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The development of scalable, high-fidelity qubits is a key challenge in quantum information science. Neutral atom qubits have progressed rapidly in recent years, demonstrating programmable processors 1 , 2 and quantum simulators with scaling to hundreds of atoms 3 , 4 . Exploring new atomic species, such as alkaline earth atoms 5 – 7 , or combining multiple species 8 can provide new paths to improving coherence, control and scalability. For example, for eventual application in quantum error correction, it is advantageous to realize qubits with structured error models, such as biased Pauli errors 9 or conversion of errors into detectable erasures 10 . Here we demonstrate a new neutral atom qubit using the nuclear spin of a long-lived metastable state in 171 Yb. The long coherence time and fast excitation to the Rydberg state allow one- and two-qubit gates with fidelities of 0.9990(1) and 0.980(1), respectively. Importantly, a large fraction of all gate errors result in decays out of the qubit subspace to the ground state. By performing fast, mid-circuit detection of these errors, we convert them into erasure errors; during detection, the induced error probability on qubits remaining in the computational space is less than 10 −5 . This work establishes metastable 171 Yb as a promising platform for realizing fault-tolerant quantum computing. This study reports gates between qubits encoded in the nuclear spin state of Yb atoms trapped in optical tweezers, reaching very high fidelity and demonstrating mid-circuit conversion of errors into erasure errors.

Neutral atom arrays are a rapidly developing platform for quantum science. Recently, alkaline earth atoms (AEAs) have attracted interest because their unique level structure provides several opportunities for improved performance. In this work, we present the first demonstration of a universal set of quantum gate operations on a nuclear spin qubit in an AEA, using ¹71Yb. We implement narrow-line cooling and imaging using a newly discovered magic trapping wavelength at λ=486.78 nm. We also demonstrate nuclear spin initialization, readout, and single-qubit gates and observe long coherence times [T₁≈20 s and T₂^(*)=1.24(5) s] and a single-qubit operation fidelity F₁Q=0.99959(6). We also demonstrate two-qubit entangling gates using the Rydberg blockade, as well as coherent control of these gate operations using light shifts on the Yb⁺ ion core transition at 369 nm. These results are a significant step toward highly coherent quantum gates in AEA tweezer arrays.

Excessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases. The visceral fat is highly susceptible to the availability of external nutrients. Nutrient flux into the hexosamine biosynthetic pathway leads to protein posttranslational modification by O -linked β-N-acetylglucosamine ( O -GlcNAc) moieties. O -GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Here, we report that inducible deletion of adipose OGT causes a rapid visceral fat loss by specifically promoting lipolysis in visceral fat. Mechanistically, visceral fat maintains a high level of O -GlcNAcylation during fasting. Loss of OGT decreases O -GlcNAcylation of lipid droplet-associated perilipin 1 (PLIN1), which leads to elevated PLIN1 phosphorylation and enhanced lipolysis. Moreover, adipose OGT overexpression inhibits lipolysis and promotes diet-induced obesity. These findings establish an essential role for OGT in adipose tissue homeostasis and indicate a unique potential for targeting O -GlcNAc signaling in the treatment of obesity. Post-translational O-linked β-N acetylglucosamine (O-GlcNAc) modification acts as a nutrient-sensing mechanism. Here the authors report that O-GlcNAc transferase inhibits adipose tissue lipolysis via O-GlcNAcylation of the lipid droplet protein perilipin 1 and thus promotes diet-induced obesity.

Cancer cells are known to adopt aerobic glycolysis in order to fuel tumor growth, but the molecular basis of this metabolic shift remains largely undefined. O-GlcNAcase (OGA) is an enzyme harboring O-linked β-N-acetylglucosamine (O-GlcNAc) hydrolase and cryptic lysine acetyltransferase activities. Here, we report that OGA is upregulated in a wide range of human cancers and drives aerobic glycolysis and tumor growth by inhibiting pyruvate kinase M2 (PKM2). PKM2 is dynamically O-GlcNAcylated in response to changes in glucose availability. Under high glucose conditions, PKM2 is a target of OGA-associated acetyltransferase activity, which facilitates O-GlcNAcylation of PKM2 by O-GlcNAc transferase (OGT). O-GlcNAcylation inhibits PKM2 catalytic activity and thereby promotes aerobic glycolysis and tumor growth. These studies define a causative role for OGA in tumor progression and reveal PKM2 O-GlcNAcylation as a metabolic rheostat that mediates exquisite control of aerobic glycolysis.

Glycogenolysis and gluconeogenesis ensure sufficient hepatic glucose production during energy shortages. Here, we report that hepatic glycogen levels control the phosphorylation of a transcriptional coactivator to determine the amplitude of gluconeogenesis. Decreased liver glycogen during fasting promotes gluconeogenic gene expression, while feeding-induced glycogen accumulation suppresses it. Liver-specific deletion of the glycogen scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels, increases the expression of gluconeogenic genes, and promotes glucose production in primary hepatocytes. In contrast, liver glycogen phosphorylase (PYGL) knockdown or inhibition increases glycogen levels and represses gluconeogenic gene expression. These changes in hepatic glycogen levels are sensed by AMP-activated protein kinase (AMPK). AMPK activity is increased when glycogen levels decline, resulting in the phosphorylation and stabilization of CREB-regulated transcriptional coactivator 2 (CRTC2), which is crucial for the full activation of the cAMP-responsive transcriptional factor CREB. High glycogen allosterically inhibits AMPK, leading to CRTC2 degradation and reduced CREB transcriptional activity. Hepatocytes with low glycogen levels or high AMPK activity show higher CRTC2 protein levels, priming the cell for gluconeogenesis through transcriptional regulation. Thus, glycogen plays a regulatory role in controlling hepatic glucose metabolism through the glycogen/AMPK/CRTC2 signaling axis, safeguarding efficient glucose output during fasting and suppressing it during feeding.

