HIV-1 Nef limits communication between linker of activated T cells and SLP-76 to reduce formation of SLP-76-signaling microclusters following TCR stimulation

Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1-infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef's ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76-signaling MCs.

Design and testing of transonic linear cascade tunnel with optimized slotted walls

In linear cascade wind tunnel tests, a high level of pitchwise periodicity is desirable to reproduce the azimuthal periodicity in the stage of an axial compressor or turbine. Transonic tests in a cascade wind tunnel with open jet boundaries have been shown to suffer from spurious waves, reflected at the jet boundary, that compromise the flow periodicity in pitch. This problem can be tackled by placing at this boundary a slotted tailboard with a specific wall void ratio s and pitch angle a. The optimal value of the s-a pair depends on the test section geometry and on the tunnel running conditions. An inviscid two-dimensional numerical method has been developed to predict transonic linear cascade flows, with and without a tailboard, and quantify the nonperiodicity in the discharge. This method includes a new computational boundary condition to model the effects of the tailboard slots on the cascade interior flow. This method has been applied to a six-blade turbine nozzle cascade, transonically tested at the University of Leicester. The numerical results identified a specific slotted tailboard geometry, able to minimize the spurious reflected waves and regain some pitchwise flow periodicity. The wind tunnel open jet test section was redesigned accordingly. Pressure measurements at the cascade outlet and synchronous spark schlieren visualization of the test section, with and without the optimized slotted tailboard, have confirmed the gain in pitchwise periodicity predicted by the numerical model. Copyright © 2006 by ASME.

Acridine orange leukocyte fluorography in mice

Simultaneous non-invasive visualization of blood vessels and nerves in patients can be obtained in the eye. The retinal vasculature is a target of many retinopathies. Inflammation, readily manifest by leukocyte adhesion to the endothelial lining, is a key pathophysiological mechanism of many retinopathies, making it a valuable and ubiquitous target for disease research. Leukocyte fluorography has been extensively used in the past twenty years; however, fluorescent markers, visualization techniques, and recording methods have differed between studies. The lack of detailed protocol papers regarding leukocyte fluorography, coupled with lack of uniformity between studies, has led to a paucity of standards for leukocyte transit (velocity, adherence, extravasation) in the retina. Here, we give a detailed description of a convenient method using acridine orange (AO) and a commercially available scanning laser ophthalmoscope (SLO, HRA-OCT Spectralis) to view leukocyte behavior in the mouse retina. Normal mice are compared to mice with acute and chronic inflammation. This method can be readily adopted in many research labs.

Probing charge screening dynamics and electrochemical processes at the solid–liquid interface with electrochemical force microscopy

The presence of mobile ions complicates the implementation of voltage-modulated scanning probe microscopy techniques such as Kelvin probe force microscopy (KPFM). Overcoming this technical hurdle, however, provides a unique opportunity to probe ion dynamics and electrochemical processes in liquid environments and the possibility to unravel the underlying mechanisms behind important processes at the solid–liquid interface, including adsorption, electron transfer and electrocatalysis. Here we describe the development and implementation of electrochemical force microscopy (EcFM) to probe local bias- and time-resolved ion dynamics and electrochemical processes at the solid–liquid interface. Using EcFM, we demonstrate contact potential difference measurements, consistent with the principles of open-loop KPFM operation. We also demonstrate that EcFM can be used to investigate charge screening mechanisms and electrochemical reactions in the probe–sample junction. We further establish EcFM as a force-based imaging mode, allowing visualization of the spatial variability of sample-dependent local electrochemical properties.

