Imaging and sensing of pH and chemical state with nuclear-spin-correlated cascade gamma rays via radioactive tracer

Single-photon-emission computed tomography (SPECT) and positron-emission tomography (PET) are highly sensitive molecular detection and imaging techniques that generally measure accumulation of radio-labeled molecules by detecting gamma rays. Quantum sensing of local molecular environment via spin, such as nitrogen vacancy (NV) centers, has also been reported. Here, we describe quantum sensing and imaging using nuclear-spin time-space correlated cascade gamma-rays via a radioactive tracer. Indium-111 (111In) is widely used in SPECT to detect accumulation using a single gamma-ray photon. The time-space distribution of two successive cascade gamma-rays emitted from an 111In atom carries significant information on the chemical and physical state surrounding molecules with double photon coincidence detection. We propose and demonstrate quantum sensing capability of local micro-environment (pH and chelating molecule) in solution along with radioactive tracer accumulation imaging, by using multiple gamma-rays time-and-energy detection. Local molecular environment is extracted through electric quadrupole hyperfine interaction in the intermediate nuclear spin state by the explicit distribution of sub-MeV gamma rays. This work demonstrates a proof of concept, and further work is necessary to increase the sensitivity of the technique for in vivo imaging and to study the effect of scattered radiation for possible application in nuclear medicine.

Mammalian octopus cells are direction selective to frequency sweeps by synaptic sequence detection

Octopus cells are remarkable projection neurons of the mammalian cochlear nucleus, with extremely fast membranes and wide frequency tuning. They are considered prime examples of coincidence detectors but are poorly characterized in vivo. We discover that octopus cells are selective to frequency sweep direction, a feature that is absent in their auditory nerve inputs. In vivo intracellular recordings reveal that direction selectivity does not derive from cross-channel coincidence detection but hinges on the amplitudes and activation sequence of auditory nerve inputs tuned to clusters of hotspot frequencies. A simple biophysical model of octopus cells excited with real nerve spike trains recreates direction selectivity through interaction of intrinsic membrane conductances with activation sequence of clustered inputs. We conclude that octopus cells are sequence detectors, sensitive to temporal patterns across cochlear frequency channels. The detection of sequences rather than coincidences is a much simpler but powerful operation to extract temporal information.

A design of forceps-type coincidence radiation detector for intraoperative LN diagnosis: clinical impact estimated from LNs data of 20 esophageal cancer patients

Purpose To reduce postoperative complications, intraoperative lymph node (LN) diagnosis with 18F-fluoro-2-deoxy-D-glucose (FDG) is expected to optimize the extent of LN dissection, leading to less invasive surgery. However, such a diagnostic device has not yet been realized. We proposed the concept of coincidence detection wherein a pair of scintillation crystals formed the head of the forceps. To estimate the clinical impact of this detector, we determined the cut-off value using FDG as a marker for intraoperative LN diagnosis in patients with esophageal cancer, the specifications needed for the detector, and its feasibility using numerical simulation. Methods We investigated the dataset including pathological diagnosis and radioactivity of 1073 LNs resected from 20 patients who underwent FDG-positron emission tomography followed by surgery for esophageal cancer on the same day. The specifications for the detector were determined assuming that it should measure 100 counts (less than 10% statistical error) or more within the intraoperative measurement time of 30 s. The detector sensitivity was estimated using GEANT4 simulation and the expected diagnostic ability was calculated. Results The cut-off value was 620 Bq for intraoperative LN diagnosis. The simulation study showed that the detector had a radiation detection sensitivity of 0.96%, which was better than the estimated specification needed for the detector. Among the 1035 non-metastatic LNs, 815 were below the cut-off value. Conclusion The forceps-type coincidence detector can provide sufficient sensitivity for intraoperative LN diagnosis. Approximately 80% of the prophylactic LN dissections in esophageal cancer can be avoided using this detector.

The phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes

Uptake of large volumes of extracellular fluid by actin-dependent macropinocytosis has an important role in infection, immunity and cancer development. A key question is how actin assembly and disassembly are coordinated around macropinosomes to allow them to form and subsequently pass through the dense actin network underlying the plasma membrane to move towards the cell center for maturation. Here we show that the PH and FYVE domain protein Phafin2 is recruited transiently to newly-formed macropinosomes by a mechanism that involves coincidence detection of PtdIns3P and PtdIns4P. Phafin2 also interacts with actin via its PH domain, and recruitment of Phafin2 coincides with actin reorganization around nascent macropinosomes. Moreover, forced relocalization of Phafin2 to the plasma membrane causes rearrangement of the subcortical actin cytoskeleton. Depletion of Phafin2 inhibits macropinosome internalization and maturation and prevents KRAS-transformed cancer cells from utilizing extracellular protein as an amino acid source. We conclude that Phafin2 promotes macropinocytosis by controlling timely delamination of actin from nascent macropinosomes for their navigation through the dense subcortical actin network.

