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Abstract Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation in prostate cancer patients.

Abstract Background Cardiac pathological outcome of metabolic remodeling is difficult to model using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) due to low metabolic maturation. Methods hiPSC-CM spheres were treated with AMP-activated protein kinase (AMPK) activators and examined for hiPSC-CM maturation features, molecular changes and the response to pathological stimuli. Results Treatment of hiPSC-CMs with AMPK activators increased ATP content, mitochondrial membrane potential and content, mitochondrial DNA, mitochondrial function and fatty acid uptake, indicating increased metabolic maturation. Conversely, the knockdown of AMPK inhibited mitochondrial maturation of hiPSC-CMs. In addition, AMPK activator-treated hiPSC-CMs had improved structural development and functional features—including enhanced Ca2+ transient kinetics and increased contraction. Transcriptomic, proteomic and metabolomic profiling identified differential levels of expression of genes, proteins and metabolites associated with a molecular signature of mature cardiomyocytes in AMPK activator-treated hiPSC-CMs. In response to pathological stimuli, AMPK activator-treated hiPSC-CMs had increased glycolysis, and other pathological outcomes compared to untreated cells. Conclusion AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.

The Lobster Eye Imager for Astronomy (LEIA) is the pathfinder of the wide-field X-ray telescope used in the Einstein Probe mission. In this study, we present an image of the Virgo Cluster taken by LEIA in the 0.5–4.5 keV band with an exposure time of ∼17.3 ks in the central region. This extended emission is generally consistent with the results obtained by ROSAT. However, the field is affected by bright point sources due to the instrument’s Point Spread Function (PSF) effect. Through fitting of the LEIA spectrum of the Virgo Cluster, we obtained a temperature of 2.1−0.1+0.3 keV, which is consistent with the XMM-Newton results (∼2.3 keV). Above 1.6 keV, the spectrum is dominated by the X-ray background. In summary, this study validates LEIA’s extended source imaging and spectral resolution capabilities for the first time.

The early afterglow of a gamma-ray burst (GRB) can provide critical information on the jet and progenitor of the GRB. The extreme brightness of GRB 221009A allows us to probe its early afterglow in unprecedented detail. In this Letter, we report comprehensive observation results of the early afterglow of GRB 221009A (from T _0 +660 s to T _0 +1860 s, where T _0 is the Insight-HXMT/HE trigger time) in X-ray/gamma-ray energy band (from 20 keV to 20 MeV) by Insight-HXMT High Energy X-ray Telescope, GECAM-C, and Fermi/Gamma-ray Burst Monitor. We find that the spectrum of the early afterglow in 20 keV–20 MeV can be well described by a cutoff power law with an extra power law that dominates the low- and high-energy bands, respectively. The cutoff power law E _peak is ∼30 keV, and the power-law photon index is ∼1.8 throughout the early afterglow phase. By fitting the light curves in different energy bands, we find that a significant achromatic break (from keV to TeV) is required at T _0 + ${1246}_{-26}^{+27}$ s (i.e., 1021 s since the afterglow starting time T _AG = T _0 +225 s), providing compelling evidence of a jet break. Interestingly, both the pre-break and post-break decay slopes vary with energy, and these two slopes become closer in the lower energy band, making the break less identifiable. Intriguingly, the spectrum of the early afterglow experienced a slight hardening before the break and a softening after the break. These results provide new insights into the physics of this remarkable GRB.

The power density spectrum (PDS) is a powerful tool to study light curves of gamma-ray bursts (GRBs). We show the average PDS and individual PDS analysis with GRB data from the Hard X-ray Modulation Telescope (also named Insight-HXMT). The values of the power-law index of the average PDS ( ${\alpha }_{\bar{P}}$ ) for long GRBs (LGRBs) vary from 1.58 to 1.29 (for 100–245, 245–600, and 600–2000 keV). The Insight-HXMT data allow us to extend the energy of the LGRBs up to 2000 keV, and a relation between ${\alpha }_{\bar{P}}$ and energy E is obtained: ${\alpha }_{\bar{P}}\propto {E}^{-0.09}$ (8–2000 keV). We first systematically investigate the average PDS and individual PDSs for short GRBs (SGRBs), and obtain ${\alpha }_{\bar{P}}\propto {E}^{-0.07}$ (8–1000 keV), where the values of ${\alpha }_{\bar{P}}$ vary from 1.86 to 1.34. The distribution of the power-law index of an individual PDS ( α ) of an SGRB is consistent with that of an LGRB, and the α value for the group with a dominant timescale (the bent power law) is higher than that for the group with no dominant timescale (the single power law). Both LGRBs and SGRBs show similar α and ${\alpha }_{\bar{P}}$ , which indicates that they may be the result of similar stochastic processes. Typical values of the dominant timescale τ for LGRBs and SGRBs are 1.58 s and 0.02 s, respectively. It seems that τ varies in proportion to the duration of GRBs T _90 , with a relation $\tau \propto {T}_{90}^{0.86}$ . The GRB light curve may result from superposing a number of pulses with different timescales. No periodic or quasi-periodic signal above the 3 σ significance threshold is found in our sample.

The milestone discovery of GW170817-GRB 170817A-AT 2017gfo has shown that gravitational waves (GWs) could be produced during the merger of a neutron star–neutron star/black hole and that in electromagnetic (EM) waves, a gamma-ray burst (GRB) and a kilonova (KN) are generated in sequence after the merger. Observationally, however, EM properties before the merger phase are still unclear. Here we report a peculiar precursor in a KN-associated long-duration GRB 211211A, providing evidence of the EM before the merger. This precursor lasts ∼0.2 s, and the waiting time between the precursor and the main burst is ∼1 s, comparable to that between GW170817 and GRB 170817A. The spectrum of the precursor could be well fit with a nonthermal cutoff power-law model instead of a blackbody. In particular, a ∼22 Hz quasiperiodic oscillation candidate (∼3 σ ) is detected in the precursor. These temporal and spectral properties indicate that this precursor is probably produced by a catastrophic flare accompanied with magnetoelastic or crustal oscillations of a magnetar in a binary compact merger. The strong magnetic field of the magnetar can also account for the prolonged duration of GRB 211211A. However, it poses a challenge to reconcile the rather short lifetime of a magnetar with the rather long spiraling time of a binary neutron star system only by the GW radiation before the merger.

While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here, we report that the deletion of Ptpmt1, a mitochondria-based phosphatase, critically alters mitochondrial fuel selection – the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. Ptpmt1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, Ptpmt1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that Ptpmt1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.

Abstract Amino acid-mediated metabolism is one of the key catabolic and anabolic processes involved in diverse cellular functions. However, the role of the semi-essential amino acid arginine in normal and malignant hematopoietic cell development is poorly understood. Here we report that a continuous supply of exogenous arginine is required for the maintenance/function of normal hematopoietic stem cells (HSCs). Surprisingly, knockout of Slc7a3 (CAT3), a major L-arginine transporter, does not affect HSCs in steady-state or under stress. Although Slc7a3 is highly expressed in naïve and activated CD8 T cells, neither T cell development nor activation/proliferation is impacted by Slc7a3 depletion. Furthermore, the Slc7a3 deletion does not attenuate leukemia development driven by Pten loss or the oncogenic Ptpn11 E76K mutation. Arginine uptake assays reveal that L-arginine uptake is not disrupted in Slc7a3 knockout cells. These data suggest that extracellular arginine is critically important for HSCs, but CAT3 is dispensable for normal hematopoiesis and leukemogenesis.