Current Fluctuations in Nanopores Reveal the Polymer-Wall Adsorption Potential.

Modification of surface properties by polymer adsorption is a widely used technique to tune interactions in molecular experiments such as nanopore sensing. Here, we investigate how the ionic current noise through solid-state nanopores reflects the adsorption of short, neutral polymers to the pore surface. The power spectral density of the noise shows a characteristic change upon adsorption of polymer, the magnitude of which is strongly dependent on both polymer length and salt concentration. In particular, for short polymers at low salt concentrations no change is observed, despite the verification of comparable adsorption in these systems using quartz crystal microbalance measurements. We propose that the characteristic noise is generated by the movement of polymers on and off the surface and perform simulations to assess the feasibility of this model. Excellent agreement with experimental data is obtained using physically motivated simulation parameters, providing deep insight into the shape of the adsorption potential and underlying processes. This paves the way toward using noise spectral analysis for in situ characterization of functionalized nanopores.

PKP3 interactions with MAPK-JNK-ERK1/2-mTOR pathway regulates autophagy and invasion in ovarian cancer.

Armadillo-related proteins function in both signal transduction and cell adhesion, it also plays a central role in tumorigenesis. Plakophilin 3 (PKP3) is a member of the armadillo protein family. PKP3 has demonstrated a role in melanoma, breast cancer, gastric cancer, and other kind of cancers; however its role in ovarian cancer was not fully understood. In this study we explored the function and mechanisms of PKP3 in ovarian cancer. An elevated level of PKP3 was found in ovarian cancer tissues compared with normal tissues. PKP3 also modulate cellular proliferation and invasion in ovarian cancer. The ability of cellular proliferation, formation, and invasion was significantly decreased after the silencing of PKP3 in SKOV3 cells. While an over-expression of PKP3 in A2780 cells up-regulates the ability of cellular proliferation, formation, and invasion. As for the mechanism of PKP3, mTOR pathway was activated to regulate autophagy according to the interaction of PKP3 with the upstream of MAPK pathway. The result of this study support PKP3 as the oncogene candidate and a potential target for the treatment of ovarian cancer.

FAM83D inhibits autophagy and promotes proliferation and invasion of ovarian cancer cells via PI3K/AKT/mTOR pathway.

Ovarian cancer is one of the most lethal malignant tumors in women. The family with sequence similarity 83, member D (FAM83D) plays an important role in several cancers, but its function and underlying mechanism in ovarian cancer remain unknown. To investigate the role of FAM83D in ovarian cancer, the expression of FAM83D was determined by immunohistochemistry in tissue microarray slide. Cellular proliferation and invasion were detected by 5-Ethynyl-2'-deoxyuridine assays and transwell invasion assays. The correlations between FAM83D and autophagy were detected by western blot analysis and confocal microscopy. Western blot analysis was used to identify the protein expression of FAM83D, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR) and Sequestosome 1 (P62). Tumorigenesis in nude mice was used to explore the function of FAM83D in vivo. We found high expression level of FAM83D in ovarian cancer tissues as compared to the normal ovarian tissues. Knockdown of FAM83D in SKOV3 cells enhanced autophagy and inhibited the proliferation and invasion in vitro, whereas ectopic expression of FAM83D in A2780 cells exerted an opposite effect. Mechanistically, overexpression of FAM83D activated the PI3K/AKT/mTOR pathway, and Torin1 could suppress FAM83D-induced cell proliferation and invasion. In vivo, overexpression FAM83D promoted tumor growth. Overall, FAM83D promoted ovarian cancer cell invasion and proliferation, while inhibited autophagy via the PI3K/AKT/mTOR signaling pathway. Our results suggest that FAM83D may be a candidate oncogene in ovarian cancer, which provides a fresh perspective of FAM83D in ovarian cancer.

Gas Hydrate Formation Probability Distributions: The Effect of Shear and Comparisons with Nucleation Theory.

