Nucleotides are required for a wide variety of biological processes and are constantly synthesized de novo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA ...replication and for RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore the synthesis of the precursor nucleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across different cell compartments and several sources of carbon and nitrogen. The processes are regulated at the transcription level by a set of master transcription factors but also at the enzyme level by allosteric regulation and feedback inhibition. Here we review the cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle. The use of stable isotope tracers for delineating the biosynthetic routes of the multiple intersecting pathways and how these are quantitatively controlled under different conditions is also highlighted. Moreover, the importance of nucleotide synthesis for cell viability is discussed and how this may lead to potential new approaches to drug development in diseases such as cancer.
A recursive rotational-coordinate-based formulation of a planar Euler–Bernoulli beam is developed, where large displacements, deformations, and rotations are considered. Different from the ...traditional rotational-coordinate-based formulations, relative rotational angles rather than absolute ones are used as generalized coordinates. The number of generalized coordinates is minimized, which is inherited from traditional rotational-coordinate-based formulations. A recursive scheme is used for adjacent elements of the beam that is considered as a chain-like structure. Integrals in the mass matrix and generalized force vector of each element of the beam can be analytically derived, and a numerical trick based on Taylor polynomial approximations is adopted to avoid numerical singularity. The current formulation entirely avoids the evaluation of integrals in each time step, which greatly improves the computational efficiency. Three widely-used examples are studied to illustrate the performance of the proposed method. Results indicate that the present formulation can achieve the same accuracy, as well as much higher efficiency, compared to some traditional formulations. In addition, calculation time of the current formulation almost linearly increases with the increasing number of elements of the beam, indicating that the computational complexity of the current formulation is
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Atomistic modelling of magnetic materials provides unprecedented detail about the underlying physical processes that govern their macroscopic properties, and allows the simulation of complex effects ...such as surface anisotropy, ultrafast laser-induced spin dynamics, exchange bias, and microstructural effects. Here we present the key methods used in atomistic spin models which are then applied to a range of magnetic problems. We detail the parallelization strategies used which enable the routine simulation of extended systems with full atomistic resolution.
Anabolic biosynthesis requires precursors supplied by the Krebs cycle, which in turn requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and ...glutamine, which require the activity of pyruvate carboxylase (PC) and glutaminase 1 (GLS1), respectively. Due to their rapid proliferation, cancer cells have increased anabolic and energy demands; however, different cancer cell types exhibit differential requirements for PC- and GLS-mediated pathways for anaplerosis and cell proliferation. Here, we infused patients with early-stage non-small-cell lung cancer (NSCLC) with uniformly 13C-labeled glucose before tissue resection and determined that the cancerous tissues in these patients had enhanced PC activity. Freshly resected paired lung tissue slices cultured in 13C6-glucose or 13C5,15N2-glutamine tracers confirmed selective activation of PC over GLS in NSCLC. Compared with noncancerous tissues, PC expression was greatly enhanced in cancerous tissues, whereas GLS1 expression showed no trend. Moreover, immunohistochemical analysis of paired lung tissues showed PC overexpression in cancer cells rather than in stromal cells of tumor tissues. PC knockdown induced multinucleation, decreased cell proliferation and colony formation in human NSCLC cells, and reduced tumor growth in a mouse xenograft model. Growth inhibition was accompanied by perturbed Krebs cycle activity, inhibition of lipid and nucleotide biosynthesis, and altered glutathione homeostasis. These findings indicate that PC-mediated anaplerosis in early-stage NSCLC is required for tumor survival and proliferation.
Abstract
Constrained by the Nielsen-Ninomiya no-go theorem, in all so-far experimentally determined Weyl semimetals (WSMs) the Weyl points (WPs) always appear in pairs in the momentum space with no ...exception. As a consequence, Fermi arcs occur on surfaces which connect the projections of the WPs with opposite chiral charges. However, this situation can be circumvented in the case of unpaired WP, without relevant surface Fermi arc connecting its surface projection, appearing singularly, while its Berry curvature field is absorbed by nontrivial charged nodal walls. Here, combining angle-resolved photoemission spectroscopy with density functional theory calculations, we show experimentally that a singular Weyl point emerges in PtGa at the center of the Brillouin zone (BZ), which is surrounded by closed Weyl nodal walls located at the BZ boundaries and there is no Fermi arc connecting its surface projection. Our results reveal that nontrivial band crossings of different dimensionalities can emerge concomitantly in condensed matter, while their coexistence ensures the net topological charge of different dimensional topological objects to be zero. Our observation extends the applicable range of the original Nielsen-Ninomiya no-go theorem which was derived from zero dimensional paired WPs with opposite chirality.
