Are we surprised to find SMBHs with JWST at z > 9?

JWST is unveiling for the first time accreting black holes (BHs) with masses of 10^6 - 10^7 Msun at z > 4, with the most distant residing in GNz11 at z = 10.6. Are we really surprised to find them in the nuclei of z = 5 - 11 galaxies? Here we predict the properties of 4 < z < 11 BHs and their host galaxies considering an Eddington-limited (EL) and a super-Eddington (SE) BH accretion scenario, using the Cosmic Archaeology Tool (CAT) semi-analytical model. We calculate the transmitted spectral energy distribution of CAT synthetic candidates, representative of the BH/galaxy properties of GNz11. We also examine the possibility that the z = 8.7 galaxy CEERS-1019 could host an active BH. We find that the luminosity of high-z JWST detected BHs are better reproduced by the SE model, where BHs descend from efficiently growing light and heavy seeds. Conversely, the host galaxy stellar masses are better matched in the EL model, in which all the systems detectable with JWST surveys JADES and CEERS descend from heavy BH seeds. We support the interpretation that the central point source of GNz11 could be powered by a SE (lambda_Edd = 2 - 3) accreting BH with mass 1.5 10^6 Msun, while the emission from CEERS-1019 is dominated by the host galaxy; if it harbours an active BH, we find it to have a mass of M_BH = 10^7 Msun, and to be accreting at sub-Eddington rates (lambda_Edd = 0.5).Comment: 11 pages, 5 figures, accepted by MNRAS after minor revision and updated with recent observation

Inorganic polyphosphate regulates AMPA and NMDA receptors and protects against glutamate excitotoxicity via activation of P2Y receptors

Glutamate is one of the most important neurotransmitters in the process of signal transduction in the central nervous system. Excessive amounts of this neurotransmitter lead to glutamate excitotoxicity which is accountable for neuronal death in acute neurological disorders including stroke, trauma, and in neurodegenerative diseases. Inorganic polyphosphate (PolyP) plays multiple roles in the mammalian brain, including function as a calcium-dependent gliotransmitter mediating communication between astrocytes, while its role in the regulation of neuronal activity is unknown. Here we studied the effect of polyP on glutamate-induced calcium signal in primary rat neurons in both physiological and pathological conditions. We found that pre-incubation of primary neurons with polyP reduced glutamate- and AMPA- but not the NMDA-induced calcium signal. However, in rat hippocampal acute slices polyP reduced ion flux through NMDA and AMPA receptors in native neurons. The effect of polyP on glutamate and specifically on the AMPA receptors was dependent on the presence of P2Y1 but not of P2X receptor inhibitors and also could be mimicked by P2Y1 agonist 2MeSADP. Pre-incubation of cortical neurons with polyP significantly reduced the initial calcium peak as well as the number of neurons with delayed calcium deregulation in response to high concentrations of glutamate and resulted in protection of neurons against glutamate-induced cell death. As a result, activation of P2Y1 receptors by polyP reduced calcium signal acting through AMPA receptors, thus protecting neurons against glutamate excitotoxicity by reduction of the calcium overload and restoration of mitochondrial function.Significance StatementOne of the oldest polymers in the evolution of living matter is the inorganic polyphosphate. It is shown to play a role of gliotransmitter in the brain; however, the role of polyphosphate in neuronal signalling is not clear. Here we demonstrate that inorganic polyphosphate is able to reduce calcium signal, induced by physiological or high concentrations of glutamate. The effect of polyphosphate on glutamate-induced calcium signal in neurons is due to the effect of this polymer on the AMPA receptors.The effect of polyP on glutamate- and AMPA-induced calcium signal is dependent on P2Y receptor antagonist. The ability of polyphosphate to restrict glutamate-induced calcium signal lies in the basis of its protection of neurons against glutamate excitotoxicity

Role of the Na+/Ca+ exchanger 1 (NCX1) in the protective response elicited by glutamate in cardiac cells exposed to hypoxia/reoxygenation (H/R)

