Incongruent active head rotations increase visual motion detection thresholds.

Attributing a visual motion signal to its correct source-be that external object motion, self-motion, or some combination of both-seems effortless, and yet often involves disentangling a complex web of motion signals. Existing literature focuses on either translational motion (heading) or eye movements, leaving much to be learnt about the influence of a wider range of self-motions, such as active head rotations, on visual motion perception. This study investigated how active head rotations affect visual motion detection thresholds, comparing conditions where visual motion and head-turn direction were either congruent or incongruent. Participants judged the direction of a visual motion stimulus while rotating their head or remaining stationary, using a fixation-locked Virtual Reality display with integrated head-movement recordings. Thresholds to perceive visual motion were higher in both active-head rotation conditions compared to stationary, though no differences were found between congruent or incongruent conditions. Participants also showed a significant bias to report seeing visual motion travelling in the same direction as the head rotation. Together, these results demonstrate active head rotations increase visual motion perceptual thresholds, particularly in cases of incongruent visual and active vestibular stimulation.

A new 'CFS tracking' paradigm reveals uniform suppression depth regardless of target complexity or salience.

When the eyes view separate and incompatible images, the brain suppresses one image and promotes the other into visual awareness. Periods of interocular suppression can be prolonged during continuous flash suppression (CFS) - when one eye views a static 'target' while the other views a complex dynamic stimulus. Measuring the time needed for a suppressed image to break CFS (bCFS) has been widely used to investigate unconscious processing, and the results have generated controversy regarding the scope of visual processing without awareness. Here, we address this controversy with a new 'CFS tracking' paradigm (tCFS) in which the suppressed monocular target steadily increases in contrast until breaking into awareness (as in bCFS) after which it decreases until it again disappears (reCFS), with this cycle continuing for many reversals. Unlike bCFS, tCFS provides a measure of suppression depth by quantifying the difference between breakthrough and suppression thresholds. tCFS confirms that (i) breakthrough thresholds indeed differ across target types (e.g. faces vs gratings, as bCFS has shown) - but (ii) suppression depth does not vary across target types. Once the breakthrough contrast is reached for a given stimulus, all stimuli require a strikingly uniform reduction in contrast to reach the corresponding suppression threshold. This uniform suppression depth points to a single mechanism of CFS suppression, one that likely occurs early in visual processing because suppression depth was not modulated by target salience or complexity. More fundamentally, it shows that variations in bCFS thresholds alone are insufficient for inferring whether the barrier to achieving awareness exerted by interocular suppression is weaker for some categories of visual stimuli compared to others.

Microinterfaces in biopolymer-based bicontinuous hydrogels guide rapid 3D cell migration.

Cell migration is critical for tissue development and regeneration but requires extracellular environments that are conducive to motion. Cells may actively generate migratory routes in vivo by degrading or remodeling their environments or instead utilize existing extracellular matrix microstructures or microtracks as innate pathways for migration. While hydrogels in general are valuable tools for probing the extracellular regulators of 3-dimensional migration, few recapitulate these natural migration paths. Here, we develop a biopolymer-based bicontinuous hydrogel system that comprises a covalent hydrogel of enzymatically crosslinked gelatin and a physical hydrogel of guest and host moieties bonded to hyaluronic acid. Bicontinuous hydrogels form through controlled solution immiscibility, and their continuous subdomains and high micro-interfacial surface area enable rapid 3D migration, particularly when compared to homogeneous hydrogels. Migratory behavior is mesenchymal in nature and regulated by biochemical and biophysical signals from the hydrogel, which is shown across various cell types and physiologically relevant contexts (e.g., cell spheroids, ex vivo tissues, in vivo tissues). Our findings introduce a design that leverages important local interfaces to guide rapid cell migration.

Walking modulates visual detection performance according to stride cycle phase.

