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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 all experimentally observed Weyl semimetals so far, the Weyl points always appear in pairs in the momentum space. Here, the authors report one unpaired Weyl point without surface Fermi arc emerging at the center of the Brillouin zone, which is surrounded by charged Weyl nodal walls in PtGa.

Neurotensin, a peptide expressed in the enteroendocrine cells of the small intestine that is released upon fat ingestion, is shown to increase fatty acid absorption, with neurotensin-deficient mice being protected from obesity induced by a high-fat diet. Neurotensin is a factor in obesity Neurotensin (NT) is a 13-amino-acid peptide expressed in the enteroendocrine cells of the small bowel, and is released upon fat ingestion to facilitate fatty acid translocation. There are three known NT receptors, termed NTR1, NTR2 and NTR3. These authors show that NT increases fatty acid absorption and inhibition of downstream AMPK activity in intestinal cells via NTR1 and NTR3. Mice deficient in NT and on a high fat diet are protected from obesity, hepatic steatosis and insulin resistance, unlike their wild-type counterparts. Expression of NT in enteroendocrine cells of the fly increases lipid accumulation in the midgut, fat body and oenocytes, and also decreases AMPK activity, suggesting conservation of the pathway. Obese and insulin-resistant humans are shown to have elevated plasma levels of pro-NT, a precursor of NT, and high levels of pro-NT double the risk of obesity later in life. Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually 1 and are among the most prevalent and challenging conditions confronting the medical profession 2 , 3 . Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine 4 and released by fat ingestion 5 , facilitates fatty acid translocation in rat intestine 6 , and stimulates the growth of various cancers 7 . The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively) 8 . Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality 9 ; however, a role for NT as a causative factor in these diseases is unknown. Here we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates fatty acid absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3 (also known as sortilin). Consistent with the findings in mice, expression of NT in Drosophila midgut enteroendocrine cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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.

Profound metabolic changes are characteristic of macrophages during classical activation and have been implicated in this phenotype. Here we demonstrate that nitric oxide (NO) produced by murine macrophages is responsible for TCA cycle alterations and citrate accumulation associated with polarization. 13 C tracing and mitochondrial respiration experiments map NO-mediated suppression of metabolism to mitochondrial aconitase (ACO2). Moreover, we find that inflammatory macrophages reroute pyruvate away from pyruvate dehydrogenase (PDH) in an NO-dependent and hypoxia-inducible factor 1α (Hif1α)-independent manner, thereby promoting glutamine-based anaplerosis. Ultimately, NO accumulation leads to suppression and loss of mitochondrial electron transport chain (ETC) complexes. Our data reveal that macrophages metabolic rewiring, in vitro and in vivo, is dependent on NO targeting specific pathways, resulting in reduced production of inflammatory mediators. Our findings require modification to current models of macrophage biology and demonstrate that reprogramming of metabolism should be considered a result rather than a mediator of inflammatory polarization. Production of inflammatory mediators by M1-polarized macrophages is thought to rely on suppression of mitochondrial metabolism in favor of glycolysis. Refining this concept, here the authors define metabolic targets of nitric oxide as responsible for the mitochondrial rewiring resulting from polarization.

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.

Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH + subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival. In mouse xenograft tumor, PDK1 is accumulated in hypoxic regions and activates glycolysis to promote stem-like traits. Moreover, through screening hypoxia-related long non-coding RNAs (lncRNAs) in PDK1-positive tissue, we find that lncRNA H19 is responsible for glycolysis and BCSC maintenance. Furthermore, H19 knockdown decreases PDK1 expression in hypoxia, and ablation of PDK1 counteracts H19-mediated glycolysis and self-renewal ability in vitro and in vivo . Accordingly, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. H19 acting as a competitive endogenous RNA sequesters miRNA let-7 to release Hypoxia-inducible factor 1α, leading to an increase in PDK1 expression. Lastly, aspirin markedly attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Thus, these novel findings demonstrate that the glycolysis gatekeeper PDK1 has a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy.

T cells undergo metabolic rewiring to meet their bioenergetic, biosynthetic and redox demands following antigen stimulation. To fulfil these needs, effector T cells must adapt to fluctuations in environmental nutrient levels at sites of infection and inflammation. Here, we show that effector T cells can utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose in vitro. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase. We demonstrate that the ribose subunit of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors, and that cancer cells display diverse capacities to utilize inosine as a carbon source. Moreover, the supplementation with inosine enhances the anti-tumour efficacy of immune checkpoint blockade and adoptive T-cell transfer in solid tumours that are defective in metabolizing inosine, reflecting the capability of inosine to relieve tumour-imposed metabolic restrictions on T cells. Lymphocytes encounter fluctuations in nutrient availability at sites of infection and inflammation. Wang et al. report that inosine can fulfil the metabolic needs of glucose-restricted anti-tumour effector CD8 + T cells.

