Structure determination by cryoEM at 100 keV.

Electron cryomicroscopy can, in principle, determine the structures of most biological molecules but is currently limited by access, specimen preparation difficulties, and cost. We describe a purpose-built instrument operating at 100 keV-including advances in electron optics, detection, and processing-that makes structure determination fast and simple at a fraction of current costs. The instrument attains its theoretical performance limits, allowing atomic resolution imaging of gold test specimens and biological molecular structure determination in hours. We demonstrate its capabilities by determining the structures of eleven different specimens, ranging in size from 140 kDa to 2 MDa, using a fraction of the data normally required. CryoEM with a microscope designed specifically for high-efficiency, on-the-spot imaging of biological molecules will expand structural biology to a wide range of previously intractable problems.

ABEL-FRET: tether-free single-molecule FRET with hydrodynamic profiling.

Single-molecule Förster resonance energy transfer (smFRET) has become a versatile and widespread method to probe nanoscale conformation and dynamics. However, current experimental modalities often resort to molecule immobilization for long observation times and do not always approach the resolution limit of FRET-based nanoscale metrology. Here we present ABEL-FRET, an immobilization-free platform for smFRET measurements with ultrahigh resolving power in FRET efficiency. Importantly, single-molecule diffusivity is used to provide additional size and shape information for hydrodynamic profiling of individual molecules, which, together with the concurrently measured intramolecular conformation through FRET, enables a holistic and dynamic view of biomolecules and their complexes.

Single-molecule diffusometry reveals no catalysis-induced diffusion enhancement of alkaline phosphatase as proposed by FCS experiments.

Theoretical and experimental observations that catalysis enhances the diffusion of enzymes have generated exciting implications about nanoscale energy flow, molecular chemotaxis, and self-powered nanomachines. However, contradictory claims on the origin, magnitude, and consequence of this phenomenon continue to arise. To date, experimental observations of catalysis-enhanced enzyme diffusion have relied almost exclusively on fluorescence correlation spectroscopy (FCS), a technique that provides only indirect, ensemble-averaged measurements of diffusion behavior. Here, using an anti-Brownian electrokinetic (ABEL) trap and in-solution single-particle tracking, we show that catalysis does not increase the diffusion of alkaline phosphatase (ALP) at the single-molecule level, in sharp contrast to the ∼20% enhancement seen in parallel FCS experiments using p-nitrophenyl phosphate (pNPP) as substrate. Combining comprehensive FCS controls, ABEL trap, surface-based single-molecule fluorescence, and Monte Carlo simulations, we establish that pNPP-induced dye blinking at the ∼10-ms timescale is responsible for the apparent diffusion enhancement seen in FCS. Our observations urge a crucial revisit of various experimental findings and theoretical models--including those of our own--in the field, and indicate that in-solution single-particle tracking and ABEL trap are more reliable means to investigate diffusion phenomena at the nanoscale.

Evolution of the Wilson-Cowan equations.

The Wilson-Cowan equations were developed to provide a simplified yet powerful description of neural network dynamics. As such, they embraced nonlinear dynamics, but in an interpretable form. Most importantly, it was the first mathematical formulation to emphasize the significance of interactions between excitatory and inhibitory neural populations, thereby incorporating both cooperation and competition. Subsequent research by many has documented the Wilson-Cowan significance in such diverse fields as visual hallucinations, memory, binocular rivalry, and epilepsy. The fact that these equations are still being used to elucidate a wide range of phenomena attests to their validity as a dynamical approximation to more detailed descriptions of complex neural computations.

Faecal immunochemical test to triage patients with abdominal symptoms for suspected colorectal cancer in primary care: review of international use and guidelines.

