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The Heisenberg triangular lattice quantum spin liquid and the phasetransitions to nearby magnetic orders have received much theoretical attention,but clear experimental manifestations of these states are rare. This workinvestigates a new spin-half Yb$^{3+}$ delafossite material, KYbSe$_2$, whoseinelastic neutron scattering spectra reveal a diffuse continuum with a sharplower bound. Applying entanglement witnesses to the data reveals significantmultipartite entanglement spread between its neighbors, and analysis of itsmagnetic exchange couplings shows close proximity to the triangular latticeHeisenberg quantum spin liquid. Key features of the data are reproduced bySchwinger-boson theory and tensor network calculations with a significantsecond-neighbor coupling $J_2$. The strength of the dynamical structure factorat the $K$ point shows a scaling collapse in $\hbar\omega/k_\mathrm{B}T$ downto 0.3 K, indicating a second-order quantum phase transition. Comparing this toprevious theoretical work suggests that the proximate phase at larger $J_2$ isa gapped $\mathbb{Z}_2$ spin liquid, resolving a long-debated issue. We thusshow that KYbSe$_2$ is close to a spin liquid phase, which in turn sheds lighton the theoretical phase diagram itself.

Classical hydrodynamics is a remarkably versatile description of the coarse-grained behaviour of many-particle systems once local equilibrium has been established1. The form of the hydrodynamical equations is determined primarily by the conserved quantities present in a system. Some quantum spin chains are known to possess, even in the simplest cases, a greatly expanded set of conservation laws, and recent work suggests that these laws strongly modify collective spin dynamics, even at high temperature2,3. Here, by probing the dynamical exponent of the one-dimensional Heisenberg antiferromagnet KCuF3 with neutron scattering, we find evidence that the spin dynamics are well described by the dynamical exponent z = 3/2, which is consistent with the recent theoretical conjecture that the dynamics of this quantum system are described by the Kardar–Parisi–Zhang universality class4,5. This observation shows that low-energy inelastic neutron scattering at moderate temperatures can reveal the details of emergent quantum fluid properties like those arising in non-Fermi liquids in higher dimensions.

The notion of a quasiparticle, such as a phonon, a roton or a magnon, is used in modern condensed matter physics to describe an elementary collective excitation. The intrinsic zero-temperature magnon damping in quantum spin systems can be driven by the interaction of the one-magnon states and multi-magnon continuum. However, detailed experimental studies on this quantum many-body effect induced by an applied magnetic field are rare. Here we present a high-resolution neutron scattering study in high fields on an S=1/2 antiferromagnet C9H18N2CuBr4. Compared with the non-interacting linear spin-wave theory, our results demonstrate a variety of phenomena including field-induced renormalization of one-magnon dispersion, spontaneous magnon decay observed via intrinsic linewidth broadening, unusual non-Lorentzian two-peak structure in the excitation spectra and a dramatic shift of spectral weight from one-magnon state to the two-magnon continuum.

Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

van der Waals (vdW) magnets have rapidly emerged as a fertile playground for fundamental physics and exciting applications. Despite the impressive developments over the past few years, technical limitations pose a severe challenge to many other potential breakthroughs. High on the list is the lack of suitable experimental tools for studying spin dynamics on atomically thin samples. Here, Raman scattering techniques are employed to directly observe the low-lying magnon (∼1 meV) even in bilayer NiPS 3 . The advantage is that it offers excellent energy resolutions far better on low-energy sides than most inelastic neutron spectrometers can offer. More importantly, with appropriate theoretical analysis, the polarization dependence of the Raman scattering by those low-lying magnons also provides otherwise hidden information on the dominant spin-exchange scattering paths for different magnons. By comparing with high-resolution inelastic neutron scattering data, these low-energy Raman modes are confirmed to be indeed of magnon origin. Because of the different scattering mechanisms involved in inelastic neutron and Raman scattering, this information is fundamental in pinning down the final spin Hamiltonian. This work demonstrates the capability of Raman spectroscopy to probe the genuine two-dimensional spin dynamics in atomically thin vdW magnets, which can provide insights that are obscured in bulk spin dynamics.

Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated T cell cytokine production and metabolic phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether inflammatory cytokines released by differentiating T cells amplified their metabolic changes. We found that tumor necrosis factor-α (TNF-α) released by human naïve CD4 + T cells upon activation stimulated the expression of a metabolic transcriptome and increased glycolysis, amino acid uptake, mitochondrial oxidation of glutamine, and mitochondrial biogenesis. The effects of TNF-α were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-κB pathway. TNF-α stimulated the differentiation of naïve cells into proinflammatory T helper 1 (T H 1) and T H 17 cells, but not that of regulatory T cells. CD4 + T cells from patients with RA showed increased TNF-α production and consequent Akt phosphorylation upon activation. These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell-derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.