Walking is among our most frequent and natural of voluntary behaviours, yet the consequences of locomotion upon perceptual and cognitive function remain largely unknown. Recent work has highlighted that although walking feels smooth and continuous, critical phases exist within each step for the successful coordination of perceptual and motor function. Here, we test whether these phasic demands impact upon visual perception, by assessing performance in a visual detection task during natural unencumbered walking. We finely sample visual performance over the stride cycle as participants walk along a smooth linear path at a comfortable speed in a wireless virtual reality environment. At the group-level, accuracy, reaction times, and response likelihood show strong oscillations, modulating at approximately 2 cycles per stride (~2 Hz) with a marked phase of optimal performance aligned with the swing phase of each step. At the participant level, Bayesian inference of population prevalence reveals highly prevalent oscillations in visual detection performance that cluster in two idiosyncratic frequency ranges (2 or 4 cycles per stride), with a strong phase alignment across participants.

Hierarchical Design of Tissue-Mimetic Fibrillar Hydrogel Scaffolds.

Most tissues of the human body present hierarchical fibrillar extracellular matrices (ECMs) that have a strong influence over their physicochemical properties and biological behavior. Of great interest is the introduction of this fibrillar structure to hydrogels, particularly due to the water-rich composition, cytocompatibility, and tunable properties of this class of biomaterials. Here, the main bottom-up fabrication strategies for the design and production of hierarchical biomimetic fibrillar hydrogels and their most representative applications in the fields of tissue engineering and regenerative medicine are reviewed. For example, the controlled assembly/arrangement of peptides, polymeric micelles, cellulose nanoparticles (NPs), and magnetically responsive nanostructures, among others, into fibrillar hydrogels is discussed, as well as their potential use as fibrillar-like hydrogels (e.g., those from cellulose NPs) with key biofunctionalities such as electrical conductivity or remote stimulation. Finally, the major remaining barriers to the clinical translation of fibrillar hydrogels and potential future directions of research in this field are discussed.

Multi-Material Volumetric Additive Manufacturing of Hydrogels using Gelatin as a Sacrificial Network and 3D Suspension Bath.

Volumetric additive manufacturing (VAM) is an emerging layerless method for the rapid processing of reactive resins into 3D structures, where printing is much faster (seconds) than other lithography and direct ink writing methods (minutes to hours). As a vial of resin rotates in the VAM process, patterned light exposure defines a 3D object and then resin that has not undergone gelation can be washed away. Despite the promise of VAM, there are challenges with the printing of soft hydrogel materials from non-viscous precursors, including multi-material constructs. To address this, sacrificial gelatin is used to modulate resin viscosity to support the cytocompatible VAM printing of macromers based on poly(ethylene glycol) (PEG), hyaluronic acid (HA), and polyacrylamide (PA). After printing, gelatin is removed by washing at an elevated temperature. To print multi-material constructs, the gelatin-containing resin is used as a shear-yielding suspension bath (including HA to further modulate bath properties) where ink can be extruded into the bath to define a multi-material resin that can then be processed with VAM into a defined object. Multi-material constructs of methacrylated HA (MeHA) and gelatin methacrylamide (GelMA) are printed (as proof-of-concept) with encapsulated mesenchymal stromal cells (MSCs), where the local hydrogel properties guide cell spreading behavior with culture.

Injectable MSC Spheroid and Microgel Granular Composites for Engineering Tissue.

Many cell types require direct cell-cell interactions for differentiation and function; yet, this can be challenging to incorporate into 3-dimensional (3D) structures for the engineering of tissues. Here, a new approach is introduced that combines aggregates of cells (spheroids) with similarly-sized hydrogel particles (microgels) to form granular composites that are injectable, undergo interparticle crosslinking via light for initial stabilization, permit cell-cell contacts for cell signaling, and allow spheroid fusion and growth. One area where this is important is in cartilage tissue engineering, as cell-cell contacts are crucial to chondrogenesis and are missing in many tissue engineering approaches. To address this, granular composites are developed from adult porcine mesenchymal stromal cell (MSC) spheroids and hyaluronic acid microgels and simulations and experimental analyses are used to establish the importance of initial MSC spheroid to microgel volume ratios to balance mechanical support with tissue growth. Long-term chondrogenic cultures of granular composites produce engineered cartilage tissue with extensive matrix deposition and mechanical properties within the range of cartilage, as well as integration with native tissue. Altogether, a new strategy of injectable granular composites is developed that leverages the benefits of cell-cell interactions through spheroids with the mechanical stabilization afforded with engineered hydrogels.

