Evidence for temporary and local transition of sp2 graphite-type to sp3 diamond-type bonding induced by the tip of an atomic force microscope

Artificial diamond is created by exposing graphite to pressures on the order of 10\,GPa and temperatures of about 2000\,K. Here, we provide evidence that the pressure exerted by the tip of an atomic force microscope onto graphene over the carbon buffer layer of silicon carbide can lead to a temporary transition of graphite to diamond on the atomic scale. We perform atomic force microscopy with CO terminated tips and copper oxide (CuOx) tips to image graphene and to induce the structural transition. For a local transition, DFT predicts that a repulsive barrier of $\approx13$\,nN, followed by a force reduction by $\approx4$\,nN is overcome when inducing the graphite-diamond transition. Experimental evidence for this transition is provided by the observation of third harmonics in the cantilever oscillation for relative flexible CO terminated tips and a kink in the force versus distance curve for rigid CuOx tips. The experimental observation of the third harmonic with a magnitude of about 200\,fm fits to a force with an amplitude of $\pm 3$\,nN. The large repulsive overall force of $\approx 10$\,nN is only compatible with the experiment if one assumes that the repulsive force acting on the tip when inducing the transition is compensated by an increased van-der-Waals attraction of the tip due to form fitting of tip and sample by local indentation. The transition changes flat sp$^2$ bonds to corrugated sp$^3$ bonds, resulting in a different height of the two basis atoms in the elementary cell of graphene. Both tip types show a strong asysmmetry between the two basis atoms of the lattice when using large repulsive tip forces that induce the transition. Experimental data of tunneling current, frequency shift and dissipation are consistent with the proposed transition. The experiment also shows that atomic force microscopy allows to perform high pressure physics on the atomic scale

A Next-Generation qPlus-Sensor-Based AFM Setup: Resolving Archaeal S-layer Protein Structures in Air and Liquid

Surface-layer (S-layer) proteins form the outermost envelope in many bacteria and most archaea and arrange in 2D quasi-crystalline structures via self-assembly. We investigated S-layer proteins extracted from the archaeon Pyrobaculum aerophilium with a qPlus sensor-based atomic force microscope (AFM) in both liquid and ambient conditions and compared it to transmission electron microscopy (TEM) images under vacuum conditions. For AFM scanning, a next-generation liquid cell and a new protocol for creating long and sharp sapphire tips was introduced. Initial AFM images showed only layers of residual detergent molecules (SDS), which are used to isolate the S-layer proteins from the cells. SDS was not visible in the TEM images, requiring a more thorough sample preparation for AFM measurements. These improvements allowed us to resolve the crystal-like structure of the S-layer samples with frequency-modulation AFM in both air and liquid

Comparison of efficacy of pharmacological treatments for chronic idiopathic constipation: a systematic review and network meta-analysis

Objective To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis. Data sources We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane Central, as well as original data from authors or drug companies for the medications used for CIC. Study selection Phase IIB and phase III randomised, placebo-controlled trials (RCT) of ≥4 weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least one of four end points. Data extraction and synthesis Two investigators independently evaluated all full-text articles that met inclusion criteria and extracted data for primary and secondary end points, risk of bias and quality of evidence. Outcomes Primary end points were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary end points were change from baseline (Δb) in the number of SBM/week and Δb CSBM/week. Results Twenty-one RCTs (9189 patients) met inclusion and end point criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All prespecified end points were unavailable in four polyethylene glycol studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 CSBM/week end point. No drug was superior at improving the primary end points on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary end point, Δb in number of SBM/week. Conclusions Current drugs for CIC show similar efficacy. Bisacodyl may be superior to prescription medications for Δb in the number of SBM/week in CIC

Influence of Gender on Arrhythmia Characteristics and Outcome in the Multicenter UnSustained Tachycardia Trial

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73630/1/j.1540-8167.2004.04050.x.pd

Regional Fluid-Attenuated Inversion Recovery (FLAIR) at 7 Tesla correlates with amyloid beta in hippocampus and brainstem of cognitively normal elderly subjects

Background: Accumulation of amyloid beta (Aβ) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aβ-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity. Methods: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm–Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82). Conclusions: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative processes such as AD

Inhibitors of Streptococcus pneumoniae Surface Endonuclease EndA Discovered by High-Throughput Screening Using a PicoGreen Fluorescence Assay

