Field Emission of ITO-Coated Vertically Aligned Nanowire Array

An indium tin oxide (ITO)-coated vertically aligned nanowire array is fabricated, and the field emission characteristics of the nanowire array are investigated. An array of vertically aligned nanowires is considered an ideal structure for a field emitter because of its parallel orientation to the applied electric field. In this letter, a vertically aligned nanowire array is fabricated by modified conventional UV lithography and coated with 0.1-μm-thick ITO. The turn-on electric field intensity is about 2.0 V/μm, and the field enhancement factor, β, is approximately 3,078 when the gap for field emission is 0.6 μm, as measured with a nanomanipulator in a scanning electron microscope

Essential and checkpoint functions of budding yeast ATM and ATR during meiotic prophase are facilitated by differential phosphorylation of a meiotic adaptor protein, Hop1

A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis

The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer

Background Despite recent advances in treating non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK-positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK-positive NSCLC. Methods Between 2011 and 2018, a total of 14 ALK-positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD-L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets. Results A total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2-8) courses of therapy. The study included nine patients (64.3%) who were PD-L1-high (>50%) and four (28.6%) who were PD-L1-low (<50%). The objective response rate was 14.3% (2/14). The median progression-free survival time was 2.18 months (95% confidence interval [CI] 1.13 months-not reached [NR]). The median overall survival time was 5.67 months (95% CI 3.00 months-NR). RNA expression levels of CD274 were similar between the ALK-positive and negative groups in both TCGA and NCCRI datasets. RNA levels of CD8A in both TCGA and NCCRI data sets were nonsignificantly lower in the ALK-positive group. Cytolytic activity scores including interferon-gamma-related response were lower in the ALK-positive group in the NCCRI but not TCGA dataset. Conclusions Despite high PD-L1-positive rates, ICIs show limited efficacy in ALK-positive NSCLC. Decreased interferon-gamma-related response may underlie these findings.

LPS-induced NF??B enhanceosome requires TonEBP/NFAT5 without DNA binding

NF??B is a central mediator of inflammation. Present inhibitors of NF??B are mostly based on inhibition of essential machinery such as proteasome and protein kinases, or activation of nuclear receptors; as such, they are of limited therapeutic use due to severe toxicity. Here we report an LPS-induced NF??B enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NF??B activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NF??B. Myeloid-specific deletion of TonEBP results in milder inflammation and sepsis. We discover that a natural small molecule cerulenin specifically disrupts the enhanceosome without affecting the activation of NF??B itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NF??B enhanceosome offers a promising target for useful anti-inflammatory agents.ope

Hypolipidemic effect of Salicornia herbacea in animal model of type 2 diabetes mellitus

To control blood glucose level as close to normal is a major goal of treatment of diabetes mellitus. Hyperglycemia and hyperlipidemia are the major risk factors for cardiovascular complications, the major cause of immature death among the patients with type 2 diabetes. The purpose of this study is to determine the hypoglycemic and hypolipidemic effects of Salicornia herbacea in animal model of type 2 diabetes and to investigate the possible mechanisms for the beneficial effects of S. herbacea. S. herbacea was extracted with 70% ethanol and desalted with 100% ethanol. Three week-old db/db mice (C57BL/KsJ, n=16) were fed AIN-93G semipurified diet or diet containing 1% desalted ethanol extract of S. herbacea for 6 weeks after 1 week of adaptation. Fasting plasma glucose, triglyceride, and total cholesterol were measured by enzymatic methods and blood glycated hemoglobin (HbA1C) by the chromatographic method. Body weight and food intake of S. herbacea group were not significantly different from those of the control group. Fasting plasma glucose and blood glycated hemoglobin levels tended to be lowered by S. herbacea treatment. Consumption of S. herbacea extract significantly decreased plasma triglyceride and cholesterol levels (p<0.05). The inhibition of S. herbacea extract against yeast α-glucosidase was 31.9% of that of acarbose at the concentration of 0.5 mg/mL in vitro. The inhibitory activity of ethanol extract of S. herbacea against porcine pancreatic lipase was 59.0% of that of orlistat at the concentration of 0.25 mg/mL in vitro. Thus, these results suggest that S. herbacea could be effective in controlling hyperlipidemia by inhibition of pancreatic lipase in animal model of type 2 diabetes

The Induction of MicroRNA Targeting IRS-1 Is Involved in the Development of Insulin Resistance under Conditions of Mitochondrial Dysfunction in Hepatocytes

