499 research outputs found
Antibody mimetic receptor proteins for label-free biosensors
The development of high sensitivity biosensors, for example for clinical diagnostics, requires the
identification of suitable receptor molecules which offer high stability, specificity and affinity, even when
embedded into solid-state biosensor transducers. Here, we present an electrochemical biosensor
employing small synthetic receptor proteins (Mw < 15 kDa) which emulate antibodies but with improved
stability, sensitivity and molecular recognition properties, in particular when immobilized on a solid
sensor surface. The synthetic receptor protein is a non-antibody-based protein scaffold with variable
peptide regions inserted to provide the specific binding, and was designed to bind anti-myc tag antibody
(Mw � 150 kDa), as a proof-of-principle exemplar. Both the scaffold and the selected receptor protein
were found to have high thermostability with melting temperatures of 101 �C and 85 �C, respectively.
Furthermore, the secondary structures of the receptor protein were found to be very similar to that of
the original native scaffold, despite the insertion of variable peptide loops that create the binding sites. A
label-free electrochemical sensor was fabricated by functionalising a microfabricated gold electrode
with the receptor protein. A change in the phase of the electrochemical impedance was observed when
the biosensor was subjected to anti-myc tag antibodies at concentrations between 6.7 pM and 6.7 nM.
These findings demonstrate that these non-antibody receptor proteins are excellent candidates for
recognition molecules in label-free biosensors
Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders
Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface
Getting into hot water:sick guppies frequent warmer thermal conditions
Ectotherms depend on the environmental temperature for thermoregulation and exploit thermal regimes that optimise physiological functioning. They may also frequent warmer conditions to up-regulate their immune response against parasite infection and/or impede parasite development. This adaptive response, known as ‘behavioural fever’, has been documented in various taxa including insects, reptiles and fish, but only in response to endoparasite infections. Here, a choice chamber experiment was used to investigate the thermal preferences of a tropical freshwater fish, the Trinidadian guppy (Poecilia reticulata), when infected with a common helminth ectoparasite Gyrodactylus turnbulli, in female-only and mixed-sex shoals. The temperature tolerance of G. turnbulli was also investigated by monitoring parasite population trajectories on guppies maintained at a continuous 18, 24 or 32 °C. Regardless of shoal composition, infected fish frequented the 32 °C choice chamber more often than when uninfected, significantly increasing their mean temperature preference. Parasites maintained continuously at 32 °C decreased to extinction within 3 days, whereas mean parasite abundance increased on hosts incubated at 18 and 24 °C. We show for the first time that gyrodactylid-infected fish have a preference for warmer waters and speculate that sick fish exploit the upper thermal tolerances of their parasites to self medicate
Microwave studies of the fractional Josephson effect in HgTe-based Josephson junctions
The rise of topological phases of matter is strongly connected to their
potential to host Majorana bound states, a powerful ingredient in the search
for a robust, topologically protected, quantum information processing. In order
to produce such states, a method of choice is to induce superconductivity in
topological insulators. The engineering of the interplay between
superconductivity and the electronic properties of a topological insulator is a
challenging task and it is consequently very important to understand the
physics of simple superconducting devices such as Josephson junctions, in which
new topological properties are expected to emerge. In this article, we review
recent experiments investigating topological superconductivity in topological
insulators, using microwave excitation and detection techniques. More
precisely, we have fabricated and studied topological Josephson junctions made
of HgTe weak links in contact with two Al or Nb contacts. In such devices, we
have observed two signatures of the fractional Josephson effect, which is
expected to emerge from topologically-protected gapless Andreev bound states.