L'ischemia miocardica determina una drastica riduzione della produzione di ATP, con conseguente squilibrio ionico e morte cellulare. La fornitura di substrati metabolici durante la riperfusione è in grado di aumentare significativamente la tolleranza cardiaca al danno ischemico migliorando le funzioni mitocondriali. In condizioni di normossia, il glutammato può contribuire all'equilibrio energetico del miocardio agendo come substrato per le reazioni anaplerotiche. In questo contesto, lo scambiatore Na+/Ca2+ (NCX1) svolge un ruolo fondamentale come supporto funzionale, favorendo sia l’ingresso di glutammato all’interno della cellula sia il suo conseguente utilizzo per la sintesi di ATP. A tal proposito, nel presente studio è stato valutato il ruolo svolto da NCX nel miglioramento del metabolismo energetico e della sopravvivenza cellulare indotto da glutammato in modelli cardiaci sottoposti ad uno specifico protocollo di ipossia/riossigenazione (I/R). In particolare è stato osservato in cellule H9c2-NCX1 che, i livelli di ATP, le funzioni mitocondriali e la sopravvivenza cellulare risultano significativamente compromessi in seguito al danno da I/R. La somministrazione di glutammato all'inizio della fase di riossigenazione incrementava, in modo significativo, la vitalità, migliorava le funzioni mitocondriali e normalizzava l'aumento dell'attività “inversa” di NCX1 indotto dal protocollo di I/R. Gli effetti benefici del glutammato non venivano osservati sono sorprendentemente in cellule H9c2-WT (caratterizzate da una mancata espressione di NCX1), e in cellule H9c2-NCX1 e cardiomiociti di ratto trattati con inibitori dello scambiatore e con bloccanti dei trasportatori degli amminoacidi eccitatori (EAAT), suggerendo che un'interazione funzionale tra questi due trasportatori è necessaria per ottenere la protezione indotta da glutammato. Collettivamente, i risultati ottenuti hanno rivelato per la prima volta il ruolo chiave di NCX1 nell’effetto protettivo del glutammato contro il danno cellulare da I/R.Myocardial ischemia culminates in ATP production impairment, ionic derangement and cell death. The provision of metabolic substrates during reperfusion significantly increases heart tolerance to ischemia by improving mitochondrial performance. Under normoxia, glutamate contributes to myocardial energy balance as substrate for anaplerotic reactions, and we demonstrated that the Na+/Ca2+ exchanger1 (NCX1) provides functional support for both glutamate uptake and use for ATP synthesis. Here the role of NCX1 was studied in the potential of glutamate to improve energy metabolism and survival of cardiac cells subjected to hypoxia/reoxygenation (H/R). Specifically, in H9c2-NCX1 myoblasts, ATP levels, mitochondrial activities and cell survival were significantly compromised after H/R challenge. Glutamate supplementation at the onset of the reoxygenation phase significantly promoted viability, improved mitochondrial functions and normalized the H/R-induced increase of NCX1 reverse-mode activity. The benefits of glutamate were strikingly lost in H9c2-WT (lacking NCX1 expression), or in H9c2-NCX1 and rat cardiomyocytes treated with either NCX or Excitatory Amino Acid Transporters (EAATs) blockers, suggesting that a functional interplay between these transporters is critically required for glutamate-induced protection. Collectively, these results revealed for the first time the key role of NCX1 for the beneficial effects of glutamate against H/R-induced cell injury

Sudden cardiac death: focus on the genetics of channelopathies and cardiomyopathies

Abstract Sudden cardiac death (SCD) describes a natural and unexpected death from cardiac causes occurring within a short period of time (generally within 1 h of symptom onset) in the absence of any other potentially lethal condition. Most SCD-related diseases have a genetic basis; in particular congenital cardiac channelopathies and cardiomyopathies have been described as leading causes of SCD. Congenital cardiac channelopathies are primary electric disorders caused by mutations affecting genes encoding cardiac ion channels or associated proteins, whereas cardiomyopathies are related to mutations in genes encoding several categories of proteins, including those of sarcomeres, desmosomes, the cytoskeleton, and the nuclear envelope. The purpose of this review is to provide a general overview of the main genetic variants that have been linked to the major congenital cardiac channelopathies and cardiomyopathies. Functional alterations of the related proteins are also described

