Granzyme B May Act as an Effector Molecule to Control the Inflammatory Process in COPD.

Chronic obstructive pulmonary disease (COPD) is caused by smoking, but only a small proportion of smokers have disease severe enough to develop COPD. COPD is not always progressive. The question then arises as to what explains the different trajectories of COPD. The role of autoimmunity and regulatory T (Treg) cells in the pathogenesis of COPD is increasingly being recognized. Nine published studies on Treg cells in the lung tissue or bronchoalveolar lavage fluid have shown that smokers with COPD have fewer Treg cells than smokers without COPD or nonsmokers. Three studies showed a positive correlation between Treg cell count and FEV1%, suggesting an important role for Treg cells in COPD progression. Treg cells can regulate immunological responses via the granzyme B (GzmB) pathway. Immunohistochemical staining for GzmB in surgically resected lungs with centrilobular emphysema showed that the relationship between the amount of GzmB+ cells and FEV1% was comparable to that between Treg cell count and FEV1% in the COPD lung, suggesting that GzmB could be a functional marker for Treg cells. The volume fraction of GzmB+ cells in the small airways, the number of alveolar GzmB+ cells, and GzmB expression measured by enzyme-linked immunosorbent assay in the lung tissue of smokers were significantly correlated with FEV1%. These results suggest that the GzmB content in lung tissue may determine the progression of COPD by acting as an effector molecule to control inflammatory process. Interventions to augment GzmB-producing immunosuppressive cells in the early stages of COPD could help prevent or delay COPD progression.

Butylparaben promotes phosphatidylserine exposure and procoagulant activity of human red blood cells via increase of intracellular calcium levels.

Parabens are widely used as preservatives, added to products commonly used by humans, and to which individuals are exposed orally or dermally. Once absorbed into the body, parabens move into the bloodstream and travel through the systemic circulation. We investigated the potential impact of parabens on the enhanced generation of thrombin by red blood cells (RBCs), which are the principal cellular components of blood. We tested the effects of methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), butylparaben (BuP), and p-hydroxybenzoic acid on freshly isolated human RBCs. BuP and simultaneous exposure to BuP and PrP significantly increased phosphatidylserine (PS) externalization to the outer membranes of RBCs. PS externalization by BuP was found to be mediated by increasing intracellular Ca2+ levels in RBCs. The morphological changes in BuP-treated RBCs were observed under an electron microscope. The BuP-exposed RBCs showed increased thrombin generation and adhesion to endothelial cells. Additionally, the externalization of PS exposure and thrombin generation in BuP-treated RBCs were more susceptible to high shear stress, which mimics blood turbulence under pathological conditions. Collectively, we observed that BuP induced morphological and functional changes in RBCs, especially under high shear stress, suggesting that BuP may contribute to the thrombotic risk via procoagulant activity in RBCs.

Mono-(2-ethylhexyl)-phthalate potentiates methylglyoxal-induced blood-brain barrier damage via mitochondria-derived oxidative stress and bioenergetic perturbation.

Phthalates in contaminated foods and personal care products are one of the most frequently exposed chemicals with a public health concern. Phthalate exposure is related to cardiovascular diseases, including diabetic vascular complications and cerebrovascular diseases, yet the mechanism is still unclear. The blood-brain barrier (BBB) integrity disruption is strongly associated with cardiovascular and neurological disease exacerbation. We investigated BBB damage by di-(2-ethylhexyl) phthalate (DEHP) or its metabolite mono-(2-ethylhexyl) phthalate (MEHP) using brain endothelial cells and rat models. BBB damage by the subthreshold level of MEHP, but not a DEHP, significantly increased by the presence of methylglyoxal (MG), a reactive dicarbonyl compound whose levels increase in the blood in hyperglycemic conditions in diabetic patients. Significant potentiation in apoptosis and autophagy activation, mitochondria-derived reactive oxygen species (ROS) production, and mitochondrial metabolic disturbance were observed in brain ECs by co-exposure to MG and MEHP. N-acetyl cysteine (NAC) restored autophagy activation as well as tight junction protein impairment induced by co-exposure to MG and MEHP. Intraperitoneal administration of MG and MEHP significantly altered mitochondrial membrane potential and tight junction integrity in rat brain endothelium. This study may provide novel insights into enhancing phthalate toxicity in susceptible populations, such as diabetic patients.