Effect of nozzle geometry on the flow characteristics of hydroentangling jets

Cone-capillary nozzles with varying cone angles from 10° to 120° and a capillary diameter of 120μ are experimentally investigated for their application in the hydroentanglement process. Cone-up and cone-down configurations in a range of water pressures of 30-120 bar are tested. The effects of the cone angle on flow parameters such as discharge and velocity coefficients and intact length are studied. Flow visualization techniques are used to recognize the flow regimes and characteristics and to inspect and compare the intact length and appearance of the jets. Cone-down nozzles with more consistent flow properties, lower discharges, and higher velocity coefficients are more suitable for the hydroentanglement process. Single-cone nozzles without capillaries and with varying cone angles are also tested. The flow properties of the jets from the single-cone nozzles are compared with the cone-capillary nozzles of the same cone angle to study the effect of the capillary section. The effect of the interaction of adjacent nozzles on the flow from multi-hole nozzles is studied, and the characteristics of the jets from the multi-hole nozzles are compared with the single-hole nozzles.

The Development of an Immersive Virtual Reality Environment for Manufacturing and Improving Organizational Learning

This paper examines the applicability of an immersive virtual reality (VR) system to the process of organizational learning in a manufacturing context. The work focuses on the extent to which realism has to be represented in a simulated product build scenario in order to give the user an effective learning experience for an assembly task. Current technologies allow the visualization and manipulation of objects in VR systems but physical behaviors such as contact between objects and the effects of gravity are not commonly represented in off the shelf simulation solutions and the computational power required to facilitate these functions remains a challenge. This work demonstrates how physical behaviors can be coded and represented through the development of more effective mechanisms for the computer aided design (CAD) and VR interface.

Development of a novel continuous statistical modelling technique for detecting the adulteration of extra virgin olive oil with hazelnut oil by using spectroscopic data

The adulteration of extra virgin olive oil with other vegetable oils is a certain problem with economic and health consequences. Current official methods have been proved insufficient to detect such adulterations. One of the most concerning and undetectable adulterations with other vegetable oils is the addition of hazelnut oil. The main objective of this work was to develop a novel dimensionality reduction technique able to model oil mixtures as a part of an integrated pattern recognition solution. This final solution attempts to identify hazelnut oil adulterants in extra virgin olive oil at low percentages based on spectroscopic chemical fingerprints. The proposed Continuous Locality Preserving Projections (CLPP) technique allows the modelling of the continuous nature of the produced in house admixtures as data series instead of discrete points. This methodology has potential to be extended to other mixtures and adulterations of food products. The maintenance of the continuous structure of the data manifold lets the better visualization of this examined classification problem and facilitates a more accurate utilisation of the manifold for detecting the adulterants.

Retinal microvascular network attenuation in Alzheimer's disease

INTRODUCTION:Cerebral small-vessel disease has been implicated in the development of Alzheimer’sdisease (AD). The retinal microvasculature enables non-invasive visualization andevaluation of the systemic microcirculation. We evaluated retinal microvascular parametersin a case-control study of AD patients and cognitively-normal controls. 

METHODS:Retinal images were computationally analyzed and quantitative retinal parameters (caliber,fractal dimension, tortuosity, and bifurcation) measured. Regression models were used tocompute odds ratios (OR) and confidence intervals (CI) for AD with adjustment forconfounders. 

RESULTS:Retinal images were available in 213 AD participants and 294 cognitively-normal controls.Persons with lower venular fractal dimension (OR per standard deviation [SD] increase, 0.77[CI: 0.62–0.97]) and lower arteriolar tortuosity (OR per SD increase, 0.78 [CI: 0.63–0.97])were more likely to have AD following appropriate adjustment. 
DISCUSSION:Patients with AD have a sparser retinal microvascular network and retinal microvascularvariation may represent similar pathophysiological events within the cerebralmicrovasculature of patients with AD.

