CDK6-mediated endothelial cell cycle acceleration drives arteriovenous malformations in hereditary hemorrhagic telangiectasia.

Increased endothelial cell (EC) proliferation is a hallmark of arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). The underlying mechanism and disease relevance of this abnormal cell proliferative state of the ECs remain unknown. Here, we report the identification of a CDK6-driven mechanism of cell cycle progression deregulation directly involved in EC proliferation and HHT vascular pathology. Specifically, HHT mouse liver ECs exhibited defects in their cell cycle control characterized by a G1/S checkpoint bypass and acceleration of cell cycle speed. Phosphorylated retinoblastoma (p-RB1)-a marker of G1/S transition through the restriction point-significantly accumulated in ECs of HHT mouse retinal AVMs and HHT patient skin telangiectasias. Mechanistically, ALK1 loss of function increased the expression of key restriction point mediators, and treatment with palbociclib or ribociclib, two CDK4/6 inhibitors, blocked p-RB1 increase and retinal AVMs in HHT mice. Palbociclib also improved vascular pathology in the brain and slowed down endothelial cell cycle speed and EC proliferation. Specific deletion of Cdk6 in ECs was sufficient to protect HHT mice from AVM pathology. Thus, CDK6-mediated endothelial cell cycle acceleration controls EC proliferation in AVMs and is a central determinant of HHT pathogenesis. We propose that clinically approved CDK4/6 inhibitors have repurposing potential in HHT.

Recent Advances in the Synthesis of Aromatic Azo Compounds.

Aromatic azo compounds have -N=N- double bonds as well as a larger π electron conjugation system, which endows aromatic azo compounds with wide applications in the fields of functional materials. The properties of aromatic azo compounds are closely related to the substituents on their aromatic rings. However, traditional synthesis methods, such as the coupling of diazo salts, have a significant limitation with respect to the structural design of aromatic azo compounds. Therefore, many scientists have devoted their efforts to developing new synthetic methods. Moreover, recent advances in the synthesis of aromatic azo compounds have led to improvements in the design and preparation of light-response materials at the molecular level. This review summarizes the important synthetic progress of aromatic azo compounds in recent years, with an emphasis on the pioneering contribution of functional nanomaterials to the field.

HMGB1-mediated restriction of EPO signaling contributes to anemia of inflammation.

Anemia of inflammation, also known as anemia of chronic disease, is refractory to erythropoietin (EPO) treatment, but the mechanisms underlying the EPO refractory state are unclear. Here, we demonstrate that high mobility group box-1 protein (HMGB1), a damage-associated molecular pattern molecule recently implicated in anemia development during sepsis, leads to reduced expansion and increased death of EPO-sensitive erythroid precursors in human models of erythropoiesis. HMGB1 significantly attenuates EPO-mediated phosphorylation of the Janus kinase 2/STAT5 and mTOR signaling pathways. Genetic ablation of receptor for advanced glycation end products, the only known HMGB1 receptor expressed by erythroid precursors, does not rescue the deleterious effects of HMGB1 on EPO signaling, either in human or murine precursors. Furthermore, surface plasmon resonance studies highlight the ability of HMGB1 to interfere with the binding between EPO and the EPOR. Administration of a monoclonal anti-HMGB1 antibody after sepsis onset in mice partially restores EPO signaling in vivo. Thus, HMGB1-mediated restriction of EPO signaling contributes to the chronic phase of anemia of inflammation.

The Lipid Handling Capacity of Subcutaneous Fat Is Programmed by mTORC2 during Development.

Overweight and obesity are associated with type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, but all fat is not equal, as storing excess lipid in subcutaneous white adipose tissue (SWAT) is more metabolically favorable than in visceral fat. Here, we uncover a critical role for mTORC2 in setting SWAT lipid handling capacity. We find that subcutaneous white preadipocytes differentiating without the essential mTORC2 subunit Rictor upregulate mature adipocyte markers but develop a striking lipid storage defect resulting in smaller adipocytes, reduced tissue size, lipid re-distribution to visceral and brown fat, and sex-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes transcriptional upregulation of select lipid metabolism genes controlled by PPARγ and ChREBP, including genes that control lipid uptake, synthesis, and degradation pathways as well as Akt2, which encodes a major mTORC2 substrate and insulin effector. Further exploring this pathway may uncover new strategies to improve insulin sensitivity.

Realizing a ferroelectric state and high pyroelectric performance in antiferroelectric-oxide composites.