Salvia plebeia R.Br. and Rosmarinic Acid Attenuate Dexamethasone-Induced Muscle Atrophy in C2C12 Myotubes.

Skeletal muscle atrophy occurs when protein degradation exceeds protein synthesis and is associated with increased circulating glucocorticoid levels. Salvia plebeia R.Br. (SPR) has been used as herbal remedy for a variety of inflammatory diseases and has various biological actions such as antioxidant and anti-inflammatory activities. However, there are no reports on the effects of SPR and its bioactive components on muscle atrophy. Herein, we investigated the anti-atrophic effect of SPR and rosmarinic acid (RosA), a major compound of SPR, on dexamethasone (DEX)-induced skeletal muscle atrophy in C2C12 myotubes. Myotubes were treated with 10 µM DEX in the presence or absence of SPR or RosA at different concentrations for 24 h and subjected to immunocytochemistry, western blot, and measurements of ROS and ATP levels. SPR and RosA increased viability and inhibited protein degradation in DEX-treated C2C12 myotubes. In addition, RosA promoted the Akt/p70S6K/mTOR pathway and reduced ROS production, and apoptosis. Furthermore, the treatment of RosA significantly recovered SOD activity, autophagy activity, mitochondrial contents, and APT levels in DEX-treated myotubes. These findings suggest that SPR and RosA may provide protective effects against DEX-induced muscle atrophy and have promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.

Phenotype of Chronic Obstructive Pulmonary Disease Based on Computed Tomography-Defined Underlying Pathology.

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease. Not all patients with COPD respond to available drugs. Identifying respondents to therapy is critical to delivering the most appropriate treatment and avoiding unnecessary medication. Recognition of individual patients' dominant characteristics by phenotype is a useful tool to better understand their disease and tailor treatment accordingly. To look for a suitable phenotype, it is important to understand what makes COPD complex and heterogeneous. The pathology of COPD includes small airway disease and/or emphysema. Thus, COPD is not a single disease entity. In addition, there are two types (panlobular and centrilobular) of emphysema in COPD. The coexistence of different pathological subtypes could be the reason for the complexity and heterogeneity of COPD. Thus, it is necessary to look for the phenotype based on the difference in the underlying pathology. Review of the literature has shown that clinical manifestation and therapeutic response to pharmacological therapy are different depending on the presence of computed tomography-defined airway wall thickening in COPD patients. Defining the phenotype of COPD based on the underlying pathology is encouraging as most clinical manifestations can be distinguished by the presence of increased airway wall thickness. Pharmacological therapy has shown significant effect on COPD with airway wall thickening. However, it has limited use in COPD without an airway disease. The phenotype of COPD based on the underlying pathology can be a useful tool to better understand the disease and adjust treatment accordingly.

Ablation of USP21 in skeletal muscle promotes oxidative fibre phenotype, inhibiting obesity and type 2 diabetes.