Gas hydrate formation is a stochastic phenomenon of considerable significance for any risk-based approach to flow assurance in the oil and gas industry. In principle, well-established results from nucleation theory offer the prospect of predictive models for hydrate formation probability in industrial production systems. In practice, however, heuristics are relied on when estimating formation risk for a given flowline subcooling or when quantifying kinetic hydrate inhibitor (KHI) performance. Here, we present statistically significant measurements of formation probability distributions for natural gas hydrate systems under shear, which are quantitatively compared with theoretical predictions. Distributions with over 100 points were generated using low-mass, Peltier-cooled pressure cells, cycled in temperature between 40 and -5 °C at up to 2 K·min-1 and analyzed with robust algorithms that automatically identify hydrate formation and initial growth rates from dynamic pressure data. The application of shear had a significant influence on the measured distributions: at 700 rpm mass-transfer limitations were minimal, as demonstrated by the kinetic growth rates observed. The formation probability distributions measured at this shear rate had mean subcoolings consistent with theoretical predictions and steel-hydrate-water contact angles of 14-26°. However, the experimental distributions were substantially wider than predicted, suggesting that phenomena acting on macroscopic length scales are responsible for much of the observed stochastic formation. Performance tests of a KHI provided new insights into how such chemicals can reduce the risk of hydrate blockage in flowlines. Our data demonstrate that the KHI not only reduces the probability of formation (by both shifting and sharpening the distribution) but also reduces hydrate growth rates by a factor of 2.

The Urea-to-Creatinine Ratio Is Predictive of Worsening Kidney Function in Ambulatory Heart Failure Patients.

BACKGROUND: Changes in kidney function in heart failure patients convey important prognostic information. We investigated the association of the urea-to-creatinine (BUN/Cr) ratio, the fractional excretion of urea (FeUr), and the fractional excretion of sodium (FeNa) and subsequent declines in kidney function in ambulatory heart failure patients. METHODS AND RESULTS: We prospectively enrolled adult patients with ejection fraction <40% at a multidisciplinary heart failure clinic and measured serial measurements of laboratory values from September 2008 to July 2011. The study outcome was changes in the estimated glomerular filtration rate (eGFR). In 138 patients contributing 10,350 patient-hours of follow-up, we found that participants with a decline of >25% in eGFR had higher mean BUN/Cr ratio (0.110 ± 0.043 vs 0.086 ± 0.026; P = .02) and no difference in the FeNa (1.81 vs 1.43; P = .2) or FeUr (32.3 vs 37.2; P = .9) compared with those with no change. There was an association of BUN/Cr ratio with the rate of change of eGFR (coefficient -25.67, 95% confidence interval [CI] -10.99 to -40.35; P < .0001). The BUN/Cr ratio was an independent predictor of eGFR drop >25% (odds ratio 1.19, 95% CI 1.07-1.32) and improved model discrimination (c-statistic increased from 0.624 to 0.693) and reclassification (net reclassification index 11.38% [P < .0001], integrated discrimination improvement 5.24% [P = .02]). CONCLUSIONS: The BUN/Cr ratio is associated with worsening kidney function and adds incremental risk prediction information relative to traditional predictive measures in outpatients with heart failure at risk for worsening kidney disease.

Alloying Effects on Charge-Carrier Transport in Silver-Bismuth Double Perovskites.

Alloying is widely adopted for tuning the properties of emergent semiconductors for optoelectronic and photovoltaic applications. So far, alloying strategies have primarily focused on engineering bandgaps rather than optimizing charge-carrier transport. Here, we demonstrate that alloying may severely limit charge-carrier transport in the presence of localized charge carriers (e.g., small polarons). By combining reflection-transmission and optical pump-terahertz probe spectroscopy with first-principles calculations, we investigate the interplay between alloying and charge-carrier localization in Cs2AgSbxBi1-xBr6 double perovskite thin films. We show that the charge-carrier transport regime strongly determines the impact of alloying on the transport properties. While initially delocalized charge carriers probe electronic bands formed upon alloying, subsequently self-localized charge carriers probe the energetic landscape more locally, thus turning an alloy's low-energy sites (e.g., Sb sites) into traps, which dramatically deteriorates transport properties. These findings highlight the inherent limitations of alloying strategies and provide design tools for newly emerging and highly efficient semiconductors.