BACKGROUND: Recently, faecal immunochemical tests (FITs) have been introduced for investigation of primary care patients with low-risk symptoms of colorectal cancer (CRC), but recommendations vary across the world. This systematic review of clinical practice guidelines aimed to determine how FITs are used in symptomatic primary care patients and the underpinning evidence for these guidelines. METHODS: MEDLINE, Embase and TRIP databases were systematically searched, from 1 November 2008 to 1 November 2018 for guidelines on the assessment of patients with symptoms suggestive of CRC. Known guideline databases, websites and references of related literature were searched. The following questions were addressed: (i) which countries use FIT for symptomatic primary care patients; (ii) in which populations is FIT used; (iii) what is the cut-off level used for haemoglobin in the faeces (FIT) and (iv) on what evidence are FIT recommendations based. RESULTS: The search yielded 2433 publications; 25 covered initial diagnostic assessment of patients with symptoms of CRC in 15 countries (Asia, n = 1; Europe, n = 13; Oceania, n = 4; North America, n = 5; and South America, n = 2). In three countries (Australia, Spain and the UK), FIT was recommended for patients with abdominal symptoms, unexplained weight loss, change in bowel habit or anaemia despite a low level of evidence in the symptomatic primary care patient population. CONCLUSIONS: Few countries recommend FITs in symptomatic patients in primary care either because of limited evidence or because symptomatic patients are directly referred to secondary care without triage. These results demonstrate a clear need for research on FIT in the symptomatic primary care population.

Hyperchaos in Wilson-Cowan oscillator circuits.

The Wilson-Cowan equations were originally shown to produce limit cycle oscillations for a range of parameters. Others subsequently showed that two coupled Wilson-Cowan oscillators could produce chaos, especially if the oscillator coupling was from inhibitory interneurons of one oscillator to excitatory neurons of the other. Here this is extended to show that chains, grids, and sparse networks of Wilson-Cowan oscillators generate hyperchaos with linearly increasing complexity as the number of oscillators increases. As there is now evidence that humans can voluntarily generate hyperchaotic visuomotor sequences, these results are particularly relevant to the unpredictability of a range of human behaviors. These also include incipient senescence in aging, effects of concussive brain injuries, autism, and perhaps also intelligence and creativity.NEW & NOTEWORTHY This paper represents an exploration of hyperchaos in coupled Wilson-Cowan equations. Results show that hyperchaos (number of positive Lyapunov exponents) grows linearly with the number of oscillators in the array and leads to high levels of unpredictability in the neural response.

Face perception develops similarly across viewpoint in children and adolescents with and without autism spectrum disorder.

Atypical face perception has been associated with the socio-communicative difficulties that characterize autism spectrum disorder (ASD). Growing evidence, however, suggests that a widespread impairment in face perception is not as common as once thought. One important issue arising with the interpretation of this literature is the relationship between face processing and a more general perceptual tendency to focus on local rather than global information. Previous work has demonstrated that when discriminating faces presented from the same view, older adolescents and adults with ASD perform similarly to typically developing individuals. When faces are presented from different views, however, they perform more poorly-specifically, when access to local cues is minimized. In this study, we assessed the cross-sectional development of face identity discrimination across viewpoint using same- and different-view conditions in children and adolescents with and without ASD. Contrary to the findings in adults, our results revealed that all participants experienced greater difficulty identifying faces from different views than from same views, and demonstrated similar age-expected improvements in performance across tasks. These results suggest that differences in face discrimination across views may only emerge beyond the age of 15 years in ASD.

Effect of motion discontinuities on discrimination of periodic trajectories.

Many biologically important motions are described by periodic trajectories. Radial frequency (RF) trajectories are one example, in which the motion of a difference of Gaussians (DOG) target moves along a path described by a sinusoidal deviation of the radius from a perfect circle (Or, Thabet, Wilkinson, & Wilson, 2011). Here we explore the hypothesis that visual processing of RF trajectories involves global spatio-temporal processes that are disrupted by motion discontinuity. To test this hypothesis, RF trajectories were used that interspersed smooth, continuous motion with three or four discontinuous jumps to other portions of the trajectory. These jumps were arranged so that the entire trajectory was traversed in the same amount of time as in the continuous motion control condition. The motion discontinuities increased thresholds by a factor of approximately 2.1 relative to continuous motion. This result provides support for global spatio-temporal processing of RF motion trajectories. Comparison with previous results suggests that motion discontinuities erase memory for earlier parts of the trajectory, thereby causing thresholds to be based on only the final segment viewed. Finally, it is shown that RF trajectories obey the 1/3 power law characteristic of biological motion.

