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When glucose is replete, mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is active and anchored to the lysosomal surface via the two GTPases, Ras-related GTPase (RAG) and Ras homolog enriched in brain (Rheb), which are regulated by Ragulator and tuberous sclerosis complex 2 (TSC2), respectively. When glucose is low, aldolase senses low fructose-1,6-bisphosphate level and promotes the translocation of AXIN−liver kinase B1 (LKB1) to the lysosomal surface, which leads to the activation of AMP-activated protein kinase (AMPK) and the inhibition of RAGs, sundering mTORC1 from the lysosome and causing its inactivation. AMPK can also inactivate mTORC1 by phosphorylating Raptor and TSC2. However, the hierarchy of AXIN- and AMPK-mediated inhibition of mTORC1 remains poorly defined. Here, we show that AXIN translocation does not require AMPK expression or activity. In glucose starvation conditions, knockout of AXIN extended the half-life of mTORC1 inhibition from 15 to 60 min, whereas knockout of AMPK only extended it to 30 min. RAGBGTP (constitutively active RAGB) almost entirely blocked the lysosomal dissociation and inhibition of mTORC1 under glucose starvation, but it did not inhibit AMPK, indicating that under these conditions, it is AXIN lysosomal translocation that inhibits mTORC1, and it does so via inhibition of RAGs. 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a mimetic of AMP, which activates both cytosolic AMPK and lysosomal AMPK, fully inhibited mTORC1 even when it is stably anchored to the lysosome by RAGBGTP, whereas glucose starvation mildly inhibited such anchored mTORC1. Together, we demonstrate that the lysosomal translocation of AXIN plays a primary role in glucose starvation-triggered inhibition of mTORC1 by inhibiting RAGs, and that AMPK activity inhibits mTORC1 through phosphorylating Raptor and TSC2, especially under severe stress.

The activity of 5′-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.

In this paper, a piecewise quadratic finite element method on rectangular grids for the $H^1$ problems is presented. The proposed method can be viewed as a reduced rectangular Morley element. For the source problem, the convergence rate of this scheme is $O(h^2)$ in the energy norm on uniform grids. Besides, a lower bound of the $L^2$-norm error is also proved, which makes the capacity analysis of this scheme more clear. On the other hand, for the eigenvalue problem, the numerical eigenvalues by this element are shown to be the lower bounds of the exact ones. Some numerical results are presented, which show the potential of the proposed finite element., 41 pages, 20 figures

The black oil model is widely used to describe multiphase porous media flow in the petroleum industry. The fully implicit method features strong stability and weak constraints on time step-sizes; hence, commonly used in the current mainstream commercial reservoir simulators. In this paper, a CPR-type preconditioner with an adaptive "setup phase" is developed to improve parallel efficiency of petroleum reservoir simulation. Furthermore, we propose a multi-color Gauss-Seidel (GS) algorithm for algebraic multigrid method based on the coefficient matrix of strong connections. Numerical experiments show that the proposed preconditioner can improve the parallel performance for both OpenMP and CUDA implements. Moreover, the proposed algorithm yields good parallel speedup as well as same convergence behavior as the corresponding single-threaded algorithm. In particular, for a three-phase benchmark problem, the parallel speedup of the OpenMP version is over 6.5 with 16 threads and the CUDA version reaches more than 9.5., This is a preprint manuscript, which is submitted to Computers and Geosciences Journal

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a strong production of inflammatory cytokines such as TNF and IL-6, which underlie the severity of the disease. However, the molecular mechanisms responsible for such a strong immune response remains unclear. Here, utilizing targeted tandem mass spectrometry to analyze serum metabolome and lipidome in COVID-19 patients at different temporal stages, we identified that 611 metabolites (of 1,039) were significantly altered in COVID-19 patients. Among them, two metabolites, agmatine and putrescine, were prominently elevated in the serum of patients; and 2-quinolinecarboxylate was changed in a biphasic manner, elevated during early COVID-19 infection but levelled off. When tested in mouse embryonic fibroblasts (MEFs) and macrophages, these 3 metabolites were found to activate the NF-κB pathway that plays a pivotal role in governing cytokine production. Importantly, these metabolites were each able to cause strong increase of TNF and IL-6 levels when administered to wildtype mice, but not in the mice lacking NF-κB. Intriguingly, these metabolites have little effects on the activation of interferon regulatory factors (IRFs) for the production of type I interferons (IFNs) for antiviral defenses. These data suggest that circulating metabolites resulting from COVID-19 infection may act as effectors to elicit the peculiar systemic inflammatory responses, exhibiting severely strong proinflammatory cytokine production with limited induction of the interferons. Our study may provide a rationale for development of drugs to alleviate inflammation in COVID-19 patients.