BACKGROUND: Skeletal muscle as a metabolic consumer determines systemic energy homeostasis by regulating myofibre type conversion and muscle mass control. Perturbation of the skeletal muscle metabolism elevates the risk of a variety of diseases including metabolic disorders. However, the regulatory pathways and molecules are not completely understood. The discovery of relevant responsible molecules and the associated network could be an attractive strategy to overcome diseases associated with muscle problems. METHODS: An initial screening using quantitative trait locus analysis enabled us to extract a set of genes including ubiquitin-specific proteases21 (USP21) (r = 0.738; P = 0.004) as potential targets associated with fasting blood glucose content. Given tight regulation of the ubiquitination status of proteins in muscle, we focused on USP21 and generated whole-body (KO) and skeletal muscle-specific USP21 knockout (MKO) mice. Transcriptomics, proteomics, and lipidomics assays in combination with various in vivo and in vitro experiments were performed to understand the functions of USP21 and underlying mechanisms. A high-fat diet (60%)-fed mouse model and diabetic patient-derived samples were utilized to assess the effects of USP21 on energy metabolism in skeletal muscle. RESULTS: USP21 was highly expressed in both human and mouse skeletal muscle, and controlled skeletal muscle oxidative capacity and fuel consumption. USP21-KO or USP21-MKO significantly promoted oxidative fibre type changes (Δ36.6% or Δ47.2%), muscle mass increase (Δ13.8% to Δ22.8%), and energy expenditure through mitochondrial biogenesis, fatty acid oxidation, and UCP2/3 induction (P < 0.05 or P < 0.01). Consistently, cold exposure repressed USP21 expression in mouse skeletal muscle (Δ55.3%), whereas loss of USP21 increased thermogenesis (+1.37°C or +0.84°C; P < 0.01). Mechanistically, USP21 deubiquitinated DNA-PKcs and ACLY, which led to AMPK inhibition. Consequently, USP21 ablation diminished diet-induced obesity (WT vs. USP21-KO, Δ8.02 g, 17.1%, P < 0.01; litter vs. USP21-MKO, Δ3.48 g, 7.7%, P < 0.05) and insulin resistance. These findings were corroborated in a skeletal muscle-specific gene KO mouse model. USP21 was induced in skeletal muscle of a diabetic patient (1.94-fold), which was reciprocally changed to p-AMPK (0.30-fold). CONCLUSIONS: The outcomes of this research provide novel information as to how USP21 in skeletal muscle contributes to systemic energy homeostasis, demonstrating USP21 as a key molecule in the regulation of myofibre type switch, muscle mass control, mitochondrial function, and heat generation and, thus, implicating the potential of this molecule and its downstream substrates network as targets for the treatment and/or prevention of muscle dysfunction and the associated metabolic diseases.

Virtual randomized study comparing lobectomy and particle beam therapy for clinical stage IA non-small cell lung cancer in operable patients.

To the best of our knowledge there have been no randomized controlled trials comparing lobectomy-a standard treatment for patients with early-stage non-small cell lung cancer (NSCLC)-and particle beam therapy (PBT), the best performing existing radiotherapy. We conducted a virtual randomized trial in medically operable patients with stage IA NSCLC to compare lobectomy and PBT effectiveness. A Markov model was developed to predict life expectancy after lobectomy and PBT in a cohort of patients with stage IA NSCLC. Ten thousand virtual patients were randomly assigned to each group. Sensitivity analyses were performed as model variables and scenarios changed to determine which treatment strategy was best for improving life expectancy. All estimated model parameters were determined using variables extracted from a systematic literature review of previously published articles. The preferred strategy differed depending on patient age. In young patients, lobectomy showed better life expectancy than that of PBT. The difference in life expectancy between lobectomy and PBT was statistically insignificant in older patients. Our model predicted lobectomy as the preferred strategy when operative mortality was under 5%. However, the preferred strategy changed to PBT if operative mortality post lobectomy was over 5%. For medically operable patients with stage IA NSCLC, our Markov model revealed the preferred strategy of lobectomy or PBT regarding operative mortality changed with varying age and comorbidity. Until randomized controlled trial results become available, we hope the current results will provide a rationale background for clinicians to decide treatment modalities for patients with stage IA NSCLC.

The Role of Granzyme B Containing Cells in the Progression of Chronic Obstructive Pulmonary Disease.

BACKGROUND: Lung inflammation plays a vital role in the pathogenesis of chronic obstructive pulmonary disease (COPD), but the characteristics of the inflammatory process remain unclear. There is growing interest in the role of granzyme B (GzmB) because CD8+ T cells can induce apoptosis of target cells by releasing GzmB, which in turn may cause tissue injury and remodeling. However, GzmB is also expressed by regulatory cells, which are able to suppress CD8+ T cell. The role of GzmB+ cells needs to be defined in COPD. METHODS: GzmB+ and CD8+ cells on alveolar wall of surgically resected lungs of microscopically classified 12 nonsmoking control, 12 panlobular emphysema (PLE) and 30 centrilobular emphysema (CLE) subjects were localized by immunohistochemical method. Positively stained cells on alveolar wall were counted and length of corresponding alveolar wall was measured. The results were expressed as mean number of positively stained cells per mm of alveolar wall in each subject. RESULTS: The number of GzmB+ and CD8+ cells on alveolar wall of CLE was greater than that of control or PLE subjects (p<0.05 and p<0.001, respectively). There was a positive relationship between the number of alveolar GzmB+ cells and forced expiratory volume in 1 second (FEV1) (r=0.610, p=0.003) in CLE subjects. The number of alveolar GzmB+ cells progressively decreased with decline of FEV1. CONCLUSION: Our finding that number of alveolar GzmB+ cells was associated with FEV1 suggests that GzmB+ cells might have protective role in the progression of lung destruction and airflow limitation in CLE, which is the predominant emphysema subtype of COPD.

Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages.

The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA5)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA5 upregulation in injured skin. Suppressing the activity of LPA5 with TCLPA5, a selective LPA5 antagonist, improved psoriasis symptoms, including ear thickening, skin erythema, and skin scaling in imiquimod-challenged mice. TCLPA5 administration attenuated dermal infiltration of macrophages that were found as the major cell type for LPA5 upregulation in psoriasis lesions. Notably, TCLPA5 administration attenuated the upregulation of macrophage NLRP3 in injured skin of mice with imiquimod-induced psoriasis. This critical role of LPA5 in macrophage NLRP3 was further addressed using lipopolysaccharide-primed bone marrow-derived macrophages. LPA exposure activated NLRP3 inflammasome in lipopolysaccharide-primed cells, which was evidenced by NLRP3 upregulation, caspase-1 activation, and IL-1ß maturation/secretion. This LPA-driven NLRP3 inflammasome activation in lipopolysaccharide-primed cells was significantly attenuated upon LPA5 knockdown. Overall, our findings establish a pathogenic role of LPA5 in psoriasis along with an underlying mechanism, further suggesting LPA5 antagonism as a potential strategy to treat psoriasis.

Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney.

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography-mass spectrometry-based (LC-MS-based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase-mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.

Controlling the Magnetic Anisotropy of the van der Waals Ferromagnet Fe3GeTe2 through Hole Doping.

Identifying material parameters affecting properties of ferromagnets is key to optimized materials that are better suited for spintronics. Magnetic anisotropy is of particular importance in van der Waals magnets, since it not only influences magnetic and spin transport properties, but also is essential to stabilizing magnetic order in the two-dimensional limit. Here, we report that hole doping effectively modulates the magnetic anisotropy of a van der Waals ferromagnet and explore the physical origin of this effect. Fe3-xGeTe2 nanoflakes show a significant suppression of the magnetic anisotropy with hole doping. Electronic structure measurements and calculations reveal that the chemical potential shift associated with hole doping is responsible for the reduced magnetic anisotropy by decreasing the energy gain from the spin-orbit induced band splitting. Our findings provide an understanding of the intricate connection between electronic structures and magnetic properties in two-dimensional magnets and propose a method to engineer magnetic properties through doping.

Polyunsaturated Fatty Acid Desaturation Is a Mechanism for Glycolytic NAD+ Recycling.

The reactions catalyzed by the delta-5 and delta-6 desaturases (D5D/D6D), key enzymes responsible for highly unsaturated fatty acid (HUFA) synthesis, regenerate NAD+ from NADH. Here, we show that D5D/D6D provide a mechanism for glycolytic NAD+ recycling that permits ongoing glycolysis and cell viability when the cytosolic NAD+/NADH ratio is reduced, analogous to lactate fermentation. Although lesser in magnitude than lactate production, this desaturase-mediated NAD+ recycling is acutely adaptive when aerobic respiration is impaired in vivo. Notably, inhibition of either HUFA synthesis or lactate fermentation increases the other, underscoring their interdependence. Consistent with this, a type 2 diabetes risk haplotype in SLC16A11 that reduces pyruvate transport (thus limiting lactate production) increases D5D/D6D activity in vitro and in humans, demonstrating a chronic effect of desaturase-mediated NAD+ recycling. These findings highlight key biologic roles for D5D/D6D activity independent of their HUFA end products and expand the current paradigm of glycolytic NAD+ regeneration.

Long-term Survival after Repeated Local Therapy and Salvage Chemotherapy for Recurrent Metastases from Gastric Cancer: a Case Report and Literature Review.