We report a robust room temperature ferroelectric (FE) state in (1 - x)Pb0.99Nb0.02[(Zr0.57Sn0.43)0.933Ti0.067]0.98O3-xZnO ((1 - x)PNZST-xZnO) composites, where PNZST shows a predominant antiferroelectric (AFE) nature due to ZnO-induced internal strain. Upon heating, a FE-AFE transition occurs and generates high pyroelectric performance. The composite with x = 0.1 shows a peak pyroelectric coefficient of p = 2450.7 × 10-4 C m-2 K-1 and figures of merit of current responsivity Fi = 926.9 × 10-10 m V-1, voltage responsivity Fv = 1334.3 × 10-2 m2 C-1, and detectivity Fd = 1194.8 × 10-5 Pa-1/2, which are about two orders of magnitude higher than those of most perovskite pyroelectric oxides. More interestingly, the FE-AFE transition temperature, i.e., the temperature corresponding to peak pyroelectric performance, is tunable in a wide temperature range from 30 °C to 65 °C. This work not only provides a promising material candidate for high performance pyroelectric devices, but also an alternative idea to develop ferroelectric and pyroelectric properties based on antiferroelectric materials.

MnO2 nanoflowers grown on a polypropylene separator for use as both a barrier and an accelerator of polysulfides for high-performance Li-S batteries.

The separator modification has been considered to be the most effective approach to obtain high-stability lithium-sulfur batteries (LSBs). Therefore, a separator with an ultralight modification layer plays an indispensable role to obtain LSBs with high specific capacity and high energy density. Herein, we report a novel modified separator with an ultrathin and lightweight MnO2 functional layer (500 nm, 0.1 mg cm-2), which was grown in situ on a Celgard-2400 separator (MnO2@PP) via a facile hydrothermal reaction. The MnO2@PP separator effectively suppressed the shuttle of lithium polysulfides (LiPSs) and improved the redox process. In addition, the strong chemical affinity of MnO2 for LiPSs was also verified by first-principles calculations. Benefiting from these advantages, the cell with the MnO2@PP separator delivered a high rate performance of 759 mA h g-1 at 2.5 C and an initial capacity of 825 mA h g-1 with a retention of 684 mA h g-1 after 400 cycles at 1.25 C. Even with a high sulfur loading of 6 mg cm-2, the obtained cell exhibited a reversible capacity of 747 mA h g-1 after 150 cycles.

A novel 3D porous pseudographite/Si/Ni composite anode material fabricated by a facile method.

A novel 3D porous pseudographite/Si/Ni (PG/Si/Ni) composite was prepared by a facile low-temperature calcination method using saturable starch and NiCl2·6H2O as precursors. The pseudographite matrix of PG/Si/Ni was obtained from the reaction between starch and NiCl2·6H2O during the calcination process. Compared to the C/Si electrode, the PG/Si/Ni electrode delivers a high reversible specific capacity of 659.66 mA h g-1 at a current density of 1 A g-1 even after 2000 cycles. In addition, the PG/Si/Ni electrode shows superior rate performance and still maintains a high specific capacity of 1324.01 mA h g-1 when the cycle current density returns to 0.1 A g-1. The porous pseudographite structure is able to improve Li+ diffusion efficiency, reduce pulverization and lead to the formation of stable SEI layers during the cycling process. Therefore, these results suggest that the 3D porous pseudographite/Si/Ni composite is a promising novel anode material. Besides, the low-temperature synthesis method of the pseudographite matrix can be applied for further modification of carbon-based Si anode materials.

Enhanced electrochemical performance of LiNi0.8Co0.1Mn0.1O2 with a 3D-SiO2 framework by a new negative pressure immersion method.

LiNi0.8Co0.1Mn0.1O2 is one of the most promising cathode materials for lithium ion batteries; however, during the charge/discharge process, it suffers from capacity fading, which is considered to be due to intergranular cracking. Herein we develop an original concept to alleviate this problem via negative pressure immersion treatment. A 3D-SiO2 framework is formed in the intergranular voids and at grain boundaries (functioning as the buffer zone and transfer-bridge) and the SiO2 protective layer is completely and homogeneously coated on the surfaces of the pristine particles through a hydrolytic condensation reaction involving tetraethoxysilane (TEOS). The 3D-SiO2 framework has two advantages: firstly, acting as a buffer zone, the framework can effectively inhibit the generation and extension of intergranular cracking; secondly, like the SiO2 protective layer on the surface of the particles, the 3D-SiO2 framework can impede side reactions between primary particles (grains) and electrolyte inside the particles. As a result, the as-modified LiNi0.8Co0.1Mn0.1O2 exhibits enhanced cycling performance with 92.4% capacity retention after 100 cycles at 1 C (200 mA h·g-1), while the capacity retention values for the pristine particles and normal coating treatment particles are only 55.4% and 82.6%, respectively. Moreover, the thermal stability (60 °C) is distinctly enhanced and the rate performance is significantly improved at high rates (2, 3 and 5 C).