BACKGROUND: Mitochondrial dysfunction induces insulin resistance in myocytes via a reduction of insulin receptor substrate-1 (IRS-1) expression. However, the effect of mitochondrial dysfunction on insulin sensitivity is not understood well in hepatocytes. Although research has implicated the translational repression of target genes by endogenous non-coding microRNAs (miRNA) in the pathogenesis of various diseases, the identity and role of the miRNAs that are involved in the development of insulin resistance also remain largely unknown. METHODOLOGY: To determine whether mitochondrial dysfunction induced by genetic or metabolic inhibition causes insulin resistance in hepatocytes, we analyzed the expression and insulin-stimulated phosphorylation of insulin signaling intermediates in SK-Hep1 hepatocytes. We used qRT-PCR to measure cellular levels of selected miRNAs that are thought to target IRS-1 3' untranslated regions (3'UTR). Using overexpression of miR-126, we determined whether IRS-1-targeting miRNA causes insulin resistance in hepatocytes. PRINCIPAL FINDINGS: Mitochondrial dysfunction resulting from genetic (mitochondrial DNA depletion) or metabolic inhibition (Rotenone or Antimycin A) induced insulin resistance in hepatocytes via a reduction in the expression of IRS-1 protein. In addition, we observed a significant up-regulation of several miRNAs presumed to target IRS-1 3'UTR in hepatocytes with mitochondrial dysfunction. Using reporter gene assay we confirmed that miR-126 directly targeted to IRS-1 3'UTR. Furthermore, the overexpression of miR-126 in hepatocytes caused a substantial reduction in IRS-1 protein expression, and a consequent impairment in insulin signaling. CONCLUSIONS/SIGNIFICANCE: We demonstrated that miR-126 was actively involved in the development of insulin resistance induced by mitochondrial dysfunction. These data provide novel insights into the molecular basis of insulin resistance, and implicate miRNA in the development of metabolic disease

Three little pieces for computer and relativity

Numerical relativity has made big strides over the last decade. A number of problems that have plagued the field for years have now been mostly solved. This progress has transformed numerical relativity into a powerful tool to explore fundamental problems in physics and astrophysics, and I present here three representative examples. These "three little pieces" reflect a personal choice and describe work that I am particularly familiar with. However, many more examples could be made.Comment: 42 pages, 11 figures. Plenary talk at "Relativity and Gravitation: 100 Years after Einstein in Prague", June 25 - 29, 2012, Prague, Czech Republic. To appear in the Proceedings (Edition Open Access). Collects results appeared in journal articles [72,73, 122-124

The complex X-ray spectrum of NGC 4507

XMM-Newton and Chandra/HETG spectra of the Compton-thin (NH 4x10^{23} cm^{-2}) Seyfert 2 galaxy, NGC 4507, are analyzed and discussed. The main results are: a) the soft X-ray emission is rich in emission lines; an (at least) two--zone photoionization region is required to explain the large range of ionization states. b) The 6.4 keV iron line is likely emitted from Compton-thick matter, implying the presence of two circumnuclear cold regions, one Compton-thick (the emitter), one Compton-thin (the cold absorber). c) Evidence of an Fe xxv absorption line is found in the Chandra/HETG spectrum. The column density of the ionized absorber is estimated to be a few x10^{22} cm^{-2}.Comment: accepted for publication in A&

A systematic review of the evidence for single stage and two stage revision of infected knee replacement

BACKGROUND: Periprosthetic infection about the knee is a devastating complication that may affect between 1% and 5% of knee replacement. With over 79 000 knee replacements being implanted each year in the UK, periprosthetic infection (PJI) is set to become an important burden of disease and cost to the healthcare economy. One of the important controversies in treatment of PJI is whether a single stage revision operation is superior to a two-stage procedure. This study sought to systematically evaluate the published evidence to determine which technique had lowest reinfection rates. METHODS: A systematic review of the literature was undertaken using the MEDLINE and EMBASE databases with the aim to identify existing studies that present the outcomes of each surgical technique. Reinfection rate was the primary outcome measure. Studies of specific subsets of patients such as resistant organisms were excluded. RESULTS: 63 studies were identified that met the inclusion criteria. The majority of which (58) were reports of two-stage revision. Reinfection rated varied between 0% and 41% in two-stage studies, and 0% and 11% in single stage studies. No clinical trials were identified and the majority of studies were observational studies. CONCLUSIONS: Evidence for both one-stage and two-stage revision is largely of low quality. The evidence basis for two-stage revision is significantly larger, and further work into direct comparison between the two techniques should be undertaken as a priority