Calcium Deregulation: Novel Insights to Understand Friedreich’s Ataxia Pathophysiology

Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder, characterized by degeneration of dorsal root ganglia, cerebellum and cardiomyopathy. Heart failure is one of the most common causes of death for FRDA patients. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. The focus of our study was to investigate the unexplored Ca2+ homeostasis in cerebellar granule neurons (CGNs) and in cardiomyocytes of FRDA cellular models to understand the pathogenesis of degeneration. Ca2+ homeostasis in neurons and cardiomyocytes is not only crucial for the cellular wellbeing but more importantly to generate action potential in both neurons and cardiomyocytes. By challenging Ca2+ homeostasis in CGNs, and in adult and neonatal cardiomyocytes of FRDA models, we have assessed the impact of frataxin decrease on both neuronal and cardiac physiopathology. Interestingly, we have found that Ca2+ homeostasis is altered both cell types. CGNs showed a Ca2+ mishandling under depolarizing conditions and this was also reflected in the endoplasmic reticulum (ER) content. In cardiomyocytes we found that the sarcoplasmic reticulum (SR) Ca2+ content was pathologically reduced, and that mitochondrial Ca2+ uptake was impaired. This phenomenon is due to the excess of oxidative stress under FRDA like conditions and the consequent aberrant modulation of key players at the SR/ER and mitochondrial level that usually restore the Ca2+ homeostasis. Our findings demonstrate that in both neurons and cardiomyocytes the decreased Ca2+ level within the stores has a comparable detrimental impact in their physiology. In cardiomyocytes, we found that ryanodine receptors (RyRs) may be leaking and expel more Ca2+ out from the SR. At the same time mitochondrial uptake was altered and we found that Vitamin E can restore this defect. Moreover, Vitamin E protects from cell death induced by hypoxia-reperfusion injury, revealing novel properties of Vitamin E as potential therapeutic tool for FRDA cardiomyopathy

Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

Abstract Myocardial ischemia culminates in ATP production impairment, ionic derangement and cell death. The provision of metabolic substrates during reperfusion significantly increases heart tolerance to ischemia by improving mitochondrial performance. Under normoxia, glutamate contributes to myocardial energy balance as substrate for anaplerotic reactions, and we demonstrated that the Na+/Ca2+ exchanger1 (NCX1) provides functional support for both glutamate uptake and use for ATP synthesis. Here we investigated the role of NCX1 in the potential of glutamate to improve energy metabolism and survival of cardiac cells subjected to hypoxia/reoxygenation (H/R). Specifically, in H9c2-NCX1 myoblasts, ATP levels, mitochondrial activities and cell survival were significantly compromised after H/R challenge. Glutamate supplementation at the onset of the reoxygenation phase significantly promoted viability, improved mitochondrial functions and normalized the H/R-induced increase of NCX1 reverse-mode activity. The benefits of glutamate were strikingly lost in H9c2-WT (lacking NCX1 expression), or in H9c2-NCX1 and rat cardiomyocytes treated with either NCX or Excitatory Amino Acid Transporters (EAATs) blockers, suggesting that a functional interplay between these transporters is critically required for glutamate-induced protection. Collectively, these results revealed for the first time the key role of NCX1 for the beneficial effects of glutamate against H/R-induced cell injury