Detection of periodic motion trajectories: Effects of frequency and radius.

Periodic trajectories are an important component of biological motion. Or, Thabet, Wilkinson, and Wilson (2011) studied radial frequency (RF) motion trajectory detection and concluded that, for RF2-5 trajectories, the threshold function paralleled that of static RF patterns. We have extended Or et al.'s (2011) findings to a broader range of RFs (three to 24 cycles) and across a 4-fold range of radii (1°-4°). We report that (a) thresholds for RF trajectories decrease as a power function of RF for low RF trajectories (three to six cycles) before approaching an asymptote at high RFs (12-24 cycles); (b) detection thresholds for RF trajectories scale proportionally with radius; and (c) there is no lower versus upper field advantage in the parafoveal field for stimuli displaced from fixation on the vertical midline. The results are compared to earlier findings for static RF thresholds, and we argue that our findings support the existence of parallel spatial and temporal processing channels that may contribute to both action perception and production.

Catalytic potential of highly defective (211) surfaces of zinc blende ZnO.

Zinc blende (ZB) ZnO has gained increasing research interest due to its favorable properties and its stabilization on the nanoscale. While surface properties are important on the nanoscale, the studies on ZB ZnO surface properties are rare. Here we have performed first principles calculations of the energies and structures of ZB and wurtzite (WZ) ZnO surfaces. Our results indicate that, among the four surfaces parallel to the polar axes, such as (101̄0) and (112̄0) of the WZ phase and (110) and (211) of the ZB phase, the polar (211) surface has substantially lower surface vacancy formation energies than the others, which makes ZB ZnO promising for catalytic applications. Our results also imply that the stabilization of ZB ZnO on the nanoscale is due to some mechanisms other than surface energies.

From orientations to objects: Configural processing in the ventral stream.

The ventral or form vision hierarchy comprises a sequence of cortical areas in which successively more complex visual attributes are extracted, beginning with contour orientations in V1 and culminating in face and object representations at the highest levels. In addition, ventral areas exhibit increasing receptive field diameter by a factor of approximately three from area to area, and conversely neuron density decreases. We argue here that this is consistent with configural combination of adjacent orientations to form curves or angles, followed by combination of these to form descriptions of object shapes. Substantial data from psychophysics, functional magnetic resonance imaging (fMRI), and neurophysiology support this organization, and computational models consistent with it have also been proposed. We further argue that a key to the role of the ventral stream is dimensionality reduction in object representations.

Neural correlates of radial frequency trajectory perception in the human brain.

Radial frequency (RF) motion trajectories are visual stimuli that consist of a difference of Gaussians moving along a closed trajectory defined by a sinusoidal variation of the radius relative to a circular path. In the current study, multivoxel fMRI analyses demonstrated that spatial patterns of activity in visual regions V2, V3, and MT can predict RF motion trajectory shape regardless of whether an observer can behaviorally identify the shape or not. This result suggests that processing in these regions is concerned with local properties of the trajectories and not directly linked with a conscious percept of global trajectory shape. Whole-brain analyses show that RF motion trajectories also evoke premotor and posterior parietal cortical activity that may be a neural correlate of shape recognizability. Further, comparisons with activity evoked by static versions of the RF shapes reveal cue-invariant processing in regions of the posterior parietal and occipitotemporal cortices. Interestingly, the RF motion trajectories evoke patterns of dorsal visual stream cortical activity typical of visually guided movement preparation or action observation, suggesting that these stimuli may be processed as potential motor actions rather than as purely visual experiences.

