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Molecular cloning of the cDNA encoding pp36, a tyrosine-phosphorylated adaptor protein selectively expressed by T cells and natural killer cells.
Activation of T and natural killer (NK) cells leads to the tyrosine phosphorylation of pp36 and to its association with several signaling molecules, including phospholipase Cgamma-1 and Grb2. Microsequencing of peptides derived from purified rat pp36 protein led to the cloning, in rat and man, of cDNA encoding a T- and NK cell-specific protein with several putative Src homology 2 domain-binding motifs. A rabbit antiserum directed against a peptide sequence from the cloned rat molecule recognized tyrosine phosphorylated pp36 from pervanadate-treated rat thymocytes. When expressed in 293T human fibroblast cells and tyrosine-phosphorylated, pp36 associated with phospholipase Cgamma-1 and Grb2. Studies with GST-Grb2 fusion proteins demonstrated that the association was specific for the Src homology 2 domain of Grb-2. Molecular cloning of the gene encoding pp36 should facilitate studies examining the role of this adaptor protein in proximal signaling events during T and NK cell activation
Optical detection of single non-absorbing molecules using the surface plasmon of a gold nanorod
Current optical detection schemes for single molecules require light
absorption, either to produce fluorescence or direct absorption signals. This
severely limits the range of molecules that can be detected, because most
molecules are purely refractive. Metal nanoparticles or dielectric resonators
detect non-absorbing molecules by a resonance shift in response to a local
perturbation of the refractive index, but neither has reached single-protein
sensitivity. The most sensitive plasmon sensors to date detect single molecules
only when the plasmon shift is amplified by a highly polarizable label or by a
localized precipitation reaction on the particle's surface. Without
amplification, the sensitivity only allows for the statistical detection of
single molecules. Here we demonstrate plasmonic detection of single molecules
in realtime, without the need for labeling or amplification. We monitor the
plasmon resonance of a single gold nanorod with a sensitive photothermal assay
and achieve a ~ 700-fold increase in sensitivity compared to state-of-the-art
plasmon sensors. We find that the sensitivity of the sensor is intrinsically
limited due to spectral diffusion of the SPR. We believe this is the first
optical technique that detects single molecules purely by their refractive
index, without any need for photon absorption by the molecule. The small size,
bio-compatibility and straightforward surface chemistry of gold nanorods may
open the way to the selective and local detection of purely refractive proteins
in live cells
Colossal magnetocapacitance and scale-invariant dielectric response in phase-separated manganites
Thin films of strongly-correlated electron materials (SCEM) are often grown
epitaxially on planar substrates and typically have anisotropic properties that
are usually not captured by edge-mounted four-terminal electrical measurements,
which are primarily sensitive to in-plane conduction paths. Accordingly, the
correlated interactions in the out-of-plane (perpendicular) direction cannot be
measured but only inferred. We address this shortcoming and show here an
experimental technique in which the SCEM under study, in our case a 600
Angstrom-thick (La1-yPry)0.67Ca0.33MnO3 (LPCMO) film, serves as the base
electrode in a metal-insulator-metal (MIM) trilayer capacitor structure. This
unconventional arrangement allows for simultaneous determination of colossal
magnetoresistance (CMR) associated with dc transport parallel to the film
substrate and colossal magnetocapacitance (CMC) associated with ac transport in
the perpendicular direction. We distinguish two distinct strain-related
direction-dependent insulator-metal (IM) transitions and use Cole-Cole plots to
establish a heretofore unobserved collapse of the dielectric response onto a
universal scale-invariant power-law dependence over a large range of frequency,
temperature and magnetic field.Comment: 32 pages, 4 figures, Supplementary section included, Submitted to
Nature Physic
Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): Compound heterozygous mutation in the claudin 16 (CLDN16) gene
<p>Abstract</p> <p>Background</p> <p>Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive disorder of renal calcium and magnesium wasting frequently complicated by progressive chronic renal failure in childhood or adolescence.</p> <p>Methods</p> <p>A 7 year old boy was investigated following the findings of marked renal insufficiency and nephrocalcinosis in his 18-month old sister. He too was found to have extensive nephrocalcinosis with increased fractional excretion of magnesium: 12.4% (<4%) and hypercalciuria: 5.7 mmol (< 2.5/24 hours). He had renal impairment, partial distal renal tubular acidosis and defective urinary concentrating ability. Therapy with thiazide diuretics and magnesium supplements failed to halt the progression of the disorder. Both children subsequently underwent renal transplantation. Both children's parents are unaffected and there is one unaffected sibling.</p> <p>Results</p> <p>Mutation analysis revealed 2 heterozygous mutations in the claudin 16 gene <it>(CLDN16</it>) in both affected siblings; one missense mutation in exon 4: C646T which results in an amino acid change Arg216Cys in the second extracellular loop of <it>CLDN16 </it>and loss of function of the protein and a donor splice site mutation which changes intron 4 consensus splice site from 'GT' to 'TT' resulting in decreased splice efficiency and the formation of a truncated protein with loss of 64 amino acids in the second extracellular loop.</p> <p>Conclusion</p> <p>The mutations in <it>CLDN16 </it>in this kindred affect the second extra-cellular loop of claudin 16. The clinical course and molecular findings suggest complete loss of function of the protein in the 2 affected cases and highlight the case for molecular diagnosis in individuals with FHHNC.</p
‘Content to be sad’ or ‘runaway apprentice’? The psychological contract and career agency of young scientists in the entrepreneurial university
