Toward multi-focal spot remote focusing two-photon microscopy for high speed imaging

This is the final version of the article. Available from SPIE via the DOI in this record.Optical sectioning techniques using two-photon excitation of fluorescent indicators are central to diverse imaging applications. The limitations of the technique are low speed and undesirable specimen agitation. In our design, highspeed axial scanning is carried out by moving a reference objective to axially displace the focal spot without introducing significant spherical aberration and any agitation of the specimen. Further, the system is configured to allow switching between single spot and multiple focal spot remote ...The project is funded by the Medical Research Council through project “MICA: High speed, high resolution imaging of excitable cell networks” (MR/K015877/1)

Altered intrinsic pyramidal neuron properties and pathway-specific synaptic dysfunction underlie aberrant hippocampal network function in a mouse model of Tauopathy.

Final published version of article. This article is freely available online through the J Neurosci Author Open Choice option.The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function. SIGNIFICANCE STATEMENT: Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.Medical Research Council (MRC)Royal SocietyAlzheimer's Research United Kingdo

Electrical and network neuronal properties are preferentially disrupted in dorsal, but not ventral, medial entorhinal cortex in a mouse model of Tauopathy

The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal-ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30-80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia. SIGNIFICANCE STATEMENT: The medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia

Introduction: looking beyond the walls

In its consideration of the remarkable extent and variety of non-university researchers, this book takes a broader view of ‘knowledge’ and ‘research’ than in the many hot debates about today’s knowledge society, ‘learning age’, or organisation of research. It goes beyond the commonly held image of ‘knowledge’ as something produced and owned by the full-time experts to take a look at those engaged in active knowledge building outside the university walls

A dusty origin for the correlation between protoplanetary disc accretion rates and dust masses

ABSTRACT Recent observations have uncovered a correlation between the accretion rates (measured from the UV continuum excess) of protoplanetary discs and their masses inferred from observations of the submm continuum. While viscous evolution models predict such a correlation, the predicted values are in tension with data obtained from the Lupus and Upper Scorpius star-forming regions; for example, they underpredict the scatter in accretion rates, particularly in older regions. Here, we argue that since the submm observations trace the discs’ dust, by explicitly modelling the dust grain growth, evolution, and emission, we can better understand the correlation. We show that for turbulent viscosities with α ≲ 10−3, the depletion of dust from the disc due to radial drift means we can reproduce the range of masses and accretion rates seen in the Lupus and Upper Sco data sets. One consequence of this model is that the upper locus of accretion rates at a given dust mass does not evolve with the age of the region. Moreover, we find that internal photoevaporation is necessary to produce the lowest accretion rates observed. In order to replicate the correct dust masses at the time of disc dispersal, we favour relatively low photoevaporation rates ≲ 10−9 M⊙ yr−1 for most sources but cannot discriminate between EUV or X-ray-driven winds. A limited number of sources, particularly in Lupus, are shown to have higher masses than predicted by our models which may be evidence for variations in the properties of the dust or dust trapping induced in substructures.</jats:p

Local Optical Probe of Motion and Stress in a multilayer graphene NEMS

Nanoelectromechanical systems (NEMSs) are emerging nanoscale elements at the crossroads between mechanics, optics and electronics, with significant potential for actuation and sensing applications. The reduction of dimensions compared to their micronic counterparts brings new effects including sensitivity to very low mass, resonant frequencies in the radiofrequency range, mechanical non-linearities and observation of quantum mechanical effects. An important issue of NEMS is the understanding of fundamental physical properties conditioning dissipation mechanisms, known to limit mechanical quality factors and to induce aging due to material degradation. There is a need for detection methods tailored for these systems which allow probing motion and stress at the nanometer scale. Here, we show a non-invasive local optical probe for the quantitative measurement of motion and stress within a multilayer graphene NEMS provided by a combination of Fizeau interferences, Raman spectroscopy and electrostatically actuated mirror. Interferometry provides a calibrated measurement of the motion, resulting from an actuation ranging from a quasi-static load up to the mechanical resonance while Raman spectroscopy allows a purely spectral detection of mechanical resonance at the nanoscale. Such spectroscopic detection reveals the coupling between a strained nano-resonator and the energy of an inelastically scattered photon, and thus offers a new approach for optomechanics

