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Sirtuin 6 (SIRT6) is an NAD-dependent deacetylase/deacylase/mono-ADP ribosyltransferase, a member of the sirtuin protein family. SIRT6 has been implicated in hepatic lipid homeostasis and liver health. Hepatic lipogenesis is driven by several master regulators including liver X receptor (LXR), carbohydrate response element binding protein (ChREBP), and sterol regulatory element binding protein 1 (SREBP1). Interestingly, these three transcription factors can be negatively regulated by SIRT6 through direct deacetylation. Fatty acid oxidation is regulated by peroxisome proliferator activated receptor alpha (PPARα) in the liver. SIRT6 can promote fatty acid oxidation by the activation of PPARα or the suppression of miR-122. SIRT6 can also directly modulate acyl-CoA synthetase long chain family member 5 (ACSL5) activity for fatty acid oxidation. SIRT6 also plays a critical role in the regulation of total cholesterol and low-density lipoprotein (LDL)-cholesterol through the regulation of SREBP2 and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Hepatic deficiency of Sirt6 in mice has been shown to cause hepatic steatosis, inflammation, and fibrosis, hallmarks of alcoholic and nonalcoholic steatohepatitis. SIRT6 can dampen hepatic inflammation through the modulation of macrophage polarization from M1 to M2 type. Hepatic stellate cells are a key cell type in hepatic fibrogenesis. SIRT6 plays a strong anti-fibrosis role by the suppression of multiple fibrogenic pathways including the transforming growth factor beta (TGFβ)-SMAD family proteins and Hippo pathways. The role of SIRT6 in liver cancer is quite complicated, as both tumor-suppressive and tumor-promoting activities have been documented in the literature. Overall, SIRT6 has multiple salutary effects on metabolic homeostasis and liver health, and it may serve as a therapeutic target for hepatic metabolic diseases. To date, numerous activators and inhibitors of SIRT6 have been developed for translational research.

We present consecutive observations of Flux Transfer Events (FTEs) on 10 November 2020, using MMS, THEMIS and Cluster spacecraft located at different magnetopause locations. Two typical scale FTE signatures are successively observed by low‐latitude THEMIS, mid‐latitude MMS and high latitude Cluster, reflecting their global spatial scale characteristics. Multi‐spacecraft observation also revealed the complete 3‐D structure of the FTEs, with azimuthal extended section, magnetosheath and magnetospheric arm. The simultaneous existence of different magnetic field line topologies during the FTEs indicates the generation mechanism of multiple X‐line reconnection. Successive observations with intervals of several minutes revealed some evolutionary features of FTEs, including an increase in size and flux, and disappearance of the magnetic dip region on both sides. Our observations give a complete 3‐D picture of FTEs on a global scale, which can improve our understanding of the transient magnetic reconnection and solar wind‐magnetosphere interaction at the magnetopause. Plain Language Summary Magnetic reconnection is one of the fundamental physical processes that remains to be fully understood. Flux Transfer Events (FTEs) have attracted extensive attention as a product of transient magnetic reconnection at the magnetopause. Numerical simulations have shown that FTEs can manifest as global scale structural features, but it is difficult to obtain proof from in situ spacecraft observation. We used a total of 11 satellites, including NASA's THEMIS and MMS, and ESA's Cluster, covering different latitudes and locations of the magnetopause, and comprehensively revealed the global three‐dimensional structural characteristics of FTEs. Our observations also indicated that the generation mechanism of these FTEs is the classic multiple X‐line reconnection model, and they continue to evolve slowly during subsequent transit along the magnetopause. These innovative works can help us improve the understanding of the magnetic reconnection process at the magnetopause and the solar‐terrestrial interaction. Key Points 11 spacecraft at different locations of the magnetopause reveal the global 3‐D Flux Transfer Events (FTEs) including azimuthal extension, MSH and MSP arm Existence of different magnetic topologies provide strong evidence that these FTEs originate from multiple X‐line reconnection The slightly increased size and flux of FTEs suggest that they still maintain slow evolution on the timescale of magnetopause transits