Unexpected Periodicity in Cationic Group 5 Initiators for the Ring-Opening Polymerization of Lactones.

ε-Caprolactone (ε-CL) adducts of cationic, amine tris(phenolate)-supported niobium(V) and tantalum(V) ethoxides initiate the ring-opening polymerization of lactones. The Ta(V) species prepared and applied catalytically herein exhibits higher activity in the ring-opening polymerization (ROP) of ε-caprolactone than the previously reported, isostructural Nb(V) complex, contradicting literature comparisons of Nb(V)- and Ta(V)-based protocols. Both systems also initiate the ROP of δ-valerolactone and rac-ß-butyrolactone, kinetic studies confirming retention of higher activity by the Ta congener. Polymerizations of rac-ß-butyrolactone and δ-valerolactone were previously unrealized under Group V- or Ta-mediated conditions, respectively, although the former has afforded only low molecular weight, cyclic poly-3-hydroxybutyrate. Cationic ethoxo-Nb(V) and -Ta(V) δ-valerolactone adducts are also reported, demonstrating the facility of δ-valerolactone as a ligand and the generality of the synthetic method. Both δ-valerolactone-bearing complexes initiate the ROP of ε-caprolactone, δ-valerolactone, and rac-ß-butyrolactone. Accordingly, we have elucidated trends in reactivity and investigated the initiation mechanism for such systems, the insertion event being predicated upon intramolecular nucleophilic attack on the coordinated lactone by the adjacent alkoxide moiety. This mechanism enables quantitative, stoichiometric installation of a single monomer residue distinct from the bulk of the polymer chain, and permits modification of polymer properties via both manipulation of the molecular architecture and tuning of the polymerization kinetics, and thus dispersity, through hitherto inaccessible independent control of the initiation event.

Microinterfaces in bicontinuous hydrogels guide rapid 3D cell migration.

Cell migration is critical for tissue development and regeneration but requires extracellular environments that are conducive to motion. Cells may actively generate migratory routes in vivo by degrading or remodeling their environments or may instead utilize existing ECM microstructures or microtracks as innate pathways for migration. While hydrogels in general are valuable tools for probing the extracellular regulators of 3D migration, few have recapitulated these natural migration paths. Here, we developed a biopolymer-based (i.e., gelatin and hyaluronic acid) bicontinuous hydrogel system formed through controlled solution immiscibility whose continuous subdomains and high micro-interfacial surface area enabled rapid 3D migration, particularly when compared to homogeneous hydrogels. Migratory behavior was mesenchymal in nature and regulated by biochemical and biophysical signals from the hydrogel, which was shown across various cell types and physiologically relevant contexts (e.g., cell spheroids, ex vivo tissues, in vivo tissues). Our findings introduce a new design that leverages important local interfaces to guide rapid cell migration.

Continuous peripersonal tracking accuracy is limited by the speed and phase of locomotion.

Recent evidence suggests that perceptual and cognitive functions are codetermined by rhythmic bodily states. Prior investigations have focused on the cardiac and respiratory rhythms, both of which are also known to synchronise with locomotion-arguably our most common and natural of voluntary behaviours. Compared to the cardiorespiratory rhythms, walking is easier to voluntarily control, enabling a test of how natural and voluntary rhythmic action may affect sensory function. Here we show that the speed and phase of human locomotion constrains sensorimotor performance. We used a continuous visuo-motor tracking task in a wireless, body-tracking virtual environment, and found that the accuracy and reaction time of continuous reaching movements were decreased at slower walking speeds, and rhythmically modulated according to the phases of the step-cycle. Decreased accuracy when walking at slow speeds suggests an advantage for interlimb coordination at normal walking speeds, in contrast to previous research on dual-task walking and reach-to-grasp movements. Phasic modulations of reach precision within the step-cycle also suggest that the upper limbs are affected by the ballistic demands of motor-preparation during natural locomotion. Together these results show that the natural phases of human locomotion impose constraints on sensorimotor function and demonstrate the value of examining dynamic and natural behaviour in contrast to the traditional and static methods of psychological science.