Superionic to superionic phase change in water: consequences for the interiors of uranus and neptune.

Using density functional molecular dynamics free energy calculations, we show that the body centered cubic (bcc) phase of superionic ice previously believed to be the only phase is, in fact, thermodynamically unstable compared to a novel phase with oxygen positions in face centered cubic lattice sites. The novel phase has a lower proton mobility than the bcc phase and may exhibit a higher melting temperature. We predict a transition between the two phases at a pressure of 1±0.5 Mbar, with potential consequences for the interiors of ice giants such as Uranus and Neptune.

The locus of flicker adaptation in the migraine visual system: a dichoptic study.

BACKGROUND: Flickering light has been shown to sensitize the migraine visual system at high stimulus contrast while elevating thresholds at low contrast. The present study employs a dichoptic psychophysical paradigm to ask whether the abnormal adaptation to flicker in migraine occurs before or after the binocular combination of inputs from the two eyes in the visual cortex. METHODS: Following adaptation to high contrast flicker presented to one eye only, flicker contrast increment thresholds were measured in each eye separately using dichoptic viewing. RESULTS: Modest interocular transfer of adaptation was seen in both migraine and control groups at low contrast. Sensitization at high contrast in migraine relative to control participants was seen in the adapted eye only, and an unanticipated threshold elevation occurred in the non-adapted eye. Migraineurs also showed significantly lower aversion thresholds to full field flicker than control participants, but aversion scores and increment thresholds were not correlated. CONCLUSIONS: The results are simulated with a three-stage neural model of adaptation that points to strong adaptation at monocular sites prior to binocular combination, and weaker adaptation at the level of cortical binocular neurons. The sensitization at high contrast in migraine is proposed to result from stronger adaptation of inhibitory neurons, which act as a monocular normalization pool.

Phase-separating pyrenoid proteins form complexes in the dilute phase.

While most studies of biomolecular phase separation have focused on the condensed phase, relatively little is known about the dilute phase. Theory suggests that stable complexes form in the dilute phase of two-component phase-separating systems, impacting phase separation; however, these complexes have not been interrogated experimentally. We show that such complexes indeed exist, using an in vitro reconstitution system of a phase-separated organelle, the algal pyrenoid, consisting of purified proteins Rubisco and EPYC1. Applying fluorescence correlation spectroscopy (FCS) to measure diffusion coefficients, we found that complexes form in the dilute phase with or without condensates present. The majority of these complexes contain exactly one Rubisco molecule. Additionally, we developed a simple analytical model which recapitulates experimental findings and provides molecular insights into the dilute phase organization. Thus, our results demonstrate the existence of protein complexes in the dilute phase, which could play important roles in the stability, dynamics, and regulation of condensates.

Rocky core solubility in Jupiter and giant exoplanets.

Gas giants are believed to form by the accretion of hydrogen-helium gas around an initial protocore of rock and ice. The question of whether the rocky parts of the core dissolve into the fluid H-He layers following formation has significant implications for planetary structure and evolution. Here we use ab initio calculations to study rock solubility in fluid hydrogen, choosing MgO as a representative example of planetary rocky materials, and find MgO to be highly soluble in H for temperatures in excess of approximately 10,000 K, implying the potential for significant redistribution of rocky core material in Jupiter and larger exoplanets.

An fMRI examination of the neural processing of periodic motion trajectories.

Perception of periodic or closed-circuit motion trajectories plays a crucial role in our ability to learn and perform many common skilled actions. For example, periodic trajectories are a key component of many types of biological movements when viewed relative to body translation. In the current fMRI study, we used a novel visual stimulus consisting of a target moving along a closed trajectory defined by a radial frequency (RF) pattern (i.e., a sinusoidal variation of trajectory radius relative to a circular trajectory) to determine which brain regions encode these periodic movement paths. Multivoxel pattern analyses permitted prediction of the shapes of different periodic trajectories within regions V2 and V3 indicating that these regions play a role in the processing of periodic visual motion. In addition, blood oxygen level dependent (BOLD) responses associated with the presentation of targets moving along RF trajectories compared with nonperiodic motion and static RF shapes revealed significantly greater activity in visual areas V1, V2, V3, V3A, and V4. To our knowledge, the results of this study represent the first examination of the functional brain activity underlying periodic motion processing and should inform further study.

