Surface Activity of Poly(ethylene glycol)-Coated Silver Nanoparticles in the Presence of a Lipid Monolayer

We have investigated the surface activity of poly(ethylene glycol) (PEG)-coated silver nanoparticles (Ag-PEG) in the presence or absence of lipid monolayers comprised of monounsaturated dioleoylphosphocholine and dioleoylphosphoglycerol (DOPC/DOPG; 1:1 mol ratio). Dynamic measurements of surface pressure demonstrated that Ag-PEG were surface-active at the air/water interface. Surface excess concentrations suggested that at high Ag-PEG subphase concentrations, Ag-PEG assembled as densely packed monolayers in the presence and absence of a lipid monolayer. The presence of a lipid monolayer led to only a slight decrease in the excess surface concentration of Ag-PEG. Surface pressure–area isotherms showed that in the absence of lipids Ag-PEG increased the surface pressure up to 45 mN m–1 upon compression before the Ag-PEG surface layer collapsed. Our results suggest that surface activity of Ag-PEG was due to hydrophobic interactions imparted by a combination of the amphiphilic polymer coating and the hydrophobic dodecanethiol ligands bound to the Ag-PEG surface. With lipid present, Ag-PEG + lipid surface pressure–area (π–A) isotherms reflected Ag-PEG incorporation within the lipid monolayers. At high Ag-PEG concentrations, the π–A isotherms of the Ag-PEG + lipid films closely resembled that of Ag-PEG alone with a minimal contribution from the lipids present. Analysis of the subphase silver (Ag) and phosphorus (P) concentrations revealed that most of the adsorbed material remained at the air/lipid/water interface and was not forced into the aqueous subphase upon compression, confirming the presence of a composite Ag-PEG + lipid film. While interactions between “water-soluble” nanoparticles and lipids are often considered to be dominated by electrostatic interactions, these results provide further evidence that the amphiphilic character of a nanoparticle coating can also play a significant role

Simultaneous Optimization of the Cavity Heat Load and Trip Rates in Linacs Using a Genetic Algorithm

In this paper, a genetic algorithm-based optimization is used to simultaneously minimize two competing objectives guiding the operation of the Jefferson Lab\u27s Continuous Electron Beam Accelerator Facility linacs: cavity heat load and radio frequency cavity trip rates. The results represent a significant improvement to the standard linac energy management tool and thereby could lead to a more efficient Continuous Electron Beam Accelerator Facility configuration. This study also serves as a proof of principle of how a genetic algorithm can be used for optimizing other linac-based machines

The SXS Collaboration catalog of binary black hole simulations

Accurate models of gravitational waves from merging black holes are necessary for detectors to observe as many events as possible while extracting the maximum science. Near the time of merger, the gravitational waves from merging black holes can be computed only using numerical relativity. In this paper, we present a major update of the Simulating eXtreme Spacetimes (SXS) Collaboration catalog of numerical simulations for merging black holes. The catalog contains 2018 distinct configurations (a factor of 11 increase compared to the 2013 SXS catalog), including 1426 spin-precessing configurations, with mass ratios between 1 and 10, and spin magnitudes up to 0.998. The median length of a waveform in the catalog is 39 cycles of the dominant $\ell=m=2$ gravitational-wave mode, with the shortest waveform containing 7.0 cycles and the longest 351.3 cycles. We discuss improvements such as correcting for moving centers of mass and extended coverage of the parameter space. We also present a thorough analysis of numerical errors, finding typical truncation errors corresponding to a waveform mismatch of $\sim 10^{-4}$. The simulations provide remnant masses and spins with uncertainties of 0.03% and 0.1% ($90^{\text{th}}$ percentile), about an order of magnitude better than analytical models for remnant properties. The full catalog is publicly available at https://www.black-holes.org/waveforms .Comment: 33+18 pages, 13 figures, 4 tables, 2,018 binaries. Catalog metadata in ancillary JSON file. v2: Matches version accepted by CQG. Catalog available at https://www.black-holes.org/waveform