We report a rare case of long-term survival in a patient who received local therapy and salvage chemotherapy for recurrent metastases, along with a literature review. A 65-year-old male patient underwent subtotal gastrectomy for advanced gastric adenocarcinoma. Six months after gastrectomy, 2 metastatic intra-abdominal lymph node enlargements were detected, which were treated with radiotherapy. At 55 months after gastrectomy, an abdominal wall mass was detected, which was treated by surgical resection. The patient received 5-fluorouracil/leucovorin/irinotecan chemotherapy for 27 months before and after radiotherapy and docetaxel chemotherapy for 6 months after surgical resection of the abdominal wall metastasis. At the last visit, 7.8 years since the initial resection of the primary gastric cancer and 6.2 years since detection of the first metastases, the patient was disease-free and required no further chemotherapy. This case suggests that repeated local therapy offers potential for long-term survival in a carefully selected subset of patients with recurrent metastases.

Enhanced Performance of Field-Effect Transistors Based on Black Phosphorus Channels Reduced by Galvanic Corrosion of Al Overlayers.

Two-dimensional (2D)-layered semiconducting materials with considerable band gaps are emerging as a new class of materials applicable to next-generation devices. Particularly, black phosphorus (BP) is considered to be very promising for next-generation 2D electrical and optical devices because of its high carrier mobility of 200-1000 cm2 V-1 s-1 and large on/off ratio of 104 to 105 in field-effect transistors (FETs). However, its environmental instability in air requires fabrication processes in a glovebox filled with nitrogen or argon gas followed by encapsulation, passivation, and chemical functionalization of BP. Here, we report a new method for reduction of BP-channel devices fabricated without the use of a glovebox by galvanic corrosion of an Al overlayer. The reduction of BP induced by an anodic oxidation of Al overlayer is demonstrated through surface characterization of BP using atomic force microscopy, Raman spectroscopy, and X-ray photoemission spectroscopy along with electrical measurement of a BP-channel FET. After the deposition of an Al overlayer, the FET device shows a significantly enhanced performance, including restoration of ambipolar transport, high carrier mobility of 220 cm2 V-1 s-1, low subthreshold swing of 0.73 V/decade, and low interface trap density of 7.8 × 1011 cm-2 eV-1. These improvements are attributed to both the reduction of the BP channel and the formation of an Al2O3 interfacial layer resulting in a high- k screening effect. Moreover, ambipolar behavior of our BP-channel FET device combined with charge-trap behavior can be utilized for implementing reconfigurable memory and neuromorphic computing applications. Our study offers a simple device fabrication process for BP-channel FETs with high performance using galvanic oxidation of Al overlayers.

Charge-Spin Correlation in van der Waals Antiferromagnet NiPS_{3}.

Strong charge-spin coupling is found in a layered transition-metal trichalcogenide NiPS_{3}, a van der Waals antiferromagnet, from studies of the electronic structure using several experimental and theoretical tools: spectroscopic ellipsometry, x-ray absorption, photoemission spectroscopy, and density functional calculations. NiPS_{3} displays an anomalous shift in the optical spectral weight at the magnetic ordering temperature, reflecting strong coupling between the electronic and magnetic structures. X-ray absorption, photoemission, and optical spectra support a self-doped ground state in NiPS_{3}. Our work demonstrates that layered transition-metal trichalcogenide magnets are useful candidates for the study of correlated-electron physics in two-dimensional magnetic materials.

Sequential spinal and intracranial dural metastases in gastric adenocarcinoma: A case report.

Dural metastasis from primary gastric adenocarcinoma has been rarely reported, and its prognosis is very poor because it frequently leads to acute subdural hematoma. Here, we describe a case with sequential spinal and cranial dural metastases from gastric adenocarcinoma without subdural hematoma. A 43-year-old woman with gastric adenocarcinoma and well-controlled peritoneal carcinomatosis presented with back pain, right radiating leg pain, left facial palsy, and hearing loss. Magnetic resonance imaging of the spine and brain revealed dural masses at the lumbosacral junction with invasion to the L5 and S1 nerve roots and at the skull base with invasion to the internal auditory canal. She was treated with local radiotherapy, and her pain and neurologic symptoms improved after palliative radiotherapy. This is the first reported case of dural metastases of gastric adenocarcinoma of the spine and skull base but with a relatively indolent course and without subdural hematoma.