Coordination of ε-Caprolactone to a Cationic Niobium(V) Alkoxide Complex: Fundamental Insight into Ring-Opening Polymerization via Coordination-Insertion.

We report three niobium-based initiators for the catalytic ring-opening polymerization (ROP) of ε-caprolactone, exhibiting good activity and molecular weight control. In particular, we have prepared on the gram-scale and fully characterized a monometallic cationic alkoxo-Nb(V) ε-caprolactone adduct representing, to the best of our knowledge, an unprecedented example of a metal complex with an intact lactone monomer and a functional ROP-initiating group simultaneously coordinated at the metal center. At 80 °C, all three systems initiate the immortal solution-state ROP of ε-caprolactone via a coordination-insertion mechanism, which has been confirmed through experimental studies, and is supported by computational data. Natural bond orbital calculations further indicate that polymerization may necessitate isomerization about the metal center between the alkoxide chain and the coordinated monomer. The observations made in this work are expected to inform mechanistic understanding both of amine tris(phenolate)-supported metal alkoxide ROP initiators, including various highly stereoselective systems for the polymerization of lactides and of coordination-insertion-type ROP protocols more broadly.

Sustainable Syntheses of Paracetamol and Ibuprofen from Biorenewable ß-pinene.

Scalable processes have been developed to convert ß-pinene into 4-isopropenylcyclohexanone, which is then used as a feedstock for the divergent synthesis of sustainable versions of the common painkillers, paracetamol and ibuprofen. Both synthetic routes use Pd0 catalysed reactions to aromatize the cyclohexenyl rings of key intermediates to produce the benzenoid ring systems of both drugs. The potential of using bioderived 4-hydroxyacetophenone as a drop-in feedstock replacement to produce sustainable aromatic products is also discussed within a terpene biorefinery context.

Feedback information transfer in the human brain reflects bistable perception in the absence of report.

In the search for the neural basis of conscious experience, perception and the cognitive processes associated with reporting perception are typically confounded as neural activity is recorded while participants explicitly report what they experience. Here, we present a novel way to disentangle perception from report using eye movement analysis techniques based on convolutional neural networks and neurodynamical analyses based on information theory. We use a bistable visual stimulus that instantiates two well-known properties of conscious perception: integration and differentiation. At any given moment, observers either perceive the stimulus as one integrated unitary object or as two differentiated objects that are clearly distinct from each other. Using electroencephalography, we show that measures of integration and differentiation based on information theory closely follow participants' perceptual experience of those contents when switches were reported. We observed increased information integration between anterior to posterior electrodes (front to back) prior to a switch to the integrated percept, and higher information differentiation of anterior signals leading up to reporting the differentiated percept. Crucially, information integration was closely linked to perception and even observed in a no-report condition when perceptual transitions were inferred from eye movements alone. In contrast, the link between neural differentiation and perception was observed solely in the active report condition. Our results, therefore, suggest that perception and the processes associated with report require distinct amounts of anterior-posterior network communication and anterior information differentiation. While front-to-back directed information is associated with changes in the content of perception when viewing bistable visual stimuli, regardless of report, frontal information differentiation was absent in the no-report condition and therefore is not directly linked to perception per se.

A Highly Active and Selective Zirconium-Based Catalyst System for the Industrial Production of Poly(lactic acid).