Seeking the growth of the first black hole seeds with JWST

In this paper, we provide predictions for the black hole (BH) population that would be observable with planned JWST surveys at 5 ≤ z ≤ 15. We base our study on the recently developed Cosmic Archaeology Tool, which allows us to model BH seeds formation and growth while being consistent with the general population of active galactic nuclei (AGNs) and galaxies observed at 4 ≤ z ≤ 7. We find that JWST planned surveys will provide a complementary view on active BHs at z > 5, with JADES-Medium/-Deep being capable of detecting the numerous BHs that populate the faint-end of the distribution, COSMOS-Web sampling a large enough area to detect the rarest brightest systems, and CEERS/PRIMER bridging the gap between these two regimes. The relatively small field of view of the above surveys preferentially selects BHs with masses 6 ≤ Log(MBH/M⊙) < 8 at 7 ≤ z < 10, residing in relatively metal poor (Log(Z/Z⊙) ≥ −2) and massive (8 ≤ Log(M*/M⊙) < 10) galaxies. At z ≥ 10, only JADES-Deep will have the sensitivity to detect growing BHs with masses 4 ≤ Log(MBH/M⊙) < 6, hosted by more metal poor (−3 ≤ Log(Z/Z⊙) < −2) and less massive (6 ≤ Log(M*/M⊙) < 8) galaxies. In our model, the latter population corresponds to heavy BH seeds formed by the direct collapse of supermassive stars in their earliest phases of mass growth. Detecting these systems would provide invaluable insights on the nature and early growth of the first BH seeds.STFC ERC Royal Society Professorshi

Are we surprised to find SMBHs with JWST at z > 9?

International audienceThe recent discovery of new Active Galactic Nuclei (AGN) at z > 4 with JWST is revolutionising the black hole (BH) landscape at cosmic dawn, unveiling for the first time accreting BHs with masses of 10^6 - 10^7 Msun. To date, the most distant reside in CEERS-1019 at z=8.7 and GNz11 at z=10.6. Given the high rate of newly discovered high-z AGNs, more than 10 at z > 4, we wonder: are we really surprised to find them in the nuclei of z = 5 - 11 galaxies? Can we use the estimated properties to trace their origin? In this work, we predict the properties of 4 4 AGNs and galaxies. We then calculate the transmitted spectral energy distribution of CAT synthetic candidates, representative of the estimated BH properties in CEERS-1019 and GNz11. We find that the estimated luminosity of high-z JWST detected AGNs are better reproduced by the SE model, where BHs descend from efficiently growing light and heavy seeds. Conversely, the host galaxy stellar masses are better matched in the EL model, in which all the systems detectable with JWST surveys JADES and CEERS appear to be descendants of heavy BH seeds. Our study suggests an evolutionary connection between systems similar to GNz11 at z=10.6 and CEERS-1019 at z=8.7 and supports the interpretation that the central point source of GNz11 could be powered by a super-Eddington (lambda_Edd = 2 - 3) accreting BH with mass 1.5 10^6 Msun, while CEERS-1019 harbours a more massive BH, with M_{BH} = 10^7 Msun, accreting sub-Eddington (lambda_Edd = 0.45 - 1), with a dominant emission from the host galaxy

Effects of ticagrelor on the sodium/calcium exchanger 1 (NCX1) in cardiac derived H9c2 cells

Ticagrelor is a direct acting and reversibly binding P2Y12 antagonist approved for the prevention of thromboembolic events. Clinical effects of ticagrelor cannot be simply accounted for by pure platelet inhibition, and off-target mechanisms can potentially play a role. In particular, recent evidence suggests that ticagrelor may also influence heart function and improve the evolution of myocardial ischemic injury by more direct effects on myocytes. The cardiac sodium/calcium exchanger 1 (NCX1) is a critical player in the generation and control of calcium (Ca2+) signals, which orchestrate multiple myocyte activities in health and disease. Altered expression and/or activity of NCX1 can have profound consequences for the function and fate of myocytes. Whether ticagrelor affects cardiac NCX1 has not been investigated yet. To explore this hypothesis, we analyzed the expression, localization and activity of NCX1 in the heart derived H9c2-NCX1 cells following ticagrelor exposure. We found that ticagrelor concentration- and time-dependently reduced the activity of the cardiac NCX1 in H9c2 cells. In particular, the inhibitory effect of ticagrelor on the Ca2+-influx mode of NCX1 was evident within 1 h and further developed after 24 h, when NCX1 activity was suppressed by about 55% in cells treated with 1 μM ticagrelor. Ticagrelor-induced inhibition of exchanger activity was reached at clinically relevant concentrations, without affecting the expression levels and subcellular distribution of NCX1. Collectively, these findings suggest that cardiac NCX1 is a new downstream target of ticagrelor, which may contribute to the therapeutic profile of ticagrelor in clinical practice