Heterogeneous synthesis and electrochemical performance of LiMnPO4/C composites as cathode materials of lithium ion batteries.

In this study, a facile yet efficient interfacial hydrothermal process was successfully developed to fabricate LiMnPO4/C composites. In this strategy, the walls of carbon nanotubes were employed as heterogeneous nucleation interfaces and biomass of phytic acid (PA) as an eco-friendly phosphorus source. By comparing the experimental results, a reasonable nucleation-growth mechanism was proposed, suggesting the advantages of interfacial effects. Meanwhile, the as-synthesized LiMnPO4/C samples exhibited superior rate performances with discharge capacities reaching 161 mA h g-1 at C/20, 134 mA h g-1 at 1C, and 100 mA h g-1 at 5C. The composites also displayed excellent cycling stabilities by maintaining 95% of the initial capacity over 100 continuous cycles at 1C. Electrochemical impedance spectroscopy showed that the superior electrochemical performances were attributed to the low charge-transfer resistance and elevated diffusion coefficient of lithium ions. In sum, the proposed approach for the preparation of LiMnPO4/C composites looks promising for future production of composite electrode materials for high-performance lithium-ion batteries.

A facile in situ synthesis of SiC&Si@CNT composite 3D frameworks as an anode material for lithium-ion batteries.

SiC&Si@CNT composite 3D frameworks were successfully synthesized via an in situ reduction method of a C@SiO2@CNT precursor. Owing to the extremely large amount of heat derived from magnesiothermic reduction, SiC particles of the SiC&Si@CNT composite were obtained by a reaction between Si and C. The amount of SiC could be adjusted by changing the poly-dopamine coating time. The SiC&Si@CNT composite is composed of reduced nano Si, fine SiC and CNTs. The as-prepared materials, particularly the SiC&Si@CNT-1 sample, show superior cycling performance and electrochemical characteristics as anode materials for lithium-ion batteries. In particular, the specific capacity of the SiC&Si@CNT-1 electrode reaches 1051.44 mA h g-1 at 1 A g-1 even after 880 cycles. Furthermore, the SiC&Si@CNT-1 electrode delivered ideal reversible capacities of 671.58 mA h g-1 and 476.71 mA h g-1 at high current densities of 4 A g-1 and 8 A g-1, respectively. The porous nanostructure of the SiC&Si@CNT composite 3D framework is beneficial for shortening the path of lithium-ion diffusion inside the electrode, alleviating the volume expansion and contraction during the cycling process. These results suggest that the SiC&Si@CNT composite 3D frameworks can be used as appropriate anode materials for lithium-ion batteries.

Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1.

mTORC2 controls glucose and lipid metabolism, but the mechanisms are unclear. Here, we show that conditionally deleting the essential mTORC2 subunit Rictor in murine brown adipocytes inhibits de novo lipid synthesis, promotes lipid catabolism and thermogenesis, and protects against diet-induced obesity and hepatic steatosis. AKT kinases are the canonical mTORC2 substrates; however, deleting Rictor in brown adipocytes appears to drive lipid catabolism by promoting FoxO1 deacetylation independently of AKT, and in a pathway distinct from its positive role in anabolic lipid synthesis. This facilitates FoxO1 nuclear retention, enhances lipid uptake and lipolysis, and potentiates UCP1 expression. We provide evidence that SIRT6 is the FoxO1 deacetylase suppressed by mTORC2 and show an endogenous interaction between SIRT6 and mTORC2 in both mouse and human cells. Our findings suggest a new paradigm of mTORC2 function filling an important gap in our understanding of this more mysterious mTOR complex.

mTORC2/Akt activation in adipocytes is required for adipose tissue inflammation in tuberculosis.