Thermogenic activation of subcutaneous white adipocytes requires glycogen synthesis and turnover. Here we show that β-adrenergic stimulation induces a distinct glycogen metabolism gene program in inguinal white adipose tissue in a cell-autonomous and adipocyte-specific manner. Among these, Gys2 and Ppp1r3c are rapidly induced following acute β3-adrenergic receptor activation. We identify Gys2 as a direct transcriptional target of PKA-CREB signaling. In contrast, sustained expression of glycogen metabolism genes under chronic β3-adrenergic activation requires the coactivator PGC1α, whose loss blunts glycogen accumulation and thermogenic capacity. Mechanistically, PGC1α cooperates with estrogen-related receptors (ERRs) to regulate chromatin accessibility and gene transcription. Although deletion of ERRα is compensated by ERRγ, combined deletion of ERRα/β/γ abolishes expression of glycogen metabolism and thermogenic genes. Chromatin profiling confirm that ERRs directly control the glycogen metabolic program in beige adipocytes. Together, our results identify a multilayered transcriptional axis that sustains glycogen metabolism during β-adrenergic activation in male mice. Previous studies suggested that glycogen metabolism played a role in beiging of subcutaneous adipocytes. This work identifies a β-adrenergic–driven transcriptional program that promotes glycogen synthesis and turnover during thermogenic activation of adipocytes. PGC1α and estrogen-related receptors (ERRs) cooperatively sustain this program by regulating chromatin accessibility and gene expression.

Mitochondrial dysfunction is a critical driver of metabolic dysfunction-associated steatotic liver disease progression to steatohepatitis (MASH), yet the mechanisms governing mitochondrial quality control in hepatocytes remain poorly defined. Here we identify TANK-binding kinase 1 (TBK1) as an essential regulator of hepatic mitophagy and lysosomal activity. Using TBK1-deficient hepatocytes and liver-specific TBK1-knockout mice, we show that TBK1 loss leads to the accumulation of depolarized, reactive oxygen species-producing mitochondria due to impaired mitophagy flux, including defective lysosomal degradation. Mechanistically, TBK1 is required for p62 phosphorylation at Ser403 and partially modulates mTOR signaling to preserve lysosomal activity. Notably, both human samples and murine steatohepatitis models exhibited a substantial decline in TBK1 kinase activity. Therapeutic restoration of TBK1 expression via AAV8 delivery in MASH mouse model enhanced mitophagy, reduced mitochondrial burden and ameliorated liver fibrosis. Collectively, these findings establish TBK1 as a critical guardian of mitochondrial and lysosomal homeostasis in MASH. TBK1 Loss Impairs Mitochondrial Quality Control in Hepatocytes Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver condition linked to obesity. Researchers have found that a protein called TANK-binding kinase 1 (TBK1) plays a crucial role in managing the health of mitochondria in the liver. In this study, scientists used mice and human liver cells to explore how TBK1 affects liver health. They discovered that, when TBK1 is missing or not working properly, mitochondria become damaged and do not function well. This leads to increased stress and inflammation in liver cells. The researchers used various methods, including genetic modification and diet changes in mice, to study these effects. They found that TBK1 helps maintain mitochondrial quality by promoting a process called mitophagy, which removes damaged mitochondria. The study concludes that TBK1 is vital for preventing liver damage in MASLD by ensuring healthy mitochondria. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Palatable foods (fat and sweet) induce hyperphagia, and facilitate the development of obesity. Whether and how overnutrition increases appetite through the adipose-to-brain axis is unclear. O -linked beta-D- N -acetylglucosamine (O-GlcNAc) transferase (OGT) couples nutrient cues to O-GlcNAcylation of intracellular proteins at serine/threonine residues. Chronic dysregulation of O-GlcNAc signaling contributes to metabolic diseases. Here we show that adipocyte OGT is essential for high fat diet-induced hyperphagia, but is dispensable for baseline food intake. Adipocyte OGT stimulates hyperphagia by transcriptional activation of de novo lipid desaturation and accumulation of N-arachidonyl ethanolamine (AEA), an endogenous appetite-inducing cannabinoid (CB). Pharmacological manipulation of peripheral CB1 signaling regulates hyperphagia in an adipocyte OGT-dependent manner. These findings define adipocyte OGT as a fat sensor that regulates peripheral lipid signals, and uncover an unexpected adipose-to-brain axis to induce hyperphagia and obesity. Endocannabinoid signaling regulates food intake and is a potential therapeutic target for obesity. Here the authors show that adipocyte O-GlcNAc transferase (OGT) is required for high fat diet-induced hyperphagia via transcriptional activation of de novo lipid desaturation and accumulation of an endogenous appetite-inducing cannabinoid.

Enhanced inflammation is believed to contribute to overnutritioninduced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostaticmechanism maintainingwhole-body metabolism under overnutrition.