Burst control: Synaptic conditions for burst generation in cortical layer 5 pyramidal neurons

The output of neocortical layer 5 pyramidal cells (L5PCs) is expressed by a train of single spikes with intermittent bursts of multiple spikes at high frequencies. The bursts are the result of nonlinear dendritic properties, including Na+, Ca2+, and NMDA spikes, that interact with the ~10,000 synapses impinging on the neuron’s dendrites. Output spike bursts are thought to implement key dendritic computations, such as coincidence detection of bottom-up inputs (arriving mostly at the basal tree) and top-down inputs (arriving mostly at the apical tree). In this study we used a detailed nonlinear model of L5PC receiving excitatory and inhibitory synaptic inputs to explore the conditions for generating bursts and for modulating their properties. We established the excitatory input conditions on the basal versus the apical tree that favor burst and show that there are two distinct types of bursts. Bursts consisting of 3 or more spikes firing at < 200 Hz, which are generated by stronger excitatory input to the basal versus the apical tree, and bursts of ~2-spikes at ~250 Hz, generated by prominent apical tuft excitation. Localized and well-timed dendritic inhibition on the apical tree differentially modulates Na+, Ca2+, and NMDA spikes and, consequently, finely controls the burst output. Finally, we explored the implications of different burst classes and respective dendritic inhibition for regulating synaptic plasticity.

Sensory Adaptation in the Whisker-Mediated Tactile System: Physiology, Theory, and Function

In the natural environment, organisms are constantly exposed to a continuous stream of sensory input. The dynamics of sensory input changes with organism's behaviour and environmental context. The contextual variations may induce &gt;100-fold change in the parameters of the stimulation that an animal experiences. Thus, it is vital for the organism to adapt to the new diet of stimulation. The response properties of neurons, in turn, dynamically adjust to the prevailing properties of sensory stimulation, a process known as “neuronal adaptation.” Neuronal adaptation is a ubiquitous phenomenon across all sensory modalities and occurs at different stages of processing from periphery to cortex. In spite of the wealth of research on contextual modulation and neuronal adaptation in visual and auditory systems, the neuronal and computational basis of sensory adaptation in somatosensory system is less understood. Here, we summarise the recent finding and views about the neuronal adaptation in the rodent whisker-mediated tactile system and further summarise the functional effect of neuronal adaptation on the response dynamics and encoding efficiency of neurons at single cell and population levels along the whisker-mediated touch system in rodents. Based on direct and indirect pieces of evidence presented here, we suggest sensory adaptation provides context-dependent functional mechanisms for noise reduction in sensory processing, salience processing and deviant stimulus detection, shift between integration and coincidence detection, band-pass frequency filtering, adjusting neuronal receptive fields, enhancing neural coding and improving discriminability around adapting stimuli, energy conservation, and disambiguating encoding of principal features of tactile stimuli.

Coincidence Detection of EELS and EDX Spectral Events in the Electron Microscope

Recent advances in the development of electron and X-ray detectors have opened up the possibility to detect single events from which its time of arrival can be determined with nanosecond resolution. This allows observing time correlations between electrons and X-rays in the transmission electron microscope. In this work, a novel setup is described which measures individual events using a silicon drift detector and digital pulse processor for the X-rays and a Timepix3 detector for the electrons. This setup enables recording time correlation between both event streams while at the same time preserving the complete conventional electron energy loss (EELS) and energy dispersive X-ray (EDX) signal. We show that the added coincidence information improves the sensitivity for detecting trace elements in a matrix as compared to conventional EELS and EDX. Furthermore, the method allows the determination of the collection efficiencies without the use of a reference sample and can subtract the background signal for EELS and EDX without any prior knowledge of the background shape and without pre-edge fitting region. We discuss limitations in time resolution arising due to specificities of the silicon drift detector and discuss ways to further improve this aspect.

Selectivity of Lewy body protein interactions along the aggregation pathway of α-synuclein

The aggregation of alpha-synuclein (α-SYN) follows a cascade of oligomeric, prefibrillar and fibrillar forms, culminating in the formation of Lewy Bodies (LB), the pathological hallmarks of Parkinson’s Disease. Although LB contain over 70 proteins, the potential for interactions along the aggregation pathway of α-SYN is unknown. Here we propose a map of interactions of 65 proteins against different species of α-SYN. We measured binding to monomeric α-SYN using AlphaScreen, a sensitive nano-bead luminescence assay for detection of protein interactions. To access oligomeric species, we used the pathological mutants of α-SYN (A30P, G51D and A53T) which form oligomers with distinct properties. Finally, we generated amyloid fibrils from recombinant α-SYN. Binding to oligomers and fibrils was measured by two-color coincidence detection (TCCD) on a single molecule spectroscopy setup. Overall, we demonstrate that LB components are recruited to specific steps in the aggregation of α-SYN, uncovering future targets to modulate aggregation in synucleinopathies.