Signal Transmission Across Tile Assemblies: 3D Static Tiles Simulate Active Self-Assembly by 2D Signal-Passing Tiles

The 2-Handed Assembly Model (2HAM) is a tile-based self-assembly model in which, typically beginning from single tiles, arbitrarily large aggregations of static tiles combine in pairs to form structures. The Signal-passing Tile Assembly Model (STAM) is an extension of the 2HAM in which the tiles are dynamically changing components which are able to alter their binding domains as they bind together. For our first result, we demonstrate useful techniques and transformations for converting an arbitrarily complex STAM$^+$ tile set into an STAM$^+$ tile set where every tile has a constant, low amount of complexity, in terms of the number and types of ``signals'' they can send, with a trade off in scale factor. Using these simplifications, we prove that for each temperature $\tau>1$ there exists a 3D tile set in the 2HAM which is intrinsically universal for the class of all 2D STAM$^+$ systems at temperature $\tau$ (where the STAM$^+$ does not make use of the STAM's power of glue deactivation and assembly breaking, as the tile components of the 2HAM are static and unable to change or break bonds). This means that there is a single tile set $U$ in the 3D 2HAM which can, for an arbitrarily complex STAM$^+$ system $S$, be configured with a single input configuration which causes $U$ to exactly simulate $S$ at a scale factor dependent upon $S$. Furthermore, this simulation uses only two planes of the third dimension. This implies that there exists a 3D tile set at temperature $2$ in the 2HAM which is intrinsically universal for the class of all 2D STAM$^+$ systems at temperature $1$. Moreover, we show that for each temperature $\tau>1$ there exists an STAM$^+$ tile set which is intrinsically universal for the class of all 2D STAM$^+$ systems at temperature $\tau$, including the case where $\tau = 1$.Comment: A condensed version of this paper will appear in a special issue of Natural Computing for papers from DNA 19. This full version contains proofs not seen in the published versio

Cytochrome oxidase subunit VI of Trypanosoma brucei is imported without a cleaved presequence and is developmentally regulated at both RNA and protein levels

Mitochondrial respiration in the African trypanosome undergoes dramatic developmental stage regulation. This requires co-ordinated control of components encoded by both the nuclear genome and the kinetoplast, the unusual mitochondrial genome of these parasites. As a model for understanding the co-ordination of these genomes, we have examined the regulation and mitochondrial import of a nuclear-encoded component of the cytochrome oxidase complex, cytochrome oxidase subunit VI (COXVI). By generating transgenic trypanosomes expressing intact or mutant forms of this protein, we demonstrate that COXVI is not imported using a conventional cleaved presequence and show that sequences at the N-terminus of the protein are necessary for correct mitochondrial sorting. Analyses of endogenous and transgenic COXVI mRNA and protein expression in parasites undergoing developmental stage differentiation demonstrates a temporal order of control involving regulation in the abundance of, first, mRNA and then protein. This represents the first dissection of the regulation and import of a nuclear-encoded protein into the cytochrome oxidase complex in these organisms, which were among the earliest eukaryotes to possess a mitochondrion

Overcoming challenges to data quality in the ASPREE clinical trial

© 2019 The Author(s). Background: Large-scale studies risk generating inaccurate and missing data due to the complexity of data collection. Technology has the potential to improve data quality by providing operational support to data collectors. However, this potential is under-explored in community-based trials. The Aspirin in reducing events in the elderly (ASPREE) trial developed a data suite that was specifically designed to support data collectors: the ASPREE Web Accessible Relational Database (AWARD). This paper describes AWARD and the impact of system design on data quality. Methods: AWARD's operational requirements, conceptual design, key challenges and design solutions for data quality are presented. Impact of design features is assessed through comparison of baseline data collected prior to implementation of key functionality (n = 1000) with data collected post implementation (n = 18,114). Overall data quality is assessed according to data category. Results: At baseline, implementation of user-driven functionality reduced staff error (from 0.3% to 0.01%), out-of-range data entry (from 0.14% to 0.04%) and protocol deviations (from 0.4% to 0.08%). In the longitudinal data set, which contained more than 39 million data values collected within AWARD, 96.6% of data values were entered within specified query range or found to be accurate upon querying. The remaining data were missing (3.4%). Participant non-attendance at scheduled study activity was the most common cause of missing data. Costs associated with cleaning data in ASPREE were lower than expected compared with reports from other trials. Conclusions: Clinical trials undertake complex operational activity in order to collect data, but technology rarely provides sufficient support. We find the AWARD suite provides proof of principle that designing technology to support data collectors can mitigate known causes of poor data quality and produce higher-quality data. Health information technology (IT) products that support the conduct of scheduled activity in addition to traditional data entry will enhance community-based clinical trials. A standardised framework for reporting data quality would aid comparisons across clinical trials