Using 13 C 6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1 H- 13 C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release., Competing Interests: Declaration of interests G.A.R. has received grant funding from, and is a consultant for, Sun Pharmaceuticals Industries Ltd. D.J.H. receives licensing revenue from Celtarys Research for provision of chemical probes. D.J.H. has filed patents related to type 1 diabetes and type 2 diabetes therapy, unrelated to the present study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Knowledge about nonequilibrium dynamics in spin systems is of great importance to both fundamental science and technological applications. Inelastic neutron scattering (INS) is an indispensable tool to study spin excitations in complex magnetic materials. However, conventional INS spectrometers currently only perform steady-state measurements and probe averaged properties over many collision events between spin excitations in thermodynamic equilibrium, while the exact picture of re-equilibration of these excitations remains unknown. In this paper, we report on the design and implementation of a time-resolved laser-neutron pump-probe capability at hybrid spectrometer (beamline 14-B) at the Spallation Neutron Source (SNS) at Oak Ridge National Laboratory. This capability allows us to excite out-of-equilibrium magnons with a nanosecond pulsed laser source and probe the resulting dynamics using INS. Here, we discussed technical aspects to implement such a capability in a neutron beamline, including choices of suitable neutron instrumentation and material systems, laser excitation scheme, experimental configurations, and relevant firmware and software development to allow for time-synchronized pump-probe measurements. We demonstrated that the laser-induced nonequilibrium structure factor is able to be resolved by INS in a quantum magnet. The method developed in this work will provide SNS with advanced capabilities for performing out-of-equilibrium measurements, opening up an entirely new research direction to study out-of-equilibrium phenomena using neutrons., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Anoxia halts oxidative phosphorylation (OXPHOS) causing an accumulation of reduced compounds in the mitochondrial matrix which impedes dehydrogenases. By simultaneously measuring oxygen concentration, NADH autofluorescence, mitochondrial membrane potential and ubiquinone reduction extent in isolated mitochondria in real-time, we demonstrate that Complex I utilized endogenous quinones to oxidize NADH under acute anoxia. 13 C metabolic tracing or untargeted analysis of metabolites extracted during anoxia in the presence or absence of site-specific inhibitors of the electron transfer system showed that NAD +  regenerated by Complex I is reduced by the 2-oxoglutarate dehydrogenase Complex yielding succinyl-CoA supporting mitochondrial substrate-level phosphorylation (mtSLP), releasing succinate. Complex II operated amphidirectionally during the anoxic event, providing quinones to Complex I and reducing fumarate to succinate. Our results highlight the importance of quinone provision to Complex I oxidizing NADH maintaining glutamate catabolism and mtSLP in the absence of OXPHOS., (© 2024. The Author(s).)

Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on the alteration of glucose utilization., Competing Interests: D.A.T. has undertaken paid consultancy work with Sitryx. Other authors declare that they have no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology.)

Heritable renal cancer syndromes (RCS) are associated with numerous chromosomal alterations including inactivating mutations in von Hippel-Lindau (VHL) gene. Here we identify a novel aspect of the phenotype in VHL-deficient human renal cells. We call it reductive stress as it is characterised by increased NADH/NAD + ratio that is associated with impaired cellular respiration, impaired CAC activity, upregulation of reductive carboxylation of glutamine and accumulation of lipid droplets in VHL-deficient cells. Reductive stress was mitigated by glucose depletion and supplementation with pyruvate or resazurin, a redox-reactive agent. This study demonstrates for the first time that reductive stress is a part of the phenotype associated with VHL-deficiency in renal cells and indicates that the reversal of reductive stress can augment respiratory activity and CAC activity, suggesting a strategy for altering the metabolic profile of VHL-deficient tumours., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

T cells demonstrate impaired function in multiple myeloma (MM) but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8+ T-cell function is decreased in MM compared with controls, and is also consistently lower within bone marrow samples than in matched peripheral blood samples. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modeling confirmed that uptake of bone marrow lipids suppresses CD8+ T function, which is impaired in autologous bone marrow plasma but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T-cell function, thereby identifying this as a novel target to augment T-cell activity in MM. Finally, analysis of samples from cohorts of patients who had received treatment identified that CD8+ T-cell metabolic dysfunction resolves in patients with MM who are responsive to treatment but not in patients with relapsed MM, and is associated with substantial T-cell functional restoration., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Continuous spin excitations are widely recognized as one of the hallmarks of novel spin states in quantum magnets, such as quantum spin liquids (QSLs). Here, we report the observation of such kind of excitations in K_{2}Ni_{2}(SO_{4})_{3}, which consists of two sets of intersected spin-1 (Ni^{2+}) trillium lattices. Our inelastic neutron scattering measurement on single crystals clearly shows a dominant excitation continuum, which exhibits a distinct temperature-dependent behavior from that of spin waves, and is rooted in strong quantum spin fluctuations. Further using the self-consistent-Gaussian-approximation method, we determine that the fourth- and fifth-nearest-neighbor exchange interactions are dominant. These two bonds together form a unique three-dimensional network of corner-sharing tetrahedra, which we name as a "hypertrillium" lattice. Our results provide direct evidence for the existence of QSL features in K_{2}Ni_{2}(SO_{4})_{3} and highlight the potential for the hypertrillium lattice to host frustrated quantum magnetism.