PET/CT imaging for target volume delineation in curative intent radiotherapy of non-small cell lung cancer: IAEA consensus report 2014

This document describes best practice and evidence based recommendations for the use of FDG-PET/CT for the purposes of radiotherapy target volume delineation (TVD) for curative intent treatment of non-small cell lung cancer (NSCLC). These recommendations have been written by an expert advisory group, convened by the International Atomic Energy Agency (IAEA) to facilitate a Coordinated Research Project (CRP) aiming to improve the applications of PET based radiation treatment planning (RTP) in low and middle income countries. These guidelines can be applied in routine clinical practice of radiotherapy TVD, for NSCLC patients treated with concurrent chemoradiation or radiotherapy alone, where FDG is used, and where a calibrated PET camera system equipped for RTP patient positioning is available. Recommendations are provided for PET and CT image visualization and interpretation, and for tumor delineation using planning CT with and without breathing motion compensation.

Synchrophasor-Based Islanding Detection for Distributed Generation Systems Using Systematic Principal Component Analysis Approaches

Systematic principal component analysis (PCA) methods are presented in this paper for reliable islanding detection for power systems with significant penetration of distributed generations (DGs), where synchrophasors recorded by Phasor Measurement Units (PMUs) are used for system monitoring. Existing islanding detection methods such as Rate-of-change-of frequency (ROCOF) and Vector Shift are fast for processing local information, however with the growth in installed capacity of DGs, they suffer from several drawbacks. Incumbent genset islanding detection cannot distinguish a system wide disturbance from an islanding event, leading to mal-operation. The problem is even more significant when the grid does not have sufficient inertia to limit frequency divergences in the system fault/stress due to the high penetration of DGs. To tackle such problems, this paper introduces PCA methods for islanding detection. Simple control chart is established for intuitive visualization of the transients. A Recursive PCA (RPCA) scheme is proposed as a reliable extension of the PCA method to reduce the false alarms for time-varying process. To further reduce the computational burden, the approximate linear dependence condition (ALDC) errors are calculated to update the associated PCA model. The proposed PCA and RPCA methods are verified by detecting abnormal transients occurring in the UK utility network.

Unconventional Computing: A Boolean Chemical Perspective

Elementary computing operations can be arranged within molecules so that problems in chemical, biochemical, and biological situations can be addressed. Problems that are found in small and/or living spaces, where the corresponding semiconductor logic devices cannot operate conveniently, are particularly amenable to this approach. The visualization and monitoring of intracellular species is one such category. Problems in medical diagnostics and therapy form additional categories. Chemists and biologists employ chemical synthesis and molecular biology techniques to build molecular logic devices. The photochemical approach to molecular logic devices is particularly prevalent. The fluorescent photoinduced electron transfer (PET) switching principle is particularly useful for designing logic functions into small molecules.

Dublin 1916: theatre of revolt

In his essay, Anti-Object, Kengo Kuma proposes that architecture cannot and should not be understood as object alone but instead always as series of networks and connections, relationships within space and through form. Some of these relationships are tangible, others are invisible. Stan Allen and James Corner have also called for an architecture that is more performative and operative – ‘less concerned with what buildings look like and more concerned with what they do’ – as means of effecting a more intimate and promiscuous relationship between infrastructure, urbanism and buildings. According to Allen this expanding filed offers a reclamation of some of the areas ceded by architecture following disciplinary specialization:

‘Territory, communication and speed are properly infrastructural problems and architecture as a discipline has developed specific technical means to deal with these variables. Mapping, projection, calculation, notation and visualization are among architecture’s traditional tools for operating at the very large scale’.

The motorway may not look like it – partly because we are no longer accustomed to think about it as such – but it is a site for and of architecture, a territory where architecture can be critical and active. If the limits of the discipline have narrowed, then one of the functions of a school of architecture must be an attempt occupy those areas of the built environment where architecture is no longer, or has yet to reach. If this is a project about reclamation of a landscape, it is also a challenge to some of the boundaries that surround architecture and often confine it, as Kuma suggests, to the appreciation of isolated objects.