Nutrient sensing and damage sensing are two fundamental processes in living organisms. While hyperglycemia is frequently linked to diabetes-related vulnerability to microbial infection, how body glucose levels affect innate immune responses to microbial invasion is not fully understood. Here, we surprisingly found that viral infection led to a rapid and dramatic decrease in blood glucose levels in rodents, leading to robust AMPK activation. AMPK, once activated, directly phosphorylates TBK1 at S511, which triggers IRF3 recruitment and the assembly of MAVS or STING signalosomes. Consistently, ablation or inhibition of AMPK, knockin of TBK1-S511A, or increased glucose levels compromised nucleic acid sensing, while boosting AMPK-TBK1 cascade by AICAR or TBK1-S511E knockin improves antiviral immunity substantially in various animal models. Thus, we identify TBK1 as an AMPK substrate, reveal the molecular mechanism coupling a dual sensing of glucose and nuclei acids, and report its physiological necessity in antiviral defense.

Midkine (MDK), an extracellular growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with PRKAA1 (encoding AMPKα1) expression and phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.

The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis. Although much has been learned on how low energy status and glucose starvation activate AMPK, how AMPK activity is properly controlled in vivo is still poorly understood. Here we report that UHRF1, an epigenetic regulator highly expressed in proliferating and cancer cells, interacts with AMPK and serves to suppress AMPK activity under both basal and stressed conditions. As a nuclear protein, UHRF1 promotes AMPK nuclear retention and strongly suppresses nuclear AMPK activity toward substrates H2B and EZH2. Importantly, we demonstrate that UHRF1 also robustly inhibits AMPK activity in the cytoplasm compartment, most likely as a consequence of AMPK nucleocytoplasmic shuttling. Mechanistically, we found that UHRF1 has no obvious effect on AMPK activation by upstream kinases LKB1 and CAMKK2 but inhibits AMPK activity by acting as a bridging factor targeting phosphatase PP2A to dephosphorylate AMPK. Hepatic overexpression of UHRF1 showed profound effects on glucose and lipid metabolism in wild-type mice but not in those with the liver-specific knockout of AMPKα1/α2, whereas knockdown of UHRF1 in adipose tissue led to AMPK activation and reduced sizes of adipocytes and lipogenic activity, highlighting the physiological significance of this regulation in glucose and lipid metabolism. Thus, our study identifies UHRF1 as a novel AMPK gate-keeper with critical roles in cellular metabolism.

In this paper, we establish a new estimate (including lower and upper bounds) for an important quantity involved in the convergence analysis of smoothed aggregation algebraic multigrid methods. The new upper bound improves the existing ones. And our upper bound is optimal.

AMPK, a master regulator of metabolic homeostasis, is activated by both AMP-dependent and AMP-independent mechanisms. The conditions under which these different mechanisms operate, and their biological implications are unclear. Here, we show that, depending on the degree of elevation of cellular AMP, distinct compartmentalized pools of AMPK are activated, phosphorylating different sets of targets. Low glucose activates AMPK exclusively through the AMP-independent, AXIN-based pathway in lysosomes to phosphorylate targets such as ACC1 and SREBP1c, exerting early anti-anabolic and pro-catabolic roles. Moderate increases in AMP expand this to activate cytosolic AMPK also in an AXIN-dependent manner. In contrast, high concentrations of AMP, arising from severe nutrient stress, activate all pools of AMPK independently of AXIN. Surprisingly, mitochondrion-localized AMPK is activated to phosphorylate ACC2 and mitochondrial fission factor (MFF) only during severe nutrient stress. Our findings reveal a spatiotemporal basis for hierarchical activation of different pools of AMPK during differing degrees of stress severity.