Chemotherapeutic drugs are used to treat almost all types of cancer, but the intended response, i.e., elimination, is often incomplete, with a subset of cancer cells resisting treatment. Two critical factors play a role in chemoresistance: the p53 tumour suppressor gene and the X-linked inhibitor of apoptosis (XIAP). These proteins have been shown to act synergistically to elicit cellular responses upon DNA damage induced by chemotherapy, yet, the mechanism is poorly understood. This study introduces a mathematical model characterising the apoptosis pathway activation by p53 before and after mitochondrial outer membrane permeabilisation upon treatment with the chemotherapy Doxorubicin (Dox). "In-silico" simulations show that the p53 dynamics change dose-dependently. Under medium to high doses of Dox, p53 concentration ultimately stabilises to a high level regardless of XIAP concentrations. However, caspase-3 activation may be triggered or not depending on the XIAP induction rate, ultimately determining whether the cell will perish or resist. Consequently, the model predicts that failure to activate apoptosis in some cancer cells expressing wild-type p53 might be due to heterogeneity between cells in upregulating the XIAP protein, rather than due to the p53 protein concentration. Our model suggests that the interplay of the p53 dynamics and the XIAP induction rate is critical to determine the cancer cells' therapeutic response., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: The authors have no conflicts of interest to disclose.

Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5 -/- ) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5 -/- neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5 -/- neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5 -/- neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect., Competing Interests: Declaration of interests R.J. is cofounder of Fate Therapeutics, Fulcrum Therapeutics, and Omega Therapeutics and advisor to Dewpoint Therapeutics. E.S. is founder of NMN Bio Ltd. V.I.K. is a scientific advisor for Longaevus Technologies., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fractals-objects with noninteger dimensions-occur in manifold settings and length scales in nature. In this work, we identify an emergent dynamical fractal in a disorder-free, stoichiometric, and three-dimensional magnetic crystal in thermodynamic equilibrium. The phenomenon is born from constraints on the dynamics of the magnetic monopole excitations in spin ice, which restrict them to move on the fractal. This observation explains the anomalous exponent found in magnetic noise experiments in the spin ice compound Dy 2 Ti 2 O 7 , and it resolves a long-standing puzzle about its rapidly diverging relaxation time. The capacity of spin ice to exhibit such notable phenomena suggests that there will be further unexpected discoveries in the cooperative dynamics of even simple topological many-body systems.

Traditional spectroscopy, by its very nature, characterizes physical system properties in the momentum and frequency domains. However, the most interesting and potentially practically useful quantum many-body effects emerge from local, short-time correlations. Here, using inelastic neutron scattering and methods of integrability, we experimentally observe and theoretically describe a local, coherent, long-lived, quasiperiodically oscillating magnetic state emerging out of the distillation of propagating excitations following a local quantum quench in a Heisenberg antiferromagnetic chain. This "quantum wake" displays similarities to Floquet states, discrete time crystals and nonlinear Luttinger liquids. We also show how this technique reveals the non-commutativity of spin operators, and is thus a model-agnostic measure of a magnetic system's "quantumness.", (© 2022. The Author(s).)

Succinate dehydrogenase (SDH) loss-of-function mutations drive succinate accumulation in tumor microenvironments, for example in the neuroendocrine tumors pheochromocytoma (PC) and paraganglioma (PG). Control of innate immune cell activity by succinate is described, but effects on T cells have not been interrogated. Here we report that exposure of human CD4 + and CD8 + T cells to tumor-associated succinate concentrations suppresses degranulation and cytokine secretion, including of the key anti-tumor cytokine interferon-γ (IFN-γ). Mechanistically, this is associated with succinate uptake-partly via the monocarboxylate transporter 1 (MCT1)-inhibition of succinyl coenzyme A synthetase activity and impaired glucose flux through the tricarboxylic acid cycle. Consistently, pharmacological and genetic interventions restoring glucose oxidation rescue T cell function. Tumor RNA-sequencing data from patients with PC and PG reveal profound suppression of IFN-γ-induced genes in SDH-deficient tumors compared with those with other mutations, supporting a role for succinate in modulating the anti-tumor immune response in vivo., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Exploring the relationship between intriguing physical properties and structural complexity is a central topic in studying modern functional materials. Co 3 Sn 2 S 2 , a newly discovered kagome-lattice magnetic Weyl semimetal, has triggered intense interest owing to the intimate coupling between topological semimetallic states and peculiar magnetic properties. However, the origins of the magnetic phase separation and spin glass state below T C in this ordered compound are two unresolved yet important puzzles in understanding its magnetism. Here, we report the discovery of local symmetry breaking surprisingly co-emerges with the onset of ferromagnetic order in Co 3 Sn 2 S 2 , by a combined use of neutron total scattering and half-polarized neutron diffraction. An anisotropic distortion of the cobalt kagome lattice at the atomic/nano level is also found, with distinct distortion directions among the two Co1 and four Co2 atoms. The mismatch of local and average symmetries occurs below T C , indicating that Co 3 Sn 2 S 2 evolves to an intrinsically lattice disordered system when the ferromagnetic order is established. The local symmetry breaking with intrinsic lattice disorder provides new understanding of the puzzling magnetic properties. Our density functional theory (DFT) calculation indicates that the local symmetry breaking is expected to reorient local ferromagnetic moments, unveiling the existence of the ferromagnetic instability associated with the lattice instability. Furthermore, DFT calculation unveils that the local symmetry breaking could affect the Weyl property by breaking the mirror plane. Our findings highlight the fundamentally important role that the local symmetry breaking plays in advancing our understanding on the magnetic and topological properties in Co 3 Sn 2 S 2 , which may draw attention to explore the overlooked local symmetry breaking in Co 3 Sn 2 S 2 , its derivatives and more broadly in other topological Dirac/Weyl semimetals and kagome-lattice magnets.

