Towards a quantum representation of the ampere using single electron pumps

Electron pumps generate a macroscopic electric current by controlled manipulation of single electrons. Despite intensive research towards a quantum current standard over the last 25 years, making a fast and accurate quantised electron pump has proved extremely difficult. Here we demonstrate that the accuracy of a semiconductor quantum dot pump can be dramatically improved by using specially designed gate drive waveforms. Our pump can generate a current of up to 150 pA, corresponding to almost a billion electrons per second, with an experimentally demonstrated current accuracy better than 1.2 parts per million (ppm) and strong evidence, based on fitting data to a model, that the true accuracy is approaching 0.01 ppm. This type of pump is a promising candidate for further development as a realisation of the SI base unit ampere, following a re-definition of the ampere in terms of a fixed value of the elementary charge.Comment: 8 pages, 7 figure

CR1 Knops blood group alleles are not associated with severe malaria in the Gambia

The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-value <0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McC(b) have arisen to confer a selective advantage against infectious disease that, in view of these case-control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McC(b) with severe malaria may involve variation in CR1 expression levels

Seton drainage prior to transanal advancement flap repair: useful or not?

Introduction: Transanal advancement flap repair (TAFR) provides a useful tool in the treatment of high transsphincteric fistulas. Recent studies indicate that TAFR fails in one out of three patients. Until now, no definite predictive factor for failure has been identified. Although some authors have reported that preoperative seton drainage might improve the outcome of TAFR, this could not be confirmed by others. We conducted the present study to assess the influence of preoperative seton drainage on the outcome of TAFR in a relatively large series. Methods: Between December 1992 and June 2008, a consecutive series of 278 patients [M/F = 179:99, median age 46 years (range, 19-73 years)] with cryptoglandular, transsphincteric fistula, passing through the upper or middle third of the external anal sphincter underwent TAFR. Patients were recruited from the colorectal units of two university hospitals (Erasmus Medical Center, Rotterdam, n = 211; and Leiden University Medical Center, Leiden, n = 67). Baseline characteristics did not differ between the two clinics. Sixty-eight of these patients underwent preoperative seton drainage for at least 2 months and until the day of the flap repair. Results: Median healing time was 2.2 months. In patients without preoperative seton drainage, the healing rate was 63%, whereas the healing rate was 67% in patients who underwent preoperative seton drainage. This difference was not statistically significant. No differences in healing rates were found between the series from Leiden and Rotterdam. Conclusion: Preoperative seton drainage does not improve the outcome of TAFR

Identification of epithelialization in high transsphincteric fistulas

textabstractBackground At present, transanal advancement flap repair (TAFR) is the treatment of choice for transsphincteric fistulas passing through the upper and middle third of the external anal sphincter. It has been suggested that epithelialization of the fistula tract contributes to the failure of the treatment. The aim of this study was to assess the prevalence of epithelialization of the fistula tract and to study its effect on the outcome of TAFR and TAFR combined with ligation of the intersphincteric fistula tract (LIFT). Methods Forty-four patients with a high transsphincteric fistula of cryptoglandular origin underwent TAFR. Nine of these patients underwent a combined procedure of TAFR with LIFT. In all patients the fistula tract was excised from the external opening up to the outer border of the external anal sphincter. In patients undergoing TAFR combined with LIFT an additional central part of the intersphincteric fistula tract was excised. A total of 53 specimens were submitted. Histopathological examination of the specimens was carried out by a pathologist, blinded for clinical data. Results Epithelialization of the distal and intersphincteric fistula tract was observed in only 25 and 22% of fistulas, respectively. There was no difference in outcome between fistulas with or without epithelialization. Conclusions Epithelialization of high transsphincteric fistulas is rare and does not affect the outcome of TAFR and TAFR combined with LIFT

Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss

Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma

From the stable to the exotic: clustering in light nuclei

A great deal of research work has been undertaken in alpha-clustering study since the pioneering discovery of 12C+12C molecular resonances half a century ago. Our knowledge on physics of nuclear molecules has increased considerably and nuclear clustering remains one of the most fruitful domains of nuclear physics, facing some of the greatest challenges and opportunities in the years ahead. The occurrence of "exotic" shapes in light N=Z alpha-like nuclei is investigated. Various approaches of the superdeformed and hyperdeformed bands associated with quasimolecular resonant structures are presented. Evolution of clustering from stability to the drip-lines is examined: clustering aspects are, in particular, discussed for light exotic nuclei with large neutron excess such as neutron-rich Oxygen isotopes with their complete spectroscopy.Comment: 15 pages, 5 figures, Presented at the International Symposium on "New Horizons in Fundamental Physics - From Neutrons Nuclei via Superheavy Elements and Supercritical Fields to Neutron Stars and Cosmic Rays" held at Makutsi Safari Farm, South Africa, December 23-29, 2015. arXiv admin note: substantial text overlap with arXiv:1402.6590, arXiv:1303.0960, arXiv:1408.0684, arXiv:1011.342

Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling

Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size

Protocol for a randomised controlled trial examining the impact of a web-based personally controlled health management system on the uptake of influenza vaccination rates

<p>Abstract</p> <p>Background</p> <p>Online social networking and personally controlled health management systems (PCHMS) offer a new opportunity for developing innovative interventions to prevent diseases of public health concern (e.g., influenza) but there are few comparative studies about patterns of use and impact of these systems.</p> <p>Methods/Design</p> <p>A 2010 CONSORT-compliant randomised controlled trial with a two-group parallel design will assess the efficacy of a web-based PCHMS called <it>Healthy.me </it>in facilitating the uptake of influenza vaccine amongst university students and staff. Eligible participants are randomised either to obtain access to <it>Healthy.me </it>or a 6-month waitlist. Participants complete pre-study, post-study and monthly surveys about their health and utilisation of health services. A post-study clinical audit will be conducted to validate self-reports about influenza vaccination and visits to the university health service due to influenza-like illness (ILI) amongst a subset of participants. 600 participants older than 18 years with monthly access to the Internet and email will be recruited. Participants who (i) discontinue the online registration process; (ii) report obtaining an influenza vaccination in 2010 before the commencement of the study; or (iii) report being influenced by other participants to undertake influenza vaccination will be excluded from analysis. The primary outcome measure is the number of participants obtaining influenza vaccination during the study. Secondary outcome measures include: number of participants (i) experiencing ILI symptoms, (ii) absent from or experiencing impairment in work or study due to ILI symptoms, (iii) using health services or medications due to ILI symptoms; (iv) expressing positive or negative attitudes or experiences towards influenza vaccination, via their reasons of receiving (or not receiving) influenza vaccine; and (v) their patterns of usage of <it>Healthy.me </it>(e.g., frequency and timing of hits, duration of access, uptake of specific functions).</p> <p>Discussion</p> <p>This study will provide new insights about the utility of online social networking and PCHMS for public health and health promotion. It will help to assess whether a web-based PCHMS, with connectivity to a health service provider, containing information and self-management tools, can improve the uptake of preventive health services amongst university students and staff.</p> <p>Trial registration</p> <p><a href="http://www.anzctr.org.au/ACTRN12610000386033.aspx">ACTRN12610000386033</a> (Australian New Zealand Clinical Trials Registry)</p

Prediction of peptide and protein propensity for amyloid formation

Understanding which peptides and proteins have the potential to undergo amyloid formation and what driving forces are responsible for amyloid-like fiber formation and stabilization remains limited. This is mainly because proteins that can undergo structural changes, which lead to amyloid formation, are quite diverse and share no obvious sequence or structural homology, despite the structural similarity found in the fibrils. To address these issues, a novel approach based on recursive feature selection and feed-forward neural networks was undertaken to identify key features highly correlated with the self-assembly problem. This approach allowed the identification of seven physicochemical and biochemical properties of the amino acids highly associated with the self-assembly of peptides and proteins into amyloid-like fibrils (normalized frequency of β-sheet, normalized frequency of β-sheet from LG, weights for β-sheet at the window position of 1, isoelectric point, atom-based hydrophobic moment, helix termination parameter at position j+1 and ΔGº values for peptides extrapolated in 0 M urea). Moreover, these features enabled the development of a new predictor (available at http://cran.r-project.org/web/packages/appnn/index.html) capable of accurately and reliably predicting the amyloidogenic propensity from the polypeptide sequence alone with a prediction accuracy of 84.9 % against an external validation dataset of sequences with experimental in vitro, evidence of amyloid formation