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Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.

Strontium optical lattice clocks have the potential to simultaneously interrogate millions of atoms with a high spectroscopic quality factor of 4 × 1017. Previously, atomic interactions have forced a compromise between clock stability, which benefits from a large number of atoms, and accuracy, which suffers from density-dependent frequency shifts. Here we demonstrate a scalable solution that takes advantage of the high, correlated density of a degenerate Fermi gas in a three-dimensional (3D) optical lattice to guard against on-site interaction shifts. We show that contact interactions are resolved so that their contribution to clock shifts is orders of magnitude lower than in previous experiments. A synchronous clock comparison between two regions of the 3D lattice yields a measurement precision of 5 × 10−19 in 1 hour of averaging time.

A dome-shaped superconducting region appears in the phase diagrams of many unconventional superconductors. In doped band insulators, however, reaching optimal superconductivity by the fine-tuning of carriers has seldom been seen. We report the observation of a superconducting dome in the temperature—carrier density phase diagram of MoS₂, an archetypal band insulator. By quasi-continuous electrostatic carrier doping achieved through a combination of liquid and solid gating, we revealed a large enhancement in the transition temperature T c occurring at optimal doping in the chemically inaccessible low-carrier density regime. This observation indicates that the superconducting dome may anse even in doped band insulators.

Tungsten diselenide (WSe2) and related transition metal dichalcogenides exhibit interesting optoelectronic properties owing to their peculiar band structures originating from the valley degree of freedom. Although the optical generation and detection of valley polarization has been demonstrated, it has been difficult to realize active valley-dependent functions suitable for device applications. We report an electrically switchable, circularly polarized light source based on the material's valley degree of freedom. Our WSe2-based ambipolar transistors emit circularly polarized electroluminescence from p-i-n junctions electrostatically formed in transistor channels. This phenomenon can be explained qualitatively by the electron-hole overlap controlled by the in-plane electric field. Our device demonstrates a route to exploit the valley degree of freedom and the possibility to develop a valley-optoelectronics technology.

In Cooper pairs--pairs of electrons responsible for the exotic properties of superconductors--the two electrons' spins typically point in opposite directions. A strong-enough external magnetic field will destroy superconductivity by making the spins point in the same direction. Lu et al. observed a two-dimensional superconducting state in the material MoS2 that was surprisingly immune to a magnetic field applied in the plane of the sample (see the Perspective by Suderow). The band structure of MoS2 and its spin-orbit coupling conspired to create an effective magnetic field that reinforced the electron pairing, with spins aligned perpendicular to the sample. Science, this issue p. 1353; see also p. 1316 The Zeeman effect, which is usually detrimental to superconductivity, can be strongly protective when an effective Zeeman field from intrinsic spin-orbit coupling locks the spins of Cooper pairs in a direction orthogonal to an external magnetic field. We performed magnetotransport experiments with ionic-gated molybdenum disulfide transistors, in which gating prepared individual superconducting states with different carrier dopings, and measured an in-plane critical field Bc2 far beyond the Pauli paramagnetic limit, consistent with Zeeman-protected superconductivity. The gating-enhanced Bc2 is more than an order of magnitude larger than it is in the bulk superconducting phases, where the effective Zeeman field is weakened by interlayer coupling. Our study provides experimental evidence of an Ising superconductor, in which spins of the pairing electrons are strongly pinned by an effective Zeeman field.

Background/Objectives: It has been reported that irisin regulated exercise-mediated adipocyte browning; however, the systematical effects of irisin on the metabolism of glucose and lipid in diabetes are largely unknown. In the present study, we investigated the role and underlying mechanism of irisin in glucose utilization and lipid metabolism in diabetic mice. Methods: A mouse model of diabetes was established by feeding C57BL/6 mice with high-fat diet. The diabetic mice were then treated with irisin. To mimic type 2 diabetes in vitro , myocytes and hepatocytes were cultured in a medium of high glucose and high fat. Glucose uptake, fatty acid oxidation and the expression of related protein were evaluated. Results: Irisin improved glucose tolerance and glucose uptake as evidenced by increased 18 F-FDG accumulation and GLUT4 translocation in diabetic skeletal muscle. Irisin also increased glucose uptake in myocytes cultured in high glucose/high fatty acid medium. In contrast, irisin reduced the expression of PEPCK and G6Pase, which are involved in gluconeogenesis, in diabetic liver. Consistently, irisin reduced fat weight and serum total cholesterol and triglyceride levels in diabetic mice, but increased acetyl coenzyme A carboxylase-β phosphorylation in muscle tissue and uncoupling protein 1 expression in fat tissue. In addition, irisin increased the oxidation of fatty acid in myocytes. Knockdown of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) attenuated the effects of irisin on glucose uptake and fatty acid β-oxidation in myocytes. Similarly, inhibition of AMPK by a specific inhibitor reduced the effects of irisin on PEPCK and G6Pase expression in hepatocytes. Conclusions: Our results suggest that irisin has an essential role in glucose utilization and lipid metabolism, and irisin is a promising pharmacological target for the treatment of diabetes and its complications.