M:NI 2014-15
We tend to think of the motorway as a thing or an object, something that has a singular function. Historically this is how it has been seen, with engineers designing bridges and embankments and suchlike with zeal … These objects like the M3 Urban Motorway, Belfast’s own Westway, are beautiful of course, but they have caused considerable damage to the city they were inflicted upon.

Actually, it’s the fact that we have seen the motorway as a solid object that has caused this problem. The motorway actually is a fluid and dynamic thing, and it should be seen as such: in fact it’s not an organ at all but actually tissue – something that connects rather than is. Once we start to see the motorway as tissue, it opens up new propositions about what the motorway is, is used for and does. This new dynamic and connective view unlocks the stasis of the motorway as edifice, and allows adaptation to happen: adaptation to old contexts that were ignored by the planners, and adaptation to new contexts that have arisen because of or in spite of our best efforts.

Motorways as tissue are more than just infrastructures: they are landscapes. These landscapes can be seen as surfaces on which flows take place, not only of cars, buses and lorries, but also of the globalized goods carried and the lifestyles and mobilities enabled. Here the infinite speed of urban change of thought transcends the declared speed limit [70 mph] of the motorway, in that a consignment of bananas can cause soil erosion in Equador, or the delivery of a new iphone can unlock connections and ideas the world over.

So what is this new landscape to be like? It may be a parallax-shifting, cognitive looking glass; a drone scape of energy transformation; a collective farm, or maybe part of a hospital. But what’s for sure, is that it is never fixed nor static: it pulses like a heartbeat through that most bland of landscapes, the countryside. It transmits forces like a Caribbean hurricane creating surf on an Atlantic Storm Beach: alien forces that mutate and re-form these places screaming into new, unclear and unintended futures.

And this future is clear: the future is urban. In this small rural country, motorways as tissue have made the whole of it: countryside, mountain, sea and town, into one singular, homogenous and hyper-connected, generic city.

Goodbye, place. Hello, surface!

MNI: Motorway Notation Network

In his essay, Anti-Object, Kengo Kuma proposes that architecture cannot and should not be understood as object alone but instead always as series of networks and connections, relationships within space and through form. Some of these relationships are tangible, others are invisible. Stan Allen and James Corner have also called for an architecture that is more performative and operative – ‘less concerned with what buildings look like and more concerned with what they do’ – as means of effecting a more intimate and promiscuous relationship between infrastructure, urbanism and buildings. According to Allen this expanding filed offers a reclamation of some of the areas ceded by architecture following disciplinary specialization:

‘Territory, communication and speed are properly infrastructural problems and architecture as a discipline has developed specific technical means to deal with these variables. Mapping, projection, calculation, notation and visualization are among architecture’s traditional tools for operating at the very large scale’.

The motorway may not look like it – partly because we are no longer accustomed to think about it as such – but it is a site for and of architecture, a territory where architecture can be critical and active. If the limits of the discipline have narrowed, then one of the functions of a school of architecture must be an attempt occupy those areas of the built environment where architecture is no longer, or has yet to reach. If this is a project about reclamation of a landscape, it is also a challenge to some of the boundaries that surround architecture and often confine it, as Kuma suggests, to the appreciation of isolated objects.

M:NI 2014-15
We tend to think of the motorway as a thing or an object, something that has a singular function. Historically this is how it has been seen, with engineers designing bridges and embankments and suchlike with zeal … These objects like the M3 Urban Motorway, Belfast’s own Westway, are beautiful of course, but they have caused considerable damage to the city they were inflicted upon.

Actually, it’s the fact that we have seen the motorway as a solid object that has caused this problem. The motorway actually is a fluid and dynamic thing, and it should be seen as such: in fact it’s not an organ at all but actually tissue – something that connects rather than is. Once we start to see the motorway as tissue, it opens up new propositions about what the motorway is, is used for and does. This new dynamic and connective view unlocks the stasis of the motorway as edifice, and allows adaptation to happen: adaptation to old contexts that were ignored by the planners, and adaptation to new contexts that have arisen because of or in spite of our best efforts.