In CD4 + T helper cells, the active form of vitamin D 3 , 1,25-dihydroxyvitamin D 3 (1,25D) suppresses production of inflammatory cytokines, including interferon-gamma (IFN-γ), but the mechanisms for this are not yet fully defined. In innate immune cells, response to 1,25D has been linked to metabolic reprogramming. It is unclear whether 1,25D has similar effects on CD4 + T cells, although it is known that antigen stimulation of these cells promotes an anabolic metabolic phenotype, characterized by high rates of aerobic glycolysis to support clonal expansion and effector cytokine expression. Here, we performed in-depth analysis of metabolic capacity and pathway usage, employing extracellular flux and stable isotope-based tracing approaches, in CD4 + T cells treated with 1,25D. We report that 1,25D significantly decreases rates of aerobic glycolysis in activated CD4 + T cells, whilst exerting a lesser effect on mitochondrial glucose oxidation. This is associated with transcriptional repression of Myc, but not repression of mTOR activity under these conditions. Consistent with the modest effect of 1,25D on mitochondrial activity, it also did not impact CD4 + T-cell mitochondrial mass or membrane potential. Finally, we demonstrate that inhibition of aerobic glycolysis by 1,25D substantially contributes to its immune-regulatory capacity in CD4 + T cells, since the suppression of IFN-γ expression was significantly blunted in the absence of aerobic glycolysis. 1,25-Dihydroxyvitamin D 3 (1,25D) suppresses the production of inflammatory cytokines such as interferon-gamma (IFN-γ) by CD4 + T cells, but the underpinning mechanisms are not yet fully defined. Here, we identify that 1,25D inhibits aerobic glycolysis in activated CD4 + T cells, associated with decreased c-Myc expression. This mechanism appears to substantially contribute to the suppression of IFN-γ by 1,25D, since this is significantly blunted in the absence of aerobic glycolysis., (© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.)

Quantum phase transitions in quantum matter occur at zero temperature between distinct ground states by tuning a nonthermal control parameter. Often, they can be accurately described within the Landau theory of phase transitions, similarly to conventional thermal phase transitions. However, this picture can break down under certain circumstances. Here, we present a comprehensive study of the effect of hydrostatic pressure on the magnetic structure and spin dynamics of the spin-1/2 ladder compound C 9 H 18 N 2 CuBr 4 . Single-crystal heat capacity and neutron diffraction measurements reveal that the Néel-ordered phase breaks down beyond a critical pressure of P c  ∼ 1.0 GPa through a continuous quantum phase transition. Estimates of the critical exponents suggest that this transition may fall outside the traditional Landau paradigm. The inelastic neutron scattering spectra at 1.3 GPa are characterized by two well-separated gapped modes, including one continuum-like and another resolution-limited excitation in distinct scattering channels, which further indicates an exotic quantum-disordered phase above P c ., (© 2022. The Author(s).)

Noise generated by motion of charge and spin provides a unique window into materials at the atomic scale. From temperature of resistors to electrons breaking into fractional quasiparticles, "listening" to the noise spectrum is a powerful way to decode underlying dynamics. Here, we use ultrasensitive superconducting quantum interference device (SQUIDs) to probe the puzzling noise in a frustrated magnet, the spin-ice compound Dy 2 Ti 2 O 7 (DTO), revealing cooperative and memory effects. DTO is a topological magnet in three dimensions-characterized by emergent magnetostatics and telltale fractionalized magnetic monopole quasiparticles-whose real-time dynamical properties have been an enigma from the very beginning. We show that DTO exhibits highly anomalous noise spectra, differing significantly from the expected Brownian noise of monopole random walks, in three qualitatively different regimes: equilibrium spin ice, a "frozen" regime extending to ultralow temperatures, and a high-temperature "anomalous" paramagnet. We present several distinct mechanisms that give rise to varied colored noise spectra. In addition, we identify the structure of the local spin-flip dynamics as a crucial ingredient for any modeling. Thus, the dynamics of spin ice reflects the interplay of local dynamics with emergent topological degrees of freedom and a frustration-generated imperfectly flat energy landscape, and as such, it points to intriguing cooperative and memory effects for a broad class of magnetic materials., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

