Dysregulation of RyR Calcium Channel Causes the Onset of Mitochondrial Retrograde Signaling

This study shows that multiple modes of mitochondrial stress generated by partial mtDNA depletion or cytochrome c oxidase disruption cause ryanodine receptor channel (RyR) dysregulation, which instigates the release of Ca2+ in the cytoplasm of C2C12 myoblasts and HCT116 carcinoma cells. We also observed a reciprocal downregulation of IP3R channel activity and reduced mitochondrial uptake of Ca2+. Ryanodine, an RyR antagonist, abrogated the mitochondrial stress-mediated increase in [Ca2+]c and the entire downstream signaling cascades of mitochondrial retrograde signaling. Interestingly, ryanodine also inhibited mitochondrial stress-induced invasive behavior in mtDNA-depleted C2C12 cells and HCT116 carcinoma cells. In addition, co-immunoprecipitation shows reduced FKBP12 protein binding to RyR channel proteins, suggesting the altered function of the Ca2+ channel. These results document how the endoplasmic reticulum-associated RyR channels, in combination with inhibition of the mitochondrial uniporter system, modulate cellular Ca2+ homeostasis and signaling under mitochondrial stress conditions

Handling Location Uncertainty in Event Driven Experimentation

Singapore National Research Foundation under International Research Centre @ Singapore Funding Initiativ

Local Pulsars; A note on the Birth-Velocity Distribution

We explore a simple model for the representation of the observed distributions of the motions, and the characteristic ages of the local population of pulsars. The principal difference from earlier models is the introduction of a unique value, S, for the kick velocity with which pulsars are born. We consider separately the proper motion components in galactic longitude and latitude, and find that the distributions of the velocity components parallel and perpendicular to the galactic plane are represented satisfactorily by S=200 km/sec, and leave no room for a significant fraction of much higher velocities. The successful proposition of a unique value for the kick velocity may provide an interesting tool in attempts to understand the physical process leading to the expulsion of the neutron star.Comment: To be published in JAA, 14 pages, 7 figure

Bondi Accretion and the Problem of the Missing Isolated Neutron Stars

A large number of neutron stars (NSs), ~10^9, populate the Galaxy, but only a tiny fraction of them is observable during the short radio pulsar lifetime. The majority of these isolated NSs, too cold to be detectable by their own thermal emission, should be visible in X-rays as a result of accretion from the interstellar medium. The ROSAT all sky survey has however shown that such accreting isolated NSs are very elusive: only a few tentative candidates have been identified, contrary to theoretical predictions that up to several thousands should be seen. We suggest that the fundamental reason for this discrepancy lies in the use of the standard Bondi formula to estimate the accretion rates. We compute the expected source counts using updated estimates of the pulsar velocity distribution, realistic hydrogen atmosphere spectra, and a modified expression for the Bondi accretion rate as suggested by recent MHD simulations, and supported by direct observations in the case of accretion around supermassive black holes in nearby galaxies and in our own. We find that, whereas the inclusion of atmospheric spectra partly compensates for the reduction in the counts due to the higher mean velocities of the new distribution, the modified Bondi formula dramatically suppresses the source counts. The new predictions are consistent with a null detection at the ROSAT sensitivity.Comment: accepted to ApJ; 19 pages, 4 figure

The elusiveness of old neutron stars

Old neutron stars (ONSs) which have radiated away their internal and rotational energy may still shine if accreting the interstellar medium. Despite their large number, only two promising candidates have been detected so far and rather stringent limits on their observability follow from the analysis of ROSAT surveys. This contrasts with optimistic theoretical estimates that predicted a large number of sources in ROSAT fields. We have reconsidered the issue of ONSs observability, accounting for the spin and magnetic field evolution over the neutron star lifetime. In the framework of a spin-induced field decay model, we show that the total number of ONSs which are, at present, in the accretion stage is reduced by a factor ~5 over previous figures if the characteristic timescale for crustal current dissipation is ~ 10^8 - 10^9 yr. This brings theoretical predictions much closer to observational limits. Most ONSs should be at present in the propeller phase and, if subject to episodic flaring, they could be observable.Comment: 10 pages Latex, 5 ps figures. To be formatted with the AASTeX package. Accepted for publication in Ap

hnRNPA2 Mediated Acetylation Reduces Telomere Length in Response to Mitochondrial Dysfunction