In this paper, numerical simulation of a hemodynamic fluid-structure interaction (FSI) problem with an immersed rotating structure is carried out. A dynamic FSI problem involving a rotational elastic solid, which is modeled by the incompressible shear stress transport (SST) k–ω turbulence model in the fluid domain and by a co-rotational linearized St. Venant–Kirchhoff model in the structure domain, is studied and applied to a type of artificial heart pump. A monolithic arbitrary Lagrangian–Eulerian mixed finite element method, which is modified to adapt to the interaction between fluid and an immersed rotating structure, is employed to discretize the coupled FSI system. The Newton's linearization and the streamline-upwind/Petrov–Galerkin (SUPG) stabilization are employed to overcome strong nonlinearity and dominant convection effects, respectively. Numerical validations are preformed and compared with a commercial CFD software. This paper is an extension to our recent conference paper [1] .

Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1–4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action4,5; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation6. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase7, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase8, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.

Multigrid is one of the most efficient methods for solving large-scale linear systems that arise from discretized partial differential equations. As a foundation for multigrid analysis, two-grid theory plays an important role in motivating and analyzing multigrid algorithms. For symmetric positive definite problems, the convergence theory of two-grid methods with exact solution of the Galerkin coarse-grid system is mature, and the convergence factor of exact two-grid methods can be characterized by an identity. Compared with the exact case, the convergence theory of inexact two-grid methods (i.e., the coarse-grid system is solved approximately) is of more practical significance, while it is still less developed in the literature (one reason is that the error propagation matrix of inexact coarse-grid correction is not a projection). In this paper, we develop a theoretical framework for the convergence analysis of inexact two-grid methods. More specifically, we present two-sided bounds for the energy norm of the error propagation matrix of inexact two-grid methods, from which one can readily obtain the identity for exact two-grid convergence. As an application, we establish a unified convergence theory for multigrid methods, which allows the coarsest-grid system to be solved approximately.

Multidrug resistance (MDR) in cancer remains a major challenge for the success of chemotherapy. Natural products have been a rich source for the discovery of drugs against MDR cancers. Here, we applied high-throughput cytotoxicity screening of an in-house natural product library against MDR SGC7901/VCR cells and identified that the cyclodepsipeptide verucopeptin demonstrated notable antitumor potency. Cytological profiling combined with click chemistry-based proteomics revealed that ATP6V1G directly interacted with verucopeptin. ATP6V1G, a subunit of the vacuolar H

Various algebraic multigrid algorithms have been developed for solving problems in scientific and engineering computation over the past decades. They have been shown to be well-suited for solving discretized partial differential equations on unstructured girds in practice. One key ingredient of algebraic multigrid algorithms is a strategy for constructing an effective prolongation operator. Among many questions on constructing a prolongation, an important question is how to evaluate its quality. In this paper, we establish new characterizations (including sufficient condition, necessary condition, and equivalent condition) of the so-called ideal interpolation operator. Our result suggests that, compared with common wisdom, one has more room to construct an ideal interpolation, which can provide new insights for designing algebraic multigrid algorithms. Moreover, we derive a new expression for a class of ideal interpolation operators.

Deficiency of glucose, even under sufficient amino acid supply, turns off translation and promotes catabolic processes to aid cell survival. A recent report by Yoon et al. (2020) shows that glucose is required for the full activity of the leucyl-tRNA synthetase LARS1 and maintains mTORC1 function via LARS1 to enhance translation. Glucose starvation abolishes both effects via phosphorylation of LARS1 by the AMPK-ULK1 signaling pathway. This study supports the idea that glucose starvation inhibits translation at multiple levels.