Eszopiclone prevents excitotoxicity and neurodegeneration in the hippocampus induced by experimental apnea.

STUDY OBJECTIVE: This study was designed to determine the effects of eszopiclone on apnea-induced excitotoxic synaptic processes and apoptosis in the hippocampus. DESIGN: Recurrent periods of apnea, which consisted of a sequence of apnea (75% SpO2), followed by ventilation with recovery to normoxia (> 95% SpO2), were induced for a period of three hours in anesthetized guinea pigs. The CA3 Schaffer collateral pathway in the hippocampus was stimulated and the field excitatory postsynaptic potential (fEPSP) response was recorded in CA1. Animals in the experimental group received an intravenous injection of eszopiclone (3 mg/kg) 10 min prior to the initiation of the periods of recurrent apnea, and once every 60 min thereafter; control animals received comparable injections of vehicle. At the end of the 3-h period of recurrent apnea, the animals were perfused, and hippocampal sections were immunostained in order to determine the presence of apoptosis, i.e., programmed cell death. ANALYSES AND RESULTS: Apnea resulted in a persistent increase in synaptic responsiveness of CA1 neurons as determined by analyses of the fEPSP. Eszopiclone antagonized the apnea-induced increase in the fEPSP. Morphological analyses revealed significant apoptosis of CA1 neurons in control animals; however, there was no significant apoptosis in eszopiclone-treated animals. CONCLUSIONS: Eszopiclone was determined to suppress the apnea-induced hyperexcitability of hippocampal CA1 neurons, thereby reducing/eliminating neurotoxicity. These data lend credence to our hypothesis that eszopiclone, exclusive of its hypnotic actions, has the capacity to function as a potent neuroprotective agent.

Quantitative analysis of the excitability of hypoglossal motoneurons during natural sleep in the rat.

We describe a novel approach to assess the excitability of hypoglossal motoneurons in rats during naturally occurring states of sleep and wakefulness. Adult rats were surgically prepared with permanently placed electrodes to record the EEG, EOG and neck EMG. A stimulating/recording miniature tripolar cuff electrode was implanted around the intact hypoglossal nerve and a head-restraining device was bonded to the calvarium. After a period of adaptation to head-restraint, the animals did not exhibit any sign of discomfort and readily transitioned between the states of wakefulness, NREM and REM sleep. There was no spontaneous respiratory or tonic activity present in the hypoglossal nerve during sleep or wakefulness. Hypoglossal motoneurons were activated by electrical stimulation of the hypoglossal nerve (antidromically) or by microstimulation directly applied to the hypoglossal nucleus. Microstimulation of hypoglossal motoneurons evoked compound action potentials in the ipsilateral hypoglossal nerve. The magnitude of their integrals tended to be higher during wakefulness (112.6% ± 15; standard deviation) and were strongly depressed during REM sleep (24.7% ± 3.4), compared to the integral magnitude during NREM sleep. Lidocaine, which was delivered using pressure microinjection to the microstimulation site, verified that the responses evoked in hypoglossal nerve can be affected pharmacologically. We conclude that this animal model can be utilized to study the neurotransmitter mechanisms that control the excitability of hypoglossal motoneurons during naturally occurring states of sleep and wakefulness.

Clinical characteristics and outcomes of hospitalized patients with 2009 H1N1 influenza in a large acute care tertiary hospital, Singapore.

This study describes the clinical characteristics and outcomes of hospitalized patients with 2009 H1N1 influenza in a large, acute care, tertiary hospital in Singapore. Of the 265 hospitalized patients with laboratory-confirmed 2009 influenza A (H1N1) during the height of the H1N1 flu pandemic, 13% (35) suffered severe outcomes including a mortality rate of 4.5% (12). Severe outcomes were associated with patients aged 40 years or more, underlying comorbidities, and complicated by pneumonia.

The role of mesopontine NGF in sleep and wakefulness.