The demands of cancer cell proliferation alongside an inadequate angiogenic response lead to insufficient oxygen availability in the tumor microenvironment. Within the mitochondria, oxygen is the major electron acceptor for NADH, with the result that the reducing potential produced through tricarboxylic acid (TCA) cycle activity and mitochondrial respiration are functionally linked. As the oxidizing activity of the TCA cycle is required for efficient synthesis of anabolic precursors, tumoral hypoxia could lead to a cessation of proliferation without another means of correcting the redox imbalance. We show that in hypoxic conditions, mitochondrial pyrroline 5-carboxylate reductase 1 (PYCR1) activity is increased, oxidizing NADH with the synthesis of proline as a by-product. We further show that PYCR1 activity is required for the successful maintenance of hypoxic regions by permitting continued TCA cycle activity, and that its loss leads to significantly increased hypoxia in vivo and in 3D culture, resulting in widespread cell death., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (C c O), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of C c O remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48 , which orchestrates the substitution of the C c O subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions.

Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (ROS). Recent findings suggest that proline biosynthesis and catabolism are essential processes in disease; not only due to the role in new protein synthesis as part of pathogenic processes but also due to the impact of proline metabolism on the wider metabolic network through its significant role in redox homeostasis. This is particularly clear in cancer proliferation and metastatic outgrowth. Nevertheless, the precise identity of the drivers of cellular proline catabolism and biosynthesis, and the overall cost of maintaining appropriate balance is not currently known. In this review, we explore the major drivers of proline availability and consumption at a local and systemic level with a focus on cancer. Unraveling the main factors influencing proline metabolism in normal physiology and disease will shed light on new effective treatment strategies., (© 2021. The Author(s).)

Understanding magnetism and its possible correlations to topological properties has emerged to the forefront as a difficult topic in studying magnetic Weyl semimetals. Co_{3}Sn_{2}S_{2} is a newly discovered magnetic Weyl semimetal with a kagome lattice of cobalt ions and has triggered intense interest for rich fantastic phenomena. Here, we report the magnetic exchange couplings of Co_{3}Sn_{2}S_{2} using inelastic neutron scattering and two density functional theory (DFT) based methods: constrained magnetism and multiple-scattering Green's function methods. Co_{3}Sn_{2}S_{2} exhibits highly anisotropic magnon dispersions and linewidths below T_{C}, and paramagnetic excitations above T_{C}. The spin-wave spectra in the ferromagnetic ground state is well described by the dominant third-neighbor "across-hexagon" J_{d} model. Our density functional theory calculations reveal that both the symmetry-allowed 120° antiferromagnetic orders support Weyl points in the intermediate temperature region, with distinct numbers and the locations of Weyl points. Our study highlights the important role Co_{3}Sn_{2}S_{2} can play in advancing our understanding of kagome physics and exploring the interplay between magnetism and band topology.

The α-ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is an HIF target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. Although PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about the effects of this highly conserved enzyme in insulin-secreting β cells in vivo. Here, we show that the deletion of PHD3 specifically in β cells (βPHD3KO) was associated with impaired glucose homeostasis in mice fed a high-fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewired, leading to defects in the management of pyruvate fate and a shift from glycolysis to increased fatty acid oxidation (FAO). However, under more prolonged metabolic stress, this switch to preferential FAO in βPHD3KO islets was associated with impaired glucose-stimulated ATP/ADP rises, Ca2+ fluxes, and insulin secretion. Thus, PHD3 might be a pivotal component of the β cell glucose metabolism machinery in mice by suppressing the use of fatty acids as a primary fuel source during the early phases of metabolic stress.

The lack of methods to experimentally detect and quantify entanglement in quantum matter impedes our ability to identify materials hosting highly entangled phases, such as quantum spin liquids. We thus investigate the feasibility of using inelastic neutron scattering (INS) to implement a model-independent measurement protocol for entanglement based on three entanglement witnesses: one-tangle, two-tangle, and quantum Fisher information (QFI). We perform high-resolution INS measurements on Cs_{2}CoCl_{4}, a close realization of the S=1/2 transverse-field XXZ spin chain, where we can control entanglement using the magnetic field, and compare with density-matrix renormalization group calculations for validation. The three witnesses allow us to infer entanglement properties and make deductions about the quantum state in the material. We find QFI to be a particularly robust experimental probe of entanglement, whereas the one and two-tangles require more careful analysis. Our results lay the foundation for a general entanglement detection protocol for quantum spin systems.