We first recall the theoretical background on topological Josephson junctions,
then move to the experimental observations. Then, we assess the topological
origin of the observed features and conclude with an outlook towards more
advanced microwave spectroscopy experiments, currently under development.Comment: Lectures given at the San Sebastian Topological Matter School 2017,
published in "Topological Matter. Springer Series in Solid-State Sciences,
vol 190. Springer
Lithic technological responses to Late Pleistocene glacial cycling at Pinnacle Point Site 5-6, South Africa
There are multiple hypotheses for human responses to glacial cycling in the Late Pleistocene, including changes in population size, interconnectedness, and mobility. Lithic technological analysis informs us of human responses to environmental change because lithic assemblage characteristics are a reflection of raw material transport, reduction, and discard behaviors that depend on hunter-gatherer social and economic decisions. Pinnacle Point Site 5-6 (PP5-6), Western Cape, South Africa is an ideal locality for examining the influence of glacial cycling on early modern human behaviors because it preserves a long sequence spanning marine isotope stages (MIS) 5, 4, and 3 and is associated with robust records of paleoenvironmental change. The analysis presented here addresses the question, what, if any, lithic assemblage traits at PP5-6 represent changing behavioral responses to the MIS 5-4-3 interglacial-glacial cycle? It statistically evaluates changes in 93 traits with no a priori assumptions about which traits may significantly associate with MIS. In contrast to other studies that claim that there is little relationship between broad-scale patterns of climate change and lithic technology, we identified the following characteristics that are associated with MIS 4: increased use of quartz, increased evidence for outcrop sources of quartzite and silcrete, increased evidence for earlier stages of reduction in silcrete, evidence for increased flaking efficiency in all raw material types, and changes in tool types and function for silcrete. Based on these results, we suggest that foragers responded to MIS 4 glacial environmental conditions at PP5-6 with increased population or group sizes, 'place provisioning', longer and/or more intense site occupations, and decreased residential mobility. Several other traits, including silcrete frequency, do not exhibit an association with MIS. Backed pieces, once they appear in the PP5-6 record during MIS 4, persist through MIS 3. Changing paleoenvironments explain some, but not all temporal technological variability at PP5-6.Social Science and Humanities Research Council of Canada; NORAM; American-Scandinavian Foundation; Fundacao para a Ciencia e Tecnologia [SFRH/BPD/73598/2010]; IGERT [DGE 0801634]; Hyde Family Foundations; Institute of Human Origins; National Science Foundation [BCS-9912465, BCS-0130713, BCS-0524087, BCS-1138073]; John Templeton Foundation to the Institute of Human Origins at Arizona State Universit
Novel ketone diet enhances physical and cognitive performance.
Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.A.J.M. thanks the Research Councils UK for supporting
his Academic Fellowship. This work was supported by the
Defense Advanced Research Projects Agency.This is the final version of the article. It first appeared from FASEB at https://doi.org/10.1096/fj.201600773R
Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability
Abstract The scaffold protein DLGAP1 is localized at the post-synaptic density (PSD) of glutamatergic neurons and is a component of supramolecular protein complexes organized by PSD95. Gain-of-function variants of DLGAP1 have been associated with obsessive-compulsive disorder (OCD), while haploinsufficient variants have been linked to autism spectrum disorder (ASD) and schizophrenia in human genetic studies. We tested male and female Dlgap1 wild type (WT), heterozygous (HT), and knockout (KO) mice in a battery of behavioral tests: open field, dig, splash, prepulse inhibition, forced swim, nest building, social approach, and sucrose preference. We also used biochemical approaches to examine the role of DLGAP1 in the organization of PSD protein complexes. Dlgap1 KOÂ mice were most notable for disruption of protein interactions in the PSD, and deficits in sociability. Other behavioral measures were largely unaffected. Our data suggest that Dlgap1 knockout leads to PSD disruption and reduced sociability, consistent with reports of DLGAP1 haploinsufficient variants in schizophrenia and ASD
The Expanding Fireball of Nova Delphini 2013
A classical nova occurs when material accreting onto the surface of a white
dwarf in a close binary system ignites in a thermonuclear runaway. Complex
structures observed in the ejecta at late stages could result from interactions
with the companion during the common envelope phase. Alternatively, the
explosion could be intrinsically bipolar, resulting from a localized ignition
on the surface of the white dwarf or as a consequence of rotational distortion.
Studying the structure of novae during the earliest phases is challenging
because of the high spatial resolution needed to measure their small sizes.
Here we report near-infrared interferometric measurements of the angular size
of Nova Delphini 2013, starting from one day after the explosion and continuing
with extensive time coverage during the first 43 days. Changes in the apparent
expansion rate can be explained by an explosion model consisting of an
optically thick core surrounded by a diffuse envelope. The optical depth of the
ejected material changes as it expands. We detect an ellipticity in the light
distribution, suggesting a prolate or bipolar structure that develops as early
as the second day. Combining the angular expansion rate with radial velocity
measurements, we derive a geometric distance to the nova of 4.54 +/- 0.59 kpc
from the Sun.Comment: Published in Nature. 32 pages. Final version available at
http://www.nature.com/nature/journal/v515/n7526/full/nature13834.htm
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