Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension.

Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan. Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.

The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex.

SGK1 is an AGC kinase that regulates the expression of membrane sodium channels in renal tubular cells in a manner dependent on the metabolic checkpoint kinase complex mTORC2. We hypothesized that SGK1 might represent an additional mTORC2-dependent regulator of the differentiation and function of T cells. Here we found that after activation by mTORC2, SGK1 promoted T helper type 2 (TH2) differentiation by negatively regulating degradation of the transcription factor JunB mediated by the E3 ligase Nedd4-2. Simultaneously, SGK1 repressed the production of interferon-γ (IFN-γ) by controlling expression of the long isoform of the transcription factor TCF-1. Consistent with those findings, mice with selective deletion of SGK1 in T cells were resistant to experimentally induced asthma, generated substantial IFN-γ in response to viral infection and more readily rejected tumors.

Surprising genetic and pathological findings in a patient with giant bilateral periadrenal tumours: PEComas and mutations of PTCH1 in Gorlin-Goltz syndrome.

Gorlin-Goltz syndrome (GGS) or nevoid basal cell carcinoma syndrome is a rare tumour-overgrowth syndrome associated with multiple developmental anomalies and a wide variety of tumours. Here, we describe a case of a man aged 23 years with GGS with bilateral giant tumours adjacent to both adrenals that raised the suspicion of malignancy on imaging. Histological analysis of both surgically resected tumours revealed perivascular epitheloid cell tumours (PEComas) that were independent of the adrenals. Exome sequencing of the patient's blood sample revealed a novel germline heterozygous frameshift mutation in the PTCH1 gene. As a second hit, a somatic five nucleotide long deletion in the PTCH1 gene was demonstrated in the tumour DNA of both PEComas. To the best of our knowledge, this is the first report on PEComa in GGS, and this finding also raises the potential relevance of PTCH1 mutations and altered sonic hedgehog signalling in PEComa pathogenesis. The presence of the same somatic mutation in the bilateral tumours might indicate the possibility of a postzygotic somatic mutation that along with the germline mutation of the same gene could represent an intriguing genetic phenomenon (type 2 segmental mosaicism).

Activating Hidden Metrological Usefulness.

We consider bipartite entangled states that cannot outperform separable states in any linear interferometer. Then, we show that these states can still be more useful metrologically than separable states if several copies of the state are provided or an ancilla is added to the quantum system. We present a general method to find the local Hamiltonian for which a given quantum state performs the best compared to separable states. We obtain analytically the optimal Hamiltonian for some quantum states with a high symmetry. We show that all bipartite entangled pure states outperform separable states in metrology. Some potential applications of the results are also suggested.

Unusual onset of thyroid associated orbitopathy during pregnancy: case report and review of literature.

BACKGROUND: Thyroid associated orbitopathy (TAO) is the most common extrathyroidal complication of Graves' disease. The disease course ranges from mild, where symptomatic therapy is sufficient, to severe, where high dose steroid administration or orbital decompression surgery is required. Women of their reproductive age are more likely to be affected. Although pregnancy is a state of enhanced immune tolerance, TAO may develop or worsen in 0.2-0.4% of pregnant women. CASE PRESENTATION: We present the case of a 19-year-old woman who has developed hyperthyroidism and progressive TAO during the second trimester of her third pregnancy, which has improved postpartum. The possible mechanisms and the importance of follow up in pregnancy is discussed. CONCLUSIONS: Expectant mothers with Graves' disease require follow up of eye signs throughout pregnancy, preferably in the setting of a thyroid-eye clinic.

WS2 and MoS2 thin film gas sensors with high response to NH3 in air at low temperature.

Transition metal dichalcogenides (TMDs) have received immense research interest in particular for their outstanding electrochemical and optoelectrical properties. Lately, chemical gas sensor applications of TMDs have been recognized as well owing to the low operating temperatures of devices, which is a great advantage over conventional metal oxide based sensors. In this work, we elaborate on the gas sensing properties of WS2 and MoS2 thin films made by simple and straightforward thermal sulfurization of sputter deposited metal films on silicon chips. The sensor response to H2, H2S, CO and NH3 analytes in air at 30 °C has been assessed and both MoS2 and WS2 were found to have an excellent selectivity to NH3 with a particularly high sensitivity of 0.10 ± 0.02 ppm-1 at sub-ppm concentrations in the case of WS2. The sensing behavior is explained on the bases of gas adsorption energies as well as carrier (hole) localization induced by the surface adsorbed moieties having reductive nature.

Quantum States with a Positive Partial Transpose are Useful for Metrology.