Factor H autoantibody is associated with atypical hemolytic uremic syndrome in children in the United Kingdom and Ireland

Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood. There are no trials investigating treatment, and clinical practice is only informed by retrospective cohort analysis. Here we examined 175 children presenting with atypical hemolytic uremic syndrome in the United Kingdom and Ireland for factor H autoantibodies that included 17 children with titers above the international standard. Of the 17, seven had a concomitant rare genetic variant in a gene encoding a complement pathway component or regulator. Two children received supportive treatment; both developed established renal failure. Plasma exchange was associated with a poor rate of renal recovery in seven of 11 treated. Six patients treated with eculizumab recovered renal function. Contrary to global practice, immunosuppressive therapy to prevent relapse in plasma exchange–treated patients was not adopted due to concerns over treatment-associated complications. Without immunosuppression, the relapse rate was high (five of seven). However, reintroduction of treatment resulted in recovery of renal function. All patients treated with eculizumab achieved sustained remission. Five patients received renal transplants without specific factor H autoantibody–targeted treatment with recurrence in one who also had a functionally significant CFI mutation. Thus, our current practice is to initiate eculizumab therapy for treatment of factor H autoantibody–mediated atypical hemolytic uremic syndrome rather than plasma exchange with or without immunosuppression. Based on this retrospective analysis we see no suggestion of inferior treatment, albeit the strength of our conclusions is limited by the small sample siz

Isolated and dynamical horizons and their applications

Over the past three decades, black holes have played an important role in quantum gravity, mathematical physics, numerical relativity and gravitational wave phenomenology. However, conceptual settings and mathematical models used to discuss them have varied considerably from one area to another. Over the last five years a new, quasi-local framework was introduced to analyze diverse facets of black holes in a unified manner. In this framework, evolving black holes are modeled by dynamical horizons and black holes in equilibrium by isolated horizons. We review basic properties of these horizons and summarize applications to mathematical physics, numerical relativity and quantum gravity. This paradigm has led to significant generalizations of several results in black hole physics. Specifically, it has introduced a more physical setting for black hole thermodynamics and for black hole entropy calculations in quantum gravity; suggested a phenomenological model for hairy black holes; provided novel techniques to extract physics from numerical simulations; and led to new laws governing the dynamics of black holes in exact general relativity.Comment: 77 pages, 12 figures. Typos and references correcte

Characterisation of subglacial water using a constrained transdimensional Bayesian transient electromagnetic inversion

Subglacial water modulates glacier-bed friction and therefore is of fundamental importance when characterising the dynamics of ice masses. The state of subglacial pore water, whether liquid or frozen, is associated with differences in electrical resistivity that span several orders of magnitude; hence, liquid water can be inferred from electrical resistivity depth profiles. Such profiles can be obtained from inversions of transient (time-domain) electromagnetic (TEM) soundings, but these are often non-unique. Here, we adapt an existing Bayesian transdimensional algorithm (Multimodal Layered Transdimensional Inversion – MuLTI) to the inversion of TEM data using independent depth constraints to provide statistical properties and uncertainty analysis of the resistivity profile with depth. The method was applied to ground-based TEM data acquired on the terminus of the Norwegian glacier, Midtdalsbreen, with depth constraints provided by co-located ground-penetrating radar data. Our inversion shows that the glacier bed is directly underlain by material of resistivity 102 Ωm ± 1000 %, with thickness 5–40 m, in turn underlain by a highly conductive basement (100 Ωm ± 15 %). High-resistivity material, 5×104 Ωm ± 25 %, exists at the front of the glacier. All uncertainties are defined by the interquartile range of the posterior resistivity distribution. Combining these resistivity profiles with those from co-located seismic shear-wave velocity inversions to further reduce ambiguity in the hydrogeological interpretation of the subsurface, we propose a new 3-D interpretation in which the Midtdalsbreen subglacial material is partitioned into partially frozen sediment, frozen sediment/permafrost and weathered/fractured bedrock with saline water