Aims. This study aims at constraining the origin of the nearby Type Ia supernovae (SNe), 2011fe and 2014J. The two most favoured scenarios for triggering the explosion of the white dwarf supernova ...progenitor is either mass loss from a non-degenerate companion or merger with another white dwarf. In the former, there could be a significant amount of leftover material from the companion at the centre of the supernova. Detecting such material would therefore favour the single-degenerate scenario. Methods. The left-over material from a possible non-degenerate companion can reveal itself after about one year, and in this study such material was searched for in the spectra of SN 2011fe (at 294 days after the explosion) using the Large Binocular Telescope and for SN 2014J using the Nordic Optical Telescope (315 days past explosion). The observations were interpreted using numerical models simulating the expected line emission from ablated material from the companion star. The spectral lines sought for are Hα, O I λ6300, and Ca II λλ7291,7324, and the expected width of these lines is ~1000 km s-1, which in the case of the Ca II lines blend to a broader feature. Results. No signs of Hα, O I λ6300, or Ca II λλ7291, 7324 could be traced for in any of the two supernovae. When systematic uncertainties are included, the limits on hydrogen-rich ablated gas are 0.003 M⊙ in SN 2011fe and 0.0085 M⊙ in SN 2014J, where the limit for SN 2014J is the second lowest ever, and the limit for SN 2011fe is a revision of a previous limit. Limits are also put on helium-rich ablated gas, and here limits from O I λ6300 provide the upper mass limits 0.002 M⊙ and 0.005 M⊙ for SNe 2011fe and 2014J, respectively. These numbers are used in conjunction with other data to argue that these supernovae can stem from double-degenerate systems or from single-degenerate systems with a spun-up/spun-down super-Chandrasekhar white dwarf. For SN 2011fe, other types of hydrogen-rich donors can very likely be ruled out, whereas a main-sequence donor system with large intrinsic separation is still possible for SN 2014J. Helium-rich donor systems cannot be ruled out for any of the two supernovae, but the expected short delay time for such progenitors makes this possibility less likely, especially for SN 2011fe. Published data for SNe 1998bu, 2000cx, 2001el, 2005am, and 2005cf are used to constrain their origin. We emphasise that the results of this study depend on the sought-after lines emerging unattenuated from the central regions of the nebula. Detailed radiative transfer calculations with longer line lists than are presently used are needed to confirm that this is, in fact, true. Finally, the broad lines of SNe 2011fe and 2014J are discussed, and it is found that the Ni II λ7378 emission is redshifted by ~+1300 kms-1, as opposed to the known blueshift of ~−1100 kms-1 for SN 2011fe. Fe II λ7155 is also redshifted in SN 2014J. SN 2014J belongs to a minority of SNe Ia that both have a nebular redshift of Fe II λ7155 and Ni II λ7378, and a slow decline of the Si II λ6355 absorption trough just after B-band maximum.
Ribosomal protein (RP) expression in higher eukaryotes is regulated translationally through the 5′TOP sequence. This mechanism evolved to more rapidly produce RPs on demand in different tissues. Here ...we show that 40S ribosomes, in a complex with the mRNA binding protein LARP1, selectively stabilize 5′TOP mRNAs, with disruption of this complex leading to induction of the impaired ribosome biogenesis checkpoint (IRBC) and p53 stabilization. The importance of this mechanism is underscored in 5q− syndrome, a macrocytic anemia caused by a large monoallelic deletion, which we found to also encompass the LARP1 gene. Critically, depletion of LARP1 alone in human adult CD34+ bone marrow precursor cells leads to a reduction in 5′TOP mRNAs and the induction of p53. These studies identify a 40S ribosome function independent of those in translation that, with LARP1, mediates the autogenous control of 5′TOP mRNA stability, whose disruption is implicated in the pathophysiology of 5q− syndrome.
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•LARP1 controls the stability but not the translation of 5′TOP mRNAs•The 40S ribosome is required for LARP1 stabilization of 5′TOP mRNAs•Disruption of 5′TOP stability elicits the IRBC response and p53 stabilization•LARP1 is lost in 5q− syndrome, and its deficit mirrors the pathology
Ribosomal proteins (RPs) are essential components of the translational machinery. Gentilella et al. show that the 40S ribosome and LARP1 form a complex that has a high affinity for 5′TOP mRNAs, particularly RPs. This association preserves 5′TOP mRNA stability, constituting an anabolic reservoir that can be utilized upon demand.
Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for ...oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent.