We show that multipartite quantum states that have a positive partial transpose with respect to all bipartitions of the particles can outperform separable states in linear interferometers. We introduce a powerful iterative method to find such states. We present some examples for multipartite states and examine the scaling of the precision with the particle number. Some bipartite examples are also shown that possess an entanglement very robust to noise. We also discuss the relation of metrological usefulness to Bell inequality violation. We find that quantum states that do not violate any Bell inequality can outperform separable states metrologically. We present such states with a positive partial transpose, as well as with a nonpositive partial transpose.

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways.

OBJECTIVE: Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms. APPROACH AND RESULTS: Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury. MMRKO reduced intima area and intima/media ratio, Ki67- and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67- and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-ß and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages. CONCLUSIONS: Selective deletion of MR in myeloid cells limits macrophage accumulation and vascular inflammation and, therefore, inhibits neointimal hyperplasia and vascular remodeling. Mechanistically, MR deficiency suppresses migration and proliferation of macrophages and leads to less vascular smooth muscle cell activation. At the molecular level, MR deficiency suppresses macrophage inflammatory response via SGK1-AP1/NF-κB pathways.

[Hereditary phaeochromocytoma in twins]. / Ikerpárban eloforduló örökletes phaeochromocytoma.

Phaeochromocytoma is a tumor of the catecholamine-producing cells of the adrenal gland. Extraadrenal phaeochromocytomas are frequently called paragangliomas. The majority of phaeochromocytomas are sporadic, however, about 25-30% are caused by genetic mutation. These tumor are frequently referred as hereditary phaeochromocytomas/paragangliomas. Their incidence increases continuously which can be attributed to availability of genetic examination and to the discovery of novel genes. The 47-year-old female patient underwent abdominal computed tomography which revealed bilateral adrenal gland enlargement. Abdominal magnetic resonance imaging, the 131-I- metaiodobenzylguanidine scintigraphy, urinary catecholamines and serum chomogranin A measurements confirmed the diagnosis of bilateral phaeochromocytomas. The genetically identical twin sister of the patient was also diagnosed with hormonally active bilateral phaechromocytoma, suggesting the genetic origin of phaeochromocytoma. Mutation screening confirmed a germline mutation of the transmembrane protein 127 tumorsupressor gene in both patients. Both patients underwent cortical-sparing adrenalectomy. The adrenal gland with the larger tumor was totally resected, while in the opposite side only the tumor was resected and a small part of the cortex was saved. After the operation urinary catecholamines and serum chromogranin A returned to normal in both patients. Adrenocortical deficiency was absent in the first patient, but her sister developed adrenal insufficiency requiring glucocorticoid replacement. To the best of the authors' knowledge phaeochromocytoma affecting twins has never been described earlier. Genetic examination performed in siblings confirmed the presence of the mutant gene through four generations. Orv. Hetil., 2016, 157(33), 1326-1330.

Evaluating convex roof entanglement measures.

We show a powerful method to compute entanglement measures based on convex roof constructions. In particular, our method is applicable to measures that, for pure states, can be written as low order polynomials of operator expectation values. We show how to compute the linear entropy of entanglement, the linear entanglement of assistance, and a bound on the dimension of the entanglement for bipartite systems. We discuss how to obtain the convex roof of the three-tangle for three-qubit states. We also show how to calculate the linear entropy of entanglement and the quantum Fisher information based on partial information or device independent information. We demonstrate the usefulness of our method by concrete examples.

Hepatic serum- and glucocorticoid-regulated protein kinase 1 (SGK1) regulates insulin sensitivity in mice via extracellular-signal-regulated kinase 1/2 (ERK1/2).

Insulin resistance is a major hallmark of metabolic syndromes, including Type 2 diabetes. Although numerous functions of SGK1 (serum- and glucocorticoid-regulated kinase 1) have been identified, a direct effect of SGK1 on insulin sensitivity has not been previously reported. In the present study, we generated liver-specific SGK1-knockout mice and found that these mice developed glucose intolerance and insulin resistance. We also found that insulin signalling is enhanced or impaired in Hep1-6 cells infected with adenoviruses expressing SGK1 (Ad-SGK1) or shRNA directed against the coding region of SGK1 (Ad-shSGK1) respectively. In addition, we determined that SGK1 inhibits ERK1/2 (extracellular-signal-regulated kinase 1/2) activity in liver and Ad-shERK1/2-mediated inhibition of ERK1/2 reverses the attenuated insulin sensitivity in Ad-shSGK1 mice. Finally, we found that SGK1 functions are compromised under insulin-resistant conditions and overexpression of SGK1 by Ad-SGK1 significantly ameliorates insulin resistance in both glucosamine-treated HepG2 cells and livers of db/db mice, a genetic model of insulin resistance.