We present Vision , a tool for annotating the sources of variation in single cell RNA-seq data in an automated and scalable manner. Vision operates directly on the manifold of cell-cell similarity and employs a flexible annotation approach that can operate either with or without preconceived stratification of the cells into groups or along a continuum. We demonstrate the utility of Vision in several case studies and show that it can derive important sources of cellular variation and link them to experimental meta-data even with relatively homogeneous sets of cells. Vision produces an interactive, low latency and feature rich web-based report that can be easily shared among researchers, thus facilitating data dissemination and collaboration. The increasing accessibility of single cell RNA sequencing demands tools that enable data visualization and interpretation. Here, the authors introduce Vision, a flexible annotation tool that operates directly on the manifold of cell-cell similarity and aids interpretation of cellular heterogeneity.

The kinetics of the hydroxyl radical (OH) + carbon monoxide (CO) reaction, which is fundamental to both atmospheric and combustion chemistry, are complex because of the formation of the hydrocarboxyl radical (HOCO) intermediate. Despite extensive studies of this reaction, HOCO has not been observed under thermal reaction conditions. Exploiting the sensitive, broadband, and high-resolution capabilities of time-resolved cavity-enhanced direct frequency comb spectroscopy, we observed deuteroxyl radical (OD) + CO reaction kinetics and detected stabilized trans-DOCO, the deuterated analog of trans-HOCO. By simultaneously measuring the time-dependent concentrations of the trans-DOCO and OD species, we observed unambiguous low-pressure termolecular dependence of the reaction rate coefficients for N₂ and CO bath gases. These results confirm the HOCO formation mechanism and quantify its yield.

Immunotherapies with chimeric antigen receptor (CAR) T cells and checkpoint inhibitors (including antibodies that antagonize programmed cell death protein 1 [PD-1]) have both opened new avenues for cancer treatment, but the clinical potential of combined disruption of inhibitory checkpoints and CAR T cell therapy remains incompletely explored. Here we show that programmed death ligand 1 (PD-L1) expression on tumor cells can render human CAR T cells (anti-CD19 4-1BBζ) hypo-functional, resulting in impaired tumor clearance in a sub-cutaneous xenograft model. To overcome this suppressed anti-tumor response, we developed a protocol for combined Cas9 ribonucleoprotein (Cas9 RNP)-mediated gene editing and lentiviral transduction to generate PD-1 deficient anti-CD19 CAR T cells. Pdcd1 (PD-1) disruption augmented CAR T cell mediated killing of tumor cells in vitro and enhanced clearance of PD-L1+ tumor xenografts in vivo . This study demonstrates improved therapeutic efficacy of Cas9-edited CAR T cells and highlights the potential of precision genome engineering to enhance next-generation cell therapies.

State-of-the-art laser frequency stabilization by high-finesse optical cavities is limited fundamentally by thermal noise-induced cavity length fluctuations. We present a novel design to reduce this thermal noise limit by an order of magnitude as well as an experimental realization of this new cavity system, demonstrating the most stable oscillator of any kind to date for averaging times of 0.1–10 s. The cavity spacer and the mirror substrates are both constructed from single-crystal silicon and are operated at 124 K, where the silicon thermal expansion coefficient is zero and the mechanical loss is small. The cavity is supported in a vibration-insensitive configuration, which, together with the superior stiffness of the silicon crystal, reduces the vibration-related noise. With rigorous analysis of heterodyne beat signals among three independent stable lasers, the silicon system demonstrates a fractional frequency instability of 1 × 10 −16 at short timescales and supports a laser linewidth of <40 mHz at 1.5 µm. Frequency stabilization in a high-finesse optical cavity is limited fundamentally by thermal-noise-induced cavity length fluctuations. Scientists have now developed a single-crystal silicon system that offers a fractional frequency instability of 1 × 10 −16 at short timescales and supports a laser linewidth of less than 40 mHz at 1.5 µm.