Recent Progress at SLAC Extracting High Charge from Highly-Polarized Photocathodes for Future-Collider Applications

Future colliders such as NLC and JLC will require a highly-polarized macropulse with charge that is more than an order of magnitude beyond that which could be produced for the SLC. The maximum charge from the SLC uniformly-doped GaAs photocathode was limited by the surface charge limit (SCL). The SCL effect can be overcome by using an extremely high (>1019 cm-3) surface dopant concentration. When combined with a medium dopant concentration in the majority of the active layer (to avoid depolarization), the surface concentration has been found to degrade during normal heat cleaning (1 hour at 600 C). The Be dopant as typically used in an MBE-grown superlattice cathode is especially susceptible to this effect compared to Zn or C dopant. Some relief can be found by lowering the cleaning temperature, but the long-term general solution appears to be atomic hydrogen cleaning.Comment: 11 pages, 3 figures, 1 table, contributed to 10th Workshop on Polarized Sources and Targets, Novosibirsk, Sept. 22-26, 2003, to be submitted to Nucl. Instrum. and Meth.

Changes in the immune landscape of TNBC after neoadjuvant chemotherapy: correlation with relapse

Introduction: Patients with high-risk, triple negative breast cancer (TNBC) often receive neoadjuvant chemotherapy (NAC) alone or with immunotherapy. Various single-cell and spatially resolved techniques have demonstrated heterogeneity in the phenotype and distribution of macrophages and T cells in this form of breast cancer. Furthermore, recent studies in mice have implicated immune cells in perivascular (PV) areas of tumors in the regulation of metastasis and anti-tumor immunity. However, little is known of how the latter change during NAC in human TNBC or their impact on subsequent relapse, or the likely efficacy of immunotherapy given with or after NAC. Methods: We have used multiplex immunofluorescence and AI-based image analysis to compare the immune landscape in untreated and NAC-treated human TNBCs. We quantified changes in the phenotype, distribution and intercellular contacts of subsets of tumor-associated macrophages (TAMs), CD4+ and CD8+ T cells, and regulatory T cells (Tregs) in PV and non-PV various areas of the stroma and tumor cell islands. These were compared in tumors from patients who had either developed metastases or were disease-free (DF) after a three-year follow up period. Results: In tumors from patients who remained DF after NAC, there was a marked increase in stromal CD163+ TAMs, especially those expressing the negative checkpoint regulator, T-cell immunoglobulin and mucin domain 3 (TIM-3). Whereas CD4+ T cells preferentially located to PV areas in the stroma of both untreated and NAC-treated tumors, specific subsets of TAMs and Tregs only did so only after NAC. Distinct subsets of CD4+ and CD8+ T cells formed PV clusters with CD163+ TAMs and Tregs. These were retained after NAC. Discussion: Quantification of stromal TIM-3+CD163+ TAMs in tumor residues after NAC may represent a new way of identifying patients at high risk of relapse. PV clustering of immune cells is highly likely to regulate the activation and function of T cells, and thus the efficacy of T cell-based immunotherapies administered with or after NAC

A multilevel neo-institutional analysis of infection prevention and control in English hospitals: coerced safety culture change?