Water&ndash, rock interactions can alter rock properties through chemical reactions during subsurface transport processes like geological CO2 sequestration (GCS), matrix acidizing, and waterflooding in carbonate formations. Dynamic changes in rock properties cause a failure of waterflooding and GCS and could also dramatically affect the efficiency of the acidizing. Efficient numerical simulations are thus essential to the optimized design of those subsurface processes. In this paper, we develop a three-dimensional (3D) numerical model for simulating the coupled processes of fluid flow and chemical reactions in fractured carbonate formations. In the proposed model, we employ the Stokes&ndash, Brinkman equation for momentum balance, which is a single-domain formulation for modeling fluid flow in fractured porous media. We then couple the Stokes&ndash, Brinkman equation with reactive-transport equations. The model can be formulated to describe linear as well as radial flow. We employ a decoupling procedure that sequentially solves the Stokes&ndash, Brinkman equation and the reactive transport equations. Numerical experiments show that the proposed method can model the coupled processes of fluid flow, solute transport, chemical reactions, and alterations of rock properties in both linear and radial flow scenarios. The rock heterogeneity and the mineral volume fractions are two important factors that significantly affect the structure of conductive channels.

Summary Multidrug resistance (MDR) in cancer remains a major challenge for the success of chemotherapy. Natural products have been a rich source for the discovery of drugs against MDR cancers. Here, we applied high-throughput cytotoxicity screening of an in-house natural product library against MDR SGC7901/VCR cells and identified that the cyclodepsipeptide verucopeptin demonstrated notable antitumor potency. Cytological profiling combined with click chemistry-based proteomics revealed that ATP6V1G directly interacted with verucopeptin. ATP6V1G, a subunit of the vacuolar H+-ATPase (v-ATPase) that has not been previously targeted, was essential for SGC7901/VCR cell growth. Verucopeptin exhibited strong inhibition of both v-ATPase activity and mTORC1 signaling, leading to substantial pharmacological efficacy against SGC7901/VCR cell proliferation and tumor growth in vivo. Our results demonstrate that targeting v-ATPase via its V1G subunit constitutes a unique approach for modulating v-ATPase and mTORC1 signaling with great potential for the development of therapeutics against MDR cancers.

We present and analyze hybrid discretization schemes for rate-type non-Newtonian fluids models. The method employs higher order conforming approximations for velocity and pressure of the Stokes equation and lower order approximations such as piecewise linear or piecewise constant for conformation tensor. To reduce the accuracy gap, the constitutive equation is discretized on a refined mesh, which is obtained by subdividing the mesh for the velocity and pressure. The temporal discretization is made by the standard semi-Lagrangian scheme. The fully discrete nonlinear system is shown to be solved iteratively by applying the three steps:(1)?locating the characteristic feet of fluid particles, (2)?solving the constitutive equation, and (3)?solving the momentum and continuity equations (Stokes-type equation). To achieve a scalability of the solution process, we employ an auxiliary space preconditioning method for the solution to the conforming finite element methods for the Stokes equation. This method is basically two-grid method, in which lower-order finite element spaces are employed as auxiliary spaces. It is shown to not only lead to the mesh independent convergence, but also improve robustness and scalability. Stability analysis shows that if Δ t = O ( h d ) , where d is the dimension of domain, then the scheme admits a globally unique solution. A number of full 3D test cases are provided to demonstrate the advantages of the proposed numerical techniques in relation to efficiency, robustness, and weak scalability.

In this paper, we discuss an adaptive hybrid stress finite element method on quadrilateral meshes for linear elasticity problems. To deal with hanging nodes arising in the adaptive mesh refinement, we propose new transition types of hybrid stress quadrilateral elements with 5 to 7 nodes. In particular, we derive a priori error estimation for the 5-node transition hybrid stress element to show that it is free from Poisson-locking, in the sense that the error bound in the a priori estimate is independent of the Lame constant $\lambda$. We introduce, for quadrilateral meshes, refinement/coarsening algorithms, which do not require storing the refinement tree explicitly, and give an adaptive algorithm. Finally we provide some numerical results.

