Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies that includes steatosis, steatohepatitis (NASH) and fibrosis and is strongly associated with insulin resistance and type 2 diabetes. Changes in mitochondrial function are implicated in the pathogenesis of NAFLD, particularly in the transition from steatosis to NASH. Mitophagy is a mitochondrial quality control mechanism that allows for the selective removal of damaged mitochondria from the cell via the autophagy pathway. While past work demonstrated a negative association between liver fat content and rates of mitophagy, when changes in mitophagy occur during the pathogenesis of NAFLD and whether such changes contribute to the primary endpoints associated with the disease are currently poorly defined. We therefore undertook the studies described here to establish when alterations in mitophagy occur during the pathogenesis of NAFLD, as well as to determine the effects of genetic inhibition of mitophagy via conditional deletion of a key mitophagy regulator, PARKIN, on the development of steatosis, insulin resistance, inflammation and fibrosis. We find that loss of mitophagy occurs early in the pathogenesis of NAFLD and that loss of PARKIN accelerates the onset of key NAFLD disease features. These observations suggest that loss of mitochondrial quality control in response to nutritional stress may contribute to mitochondrial dysfunction and the pathogenesis of NAFLD.

Te-based chalcogenide materials for selector applications.

The implementation of dense, one-selector one-resistor (1S1R), resistive switching memory arrays, can be achieved with an appropriate selector for correct information storage and retrieval. Ovonic threshold switches (OTS) based on chalcogenide materials are a strong candidate, but their low thermal stability is one of the key factors that prevents rapid adoption by emerging resistive switching memory technologies. A previously developed map for phase change materials is expanded and improved for OTS materials. Selected materials from different areas of the map, belonging to binary Ge-Te and Si-Te systems, are explored. Several routes, including Si doping and reduction of Te amount, are used to increase the crystallization temperature. Selector devices, with areas as small as 55 × 55 nm2, were electrically assessed. Sub-threshold conduction models, based on Poole-Frenkel conduction mechanism, are applied to fresh samples in order to extract as-processed material parameters, such as trap height and density of defects, tailoring of which could be an important element for designing a suitable OTS material. Finally, a glass transition temperature estimation model is applied to Te-based materials in order to predict materials that might have the required thermal stability. A lower average number of p-electrons is correlated with a good thermal stability.

Nanoscopic structural rearrangements of the Cu-filament in conductive-bridge memories.

The electrochemical reactions triggering resistive switching in conductive-bridge resistive random access memory (CBRAM) are spatially confined in few tens of nm(3). The formation and dissolution of nanoscopic Cu-filaments rely on the displacement of ions in such confined volume, and it is driven by the electric field induced ion migration and nanoscaled redox reactions. The stochastic nature of these fundamental processes leads to a large variability of the device performance. In this work, a combination of two- and three-dimensional scanning probe microscopy (SPM) techniques are used to study the conductive filament (CF) formation, rupture and its nanoscopic structural rearrangements. The high spatial confinement of our approach enables to locally induce RS in a confined area and image it in 3D. A conical shape of the CF is consistently observed, indicating that the ion migration is the rate limiting step in the filament formation when using high quality dielectrics as switching layers. The sub-10 nm electrical contact size of the AFM tip is used to study the filament's dissolution and detect the hopping conduction of Cu during the CF rupture. We consistently observe a tunnel gap formation associated with the tip-induced filament reset. Finally, aiming to match the fundamental understanding with the integrated device operations, we apply scalpel SPM to failed memory cells and directly observe the appearance of filament multiplicity as a major source of failures and variability in CBRAM.

Switching mechanism in two-terminal vanadium dioxide devices.

Two-terminal thin film VO2 devices show an abrupt decrease of resistance when the current or voltage applied exceeds a threshold value. This phenomenon is often described as a field-induced metal-insulator transition. We fabricate nano-scale devices with different electrode separations down to 100 nm and study how the dc switching voltage and current depend on device size and temperature. Our observations are consistent with a Joule heating mechanism governing the switching. Pulsed measurements show a switching time to the high resistance state of the order of one hundred nanoseconds, consistent with heat dissipation time. In spite of the Joule heating mechanism which is expected to induce device degradation, devices can be switched for more than 10(10) cycles making VO2 a promising material for nanoelectronic applications.

Transport spectroscopy of a single dopant in a gated silicon nanowire.

We report on spectroscopy of a single dopant atom in silicon by resonant tunneling between source and drain of a gated nanowire etched from silicon on insulator. The electronic states of this dopant isolated in the channel appear as resonances in the low temperature conductance at energies below the conduction band edge. We observe the two possible charge states successively occupied by spin-up and spin-down electrons under magnetic field. The first resonance is consistent with the binding energy of the neutral D0 state of an arsenic donor. The second resonance shows a reduced charging energy due to the electrostatic coupling of the charged D- state with electrodes. Excited states and Zeeman splitting under magnetic field present large energies potentially useful to build atomic scale devices.

Synthesis of polyhydroxyindolizidines from 5,6-dihydro-2H-pyran-2-one.