In this paper, studies on dynamic modeling, simulation and experiment of power transmission belt drives are comprehensively reviewed. In the past few decades, many investigations are conducted on ...dynamic modeling, simulation and experiment of different kinds of power transmission belt drive systems. In the dynamic modeling and simulation of the belt drive systems, surveys are focused on vibrations of a single axially moving belt span, rotational vibrations of pulley components, coupled belt-pulley vibrations and contact mechanics between the belt and pulley as well as some experimental investigations. Influences of tensioner dry friction and one-way clutch on dynamics of the belt drive systems including system rotational vibrations and coupled belt-pulley vibrations are separately reported. The investigations are also surveyed on modeling and predicting complicated belt-pulley contact behaviors like belt creeps and slips on pulleys, contact force distributions of the belt and pulley, and variation of wrap angles of a belt around pulleys, etc., which are categorized by different approaches including the creep theory, shear theory, multi-body dynamics and finite element methods. Fatigue life estimation and failure analysis of power transmission belt drives are discussed in detail as well. In addition, experimental techniques are reviewed on parameters identifications, and measurements of static and dynamic performances including energy/power loss, system vibration, dynamic belt tension, belt deformation, stress and strain distribution in the belt and pulley, and contact friction force, etc. Finally, conclusion of this work is summarized and topics of future potential studies on the power transmission belt drive systems are suggested.
In addition to glycolysis, the oncogenic transcription factor c-MYC (MYC) stimulates glutamine catabolism to fuel growth and proliferation of cancer cells through up-regulating glutaminase (GLS). ...Glutamine is converted to glutamate by GLS, entering the tricarboxylic acid cycle as an important energy source. Less wellrecognized, glutamate can also be converted to proline through ∆¹-pyrroline-5-carboxylate (P5C) and vice versa. This study suggests that some MYC-induced cellular effects are due to MYC regulation of proline metabolism. Proline oxidase, also known as proline dehydrogenase (POX/PRODH), the first enzyme in proline catabolism, is a mitochondrial tumor suppressor that inhibits proliferation and induces apoptosis. MiR-23b* mediates POX/PRODH down-regulation in human kidney tumors. MiR-23b* is processed from the same transcript as miR-23b; the latter inhibits the translation of GLS. Using MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells, we showed that MYC suppressed POX/PRODH expression primarily through upregulating miR-23b*. The growth inhibition in the absence of MYC was partially reversed by POX/PRODH knockdown, indicating the importance of suppression of POX/PRODH in MYC-mediated cellular effects. Interestingly, MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. MYCinduced proline biosynthesis from glutamine was directly confirmed using ¹³ C, ¹⁵ N-glutamine as a tracer. The metabolic link between glutamine and proline afforded by MYC emphasizes the complexity of tumor metabolism. Further studies of the relationship between glutamine and proline metabolism should provide a deeper understanding of tumor metabolism while enabling the development of novel therapeutic strategies.
The past decades of advancements in NMR have made it a very powerful tool for metabolic research. Despite its limitations in sensitivity relative to mass spectrometric techniques, NMR has a number of ...unparalleled advantages for metabolic studies, most notably the rigor and versatility in structure elucidation, isotope-filtered selection of molecules, and analysis of positional isotopomer distributions in complex mixtures afforded by multinuclear and multidimensional experiments. In addition, NMR has the capacity for spatially selective in vivo imaging and dynamical analysis of metabolism in tissues of living organisms. In conjunction with the use of stable isotope tracers, NMR is a method of choice for exploring the dynamics and compartmentation of metabolic pathways and networks, for which our current understanding is grossly insufficient. In this review, we describe how various direct and isotope-edited 1D and 2D NMR methods can be employed to profile metabolites and their isotopomer distributions by stable isotope-resolved metabolomic (SIRM) analysis. We also highlight the importance of sample preparation methods including rapid cryoquenching, efficient extraction, and chemoselective derivatization to facilitate robust and reproducible NMR-based metabolomic analysis. We further illustrate how NMR has been applied in vitro, ex vivo, or in vivo in various stable isotope tracer-based metabolic studies, to gain systematic and novel metabolic insights in different biological systems, including human subjects. The pathway and network knowledge generated from NMR- and MS-based tracing of isotopically enriched substrates will be invaluable for directing functional analysis of other 'omics data to achieve understanding of regulation of biochemical systems, as demonstrated in a case study. Future developments in NMR technologies and reagents to enhance both detection sensitivity and resolution should further empower NMR in systems biochemical research.
Highlights • Intranasal insulin treatment significantly ameliorated 6-OHDA-induced sensorimotor dysfunction in rats. • Intranasal insulin treatment significantly reduced methamphetamine-induced ...rotation in 6-OHDA-lesion rats. • Intranasal insulin treatment significantly increased DA neuron survival in the SN in 6-OHDA-lesion rats. • Intranasal insulin treatment did not cause hypoglycemia in rats.
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