Obesity is characterized by excessive fatty acid conversion to triacylglycerols (TAGs) in adipose tissues. However, how signaling networks sense fatty acids and connect to the stimulation of lipid synthesis remains elusive. Here, we show that homozygous knock-in mice carrying a point mutation at the Ser86 phosphorylation site of acetyltransferase Tip60 (Tip60SA/SA) display remarkably reduced body fat mass, and Tip60SA/SA females fail to nurture pups to adulthood due to severely reduced milk TAGs. Mechanistically, fatty acids stimulate Tip60-dependent acetylation and endoplasmic reticulum translocation of phosphatidic acid phosphatase lipin 1 to generate diacylglycerol for TAG synthesis, which is repressed by deacetylase Sirt1. Inhibition of Tip60 activity strongly blocks fatty acid-induced TAG synthesis while Sirt1 suppression leads to increased adiposity. Genetic analysis of loss-of-function mutants in Saccharomyces cerevisiae reveals a requirement of ESA1, yeast ortholog of Tip60, in TAG accumulation. These findings uncover a conserved mechanism linking fatty acid sensing to fat synthesis., The acetyltransferase Tip60 mediates signaling pathways by acetylating non-histone proteins. Here the authors show that fatty acids induce Tip60–dependent acetylation of phosphatidic acid phosphatase lipin1 which, then, translocates to the ER and generates diacylglycerols for triglyceride synthesis.

Dietary carbohydrates have been demonized for presumed negative effects on health. However, Liu et al. (2018) identify new pathways for conversion of glucose into acetate that consume reactive oxygen species. A study relating human carbohydrate consumption to all-cause mortality also suggests that moderately high-carbohydrate diets can be beneficial.

Hypoxia-inducible factors (HIFs) are master regulators of adaptive responses to low oxygen, and their α-subunits are rapidly degraded through the ubiquitination-dependent proteasomal pathway after hydroxylation. Aberrant accumulation or activation of HIFs is closely linked to many types of cancer. However, how hydroxylation of HIFα and its delivery to the ubiquitination machinery are regulated remains unclear. Here we show that Rho-related BTB domain-containing protein 3 (RHOBTB3) directly interacts with the hydroxylase PHD2 to promote HIFα hydroxylation. RHOBTB3 also directly interacts with the von Hippel-Lindau (VHL) protein, a component of the E3 ubiquitin ligase complex, facilitating ubiquitination of HIFα. Remarkably, RHOBTB3 dimerizes with LIMD1, and constructs a RHOBTB3/LIMD1-PHD2-VHL-HIFα complex to effect the maximal degradation of HIFα. Hypoxia reduces the RHOBTB3-centered complex formation, resulting in an accumulation of HIFα. Importantly, the expression level of RHOBTB3 is greatly reduced in human renal carcinomas, and RHOBTB3 deficiency significantly elevates the Warburg effect and accelerates xenograft growth. Our work thus reveals that RHOBTB3 serves as a scaffold to organize a multi-subunit complex that promotes the hydroxylation, ubiquitination and degradation of HIFα.

AMPK senses decreased cellular energy levels, triggering mitochondrial autophagy or mitophagy through activating ULK1 and inhibiting mTORC1. In a recent report, Toyama et al. (2016) show that activated AMPK phosphorylation of MFF is critical for mitochondrial fission. Unphosphorylatable MFF mutants block mitophagy, connecting AMPK to mitochondrial fission and to mitophagy.

As a result of the interplay between advances in computer hardware, software, and algorithm, we are now in a new era of large-scale reservoir simulation, which focuses on accurate flow description, fine reservoir characterization, efficient nonlinear/linear solvers, and parallel implementation. In this paper, we discuss a multilevel preconditioner in a new-generation simulator and its implementation on multicore computers. This preconditioner relies on the method of subspace corrections to solve large-scale linear systems arising from fully implicit methods in reservoir simulations. We investigate the parallel efficiency and robustness of the proposed method by applying it to million-cell benchmark problems.

SummaryAMPK and mTOR play principal roles in governing metabolic programs; however, mechanisms underlying the coordination of the two inversely regulated kinases remain unclear. In this study we found, most surprisingly, that the late endosomal/lysosomal protein complex v-ATPase-Ragulator, essential for activation of mTORC1, is also required for AMPK activation. We also uncovered that AMPK is a residential protein of late endosome/lysosome. Under glucose starvation, the v-ATPase-Ragulator complex is accessible to AXIN/LKB1 for AMPK activation. Concurrently, the guanine nucleotide exchange factor (GEF) activity of Ragulator toward RAG is inhibited by AXIN, causing dissociation from endosome and inactivation of mTORC1. We have thus revealed that the v-ATPase-Ragulator complex is also an initiating sensor for energy stress and meanwhile serves as an endosomal docking site for LKB1-mediated AMPK activation by forming the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex, thereby providing a switch between catabolism and anabolism. Our current study also emphasizes a general role of late endosome/lysosome in controlling metabolic programs.