Telomeres protect against chromosomal damage. Accelerated telomere loss has been associated with premature aging syndromes such as Werner’s syndrome and Dyskeratosis Congenita, while, progressive telomere loss activates a DNA damage response leading to chromosomal instability, typically observed in cancer cells and senescent cells. Therefore, identifying mechanisms of telomere length maintenance is critical for understanding human pathologies. In this paper we demonstrate that mitochondrial dysfunction plays a causal role in telomere shortening. Furthermore, hnRNPA2, a mitochondrial stress responsive lysine acetyltransferase (KAT) acetylates telomere histone H4at lysine 8 of (H4K8) and this acetylation is associated with telomere attrition. Cells containing dysfunctional mitochondria have higher telomere H4K8 acetylation and shorter telomeres independent of cell proliferation rates. Ectopic expression of KAT mutant hnRNPA2 rescued telomere length possibly due to impaired H4K8 acetylation coupled with inability to activate telomerase expression. The phenotypic outcome of telomere shortening in immortalized cells included chromosomal instability (end-fusions) and telomerase activation, typical of an oncogenic transformation; while in non-telomerase expressing fibroblasts, mitochondrial dysfunction induced-telomere attrition resulted in senescence. Our findings provide a mechanistic association between dysfunctional mitochondria and telomere loss and therefore describe a novel epigenetic signal for telomere length maintenance

HnRNPA2 is a Novel Histone Acetyltransferase That Mediates Mitochondrial Stress-Induced Nuclear Gene Expression

Reduced mitochondrial DNA copy number, mitochondrial DNA mutations or disruption of electron transfer chain complexes induce mitochondria-to-nucleus retrograde signaling, which induces global change in nuclear gene expression ultimately contributing to various human pathologies including cancer. Recent studies suggest that these mitochondrial changes cause transcriptional reprogramming of nuclear genes although the mechanism of this cross talk remains unclear. Here, we provide evidence that mitochondria-to-nucleus retrograde signaling regulates chromatin acetylation and alters nuclear gene expression through the heterogeneous ribonucleoprotein A2 (hnRNAP2). These processes are reversed when mitochondrial DNA content is restored to near normal cell levels. We show that the mitochondrial stress-induced transcription coactivator hnRNAP2 acetylates Lys 8 of H4 through an intrinsic histone lysine acetyltransferase (KAT) activity with Arg 48 and Arg 50 of hnRNAP2 being essential for acetyl-CoA binding and acetyltransferase activity. H4K8 acetylation at the mitochondrial stress-responsive promoters by hnRNAP2 is essential for transcriptional activation. We found that the previously described mitochondria-to-nucleus retrograde signaling-mediated transformation of C2C12 cells caused an increased expression of genes involved in various oncogenic processes, which is retarded in hnRNAP2 silenced or hnRNAP2 KAT mutant cells. Taken together, these data show that altered gene expression by mitochondria-to-nucleus retrograde signaling involves a novel hnRNAP2-dependent epigenetic mechanism that may have a role in cancer and other pathologies

The characteristics of millisecond pulsar emission: I. Spectra, pulse shapes and the beaming fraction

We have monitored a large sample of millisecond pulsars using the 100-m Effelsberg radio telescope in order to compare their radio emission properties to the slowly rotating population. With some notable exceptions, our findings suggest that the two groups of objects share many common properties. A comparison of the spectral indices between samples of normal and millisecond pulsars demonstrates that millisecond pulsar spectra are not significantly different from those of normal pulsars. There is evidence, however, that millisecond pulsars are slightly less luminous and less efficient radio emitters compared to normal pulsars. We confirm recent suggestions that a diversity exists among the luminosities of millisecond pulsars with the isolated millisecond pulsars being less luminous than the binary millisecond pulsars. There are indications that old millisecond pulsars exhibit somewhat flatter spectra than the presumably younger ones. We present evidence that millisecond pulsar profiles are only marginally more complex than those found among the normal pulsar population. Moreover, the development of the profiles with frequency is rather slow, suggesting very compact magnetospheres. The profile development seems to anti-correlate with the companion mass and the spin period, again suggesting that the amount of mass transfer in a binary system might directly influence the emission properties. The angular radius of radio beams of millisecond pulsars does not follow the scaling predicted from a canonical pulsar model which is applicable for normal pulsars. Instead they are systematically smaller. The smaller inferred luminosity and narrower emission beams will need to be considered in future calculations of the birth-rate of the Galactic population.Comment: 40 pages, 14 figures, accepted for publication in Ap

Classifying depression symptom severity: Assessment of speech representations in personalized and generalized machine learning models

There is an urgent need for new methods that improve the management and treatment of Major Depressive Disorder (MDD). Speech has long been regarded as a promising digital marker in this regard, with many works highlighting that speech changes associated with MDD can be captured through machine learning models. Typically, findings are based on cross-sectional data, with little work exploring the advantages of personalization in building more robust and reliable models. This work assesses the strengths of different combinations of speech representations and machine learning models, in personalized and generalized settings in a two-class depression severity classification paradigm. Key results on a longitudinal dataset highlight the benefits of personalization. Our strongest performing model set-up utilized self-supervised learning features and convolutional neural network (CNN) and long short-term memory (LSTM) back-end