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is a potent regulator of immune function, promoting anti-inflammatory, tolerogenic T cell responses by modulating antigen presentation by dendritic cells (DC). Transcriptomic analyses indicate that DC responses to 1,25D involve changes in glycolysis, oxidative phosphorylation, electron transport and the TCA cycle. To determine the functional impact of 1,25D-mediated metabolic remodelling, human monocyte-derived DC were differentiated to immature (+vehicle, iDC), mature (+LPS, mDC), and immature tolerogenic DC (+1,25D, itolDC) and characterised for metabolic function. In contrast to mDC which showed no change in respiration, itolDC showed increased basal and ATP-linked respiration relative to iDC. Tracer metabolite analyses using 13 C -labeled glucose showed increased lactate and TCA cycle metabolites. Analysis of lipophilic metabolites of 13 C-glucose revealed significant incorporation of label in palmitate and palmitoleate, indicating that 1,25D promotes metabolic fatty acid synthesis in itolDC. Inhibition of fatty acid synthesis in itolDC altered itolDC morphology and suppressed expression of CD14 and IL-10 by these cells. These data indicate that the ability of 1,25D to induce tolerogenic DC involves metabolic remodelling leading to synthesis of fatty acids., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Succinate dehydrogenase is a key enzyme in the tricarboxylic acid cycle and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, but only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an Sdhd knockout chromaffin cell line and compared it with Sdhb- deficient cells. Both cell types exhibited similar SDH loss of function, metabolic adaptation, and succinate accumulation. In contrast, Sdhb -/- cells showed hallmarks of mesenchymal transition associated with increased DNA hypermethylation and a stronger pseudo-hypoxic phenotype compared with Sdhd -/- cells. Loss of SDHB specifically led to increased oxidative stress associated with dysregulated iron and copper homeostasis in the absence of NRF2 activation. High-dose ascorbate exacerbated the increase in mitochondrial reactive oxygen species, leading to cell death in Sdhb -/- cells. These data establish a mechanism linking oxidative stress to iron homeostasis that specifically occurs in Sdhb -deficient cells and may promote metastasis. They also highlight high-dose ascorbate as a promising therapeutic strategy for SDHB-related cancers. SIGNIFICANCE: Loss of different succinate dehydrogenase subunits can lead to different cell and tumor phenotypes, linking stronger 2-OG-dependent dioxygenases inhibition, iron overload, and ROS accumulation following SDHB mutation., (©2021 American Association for Cancer Research.)

BACKGROUNDIdiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess, and an increased risk of cardiovascular morbidity. Here we evaluate systemic and adipose specific metabolic determinants of the IIH phenotype.METHODSIn fasted, matched IIH (n = 97) and control (n = 43) patients, we assessed glucose and insulin homeostasis and leptin levels. Body composition was assessed along with an interrogation of adipose tissue function via nuclear magnetic resonance metabolomics and RNA sequencing in paired omental and subcutaneous biopsies in a case-control study.RESULTSWe demonstrate an insulin- and leptin-resistant phenotype in IIH in excess of that driven by obesity. Adiposity in IIH is preferentially centripetal and is associated with increased disease activity and insulin resistance. IIH adipocytes appear transcriptionally and metabolically primed toward depot-specific lipogenesis.CONCLUSIONThese data show that IIH is a metabolic disorder in which adipose tissue dysfunction is a feature of the disease. Managing IIH as a metabolic disease could reduce disease morbidity and improve cardiovascular outcomes.FUNDINGThis study was supported by the UK NIHR (NIHR-CS-011-028), the UK Medical Research Council (MR/K015184/1), Diabetes UK, Wellcome Trust (104612/Z/14/Z), the Sir Jules Thorn Award, and the Midlands Neuroscience Teaching and Research Fund.

Neonatal encephalopathy due to hypoxia-ischemia is associated with adverse neurodevelopmental effects. The involvement of branched chain amino acids (BCAAs) in this is largely unexplored. Transport of BCAAs at the plasma membrane is facilitated by SLC7A5/SLC3A2, which increase with hypoxia. We hypothesized that hypoxia would alter BCAA transport and metabolism in the neonatal brain. We investigated this using an organotypic forebrain slice culture model with, the SLC7A5/SLC3A2 inhibitor, 2-Amino-2-norbornanecarboxylic acid (BCH) under normoxic or hypoxic conditions. We subsequently analysed the metabolome and candidate gene expression. Hypoxia was associated with increased expression of SLC7A5 and SLC3A2 and an increased tissue abundance of BCAAs. Incubation of slices with 13 C-leucine confirmed that this was due to increased cellular uptake. BCH had little effect on metabolite abundance under normoxic or hypoxic conditions. This suggests hypoxia drives increased cellular uptake of BCAAs in the neonatal mouse forebrain, and membrane mediated transport through SLC7A5 and SLC3A2 is not essential for this process. This indicates mechanisms exist to generate the compounds required to maintain essential metabolism in the absence of external nutrient supply. Moreover, excess BCAAs have been associated with developmental delay, providing an unexplored mechanism of hypoxia mediated pathogenesis in the developing forebrain.

Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent form of liver disease worldwide. This term encompasses a spectrum of pathologies, from benign hepatic steatosis to non-alcoholic steatohepatitis, which have, to date, been challenging to model in the laboratory setting. Here, we present a human pluripotent stem cell (hPSC)-derived model of hepatic steatosis, which overcomes inherent challenges of current models and provides insights into the metabolic rewiring associated with steatosis. Following induction of macrovesicular steatosis in hepatocyte-like cells using lactate, pyruvate, and octanoate (LPO), respirometry and transcriptomic analyses revealed compromised electron transport chain activity. 13 C isotopic tracing studies revealed enhanced TCA cycle anaplerosis, with concomitant development of a compensatory purine nucleotide cycle shunt leading to excess generation of fumarate. This model of hepatic steatosis is reproducible, scalable, and overcomes the challenges of studying mitochondrial metabolism in currently available models., Competing Interests: Professor David Hay is a founder, shareholder, and director in Stemnovate Limited. All other authors declare that they have no competing interests., (© 2020 The Author(s).)

Intracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodelling occurs. Here, we assess whether acute (75 μM ouabain 100 nM blebbistatin) or chronic myocardial Na i load (PLM 3SA mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic 'fingerprint'. Control (PLM WT ), transgenic (PLM 3SA ), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by 23 Na, 31 P, 13 C NMR followed by 1 H-NMR metabolomic profiling. Elevated Na i leads to common adaptive metabolic alterations preceding energetic impairment: a switch from fatty acid to carbohydrate metabolism and changes in steady-state metabolite concentrations (glycolytic, anaplerotic, Krebs cycle intermediates). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 ameliorates the metabolic changes. In silico modelling indicates altered metabolic fluxes (Krebs cycle, fatty acid, carbohydrate, amino acid metabolism). Prevention of Na i overload or inhibition of Na/Ca mito may be a new approach to ameliorate metabolic dysregulation in heart failure.

The early 1990s saw the first useful application of pulsed neutron spectroscopy to the study of excitations in low dimensional magnetic systems, with Roger Cowley as a key participant in important early experiments. Since that time the technique has blossomed as a powerful tool utilizing vastly improved neutron instrumentation coupled with more powerful pulsed sources. Here we review representative experiments illustrating some of the fascinating physics that has been revealed in quasi-one and two dimensional systems., (© 2020 IOP Publishing Ltd.)

The electron-phonon interaction (EPI) is instrumental in a wide variety of phenomena in solid-state physics, such as electrical resistivity in metals, carrier mobility, optical transition, and polaron effects in semiconductors, lifetime of hot carriers, transition temperature in BCS superconductors, and even spin relaxation in diamond nitrogen-vacancy centers for quantum information processing. However, due to the weak EPI strength, most phenomena have focused on electronic properties rather than on phonon properties. One prominent exception is the Kohn anomaly, where phonon softening can emerge when the phonon wave vector nests the Fermi surface of metals. Here we report a new class of Kohn anomaly in a topological Weyl semimetal (WSM), predicted by field-theoretical calculations, and experimentally observed through inelastic x-ray and neutron scattering on WSM tantalum phosphide. Compared to the conventional Kohn anomaly, the Fermi surface in a WSM exhibits multiple topological singularities of Weyl nodes, leading to a distinct nesting condition with chiral selection, a power-law divergence, and non-negligible dynamical effects. Our work brings the concept of the Kohn anomaly into WSMs and sheds light on elucidating the EPI mechanism in emergent topological materials.

Background: Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11β-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation., Methods: We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD + precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO., Results: H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD + biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD + biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD + levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD + /NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD + availability., Conclusions: These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD + salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved.

Complex behavior poses challenges in extracting models from experiment. An example is spin liquid formation in frustrated magnets like Dy 2 Ti 2 O 7 . Understanding has been hindered by issues including disorder, glass formation, and interpretation of scattering data. Here, we use an automated capability to extract model Hamiltonians from data, and to identify different magnetic regimes. This involves training an autoencoder to learn a compressed representation of three-dimensional diffuse scattering, over a wide range of spin Hamiltonians. The autoencoder finds optimal matches according to scattering and heat capacity data and provides confidence intervals. Validation tests indicate that our optimal Hamiltonian accurately predicts temperature and field dependence of both magnetic structure and magnetization, as well as glass formation and irreversibility in Dy 2 Ti 2 O 7 . The autoencoder can also categorize different magnetic behaviors and eliminate background noise and artifacts in raw data. Our methodology is readily applicable to other materials and types of scattering problems.

