof of principal that some aspects of electrical remodelling during HF can be pharmacologically reversed.

Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants.

INTRODUCTION: Tricyclic antidepressants are known to induce cardiac arrhythmias at therapeutic or supratherapeutic doses. The tricyclic antidepressant, amitriptyline, is reported to induce ST segment elevation in the right precordial electrocardiogram (ECG) leads, thus unmasking Brugada syndrome (BrS). The mechanism by which antidepressants induce the BrS phenotype and associated sudden death is not well established. METHODS AND RESULTS: Action potentials (AP) were simultaneously recorded from epicardial and endocardial sites of isolated coronary-perfused canine right ventricular wedge preparations, together with a transmural pseudo-ECG. Amitriptyline alone (0.2 µM-1 mM) failed to induce a BrS phenotype. NS5806 (8 µM), a transient outward potassium channel current (I(to) ) agonist, was used to produce an outward shift of current mimicking a genetic predisposition to BrS. In the presence of NS5806, a therapeutic concentration of amitriptyline (0.2 µM) accentuated the epicardial AP notch leading to ST-segment elevation of the ECG. All-or-none repolarization at some epicardial sites but not others gave rise to phase-2-reentry and polymorphic ventricular tachycardia (VT) in 6 of 9 preparations. Isoproterenol (100 nM) or quinidine (10 µM) reversed the effects of amitriptyline aborting phase 2 reentry and VT (4/4). Using voltage-clamp techniques applied to isolated canine ventricular myocytes, 0.2 µM amitriptyline was shown to produce use-dependent inhibition of sodium channel current (I(Na) ), without significantly affecting I(to) (n = 5). CONCLUSIONS: Our data suggest that amitriptyline-induced inhibition of I(Na) unmasks the Brugada ECG phenotype and facilitates development of an arrhythmogenic substrate only in the setting of a genetic predisposition by creating repolarization heterogeneities that give rise to phase 2 reentry and VT.