The geometric multigrid method (GMG) is one of the most efficient solving techniques for discrete algebraic systems arising from elliptic partial differential equations. GMG utilizes a hierarchy of grids or discretizations and reduces the error at a number of frequencies simultaneously. Graphics processing units (GPUs) have recently burst onto the scientific computing scene as a technology that has yielded substantial performance and energy-efficiency improvements. A central challenge in implementing GMG on GPUs, though, is that computational work on coarse levels cannot fully utilize the capacity of a GPU. In this work, we perform numerical studies of GMG on CPU-GPU heterogeneous computers. Furthermore, we compare our implementation with an efficient CPU implementation of GMG and with the most popular fast Poisson solver, Fast Fourier Transform, in the cuFFT library developed by NVIDIA.

The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

Summary Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD+ levels in aged muscles, rejuvenating the animals’ running capacity. Our study elucidates that TRPVs relay the FBP-free status of aldolase to the reconfiguration of v-ATPase, leading to AMPK activation in low glucose., Graphical Abstract, Highlights • TRPV cation channels are required for glucose starvation-induced AMPK activation • FBP-unoccupied aldolase inhibits Ca2+ release of TRPVs at the ER-lysosome contact • The decrease of the local Ca2+ allow TRPV proteins to interact with v-ATPase • TRPVs interact with and alter v-ATPase to initiate activating complex for AMPK, Falling levels of glucose, and consequentially fructose-1,6-bisphosphate (FBP), are sensed by glycolytic enzyme aldolase. Li et al. demonstrate that FBP-unoccupied aldolase binds to and inhibits ER-localized TRPV channels, with the decreased calcium at the ER-lysosome contact enabling the channel proteins to interact with lysosomal v-ATPase to allow for AMPK activation.

In this paper, we consider the adaptive Eulerian---Lagrangian method (ELM) for linear convection---diffusion problems. Unlike classical a posteriori error estimations, we estimate the temporal error along the characteristics and derive a new a posteriori error bound for ELM semi-discretization. With the help of this proposed error bound, we are able to show the optimal convergence rate of ELM for solutions with minimal regularity. Furthermore, by combining this error bound with a standard residual-type estimator for the spatial error, we obtain a posteriori error estimators for a fully discrete scheme. We present numerical tests to demonstrate the efficiency and robustness of our adaptive algorithm.

We develop a simple algorithmic framework to solve large-scale symmetric positive definite linear systems. At its core, the framework relies on two components: (1) a norm-convergent iterative method (i.e., smoother) and (2) a preconditioner. The resulting preconditioner, which we refer to as a combined preconditioner, is much more robust and efficient than the iterative method and preconditioner when used in Krylov subspace methods. We prove that the combined preconditioner is positive definite and show estimates on the condition number of the preconditioned system. We combine an algebraic multigrid method and an incomplete factorization preconditioner to test the proposed framework on problems in petroleum reservoir simulation. Our numerical experiments demonstrate noticeable speed-up when we compare our combined method with the stand-alone algebraic multigrid method or the incomplete factorization preconditioner.

Metformin (N, N-dimethylbiguanide) is the most widely used first-line drug for treatment of type 2 diabetes (T2D). This anti-hyperglycemic drug offers clinical superiority over other glucose-lowering drugs, with little induction of hypoglycemia or weight gain and with the effects to reverse fatty liver, improve insulin sensitivity, and ameliorate cardiovascular dysfunctions associated with T2D (extensively reviewed by Foretz et al., 2014). Administration of metformin to nematodes (C. elegans) and mice gave rise to extended lifespan and health span (Barzilai et al., 2016).