ESTIMATION OF THE CUMULATIVE EXPOSURE FREQUENCY AND CUMULATIVE EFFECTIVE DOSE OF DIAGNOSTIC MEDICAL RADIATION IN THE KOREAN POPULATION FROM 2002 TO 2010.

Along with increase in the frequency and exposure dose from the diagnostic medical radiation procedures, the public's interest in radiation exposure has also been growing. In this study, in order to estimate the Cumulative Exposure Frequency and the cumulative effective dose of diagnostic medical radiation in the Korean population, we included 680 diagnostic medical radiation procedure codes of the Health Insurance Review & Assessment Service's health insurance medical expenses data and adopted the effective dose data from the 2008 report of the United Nations Scientific Committee on the Effects of Atomic Radiation. We combined the data of one million individuals in the national sample cohort database (2002-10) of the National Health Insurance Service. The results revealed that 93.2% (917 972) of the subjects were exposed to diagnostic medical radiation at least once in the past nine years, and the Cumulative Exposure Frequency was 17 286.4 per 1000 individuals with a cumulative effective dose of 5.7 (±17.8) mSv per person. Additionally, 93.1% (854 480) of the subjects had a cumulative effective dose less than 20 mSv, and 0.7% (6139) had a dose that exceeded 100 mSv (extreme), showing that the dosage level was mostly low. However, the number of individuals whose exposure exceeded 100 mSv/y increased 28-fold, from 18 in 2002 to 500 in 2010. In addition, the size of increase also grew each year, suggesting that cancer occurrence due to diagnostic medical radiation may have also increased. In order determine the causal relationship between cancer occurrence and diagnostic medical radiation and setup a guideline for exposure, it is necessary to monitor individual cumulative exposure doses nation-wide and follow up on heavily exposed individuals for an extended period of time.

PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection.

The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients. Here we show that the mitochondrial biogenesis regulator, PGC1α, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1α(-/-) (also known as Ppargc1a(-/-)) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1α(-/-) mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1α coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product ß-hydroxybutyrate, leading to increased production of prostaglandin PGE2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of ß-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1α-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1α-dependent stress resistance.

Skyrmion motion driven by oscillating magnetic field.

The one-dimensional magnetic skyrmion motion induced by an electric current has attracted much interest because of its application potential in next-generation magnetic memory devices. Recently, the unidirectional motion of large (20 µm in diameter) magnetic bubbles with two-dimensional skyrmion topology, driven by an oscillating magnetic field, has also been demonstrated. For application in high-density memory devices, it is preferable to reduce the size of skyrmion. Here we show by numerical simulation that a skyrmion of a few tens of nanometres can also be driven by high-frequency field oscillations, but with a different direction of motion from the in-plane component of the tilted oscillating field. We found that a high-frequency field for small skyrmions can excite skyrmion resonant modes and that a combination of different modes results in a final skyrmion motion with a helical trajectory. Because this helical motion depends on the frequency of the field, we can control both the speed and the direction of the skyrmion motion, which is a distinguishable characteristic compared with other methods.

Friction and conductance imaging of sp(2)- and sp(3)-hybridized subdomains on single-layer graphene oxide.

We investigated the subdomain structures of single-layer graphene oxide (GO) by characterizing local friction and conductance using conductive atomic force microscopy. Friction and conductance mapping showed that a single-layer GO flake has subdomains several tens to a few hundreds of nanometers in lateral size. The GO subdomains exhibited low friction (high conductance) in the sp(2)-rich phase and high friction (low conductance) in the sp(3)-rich phase. Current-voltage spectroscopy revealed that the local current flow in single-layer GO depends on the quantity of hydroxyl and carboxyl groups, and epoxy bridges within the 2-dimensional carbon layer. The presence of subdomains with different sp(2)/sp(3) carbon ratios on a GO flake was also confirmed by chemical mapping using scanning transmission X-ray microscopy. These results suggest that spatial mapping of the friction and conductance can be used to rapidly identify the composition of heterogeneous single-layer GO at nanometer scale, which is essential for understanding charge transport in nanoelectronic devices.