Motorways as tissue are more than just infrastructures: they are landscapes. These landscapes can be seen as surfaces on which flows take place, not only of cars, buses and lorries, but also of the globalized goods carried and the lifestyles and mobilities enabled. Here the infinite speed of urban change of thought transcends the declared speed limit [70 mph] of the motorway, in that a consignment of bananas can cause soil erosion in Equador, or the delivery of a new iphone can unlock connections and ideas the world over.

So what is this new landscape to be like? It may be a parallax-shifting, cognitive looking glass; a drone scape of energy transformation; a collective farm, or maybe part of a hospital. But what’s for sure, is that it is never fixed nor static: it pulses like a heartbeat through that most bland of landscapes, the countryside. It transmits forces like a Caribbean hurricane creating surf on an Atlantic Storm Beach: alien forces that mutate and re-form these places screaming into new, unclear and unintended futures.

And this future is clear: the future is urban. In this small rural country, motorways as tissue have made the whole of it: countryside, mountain, sea and town, into one singular, homogenous and hyper-connected, generic city.

Goodbye, place. Hello, surface!

Gene regulatory mechanisms underpinning prostate cancer susceptibility

Molecular characterization of genome-wide association study (GWAS) loci can uncover key genes and biological mechanisms underpinning complex traits and diseases. Here we present deep, high-throughput characterization of gene regulatory mechanisms underlying prostate cancer risk loci. Our methodology integrates data from 295 prostate cancer chromatin immunoprecipitation and sequencing experiments with genotype and gene expression data from 602 prostate tumor samples. The analysis identifies new gene regulatory mechanisms affected by risk locus SNPs, including widespread disruption of ternary androgen receptor (AR)-FOXA1 and AR-HOXB13 complexes and competitive binding mechanisms. We identify 57 expression quantitative trait loci at 35 risk loci, which we validate through analysis of allele-specific expression. We further validate predicted regulatory SNPs and target genes in prostate cancer cell line models. Finally, our integrated analysis can be accessed through an interactive visualization tool. This analysis elucidates how genome sequence variation affects disease predisposition via gene regulatory mechanisms and identifies relevant genes for downstream biomarker and drug development.

QUADrATiC: scalable gene expression connectivity mapping for repurposing FDA-approved therapeutics

Background: Gene expression connectivity mapping has proven to be a powerful and flexible tool for research. Its application has been shown in a broad range of research topics, most commonly as a means of identifying potential small molecule compounds, which may be further investigated as candidates for repurposing to treat diseases. The public release of voluminous data from the Library of Integrated Cellular Signatures (LINCS) programme further enhanced the utilities and potentials of gene expression connectivity mapping in biomedicine. Results: We describe QUADrATiC (http://go.qub.ac.uk/QUADrATiC), a user-friendly tool for the exploration of gene expression connectivity on the subset of the LINCS data set corresponding to FDA-approved small molecule compounds. It enables the identification of compounds for repurposing therapeutic potentials. The software is designed to cope with the increased volume of data over existing tools, by taking advantage of multicore computing architectures to provide a scalable solution, which may be installed and operated on a range of computers, from laptops to servers. This scalability is provided by the use of the modern concurrent programming paradigm provided by the Akka framework. The QUADrATiC Graphical User Interface (GUI) has been developed using advanced Javascript frameworks, providing novel visualization capabilities for further analysis of connections. There is also a web services interface, allowing integration with other programs or scripts.Conclusions: QUADrATiC has been shown to provide an improvement over existing connectivity map software, in terms of scope (based on the LINCS data set), applicability (using FDA-approved compounds), usability and speed. It offers potential to biological researchers to analyze transcriptional data and generate potential therapeutics for focussed study in the lab. QUADrATiC represents a step change in the process of investigating gene expression connectivity and provides more biologically-relevant results than previous alternative solutions.