Cannabinoid hyperemesis.

A 21-year-old woman presented with a 4-week history of sudden onset vomiting, nausea and anorexia. Questioning revealed that she had a 7-year history of heavy cannabis use (smoking). She did not describe abdominal pain, change in bowel habit, antibiotic use, foreign travel or contact with gastroenteritis. Biochemistry results demonstrated mild metabolic derangement with a low potassium and a low bicarbonate, and urine toxicology was positive for cannabinoids. Other investigations, including a full blood count, renal function tests, liver function tests, a coagulation sample, an ECG, urinary ß-hCG and a CT head scan, were all normal. A diagnosis of cannabinoid hyperemesis was made and her symptoms resolved after treatment with intravenous fluids, antiemetics and abstinence from cannabis. Since her discharge and abstinence she has had several relapses, each related to cannabis use and each resolving with abstinence. The patient is now seeking cognitive behavioural therapy to achieve permanent abstinence.

Face processing changes in normal aging revealed by fMRI adaptation.

We investigated the neural correlates of facial processing changes in healthy aging using fMRI and an adaptation paradigm. In the scanner, participants were successively presented with faces that varied in identity, viewpoint, both, or neither and performed a head size detection task independent of identity or viewpoint. In right fusiform face area (FFA), older adults failed to show adaptation to the same face repeatedly presented in the same view, which elicited the most adaptation in young adults. We also performed a multivariate analysis to examine correlations between whole-brain activation patterns and behavioral performance in a face-matching task tested outside the scanner. Despite poor neural adaptation in right FFA, high-performing older adults engaged the same face-processing network as high-performing young adults across conditions, except the one presenting a same facial identity across different viewpoints. Low-performing older adults used this network to a lesser extent. Additionally, high-performing older adults uniquely recruited a set of areas related to better performance across all conditions, indicating age-specific involvement of this added network. This network did not include the core ventral face-processing areas but involved the left inferior occipital gyrus, frontal, and parietal regions. Although our adaptation results show that the neuronal representations of the core face-preferring areas become less selective with age, our multivariate analysis indicates that older adults utilize a distinct network of regions associated with better face matching performance, suggesting that engaging this network may compensate for deficiencies in ventral face processing regions.

Can homeostatic plasticity in deafferented primary auditory cortex lead to travelling waves of excitation?

Travelling waves of activity in neural circuits have been proposed as a mechanism underlying a variety of neurological disorders, including epileptic seizures, migraine auras and brain injury. The highly influential Wilson-Cowan cortical model describes the dynamics of a network of excitatory and inhibitory neurons. The Wilson-Cowan equations predict travelling waves of activity in rate-based models that have sufficiently reduced levels of lateral inhibition. Travelling waves of excitation may play a role in functional changes in the auditory cortex after hearing loss. We propose that down-regulation of lateral inhibition may be induced in deafferented cortex via homeostatic plasticity mechanisms. We use the Wilson-Cowan equations to construct a spiking model of the primary auditory cortex that includes a novel, mathematically formalized description of homeostatic plasticity. In our model, the homeostatic mechanisms respond to hearing loss by reducing inhibition and increasing excitation, producing conditions under which travelling waves of excitation can emerge. However, our model predicts that the presence of spontaneous activity prevents the development of long-range travelling waves of excitation. Rather, our simulations show short-duration excitatory waves that cancel each other out. We also describe changes in spontaneous firing, synchrony and tuning after simulated hearing loss. With the exception of shifts in characteristic frequency, changes after hearing loss were qualitatively the same as empirical findings. Finally, we discuss possible applications to tinnitus, the perception of sound without an external stimulus.