BACKGROUND: Mycobacterium tuberculosis has co-evolved with the human host, adapting to exploit the immune system for persistence and transmission. While immunity to tuberculosis (TB) has been intensively studied in the lung and lymphoid system, little is known about the participation of adipose tissues and non-immune cells in the host-pathogen interaction during this systemic disease. METHODS: C57BL/6J mice were aerosol infected with M. tuberculosis Erdman and presence of the bacteria and the fitness of the white and brown adipose tissues, liver and skeletal muscle were studied compared to uninfected mice. FINDINGS: M. tuberculosis infection in mice stimulated immune cell infiltration in visceral, and brown adipose tissue. Despite the absence of detectable bacterial dissemination to fat tissues, adipocytes produced localized pro-inflammatory signals that disrupted adipocyte lipid metabolism, resulting in adipocyte hypertrophy. Paradoxically, this resulted in increased insulin sensitivity and systemic glucose tolerance. Adipose tissue inflammation and enhanced glucose tolerance also developed in obese mice after aerosol M. tuberculosis infection. We found that infection induced adipose tissue Akt signaling, while inhibition of the Akt activator mTORC2 in adipocytes reversed TB-associated adipose tissue inflammation and cell hypertrophy. INTERPRETATION: Our study reveals a systemic response to aerosol M. tuberculosis infection that regulates adipose tissue lipid homeostasis through mTORC2/Akt signaling in adipocytes. Adipose tissue inflammation in TB is not simply a passive infiltration with leukocytes but requires the mechanistic participation of adipocyte signals.

Fabrication and Characterization of ZnO Nano-Clips by the Polyol-Mediated Process.

ZnO nano-clips with better monodispersion were prepared successfully using zinc acetate hydrate (Zn(OAc)2·nH2O) as Zn source and ethylene glycol (EG) as solvent by a simple solution-based route-polyol process. The effect of solution concentration on the formation of ZnO nano-clips has been investigated deeply. We first prove that the 0.01 M Zn(OAc)2·nH2O can react with EG without added water or alkaline, producing ZnO nano-clips with polycrystalline wurtzite structure at 170 °C. As-synthesized ZnO nano-clips contain a lot of aggregated nanocrystals (~ 5 to 15 nm) with high specific surface area of 88 m2/g. The shapes of ZnO nano-clips basically keep constant with improved crystallinity after annealing at 400-600 °C. The lower solution concentration and slight amount of H2O play a decisive role in ZnO nano-clip formation. When the solution concentration is ≤ 0.0125 M, the complexing and polymerization reactions between Zn(OAc)2·nH2O and EG predominate, mainly elaborating ZnO nano-clips. When the solution concentration is ≥ 0.015 M, the alcoholysis and polycondensation reactions of Zn(OAc)2·nH2O and EG become dominant, leading to ZnO particle formation with spherical and elliptical shapes. The possible growth mechanism based on a competition between complexing and alcoholysis of Zn(OAc)2·nH2O and EG has been proposed.

Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis.

Brown adipose tissue (BAT) is a therapeutic target for metabolic diseases; thus, understanding its metabolic circuitry is clinically important. Many studies of BAT compare rodents mildly cold to those severely cold. Here, we compared BAT remodeling between thermoneutral and mild-cold-adapted mice, conditions more relevant to humans. Although BAT is renowned for catabolic ß-oxidative capacity, we find paradoxically that the anabolic de novo lipogenesis (DNL) genes encoding ACLY, ACSS2, ACC, and FASN were among the most upregulated by mild cold and that, in humans, DNL correlates with Ucp1 expression. The regulation and function of adipocyte DNL and its association with thermogenesis are not understood. We provide evidence suggesting that AKT2 drives DNL in adipocytes by stimulating ChREBPß transcriptional activity and that cold induces the AKT2-ChREBP pathway in BAT to optimize fuel storage and thermogenesis. These data provide insight into adipocyte DNL regulation and function and illustrate the metabolic flexibility of thermogenesis.

Principles for designing proteins with cavities formed by curved ß sheets.

Active sites and ligand-binding cavities in native proteins are often formed by curved ß sheets, and the ability to control ß-sheet curvature would allow design of binding proteins with cavities customized to specific ligands. Toward this end, we investigated the mechanisms controlling ß-sheet curvature by studying the geometry of ß sheets in naturally occurring protein structures and folding simulations. The principles emerging from this analysis were used to design, de novo, a series of proteins with curved ß sheets topped with α helices. Nuclear magnetic resonance and crystal structures of the designs closely match the computational models, showing that ß-sheet curvature can be controlled with atomic-level accuracy. Our approach enables the design of proteins with cavities and provides a route to custom design ligand-binding and catalytic sites.

Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease.