Cancer cells are known to upregulate aerobic glycolysis to promote growth, proliferation, and survival. However, the role of mitochondrial respiration in tumorigenesis remains elusive. Here we report that inhibition of mitochondrial function by silencing TFAM, a key transcription factor essential for mitochondrial DNA (mtDNA) replication and the transcription of mtDNA-encoded genes, markedly reduced tumor-initiating potential of colon cancer cells. Knockdown of TFAM significantly decreased mitochondrial respiration in colon cancer cells; however, the cellular levels of ATP remained largely unchanged as a result of increased glycolysis. This metabolic alteration rendered cancer cells highly susceptible to glucose deprivation. Interestingly, upregulation of glycolysis was independent of hypoxia-inducible factor-1 (HIF1) as TFAM knockdown cells fail to stabilize HIF1α under hypoxic conditions. Moreover, knockdown of TFAM results in decreased expression of genes-associated cancer stem cells downstream of Wnt/β-catenin signaling. Metabolic analysis reveals that the level of α-ketoglutarate (α-KG) was significantly upregulated in TFAM knockout cells. Silencing of prolyl hydroxylase domain-containing protein 2 (PHD2), a α-KG-dependent dioxyenase, rescued the expression of target genes of both HIF1α and Wnt/β-catenin. Furthermore, intestinal-specific knockout of TFAM prevents tumor formation in Apc-mutant mouse models of colon cancer. Taken together, our findings identify a novel role of mitochondria-mediated retrograde signaling in regulating Wnt signaling and tumor initiation in colon cancer.

An efficient Galerkin averaging-incremental harmonic balance (EGA-IHB) method is developed for steady-state nonlinear dynamic analysis of index-3 differential algebraic equations (DAEs) for general rigid multibody systems. The multibody dynamic modeling theory has made significant advances in generality and simplicity, and multibody systems are usually governed by DAEs. The bridge between the multibody dynamic modeling theory and nonlinear dynamic analysis theory is built for the first time in this work, and the EGA-IHB method can be used as a universal solver for obtaining steady-state periodic responses of DAEs for general multibody systems. Since the fast Fourier transform and EGA are used, the EGA-IHB method has excellent robustness. Since the Floquet theory cannot be directly used for stability analysis of periodic responses of DAEs, a new stability analysis procedure is developed, where perturbed, linearized DAEs are reduced to ordinary differential equations with use of independent generalized coordinates. A modified arc-length continuation method with a scaling strategy is proposed for calculating response curves and conducting parameter studies. Several examples are used to show the performance and capability of the current method. Periodic solutions of DAEs from the EGA-IHB method show excellent agreement with those from numerical integration methods. Amplitude–frequency and amplitude–parameter response curves are generated, and stability and period-doubling bifurcations are analyzed. The current method shows excellent computational efficiency and robustness in solving high-dimensional DAEs.

( ) is one of the main pathogens responsible for refractory root canal infections in the teeth and shows resistance against various antibacterial managements. Effective control of infection is a prerequisite for successful treatment of refractory apical periodontitis. This study aimed to analyze the antibacterial activity and mechanisms of Au@Ag nanoparticles (NPs) combined with photothermal therapy (PTT) against the original and Ag -resistant Au@AgNPs with optimal shell thicknesses were synthesized and characterized. The antibacterial activity of Au@AgNPs with PTT against the original or Ag -resistant was evaluated, and the antibiofilm activity was tested on biofilm on the dentin of teeth. The potential antibacterial mechanisms of Au@AgNPs combined with PTT against have also been studied. Moreover, its influence on dentin microhardness and cytotoxicity was assessed. This study revealed that Au@AgNPs combined with PTT showed enhanced antibacterial and antibiofilm effects, no negative effects on dentin microhardness, and low cytotoxicity toward human periodontal ligament cells (hPDLCs). Moreover, Au@AgNPs combined with PTT effectively inhibited the growth of Ag -resistant . Its antibacterial effects may be exerted through the release of silver ions (Ag ), destruction of the cell membrane, production of reactive oxygen species (ROS) and inhibition of adenosine triphosphate (ATP) production. Hyperthermia generated by Au@AgNPs with PTT reduced membrane fluidity and enhanced Ag sensitivity by downregulating expression. The upregulated expression of heat shock genes demonstrated that the Ag released from Au@AgNPs compromised the heat adaptation of . PTT significantly enhanced Ag sensitivity of the original and Ag -resistant . Au@AgNPs combined with PTT may have the potential to be developed as a new antibacterial agent to control infections in teeth.