Mechanistic target of rapamycin (Mtor) is required for embryonic inner cell mass proliferation during early development. However, Mtor expression levels are very low in the mouse heart during ...embryogenesis. To determine if Mtor plays a role during mouse cardiac development, cardiomyocyte specific Mtor deletion was achieved using α myosin heavy chain (α-MHC) driven Cre recombinase. Initial mosaic expression of Cre between embryonic day (E) 10.5 and E11.5 eliminated a subset of cardiomyocytes with high Cre activity by apoptosis and reduced overall cardiac proliferative capacity. The remaining cardiomyocytes proliferated and expanded normally. However loss of 50% of cardiomyocytes defined a threshold that impairs the ability of the embryonic heart to sustain the embryo's circulatory requirements. As a result 92% of embryos with cardiomyocyte Mtor deficiency died by the end of gestation. Thus Mtor is required for survival and proliferation of cardiomyocytes in the developing heart.
•Palmitic acid caused ER stress, apoptosis and insulin resistance in hepatocytes.•Oleic acid suppressed lipotoxic effects induced by palmitic acid in hepatocytes.•Palmitic acid increased S6K1 ...phosphorylation and oleic acid inhibited this effect.•S6K1 inhibition reduced ER stress-mediated lipotoxicity and insulin resistance induced by palmitic acid.
The excess of saturated free fatty acids, such as palmitic acid, that induces lipotoxicity in hepatocytes, has been implicated in the development of non-alcoholic fatty liver disease also associated with insulin resistance. By contrast, oleic acid, a monounsaturated fatty acid, attenuates the effects of palmitic acid. We evaluated whether palmitic acid is directly associated with both insulin resistance and lipoapoptosis in mouse and human hepatocytes and the impact of oleic acid in the molecular mechanisms that mediate both processes. In human and mouse hepatocytes palmitic acid at a lipotoxic concentration triggered early activation of endoplasmic reticulum (ER) stress-related kinases, induced the apoptotic transcription factor CHOP, activated caspase 3 and increased the percentage of apoptotic cells. These effects concurred with decreased IR/IRS1/Akt insulin pathway. Oleic acid suppressed the toxic effects of palmitic acid on ER stress activation, lipoapoptosis and insulin resistance. Besides, oleic acid suppressed palmitic acid-induced activation of S6K1. This protection was mimicked by pharmacological or genetic inhibition of S6K1 in hepatocytes. In conclusion, this is the first study highlighting the activation of S6K1 by palmitic acid as a common and novel mechanism by which its inhibition by oleic acid prevents ER stress, lipoapoptosis and insulin resistance in hepatocytes.
Excess levels of circulating amino acids (AAs) play a causal role in specific human pathologies, including obesity and type 2 diabetes. Moreover, obesity and diabetes are contributing factors in the ...development of cancer, with recent studies suggesting that this link is mediated in part by AA activation of mammalian target of rapamycin (mTOR) Complex 1. AAs appear to mediate this response through class III phosphatidylinositol 3-kinase (PI3K), or human vacuolar protein sorting 34 (hVps34), rather than through the canonical class I PI3K pathway used by growth factors and hormones. Here we show that AAs induce a rise in intracellular Ca(2+) (Ca(2+)(i)), which triggers mTOR Complex 1 and hVps34 activation. We demonstrate that the rise in Ca(2+)(i) increases the direct binding of Ca(2+)/calmodulin (CaM) to an evolutionarily conserved motif in hVps34 that is required for lipid kinase activity and increased mTOR Complex 1 signaling. These findings have important implications regarding the basic signaling mechanisms linking metabolic disorders with cancer progression.
Earlier, we reported that
S6K1
−/− mice have reduced body fat mass, have elevated rates of lipolysis, have severely decreased adipocyte size, and are resistant to high fat diet (HFD)-induced obesity. ...Here we report that adipocytes of
S6K1
−/− mice on a HFD have the capacity to increase in size to a degree comparable to that of wild-type (WT) mice, but not in number, indicating an unexpected lesion in adipogenesis. Tracing this lesion revealed that S6K1 is dispensable for terminal adipocyte differentiation, but is involved in the commitment of embryonic stem cells to early adipocyte progenitors. We further show that absence of S6K1 attenuates the upregulation of transcription factors critical for commitment to adipogenesis. These results led to the conclusion that a lack of S6K1 impairs the generation of de novo adipocytes when mice are challenged with a HFD, consistent with a reduction in early adipocyte progenitors.
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