This article examines employee agency in psychological contracts by exploring how young scientists proactively shape their careers in response to unmet expectations induced by academic entrepreneurialism. It uses the lens of social exchange to examine their relationships with the professors engaged in two types of activities: collaborative research characterized by diffuse/reciprocal exchange, and commercial ventures, by restricted/negotiated exchange. These two categories show how career agency varies in orientation, form and behavioural outcome depending on the relational context within which their psychological contracts evolve. Those involved in collaborative research experienced a relational psychological contract and responded to unfulfilled career promises by ‘extended investment’ in their current jobs. They use ‘proxy agency’ by enlisting the support of their professors. However, some become ‘trapped’ in perennial temporary employment and are ‘content to be sad’. By contrast, those involved in research commercialization experienced a transactional contract and assert ‘personal agency’ by crafting their own entrepreneurial careers. They are ‘runaways’ who seek autonomy. The evidence is based on interviews with 24 doctoral/postdoctoral researchers and 16 professors from three leading UK universities. The study extends psychological contract theory by incorporating career agency and sheds new light on changing academic careers
Children and older adults exhibit distinct sub-optimal cost-benefit functions when preparing to move their eyes and hands
"© 2015 Gonzalez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited"Numerous activities require an individual to respond quickly to the correct stimulus. The provision of advance information allows response priming but heightened responses can cause errors (responding too early or reacting to the wrong stimulus). Thus, a balance is required between the online cognitive mechanisms (inhibitory and anticipatory) used to prepare and execute a motor response at the appropriate time. We investigated the use of advance information in 71 participants across four different age groups: (i) children, (ii) young adults, (iii) middle-aged adults, and (iv) older adults. We implemented 'cued' and 'non-cued' conditions to assess age-related changes in saccadic and touch responses to targets in three movement conditions: (a) Eyes only; (b) Hands only; (c) Eyes and Hand. Children made less saccade errors compared to young adults, but they also exhibited longer response times in cued versus non-cued conditions. In contrast, older adults showed faster responses in cued conditions but exhibited more errors. The results indicate that young adults (18 -25 years) achieve an optimal balance between anticipation and execution. In contrast, children show benefits (few errors) and costs (slow responses) of good inhibition when preparing a motor response based on advance information; whilst older adults show the benefits and costs associated with a prospective response strategy (i.e., good anticipation)
Strong Interactions of Single Atoms and Photons near a Dielectric Boundary
Modern research in optical physics has achieved quantum control of strong
interactions between a single atom and one photon within the setting of cavity
quantum electrodynamics (cQED). However, to move beyond current
proof-of-principle experiments involving one or two conventional optical
cavities to more complex scalable systems that employ N >> 1 microscopic
resonators requires the localization of individual atoms on distance scales <
100 nm from a resonator's surface. In this regime an atom can be strongly
coupled to a single intracavity photon while at the same time experiencing
significant radiative interactions with the dielectric boundaries of the
resonator. Here, we report an initial step into this new regime of cQED by way
of real-time detection and high-bandwidth feedback to select and monitor single
Cesium atoms localized ~100 nm from the surface of a micro-toroidal optical
resonator. We employ strong radiative interactions of atom and cavity field to
probe atomic motion through the evanescent field of the resonator. Direct
temporal and spectral measurements reveal both the significant role of
Casimir-Polder attraction and the manifestly quantum nature of the atom-cavity
dynamics. Our work sets the stage for trapping atoms near micro- and
nano-scopic optical resonators for applications in quantum information science,
including the creation of scalable quantum networks composed of many
atom-cavity systems that coherently interact via coherent exchanges of single
photons.Comment: 8 pages, 5 figures, Supplemental Information included as ancillary
fil
Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort
Background
Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease.
Methods
This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis.
Results
Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection.
Conclusions
Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population
Cooperative coupling of ultracold atoms and surface plasmons
Cooperative coupling between optical emitters and light fields is one of the
outstanding goals in quantum technology. It is both fundamentally interesting
for the extraordinary radiation properties of the participating emitters and
has many potential applications in photonics. While this goal has been achieved
using high-finesse optical cavities, cavity-free approaches that are broadband
and easy to build have attracted much attention recently. Here we demonstrate
cooperative coupling of ultracold atoms with surface plasmons propagating on a
plane gold surface. While the atoms are moving towards the surface they are
excited by an external laser pulse. Excited surface plasmons are detected via
leakage radiation into the substrate of the gold layer. A maximum Purcell
factor of is reached at an optimum distance of
from the surface. The coupling leads to the observation of
a Fano-like resonance in the spectrum.Comment: 9 pages, 4 figure
Small RNA analysis in Sindbis virus infected human HEK293 cells
In contrast to the defence mechanism of RNA interference (RNAi) in plants and invertebrates, its role in the innate response to virus infection of mammals is a matter of debate. Since RNAi has a well-established role in controlling infection of the alphavirus Sindbis virus (SINV) in insects, we have used this virus to investigate the role of RNAi in SINV infection of human cells
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