Using a conjunction of Cluster in the mid‐altitude dayside magnetosphere and Swarm in the low‐altitude ionosphere, we show, by employing multi‐spacecraft analysis, that matched, strong magnetic perturbations and the corresponding mesoscale field‐aligned current (FAC) structures are measured in the high latitude polar cusp region during the 7 October 2015 storm. Two pairs of opposite (positive/negative) FACs are observed by both Cluster and Swarm, which may relate to pulsed magnetic reconnection at the dayside magnetopause. Furthermore, the current intensity of these matched FACs decreases from high to low latitude, consistent with the time elapsed since reconnection. Corresponding geomagnetic disturbances are also observed by ground stations. Our observations provide direct evidence for the coupling of mesoscale FACs between the magnetosphere, ionosphere and ground in the polar cusp region, where the signatures are driven in this case by conditions suitable for inducing reconnection. Plain Language Summary Field‐aligned currents (FACs) are the key medium for the interaction between the distant space magnetosphere (a region filled with Earth's magnetic field) and the near‐Earth space ionosphere. Magnetic reconnection is the most important process to transfer solar wind energy from dayside magnetosphere to nightside, which is accompanied by the generation of FACs extending from the high latitude region of the ionosphere to the magnetosphere. For such structures, extending across different space regions, joint observations by multiple spacecraft are necessary. Using simultaneous measurements of Cluster in the magnetosphere, Swarm in the ionosphere and geomagnetic stations on the ground, coordinated mesoscale FAC structures could show matched signatures in the magnetosphere and the ionosphere and the corresponding geomagnetic disturbances on the ground. Our observations provide direct evidence for the magnetosphere‐ionosphere‐ground coupling during the pulsed magnetic reconnection process. Key Points Multi‐spacecraft Cluster and Swarm reveal matched magnetic perturbation and corresponding mesoscale field‐aligned currents (FACs) at different altitudes in the cusp region Multiple pairs of opposite FACs associated with pulsed magnetic reconnection are dominant currents system at the dayside during storm time Direct evidence for detailed dayside mesoscale FACs coupling between magnetosphere, ionosphere and ground is provided

Forkhead transcription factors FoxO1/3/4 have pleiotrophic functions including anti-oxidative stress and metabolism. With regard to glucose metabolism, most studies have been focused on FoxO1. To further investigate their hepatic functions, we generated liver-specific FoxO1/3/4 knockout mice (LTKO) and examined their collective impacts on glucose homeostasis under physiological and pathological conditions. As compared to wild-type mice, LTKO mice had lower blood glucose levels under both fasting and non-fasting conditions and they manifested better glucose and pyruvate tolerance on regular chow diet. After challenged by a high-fat diet, wild-type mice developed type 2 diabetes, but LTKO mice remained euglycemic and insulin-sensitive. To understand the underlying mechanisms, we examined the roles of SIRT6 (Sirtuin 6) and Gck (glucokinase) in the FoxO-mediated glucose metabolism. Interestingly, ectopic expression of SIRT6 in the liver only reduced gluconeogenesis in wild-type but not LTKO mice whereas knockdown of Gck caused glucose intolerance in both wild-type and LTKO mice. The data suggest that both decreased gluconeogenesis and increased glycolysis may contribute to the overall glucose phenotype in the LTKO mice. Collectively, FoxO1/3/4 transcription factors play important roles in hepatic glucose homeostasis.

Neuroendocrine prostate cancer (NEPC) has increasingly become a clinical challenge. The mechanisms by which neuroendocrine (NE) cells arises from prostate adenocarcinoma cells are poorly understood. FOXA1 is a transcription factor of the forkhead family that is required for prostate epithelial differentiation. In this study, we demonstrated that FOXA1 loss drives NE differentiation, demarcated by phenotypical changes and NEPC marker expressions. Mechanistically, this is mediated by FOXA1 binding to the promoter of interleukin 8 ( IL-8 ), a chemokine previously shown elevated in NEPC, to directly inhibit its expression. Further, IL-8 upregulation activates the MAPK/ERK pathway, leading to ERK phosphorylation and enolase 2 (ENO2) expression. IL-8 knockdown or ERK inhibition, on the other hand, abolished FOXA1 loss-induced NE differentiation. Analysis of xenograft mouse models confirmed FOXA1 loss in NEPC tumors relative to its adenocarcinoma counterparts. Importantly, FOXA1 is downregulated in human NEPC tumors compared to primary and castration-resistant prostate cancers, and its expression is negatively correlated with that of ENO2. These findings indicate that FOXA1 transcriptionally suppresses IL-8 , the expression of which would otherwise stimulate the MAPK/ERK pathway to promote NE differentiation of prostate cancer cells. Our data strongly suggest that FOXA1 loss may play a significant role in enabling prostate cancer progression to NEPC, whereas IL-8 and MAPK/ERK pathways may be promising targets for therapeutic intervention.