The human commensal pathogen, Streptococcus pneumoniae, expresses a number of virulence factors that promote serious pneumococcal diseases, resulting in significant morbidity and mortality worldwide. These virulence factors may give S. pneumoniae the capacity to escape immune defenses, resist antimicrobial agents, or a combination of both. Virulence factors also present possible points of therapeutic intervention. The activities of the surface endonuclease, EndA, allow S. pneumoniae to establish invasive pneumococcal infection. EndA’s role in DNA uptake during transformation contributes to gene transfer and genetic diversitifcation. Moreover, EndA’s nuclease activity degrades the DNA backbone of neutrophil extracellular traps (NETs), allowing pneumococcus to escape host immune responses. Given its potential impact on pneumococcal pathogenicity, EndA is an attractive target for novel antimicrobial therapy. Herein, we describe the development of a high-throughput screening assay for the discovery of nuclease inhibitors. Nuclease-mediated digestion of double-stranded DNA was assessed using fluorescence intensity changes of the DNA dye ligand, PicoGreen. Under optimized conditions, the assay provided robust and reproducible activity data (Z'=0.87) and was used to screen 4727 small molecules against an imidazole-rescued variant of EndA. In total, 10 small molecules were confirmed as novel EndA inhibitors that may have utility as research tools for understanding pneumococcal pathogenesis, and ultimately drug discovery

Ultrafast Coherent Generation of Hot Electrons Studied via Band-to-Acceptor Luminescence in GaAs

The distribution of hot electrons excited with femtosecond laser pulses is studied via spectrally resolved band-to-acceptor luminescence. Our data demonstrate for the first time that the coherent coupling between the laser pulse and the interband polarization strongly influences the initial carrier distribution. The energetic width of carrier generation is broadened due to rapid phase-breaking scattering events. Theoretical results from a Monte Carlo solution of the semiconductor Bloch equations including on the same kinetic level coherent and incoherent phenomena, are in excellent agreement with the experimental data

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Treatment of Peritoneal Carcinomatosis by Targeted Delivery of the Radio-Labeled Tumor Homing Peptide 213Bi-DTPA-[F3]2 into the Nucleus of Tumor Cells

BACKGROUND: Alpha-particle emitting isotopes are effective novel tools in cancer therapy, but targeted delivery into tumors is a prerequisite of their application to avoid toxic side effects. Peritoneal carcinomatosis is a widespread dissemination of tumors throughout the peritoneal cavity. As peritoneal carcinomatosis is fatal in most cases, novel therapies are needed. F3 is a tumor homing peptide which is internalized into the nucleus of tumor cells upon binding to nucleolin on the cell surface. Therefore, F3 may be an appropriate carrier for alpha-particle emitting isotopes facilitating selective tumor therapies. PRINCIPAL FINDINGS: A dimer of the vascular tumor homing peptide F3 was chemically coupled to the alpha-emitter (213)Bi ((213)Bi-DTPA-[F3](2)). We found (213)Bi-DTPA-[F3](2) to accumulate in the nucleus of tumor cells in vitro and in intraperitoneally growing tumors in vivo. To study the anti-tumor activity of (213)Bi-DTPA-[F3](2) we treated mice bearing intraperitoneally growing xenograft tumors with (213)Bi-DTPA-[F3](2). In a tumor prevention study between the days 4-14 after inoculation of tumor cells 6x1.85 MBq (50 microCi) of (213)Bi-DTPA-[F3](2) were injected. In a tumor reduction study between the days 16-26 after inoculation of tumor cells 6x1.85 MBq of (213)Bi-DTPA-[F3](2) were injected. The survival time of the animals was increased from 51 to 93.5 days in the prevention study and from 57 days to 78 days in the tumor reduction study. No toxicity of the treatment was observed. In bio-distribution studies we found (213)Bi-DTPA-[F3](2) to accumulate in tumors but only low activities were found in control organs except for the kidneys, where (213)Bi-DTPA-[F3](2) is found due to renal excretion. CONCLUSIONS/SIGNIFICANCE: In conclusion we report that (213)Bi-DTPA-[F3](2) is a novel tool for the targeted delivery of alpha-emitters into the nucleus of tumor cells that effectively controls peritoneal carcinomatosis in preclinical models and may also be useful in oncology