(1aR,5aR,5bS,6S,7S)-6,7-Di-tert-butoxy-5-oxo-pyrrolidino[1,2-b]isoxazolidino[4,5-c]tetrahydropyran (8) prepared by (1,3)-dipolar cycloaddition of the cyclic nitrone 6 derived from tartaric acid to 5,6-dihydro-2H-pyran-2-one (7) was transformed into indolizidine 11 via a sequence of reactions involving methanolysis of the lactone ring, intramolecular alkylation of the nitrogen atom promoted by a carbontetrabromide-triphenylphosphine mixture and hydrogenolysis of the N single bond O bond. Decarboxylation of 11 provided known 7-hydroxylentiginosine derivative 14, whereas oxidative decarboxylation gave indolizidine 15 structurally related to castanospermine.

Coherence and polarization of light propagating through scattering media and biological tissues.

The degree of polarization of light propagating through scattering media was measured as a function of the sample thickness in a Mach-Zehnder interferometer at a wavelength of lambda = 633 nm. For polystyrene microspheres of diameters 200, 430, and 940 nm, depolarization began to appear for thicknesses larger than 23, 19, and 15 scattering mean free paths (SMFP's), respectively, where the coherently detected scattered component dominates the ballistic component. For large particles (940 nm) the initial polarization survived partially in the scattering regime and progressively vanished up to the detection limit of our setup. This phenomenon was similarly observed in diluted blood from 12.5 to 280 SMFP's. Beyond this thickness the fluctuating parallel and crossed components of polarization became random. A dual-channel interferometer allowed us to detect simultaneously the low-frequency fluctuations of both polarized components through a few millimeters in liver tissue.

[The evaluation of endometrial invasion of cervical Ib grade carcinoma]. / Wartosc rokownicza oceny naciekania trzonu macicy w przypadkach raka szyjki macicy w stopniu Ib.

Depth and extension of infiltration into uterine corpus with regard to 5 years survival in 33 patients in which Wertheim-Meigs surgery was done due to cervical cancer stage Ib is estimated in this paper. Endometrial stromal invasion or depth invasion less than 1/2 of myometrium at the site of internal ostium were of similar (91.7% > 5 years survival time) as an invasion confined solely to uterine cervix (86.9% > 5 years survival). Invasion of more than 1/2 of myometrium was associated with poor prognosis (46.7% 5-years survival). Bad prognosis (16.6% 5-year survival time) in patients with deep and extensive of uterine corpus and fundus should be tied to massive infiltration increased hematogenous and lymphatic dissemination. None of patients with deep and extensive invasion, lymph nodes metastases and uterine vasa embolies did survive 5 years period of time. These patients need individual postoperative adjuvant therapy.

[Vascular invasion and prognostic factors in cervical Ib grade cancer without metastases in lymph nodes]. / Inwazja naczyn a rokowanie w raku ograniczonym do szyjki macicy (Ib) bez przerzutów do wezlów chlonnych.

We were looking for presence, severity and extension of the invasion of vessels, with regard to the prognosis in 275 patient with infiltration limited only to uterine cervix (Ib), in which Wertheim-Meigs surgery was performed. It was found invasion of many vessels- in outside of the cervix is associated with poor prognosis, no matter weather the local lymph nodes are metastatic or not and no matter what the size of the neoplastic infiltration is. Patient with severe and extensive vascular invasion require further postoperative treatment.

[Cervical cancer Ib associated with pregnancy]. / Inwazyjny rak szyjki macicy w ciazy.

An analysis of symptoms, diagnostic methods, intra- and postoperative complications in 17 pregnant patients in which Wertheim-Meigs operation was done due to stage Ib cervical cancer, is presented in this report. The most common symptoms were contact bleeding and spotting (58.8%) as well as pathologic vaginal discharge (29.4%). 3 patient did not have any symptoms in their history. No bleeding occurred in patients in whom probatory specimen was taken from their cervix. Small 7-12 days spotting appeared in 2 out of 3 patients following diagnostic conisation, done in case of ca in situ or microinvasive cancer. Pregnancy as a such was never a cause of intraoperative difficulties or complications. Mean blood transfusion was 1250 ml, this is 150 ml more than in nonpregnant patients. Most frequent postoperative complication was retentio urinare (47%). 5-year survival rate of pregnant patients (82.3%) was worse than in nonpregnant patients (96.2%) in the same age group and in comparable expansion of cancer in stage Ib in postoperative histological evaluation.

[Cervical cancer and pregnancy: prognostic value of immunological response in nodes and cancer stroma]. / Wartosc rokownicza immunologicznych odczynów komórkowych w podscielisku raka i w regionalnych wezlach chlonnych u ciezarnych z inwazyjnym rakiem szyjki macicy Ib.

Immune response in the stroma of cancer and in regional lymph nodes with regard to 5-years survival rate in 17 pregnant patients in which Wertheim-Meigs operation due to Ib cervical cancer was done, is assessed in this paper. Activation and hyperplasia of T and B dependent layers of lymph nodes as well as infiltration by monocyte-macrophage and lympho-plasmatic mature, immunocompetent cells are related to good prognosis and these are most frequent in patients with small invasion. Lack of immune response in lymph nodes, its poor expression, hemolymphatic transformation, adiposis of nodes or their fibrosis was found in 5 patients; 3 of them died within 5 years. Scare monocyte-macrophage infiltrations and low-differentiated lymphocytes prevailed in the stroma of cancer. Inactive answer in nodes and in stroma was found in 8 out of 12 patients who had deeper infiltration than 0.5 cm. Immunologic response in nodes and in stroma should be assessed as a routine method for all prognostic purposes. Patients with inactive immunologic response should be qualified for further treatment.