Mutations in succinate dehydrogenase (SDH) lead to the development of tumors in a restricted subset of cell types, including chromaffin cells and paraganglia. The molecular basis for this specificity is currently unknown. We show that loss of SDH activity in a chromaffin cell model does not perturb complex I function, retaining the ability to oxidize NADH within the electron transport chain. This activity supports continued oxidation of substrates within the tricarboxylic acid (TCA) cycle. However, due to the block in the TCA cycle at SDH, the high glutamine oxidation activity is only maintained through an efflux of succinate. We also show that although the mitochondria of SDH-deficient cells are less active per se, their higher mass per cell results in an overall respiratory rate that is comparable with wild-type cells. Finally, we observed that when their mitochondria are uncoupled, SDH-deficient cells are unable to preserve their viability, suggesting that the mitochondrial metabolic network is unable to compensate when exposed to additional stress. We therefore show that in contrast to models of SDH deficiency based on epithelial cells, a chromaffin cell model retains aspects of metabolic "health," which could form the basis of cell specificity of this rare tumor type., (© 2019 The Authors. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.)

An abundant supply of amino acids is important for cancers to sustain their proliferative drive. Alongside their direct role as substrates for protein synthesis, they can have roles in energy generation, driving the synthesis of nucleosides and maintenance of cellular redox homoeostasis. As cancer cells exist within a complex and often nutrient-poor microenvironment, they sometimes exist as part of a metabolic community, forming relationships that can be both symbiotic and parasitic. Indeed, this is particularly evident in cancers that are auxotrophic for particular amino acids. This review discusses the stromal/cancer cell relationship, by using examples to illustrate a number of different ways in which cancer cells can rely on and contribute to their microenvironment - both as a stable network and in response to therapy. In addition, it examines situations when amino acid synthesis is driven through metabolic coupling to other reactions, and synthesis is in excess of the cancer cell's proliferative demand. Finally, it highlights the understudied area of non-proteinogenic amino acids in cancer metabolism and their potential role.

We investigate the interaction of horse heart cytochrome c (cyt c) with hematite nanowire array electrodes by cyclic voltammetry to study the electron transfer between redox active proteins and mineral surfaces. Using this model system, we quantify electron transfer rates between cyt c and hematite under varying electric potential and pH conditions. The results are consistent with two cyt c conformations adsorbed at the hematite surface: the native and a partially unfolded form. The partially unfolded protein maintained redox activity, but at a lower redox potential than the native protein. Adsorption of cyt c allowed direct electron transfer between cyt c and hematite, with an interfacial electron transfer rate, k° ET , of 0.4 s -1 for the native form and 0.55 s -1 for the partially unfolded protein at pH 7.07. At pH 4.66, protein adsorption decreased compared to neutral pH and the fraction of partially unfolded protein increased. Additionally, the diffusion controlled electron transfer rate between hematite and the electron shuttling compound anthraquinone-2,6-disulfonate (AQDS) was determined to be k° ET  = 8.0·10 -3  cm·s -1 at pH 7.07. Modulation of electron transfer rates as a result of conformational changes by redox active proteins has broad implications for describing chemical transformations at biological-mineral interfaces., (Copyright © 2019. Published by Elsevier B.V.)

Background: Skeletal muscle is central to whole body metabolic homeostasis, with age and disease impairing its ability to function appropriately to maintain health. Inadequate NAD + availability is proposed to contribute to pathophysiology by impairing metabolic energy pathway use. Despite the importance of NAD + as a vital redox cofactor in energy production pathways being well-established, the wider impact of disrupted NAD + homeostasis on these pathways is unknown. Methods: We utilised skeletal muscle myotube models to induce NAD + depletion, repletion and excess and conducted metabolic tracing to provide comprehensive and detailed analysis of the consequences of altered NAD + metabolism on central carbon metabolic pathways. We used stable isotope tracers, [1,2-13C] D-glucose and [U- 13 C] glutamine, and conducted combined 2D-1H,13C-heteronuclear single quantum coherence (HSQC) NMR spectroscopy and GC-MS analysis. Results: NAD + excess driven by nicotinamide riboside (NR) supplementation within skeletal muscle cells resulted in enhanced nicotinamide clearance, but had no effect on energy homeostasis or central carbon metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) inhibition induced NAD + depletion and resulted in equilibration of metabolites upstream of glyceraldehyde phosphate dehydrogenase (GAPDH). Aspartate production through glycolysis and TCA cycle activity was increased in response to low NAD + , which was rapidly reversed with repletion of the NAD + pool using NR. NAD + depletion reversibly inhibits cytosolic GAPDH activity, but retains mitochondrial oxidative metabolism, suggesting differential effects of this treatment on sub-cellular pyridine pools. When supplemented, NR efficiently reversed these metabolic consequences. However, the functional relevance of increased aspartate levels after NAD + depletion remains unclear, and requires further investigation. Conclusions: These data highlight the need to consider carbon metabolism and clearance pathways when investigating NAD + precursor usage in models of skeletal muscle physiology., Competing Interests: No competing interests were disclosed.