Let A ∈ C n × n and A ˜ ∈ C n × n be two normal matrices with spectra { λ i } i = 1 n and { λ ˜ i } i = 1 n , respectively. The celebrated Hoffman–Wielandt theorem states that there exists a permutation π of { 1 , … , n } such that ( ∑ i = 1 n | λ ˜ π ( i ) − λ i | 2 ) 1 2 is no larger than the Frobenius norm of A ˜ − A . However, if either A or A ˜ is non-normal, this result does not hold in general. In this paper, we present several novel upper bounds for ( ∑ i = 1 n | λ ˜ π ( i ) − λ i | 2 ) 1 2 , provided that A is normal and A ˜ is arbitrary. Some of these estimates involving the “departure from normality” of A ˜ have generalized the Hoffman–Wielandt theorem. Furthermore, we give new perturbation bounds for the spectrum of a Hermitian matrix.

We consider elliptic and parabolic variational equations and inequalities governed by integro-differential operators of order $${2s \in (0,2]}$$. Our main motivation is the pricing of European or American options under Levy processes, in particular pure jump processes or jump diffusion processes with tempered stable processes. The problem is discretized using piecewise linear finite elements in space and the implicit Euler method in time. We construct a residual-type a posteriori error estimator which gives a computable upper bound for the actual error in H s -norm. The estimator is localized in the sense that the residuals are restricted to the discrete non-contact region. Numerical experiments illustrate the accuracy of the space and time estimators, and show that they can be used to measure local errors and drive adaptive algorithms.

Summary The efficiency of intestinal absorption of dietary fat constitutes a primary determinant accounting for individual vulnerability to obesity. However, how fat absorption is controlled and contributes to obesity remains unclear. Here, we show that inhibition of endoplasmic-reticulum-associated degradation (ERAD) increases the abundance of triacylglycerol synthesis enzymes and fat absorption in small intestine. The C2-domain protein AIDA acts as an essential factor for the E3-ligase HRD1 of ERAD to downregulate rate-limiting acyltransferases GPAT3, MOGAT2, and DGAT2. Aida −/− mice, when grown in a thermal-neutral condition or fed high-fat diet, display increased intestinal fatty acid re-esterification, circulating and tissue triacylglycerol, accompanied with severely increased adiposity without enhancement of adipogenesis. Intestine-specific knockout of Aida largely phenocopies its whole-body knockout, strongly indicating that increased intestinal TAG synthesis is a primary impetus to obesity. The AIDA-mediated ERAD system may thus represent an anti-thrifty mechanism impinging on the enzymes for intestinal fat absorption and systemic fat storage.

Motivated by the pricing of American options for baskets we consider a parabolic varia- tional inequality in a bounded polyhedral domain Ω ⊂ R d with a continuous piecewise smooth obstacle. We formulate a fully discrete method by using piecewise linear finite elements in space and the back- ward Euler method in time. We define an a posteriori error estimator and show that it gives an upper bound for the error in L 2 (0 ,T ; H 1 (Ω)). The error estimator is localized in the sense that the size of the elliptic residual is only relevant in the approximate non-contact region, and the approximability of the obstacle is only relevant in the approximate contact region. We also obtain lower bound results for the space error indicators in the non-contact region, and for the time error estimator. Numerical results for d =1 , 2 show that the error estimator decays with the same rate as the actual error when the space meshsize h and the time step τ tend to zero. Also, the error indicators capture the correct behavior of the errors in both the contact and the non-contact regions. Mathematics Subject Classification. 58E35, 65N15, 65N30.

Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation.

Mitogen-activated protein kinases (MAPKs), important in a large array of signalling pathways, are tightly controlled by a cascade of protein kinases and by MAPK phosphatases (MKPs). MAPK signalling efficiency and specificity is modulated by protein–protein interactions between individual MAPKs and the docking motifs in cognate binding partners. Two types of docking interactions have been identified: D-motif-mediated interaction and FXF-docking interaction. Here we report the crystal structure of JNK1 bound to the catalytic domain of MKP7 at 2.4-Å resolution, providing high-resolution structural insight into the FXF-docking interaction. The 285FNFL288 segment in MKP7 directly binds to a hydrophobic site on JNK1 that is near the MAPK insertion and helix αG. Biochemical studies further reveal that this highly conserved structural motif is present in all members of the MKP family, and the interaction mode is universal and critical for the MKP-MAPK recognition and biological function., The important MAPK family of signalling proteins is controlled by MAPK phosphatases (MKPs). Here, the authors report the structure of MKP7 bound to JNK1 and characterise the conserved MKP-MAPK interaction.