Experimental comparison of efficient tomography schemes for a six-qubit state.

Quantum state tomography suffers from the measurement effort increasing exponentially with the number of qubits. Here, we demonstrate permutationally invariant tomography for which, contrary to conventional tomography, all resources scale polynomially with the number of qubits both in terms of the measurement effort as well as the computational power needed to process and store the recorded data. We demonstrate the benefits of combining permutationally invariant tomography with compressed sensing by studying the influence of the pump power on the noise present in a six-qubit symmetric Dicke state, a case where full tomography is possible only for very high pump powers.

Generation of macroscopic singlet states in a cold atomic ensemble.

We report the generation of a macroscopic singlet state in a cold atomic sample via quantum nondemolition measurement-induced spin squeezing. We observe 3 dB of spin squeezing and detect entanglement with 5σ statistical significance using a generalized spin-squeezing inequality. The degree of squeezing implies at least 50% of the atoms have formed singlets.

Detecting multiparticle entanglement of Dicke states.

Recent experiments demonstrate the production of many thousands of neutral atoms entangled in their spin degrees of freedom. We present a criterion for estimating the amount of entanglement based on a measurement of the global spin. It outperforms previous criteria and applies to a wider class of entangled states, including Dicke states. Experimentally, we produce a Dicke-like state using spin dynamics in a Bose-Einstein condensate. Our criterion proves that it contains at least genuine 28-particle entanglement. We infer a generalized squeezing parameter of -11.4(5) dB.

Multiple bronchial carcinoids associated with Cowden syndrome.

Cowden syndrome (CS) is a rare genetic condition due to the various germline mutations in the phosphatase and tensin homologue on chromosome ten (PTEN) tumour suppressor gene. As a result, CS is characterised by an increased risk of developing various benign and malignant tumours, such as thyroid, breast, endometrial and urogenital neoplasms, as well as gastrointestinal tract tumours. However, the neuroendocrine tumour association with CS is not elucidated yet. We present a case of a 46-year-old male patient diagnosed with testicular seminoma and follicular thyroid cancer in his medical history. Our patient met the clinical diagnostic criteria of Cowden syndrome. Genetic analysis established the clinical diagnosis; a known heterozygous PTEN mutation was detected [PTEN (LRG_311t1)c.388 C > T (p.Arg130Ter)]. Incidentally, he was also seen with multiple pulmonary lesions during his oncological follow-up. A video-assisted thoracoscopic left lingula wedge resection and later resections from the right lung were performed. Histological findings revealed typical pulmonary carcinoid tumours and smaller tumorlets. Somatostatin receptor SPECT-CT, 18F-FDG-PET-CT and 18F-FDOPA-PET-CT scans and endoscopy procedures could not identify any primary tumours in other locations. Our patient is the first published case of Cowden syndrome, associated with multifocal pulmonary carcinoids. Besides multiple endocrine neoplasia type 1, we propose Cowden syndrome as another hereditary condition predisposing to multiple pulmonary tumorlets and carcinoid tumours.

mTOR Regulates Mineralocorticoid Receptor Transcriptional Activity by ULK1-Dependent and -Independent Mechanisms.

The mineralocorticoid receptor (MR) is a transcription factor for genes mediating diverse, cell-specific functions, including trophic effects as well as promoting fluid/electrolyte homeostasis. It was reported that in intercalated cells, phosphorylation of the MR at serine 843 (S843) by Unc-51-like kinase (ULK1) inhibits MR activation and that phosphorylation of ULK1 by mechanistic target of rapamycin (mTOR) inactivates ULK1, and thereby prevents MR inactivation. We extended these findings with studies in M1 mouse cortical collecting duct cells stably expressing the rat MR and a reporter gene. Pharmacological inhibition of ULK1 dose-dependently increased ligand-induced MR transactivation, while ULK1 activation had no effect. Pharmacological inhibition of mTOR and CRISPR/gRNA gene knockdown of rapamycin-sensitive adapter protein of mTOR (Raptor) or rapamycin-insensitive companion of mTOR (Rictor) decreased phosphorylated ULK1 and ligand-induced activation of the MR reporter gene, as well as transcription of endogenous MR-target genes. As predicted, ULK1 inhibition had no effect on aldosterone-mediated transcription in M1 cells with the mutated MR-S843A (alanine cannot be phosphorylated). In contrast, mTOR inhibition dose-dependently decreased transcription in the MR-S843A cells, though not as completely as in cells with the wild-type MR-S843. mTOR, Raptor, and Rictor coprecipitated with the MR and addition of aldosterone increased their phosphorylated, active state. These results suggest that mTOR significantly regulates MR activity in at least 2 ways: by suppressing MR inactivation by ULK1, and by a yet ill-defined mechanism that involves direct association with MR. They also provide new insights into the diverse functions of ULK1 and mTOR, 2 key enzymes that monitor the cell's energy status.

Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in mice after peripheral administration.

We report the synthesis and pharmacological characterization of a novel glycosylated analog of a potent and selective endogenous µ-opioid receptor (MOP) agonist, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2), obtained by the introduction in position 3 of the tyrosine residue possessing the glucose moiety attached to the phenolic function via a ß-glycosidic bond. The improved blood-brain barrier permeability and enhanced antinociceptive effect of the novel glycosylated analog suggest that it may be a promising template for design of potent analgesics. Furthermore, the described methodology may be useful for increasing the bioavailability and delivery of opioid peptides to the CNS.

Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype.

The expression of the serum- and glucocorticoid-regulated kinase 1 (Sgk1) is induced by mineralocorticoids and, in turn, upregulates the renal epithelial Na(+) channel (ENaC). Total inactivation of Sgk1 has been associated with transient urinary Na(+) wasting with a low-Na(+) diet, while the aldosterone-mediated ENaC channel activation was unchanged in the collecting duct. Since Sgk1 is ubiquitously expressed, we aimed to study the role of renal Sgk1 and generated an inducible kidney-specific knockout (KO) mouse. We took advantage of the previously described TetOn/CreLoxP system, in which rtTA is under the control of the Pax8 promotor, allowing inducible inactivation of the floxed Sgk1 allele in the renal tubules (Sgk1fl/fl/Pax8/LC1 mice). We found that under a standard Na(+) diet, renal water and Na(+)/K(+) excretion had a tendency to be higher in doxycycline-treated Sgk1 KO mice compared with control mice. The impaired ability of Sgk1 KO mice to retain Na(+) increased significantly with a low-salt diet despite higher plasma aldosterone levels. On a low-Na(+) diet, the Sgk1 KO mice were also hyperkaliuric and lost body weight. This phenotype was accompanied by a decrease in systolic and diastolic blood pressure. At the protein level, we observed a reduction in phosphorylation of the ubiquitin protein-ligase Nedd4-2 and a decrease in the expression of the Na(+)-Cl(-)-cotransporter (NCC) and to a lesser extent of ENaC.

Sharp burnout failure observed in high current-carrying double-walled carbon nanotube fibers.

We report on the current-carrying capability and the high-current-induced thermal burnout failure modes of 5-20 µm diameter double-walled carbon nanotube (DWNT) fibers made by an improved dry-spinning method. It is found that the electrical conductivity and maximum current-carrying capability for these DWNT fibers can reach up to 5.9 × 10(5) S m(-1) and over 1 × 10(5) A cm(-2) in air. In comparison, we observed that standard carbon fiber tended to be oxidized and burnt out into cheese-like morphology when the maximum current was reached, while DWNT fiber showed a much slower breakdown behavior due to the gradual burnout in individual nanotubes. The electron microscopy observations further confirmed that the failure process of DWNT fibers occurs at localized positions, and while the individual nanotubes burn they also get aligned due to local high temperature and electrostatic field. In addition a finite element model was constructed to gain better understanding of the failure behavior of DWNT fibers.

Synthesis and photocatalytic performance of titanium dioxide nanofibers and the fabrication of flexible composite films from nanofibers.

Titanium dioxide nanofibers were synthesized and applied in flexible composite films that are easy to handle and recycle after use. The nanofibers were obtained in a multi-step procedure. First, sodium titanate nanofibers were prepared from TiO2 nanoparticles through the alkali hydrothermal method. In the next step, sodium hydrogen titanate nanofibers were made by washing the sodium titanate nanofibers in HCl solution. Finally, the sodium hydrogen titanate nanofibers were transformed to TiO2 anatase nanofibers by calcination in air. The photocatalytic activity of TiO2 anatase nanofibers were evaluated and compared to a TiO2 nanoparticle catalyst by decomposing methyl orange dye in aqueous solutions. The achieved reaction rate constant of TiO2 anatase nanofibers was comparable to that of Degussa P25. Paper-like flexible composite films were prepared by co-filtrating aqueous dispersions of TiO2 catalyst materials and cellulose. The composite films made from the nanofibers exhibit better mechanical integrity than those of the nanoparticle-cellulose composites.