Explaining efficient search for conjunctions of motion and form: Evidence from negative color effects

Dent, Humphreys, and Braithwaite (2011) showed substantial costs to search when a moving target shared its color with a group of ignored static distractors. The present study further explored the conditions under which such costs to performance occur. Experiment 1 tested whether the negative color-sharing effect was specific to cases in which search showed a highly serial pattern. The results showed that the negative color-sharing effect persisted in the case of a target defined as a conjunction of movement and form, even when search was highly efficient. In Experiment 2, the ease with which participants could find an odd-colored target amongst a moving group was examined. Participants searched for a moving target amongst moving and stationary distractors. In Experiment 2A, participants performed a highly serial search through a group of similarly shaped moving letters. Performance was much slower when the target shared its color with a set of ignored static distractors. The exact same displays were used in Experiment 2B; however, participants now responded "present" for targets that shared the color of the static distractors. The same targets that had previously been difficult to find were now found efficiently. The results are interpreted in a flexible framework for attentional control. Targets that are linked with irrelevant distractors by color tend to be ignored. However, this cost can be overridden by top-down control settings. © 2014 Psychonomic Society, Inc

A Novel, All-Optical Tool for Controllable and Non- Destructive Poration of Cells with Single-Micron Resolution

We demonstrate controllable poration within ≈1 µm regions of individual cells, mediated by a near-IR laser interacting with thin-layer amorphous silicon substrates. This technique will allow new experiments in single-cell biology, particularly in neuroscience. As our understanding of the fundamental mechanistic processes underpinning biology expands, so does the need for high-precision tools to allow the dissection of the heterogeneity and stochastic processes that dominate at the single- and sub-cellular level. Here, we demonstrate a highly controllable and reproducible optical technique for inducing poration within specific regions of a target cell’s plasma membrane, permitting localized delivery of payloads, depolarization and lysis experiments to be conducted in unprecedented detail. Experiments support a novel mechanism for the process, based upon a thermally-induced change triggered by the interactions of a near-IR laser with a biocompatible thin film substrate at powers substantially below that used in standard optoporation experiments

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

Impact of Splenic Artery Embolization on the Success Rate of Nonoperative Management for Blunt Splenic Injury

Introduction Nonoperative management (NOM) has become the treatment of choice for hemodynamically stable patients with blunt splenic injury. Results of outcome after NOM are predominantly based on large-volume studies from level 1 trauma centers in the United States. This study was designed to assess the results of NOM in a relatively low-volume Dutch level 1 trauma center. Methods An analysis of a prospective trauma registry was performed for a 6-year period before (period 1) and after the introduction and implementation of splenic artery embolization (SAE) (period 2). Primary outcome was the failure rate of initial treatment. Results A total of 151 patients were reviewed. An increased use of SAE and a reduction of splenic operations during the second period was observed. Compared with period 1, the failure rate after observation in period 2 decreased from 25% to 10%. The failure rate after SAE in period 2 was 18%. The splenic salvage rate (SSR) after observation increased from 79% in the first period to 100% in the second period. During the second period, all patients with failure after observation were successfully treated with SAE. The SSR after SAE in periods 1 and 2 was respectively 100% and 86%. Conclusions SAE of patients with blunt splenic injuries is associated with a reduction in splenic operations. The failure and splenic salvage rates in this current study were comparable with the results from large-volume studies of level 1 trauma centers. Nonoperative management also is feasible in a relatively low-volume level 1 trauma center outside the United State

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

Debris Disks: Probing Planet Formation

Debris disks are the dust disks found around ~20% of nearby main sequence stars in far-IR surveys. They can be considered as descendants of protoplanetary disks or components of planetary systems, providing valuable information on circumstellar disk evolution and the outcome of planet formation. The debris disk population can be explained by the steady collisional erosion of planetesimal belts; population models constrain where (10-100au) and in what quantity (>1Mearth) planetesimals (>10km in size) typically form in protoplanetary disks. Gas is now seen long into the debris disk phase. Some of this is secondary implying planetesimals have a Solar System comet-like composition, but some systems may retain primordial gas. Ongoing planet formation processes are invoked for some debris disks, such as the continued growth of dwarf planets in an unstirred disk, or the growth of terrestrial planets through giant impacts. Planets imprint structure on debris disks in many ways; images of gaps, clumps, warps, eccentricities and other disk asymmetries, are readily explained by planets at >>5au. Hot dust in the region planets are commonly found (<5au) is seen for a growing number of stars. This dust usually originates in an outer belt (e.g., from exocomets), although an asteroid belt or recent collision is sometimes inferred.Comment: Invited review, accepted for publication in the 'Handbook of Exoplanets', eds. H.J. Deeg and J.A. Belmonte, Springer (2018

A phase I dose-escalation study to evaluate safety and tolerability of sorafenib combined with sirolimus in patients with advanced solid cancer

Contains fulltext : 87630.pdf (publisher's version ) (Closed access)BACKGROUND: The combination of sorafenib (vascular endothelial growth factor receptor 2 inhibitor) and sirolimus (mammalian target of rapamycin inhibitor) might work synergistically. METHODS: A phase I dose-escalation study with sorafenib twice a day (b.i.d.) and sirolimus once daily (q.d.) was performed to determine the recommended dose of the combination in patients with solid tumours. Secondary objectives were to determine the safety profile and maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK) of the combination. RESULTS: Dose-limiting toxicities were transaminitis and cutaneous toxicity. The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar-plantar erythrodysaesthesia. Sirolimus did not change the PK of sorafenib; in contrast, sorafenib reduced the AUC(0-96) and C(max) of sirolimus. No objective responses were observed; eight patients showed stable disease for a median of 16.3 weeks (range 8-24). The MTD of the combination was sorafenib 200 mg b.i.d. with sirolimus 1 mg q.d. CONCLUSION: The combination of sorafenib and sirolimus showed enhanced toxicity, which could not be explained by the PK of both drugs. The relative low doses at the MTD, in combination with the PK results, do not warrant further development of this combination