The successful synthesis of superconducting infinite-layer nickelate thin films with the highest T c  ≈ 15 K has ignited great enthusiasm for this material class as potential analogs of the high- T c cuprates. Pursuing a higher T c is always an imperative task in studying a new superconducting material system. Here we report high-quality Pr 0.82 Sr 0.18 NiO 2 thin films with T c onset  ≈ 17 K synthesized by carefully tuning the amount of CaH 2 in the topotactic chemical reduction and the effect of pressure on its superconducting properties by measuring electrical resistivity under various pressures in a cubic anvil cell apparatus. We find that the onset temperature of the superconductivity, T c onset , can be enhanced monotonically from ~17 K at ambient pressure to ~31 K at 12.1 GPa without showing signatures of saturation upon increasing pressure. This encouraging result indicates that the T c of infinite-layer nickelates superconductors still has room to go higher and it can be further boosted by applying higher pressures or strain engineering in the heterostructure films. Despite much recent effort, the highest reported T c of the infinite-layer nickelates remains lower than 15 K. Here, the authors apply pressure to Pr 0.82 Sr 0.18 NiO 2 thin films and observe a monotonic increase of T c to 31 K at 12.1 GPa, an increase that does not level off with increasing pressure.

Prostate tumors develop resistance to androgen deprivation therapy (ADT) by multiple mechanisms, one of which is to express constitutively active androgen receptor (AR) splice variants lacking the ligand-binding domain. AR splice variant 7 (AR-V7, also termed AR3) is the most abundantly expressed variant that drives prostate tumor progression under ADT conditions. However, the molecular mechanism by which AR-V7 is generated remains unclear. In this manuscript, we demonstrated that RNA splicing of AR-V7 in response to ADT was closely associated with AR gene transcription initiation and elongation rates. Enhanced AR gene transcription by ADT provides a prerequisite condition that further increases the interactions between AR pre-mRNA and splicing factors. Under ADT conditions, recruitment of several RNA splicing factors to the 3′ splicing site for AR-V7 was increased. We identified two RNA splicing enhancers and their binding proteins (U2AF65 and ASF/SF2) that had critical roles in splicing AR pre-mRNA into AR-V7. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-V7 levels in prostate cancer cells.

Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 ( Irs1 ) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)—even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines—including excess follistatin (Fst)—that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance. Follistatin acts as a hepatokine to induce insulin resistance and can be targeted to improve diabetes in mice.

By analyzing continuous Magnetospheric Multiscale observations at the magnetopause boundary layer, combining both magnetohydrodynamic and kinetic signatures, we have successfully captured dynamic magnetic reconnection processes in exceptional detail. Our results demonstrate that magnetic reconnection exhibits rapid transitions between distinct operational modes, characterized by: (a) primary single X‐line reconnection punctuated by intermittent secondary reconnection, leading to large‐scale multiple X‐line formations; (b) stable single X‐line reconnection with oscillating X‐line positions; (c) rapid switching of reconnection X‐lines between opposite sides of the spacecraft; and (d) transient suppression occurring during otherwise steady reconnection periods. These observations provide definitive evidence for the inherently dynamic and intermittent behavior of magnetopause reconnection, revealing its capacity for swift configuration changes under varying conditions.

We report an unusual pressure-induced superconducting state that coexists with an antiferromagnetic ordering of Eu 2+ moments and shows a large upper critical field comparable to the Pauli paramagnetic limit in EuTe 2 . In concomitant with the emergence of superconductivity with T c  ≈ 3–5 K above P c  ≈ 6 GPa, the antiferromagnetic transition temperature T N ( P ) experiences a quicker rise with the slope increased dramatically from d T N /d P  = 0.85(14) K/GPa for P  ≤  P c to 3.7(2) K/GPa for P  ≥  P c . Moreover, the superconducting state can survive in the spin-flop state with a net ferromagnetic component of the Eu 2+ sublattice under moderate magnetic fields μ 0 H  ≥ 2 T. Our findings establish the pressurized EuTe 2 as a rare magnetic superconductor possessing an intimated interplay between magnetism and superconductivity. Here, the authors report pressure-induced superconductivity with concomitant enhancement of antiferromagnetic transition in layered EuTe 2 . The superconductivity is distinctly characterized by the high upper critical fields exceeding the Pauli limit among binary tellurides, a prerequisite of the coexistence of ferromagnetism with superconductivity.