The microinjection of nerve growth factor (NGF) into the cat pontine tegmentum rapidly induces rapid eye movement (REM) sleep. To determine if NGF is involved in naturally-occurring REM sleep, we examined whether it is present in mesopontine cholinergic structures that promote the initiation of REM sleep, and whether the blockade of NGF production in these structures suppresses REM sleep. We found that cholinergic neurons in the cat dorso-lateral mesopontine tegmentum exhibited NGF-like immunoreactivity. In addition, the microinjection of an oligodeoxyribonucleotide (OD) directed against cat NGF mRNA into this region resulted in a reduction in the time spent in REM sleep in conjunction with an increase in the time spent in wakefulness. Sleep and wakefulness returned to baseline conditions 2 to 5 days after antisense OD administration. The preceding antisense OD-induced effects occurred in conjunction with the suppression of NGF-like immunoreactivity within the site of antisense OD injection. These data support the hypothesis that NGF is involved in the modulation of naturally-occurring sleep and wakefulness.

The effect of comorbidity and age on hospital mortality and length of stay in patients with sepsis.

PURPOSE: Sepsis is believed to be responsible for substantial health care burden, but there is limited information about its magnitude and the factors affecting health outcomes in Asian population. The aim of the study was to assess the disease burden of sepsis and to test the usefulness of Charlson Comorbidity Index (CCI) and age as risk-adjusted hospital mortality predictors in patients with sepsis using hospital administrative database. METHODS: A retrospective cohort study of hospital discharge database from 2004 to 2007 to identify cases with sepsis, comorbidity, and organ failure using the International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Australian Modification codes was conducted. RESULTS: Of 305,637 hospitalized patients over 4 years, 6929 (2.27%) patients had sepsis, with 1216 (17.5%) patients associated with intensive care unit (ICU) admission. The mortality rates increased consistently in patients with CCI ranging from none to low, moderate and high grade for both patients with ICU admission (39.4%, 51.6%, 55.9%, and 54.3% respectively; P < .001) and patients without ICU admission (6.4%, 8.7%, 17.1%, and 25.3% respectively; P < .001). Logistic regression analysis showed that CCI (odds ratio, 11.8; high versus none) and age (odds ratio, 8.46; aged 85 years and older versus aged 18-54 years old) were significant and independent predictors of hospital mortality. Similar results were seen with hospital length of stay by zero-truncated negative binomial regression model analysis. CONCLUSION: The sepsis-related mortality and resource utilization are high in this population as well. Comorbidities and advanced age were some of the most important contributors to hospital mortality and resource utilization.

Thiol-disulfide exchange in an immunoglobulin-like fold: structure of the N-terminal domain of DsbD.

Escherichia coli DsbD transports electrons across the plasma membrane, a pathway that leads to the reduction of protein disulfide bonds. Three secreted thioredoxin-like factors, DsbC, DsbE, and DsbG, reduce protein disulfide bonds whereby an active site C-X-X-C motif is oxidized to generate a disulfide bond. DsbD catalyzes the reduction of the disulfide of DsbC, DsbE, and DsbG but not of the thioredoxin-like oxidant DsbA. The reduction of DsbC, DsbE, and DsbG occurs by transport of electrons from cytoplasmic thioredoxin to the C-terminal thioredoxin-like domain of DsbD (DsbD(C)). The N-terminal domain of DsbD, DsbD(N), acts as a versatile adaptor in electron transport and is capable of forming disulfides with oxidized DsbC, DsbE, or DsbG as well as with reduced DsbD(C). Isolated DsbD(N) is functional in electron transport in vitro. Crystallized DsbD(N) assumes an immunoglobulin-like fold that encompasses two active site cysteines, C103 and C109, forming a disulfide bond between beta-strands. The disulfide of DsbD(N) is shielded from the environment and capped by a phenylalanine (F70). A model is discussed whereby the immunoglobulin fold of DsbD(N) may provide for the discriminating interaction with thioredoxin-like factors, thereby triggering movement of the phenylalanine cap followed by disulfide rearrangement.