Despite committed policy, regulative and professional efforts on healthcare safety, little is known about how such macro-interventions permeate organisations and shape culture over time. Informed by neo-institutional theory, we examined how inter-organisational influences shaped safety practices and inter-subjective meanings following efforts for coerced culture change. We traced macro-influences from 2000 to 2015 in infection prevention and control (IPC). Safety perceptions and meanings were inductively analysed from 130 in-depth qualitative interviews with senior- and middle-level managers from 30 English hospitals. A total of 869 institutional interventions were identified; 69% had a regulative component. In this context of forced implementation of safety practices, staff experienced inherent tensions concerning the scope of safety, their ability to be open and prioritisation of external mandates over local need. These tensions stemmed from conflicts among three co-existing institutional logics prevalent in the NHS. In response to requests for change, staff flexibly drew from a repertoire of cognitive, material and symbolic resources within and outside their organisations. They crafted 'strategies of action', guided by a situated assessment of first-hand practice experiences complementing collective evaluations of interventions such as 'pragmatic', 'sensible' and also 'legitimate'. Macro-institutional forces exerted influence either directly on individuals or indirectly by enriching the organisational cultural repertoire

A Model for the Stray Light Contamination of the UVCS Instrument on SOHO

We present a detailed model of stray-light suppression in the spectrometer channels of the Ultraviolet Coronagraph Spectrometer (UVCS) on the SOHO spacecraft. The control of diffracted and scattered stray light from the bright solar disk is one of the most important tasks of a coronagraph. We compute the fractions of light that diffract past the UVCS external occulter and non-specularly pass into the spectrometer slit. The diffracted component of the stray light depends on the finite aperture of the primary mirror and on its figure. The amount of non-specular scattering depends mainly on the micro-roughness of the mirror. For reasonable choices of these quantities, the modeled stray-light fraction agrees well with measurements of stray light made both in the laboratory and during the UVCS mission. The models were constructed for the bright H I Lyman alpha emission line, but they are applicable to other spectral lines as well.Comment: 19 pages, 5 figures, Solar Physics, in pres

Comprehensive molecular characterization of urachal adenocarcinoma reveals commonalities with colorectal cancer, including a hypermutable phenotype

Purpose Urachal adenocarcinoma is a rare type of primary bladder adenocarcinoma that comprises less than 1% of all bladder cancers. The low incidence of urachal adenocarcinomas does not allow for an evidence-based approach to therapy. Transcriptome profiling of urachal adenocarcinomas has not been previously reported.Wehypothesized that an in-depth molecular understanding of urachal adenocarcinoma would uncover rational therapeutic strategies. Patients and Methods We performed targeted exon sequencing and global transcriptome profiling of 12 urachal tumors to generate a comprehensive molecular portrait of urachal adenocarcinoma. A single patient with an MSH6 mutation was treated with the anti-programmed death-ligand 1 antibody, atezolizumab. Results Urachal adenocarcinoma closely resembles colorectal cancer at the level of RNA expression, which extends previous observations that urachal tumors harbor genomic alterations that are found in colorectal adenocarcinoma. A subset of tumors was found to have alterations in genes that are associated with microsatellite instability (MSH2 and MSH6) and hypermutation (POLE).Apatient with anMSH6mutation was treated withimmunecheckpoint blockade, which resulted in stable disease. Conclusion Because clinical trials are next to impossible for patients with rare tumors, precision oncology may be an important adjunct for treatment decisions. Our findings demonstrate that urachal adenocarcinomas molecularly resemble colorectal adenocarcinomas at the level ofRNA expression, are the first report, to our knowledge, of MSH2andMSH6mutations in this disease, and support the consideration of immune checkpoint blockade as a rational therapeutic treatment of this exceedingly rare tumor

The first multi-wavelength campaign of AXP 4U 0142+61 from radio to hard X-rays

For the first time a quasi-simultaneous multi-wavelength campaign has been performed on an Anomalous X-ray Pulsar from the radio to the hard X-ray band. 4U 0142+61 was an INTEGRAL target for 1 Ms in July 2005. During these observations it was also observed in the X-ray band with Swift and RXTE, in the optical and NIR with Gemini North and in the radio with the WSRT. In this paper we present the source-energy distribution. The spectral results obtained in the individual wave bands do not connect smoothly; apparently components of different origin contribute to the total spectrum. Remarkable is that the INTEGRAL hard X-ray spectrum (power-law index 0.79 +/- 0.10) is now measured up to an energy of ~230 keV with no indication of a spectral break. Extrapolation of the INTEGRAL power-law spectrum to lower energies passes orders of magnitude underneath the NIR and optical fluxes, as well as the low ~30 microJy (2 sigma) upper limit in the radio band.Comment: 6 pages, 1 figure. To be published in the proceedings of the conference "Isolated Neutron Stars: from the Interior to the Surface" (April 24-28, 2006, London, UK), eds. S. Zane, R. Turolla and D. Pag