MicroRNA-1 Attenuates the Growth and Metastasis of Small Cell Lung Cancer through CXCR4/FOXM1/RRM2 Axis

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. METHODS: To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. RESULTS: A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. CONCLUSIONS: Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis

Cognitive Information Processing

Contains reports on five research projects.National Science Foundation (Grant SED76-81985)Associated Press (Grant)Providence Gravure, Inc. (Grant)Taylor Publishing Company (Grant)Sony Corporation (Grant

Malaria Prevalence in Endemic Districts of Bangladesh

BACKGROUND: Following the 1971 ban of DDT in Bangladesh, malaria cases have increased steadily. Malaria persists as a major health problem in the thirteen south-eastern and north-eastern districts of Bangladesh. At present the national malaria control program, largely supported by the Global Fund for AIDS, Tuberculosis and Malaria (GFATM), provides interventions including advocacy at community level, Insecticide Treated Net (ITN) distribution, introduction of Rapid Diagnostic Tests (RDT) and combination therapy with Coartem. It is imperative, therefore, that baseline data on malaria prevalence and other malaria indicators are collected to assess the effectiveness of the interventions and rationalize the prevention and control efforts. The objective of this study was to obtain this baseline on the prevalence of malaria and bed net use in the thirteen malaria endemic districts of Bangladesh. METHODS AND PRINCIPAL FINDINGS: In 2007, BRAC and ICDDR,B carried out a malaria prevalence survey in thirteen malaria endemic districts of Bangladesh. A multi-stage cluster sampling technique was used and 9750 blood samples were collected. Rapid Diagnostic Tests (RDT) were used for the diagnosis of malaria. The weighted average malaria prevalence in the thirteen endemic districts was 3.97%. In five south-eastern districts weighted average malaria prevalence rate was 6.00% and in the eight north-eastern districts weighted average malaria prevalence rate was (0.40%). The highest malaria prevalence was observed in Khagrachari district. The majority of the cases (90.18%) were P. falciparum infections. Malaria morbidity rates in five south-eastern districts was 2.94%. In eight north-eastern districts, morbidity was 0.07%. CONCLUSION AND SIGNIFICANCE: Bangladesh has hypoendemic malaria with P. falciparum the dominant parasite species. The malaria situation in the five north-eastern districts of Bangladesh in particular warrants urgent attention. Detailed maps of the baseline malaria prevalence and summaries of the data collected are provided along with the survey results in full, in a supplemental information

A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis

The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis. A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score [NAS] ≥4, and liver fibrosis (stages 1–3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2-point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of steatohepatitis. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary end point of NAS improvement in the intent-to-treat population and resolution of steatohepatitis was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144) (16% vs 19%, P = 0.52 and 8% vs 6%, P = 0.49, respectively). However, the fibrosis end point was met in significantly more subjects on CVC than placebo (20% vs 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. Conclusions: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of steatohepatitis compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation

Nipple aspiration and ductal lavage in women with a germline BRCA1 or BRCA2 mutation

INTRODUCTION: The aim of this study was to collect serial samples of nipple aspirate (NA) and ductal lavage (DL) fluid from women with germline BRCA1/2 mutations in order to create a biorepository for use in identifying biomarkers of breast cancer risk. METHODS: Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit. RESULTS: Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P ≤ 0.001). CONCLUSION: It is feasible to collect serial NA and DL samples from women at high genetic risk of breast cancer, and we are creating a unique, prospective collection of ductal samples that have the potential to be used for discovery of biomarkers of breast cancer risk and evaluate the ongoing effects of risk reducing BSO. DL cellular atypia was not predictive of a current breast cancer and longer follow up is needed to determine whether atypia is an additional marker of future breast cancer risk in this population already at high genetic risk of breast cancer

Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data

Background: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. Methods: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0–2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. Findings: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30–0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69–0·86] per 10 mL, pinteraction=0·29; diffusion MRI OR 0·87 [0·81–0·94] per 10 mL, pinteraction=0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. Interpretation: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Funding: Medtronic