OBJECTIVE: Normal adipose tissue growth and function is critical to maintaining metabolic homeostasis and its excess (e.g. obesity) or absence (e.g. lipodystrophy) is associated with severe metabolic disease. The goal of this study was to understand the mechanisms maintaining healthy adipose tissue growth and function. METHODS: Adipose tissue senses and responds to systemic changes in growth factor and nutrient availability; in cells mTORC1 regulates metabolism in response to growth factors and nutrients. Thus, mTORC1 is poised to be a critical intracellular regulator of adipocyte metabolism. Here, we investigate the role of mTORC1 in mature adipocytes by generating and characterizing mice in which the Adiponectin-Cre driver is used to delete floxed alleles of Raptor, which encodes an essential regulatory subunit of mTORC1. RESULTS: Raptor (Adipoq-cre) mice have normal white adipose tissue (WAT) mass for the first few weeks of life, but soon thereafter develop lipodystrophy associated with hepatomegaly, hepatic steatosis, and insulin intolerance. Raptor (Adipoq-cre) mice are also resistant to becoming obese when consuming a high fat diet (HFD). Resistance to obesity does not appear to be due to increased energy expenditure, but rather from failed adipose tissue expansion resulting in severe hepatomegaly associated with hyperphagia and defective dietary lipid absorption. Deleting Raptor in WAT also decreases C/EBPα expression and the expression of its downstream target adiponectin, providing one possible mechanism of mTORC1 function in WAT. CONCLUSIONS: mTORC1 activity in mature adipocytes is essential for maintaining normal adipose tissue growth and its selective loss in mature adipocytes leads to a progressive lipodystrophy disorder and systemic metabolic disease that shares many of the hallmarks of human congenital generalized lipodystrophy.

Improvement of electrochemical performance of nickel rich LiNi0.6Co0.2Mn0.2O2 cathode active material by ultrathin TiO2 coating.

LiNi0.6Co0.2Mn0.2O2 cathode material has been surface-modified by coating with ultrathin TiO2via atomic layer deposition (ALD) technology to improve the electrochemical performance of LiNi0.6Co0.2Mn0.2O2 cathodes for lithium ion batteries. Within the cut-off voltage of 2.5-4.3 V, the coated sample delivers an initial discharge capacity of 187.7 mA h g(-1) at 0.1 C and with a capacity retention about 85.9% after 100 cycles at 1 C, which provides a significant improvement in terms of discharge capacity and cyclability, as compared with those of the bare one. Such enhanced electrochemical performance of the coated sample is ascribed to its high-quality ultrathin coating of amorphous TiO2, which can protect the active material from HF attack, withstand the dissolution of metal ions in the electrode and favor the lithium diffusion of oxide as proved by electrochemical impedance spectroscopy (EIS) tests. TiO2 coating via the ALD process provides a potential approach for battery factories to surface-modify Ni-rich electrode materials so as to realize improvements in electrochemical performance.

Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism.

Adipose tissue de novo lipogenesis (DNL) positively influences insulin sensitivity, is reduced in obesity, and predicts insulin resistance. Therefore, elucidating mechanisms controlling adipose tissue DNL could lead to therapies for type 2 diabetes. Here, we report that mechanistic target of rapamycin complex 2 (mTORC2) functions in white adipose tissue (WAT) to control expression of the lipogenic transcription factor ChREBPß. Conditionally deleting the essential mTORC2 subunit Rictor in mature adipocytes decreases ChREBPß expression, which reduces DNL in WAT, and impairs hepatic insulin sensitivity. Mechanistically, Rictor/mTORC2 promotes ChREBPß expression in part by controlling glucose uptake, but without impairing pan-AKT signalling. High-fat diet also rapidly decreases adipose tissue ChREBPß expression and insulin sensitivity in wild-type mice, and does not further exacerbate insulin resistance in adipose tissue Rictor knockout mice, implicating adipose tissue DNL as an early target in diet-induced insulin resistance. These data suggest mTORC2 functions in WAT as part of an extra-hepatic nutrient-sensing mechanism to control glucose homeostasis.

Protein structure determination by combining sparse NMR data with evolutionary couplings.

Accurate determination of protein structure by NMR spectroscopy is challenging for larger proteins, for which experimental data are often incomplete and ambiguous. Evolutionary sequence information together with advances in maximum entropy statistical methods provide a rich complementary source of structural constraints. We have developed a hybrid approach (evolutionary coupling-NMR spectroscopy; EC-NMR) combining sparse NMR data with evolutionary residue-residue couplings and demonstrate accurate structure determination for several proteins 6-41 kDa in size.