The biodegradable, aliphatic polyester poly(lactic acid), PLA, is a leading bio-based alternative to petrochemical-derived plastic materials across a range of applications. Widely reported in the available literature as a benchmark for PLA production via the bulk ring-opening polymerization of lactides is the use of divalent tin catalysts, and particularly tin(II) bis(2-ethylhexanoate). We present an alternative zirconium-based system that combines an inexpensive Group IV metal with the robustness, high activity, control, and designed compatibility with existing facilities and processes, that are required for industrial use. We have carried out a comprehensive kinetic study and applied a combined experimental and theoretical approach to understanding the mechanism by which the polymerization of lactide proceeds in the presence of this system. In the laboratory-scale (20 g) polymerization of recrystallized racemic d,l-lactide (rac-lactide), we have measured catalyst turnover frequencies up to at least 56,000 h-1, and confirmed the reported protocols' resistance toward undesirable epimerization, transesterification, and chain scission processes, deleterious to the properties of the polymer product. Further optimization and scale-up under industrial conditions have confirmed the relevance of the catalytic protocol to the commercial production of melt-polymerized PLA. We were able to undertake the efficient preparation of high-molecular-weight PLA on the 500-2000 g scale, via the selective and well-controlled polymerization of commercial polymer-grade l-lactide under challenging, industrially relevant conditions, and at metal concentrations as low as 8-12 ppm Zr by weight ([Zr] = 1.3 × 10-3 to 1.9 × 10-3 mol %). Under those conditions, a catalyst turnover number of at least 60,000 was attained, and the activity of the catalyst was comparable to that of tin(II) bis(2-ethylhexanoate).

Photoinduced Dithiolane Crosslinking for Multiresponsive Dynamic Hydrogels.

While many hydrogels are elastic networks crosslinked by covalent bonds, viscoelastic hydrogels with adaptable crosslinks are increasingly being developed to better recapitulate time and position-dependent processes found in many tissues. In this work, 1,2-dithiolanes are presented as dynamic covalent photocrosslinkers of hydrogels, resulting in disulfide bonds throughout the hydrogel that respond to multiple stimuli. Using lipoic acid as a model dithiolane, disulfide crosslinks are formed under physiological conditions, enabling cell encapsulation via an initiator-free light-induced dithiolane ring-opening photopolymerization. The resulting hydrogels allow for multiple photoinduced dynamic responses including stress relaxation, stiffening, softening, and network functionalization using a single chemistry, which can be supplemented by permanent reaction with alkenes to further control network properties and connectivity using irreversible thioether crosslinks. Moreover, complementary photochemical approaches are used to achieve rapid and complete sample degradation via radical scission and post-gelation network stiffening when irradiated in the presence of reactive gel precursor. The results herein demonstrate the versatility of this material chemistry to study and direct 2D and 3D cell-material interactions. This work highlights dithiolane-based hydrogel photocrosslinking as a robust method for generating adaptable hydrogels with a range of biologically relevant mechanical and chemical properties that are varied on demand.

Reducing the occurrence of mouthing and jumping in a dog through conditional discrimination training.

Many approaches for reducing unwanted behavior use punishment, extinction, or noncontingent reinforcement. Other methods focus on teaching and reinforcing alternative behaviors that can replace the unwanted behavior. Another strategy can be to change the stimulus control of the unwanted behavior. The present study investigated if conditional discrimination training using positive reinforcement could reduce undesirable behaviors in a pet dog. After conditional discrimination training, two unwanted behaviors (jumping and mouthing) occurred reliably in the presence of new discriminative stimuli, while other behaviors occurred in the presence of the discriminative stimuli that had previously produced these unwanted behaviors. This experiment demonstrates that conditional discrimination training can be an effective way to control the frequency of an unwanted behavior by controlling the frequency of the presentation of a discriminative stimulus.

Alpha oscillations and stimulus-evoked activity dissociate metacognitive reports of attention, visibility, and confidence in a rapid visual detection task.

Variability in the detection and discrimination of weak visual stimuli has been linked to oscillatory neural activity. In particular, the amplitude of activity in the alpha-band (8-12 Hz) has been shown to impact the objective likelihood of stimulus detection, as well as measures of subjective visibility, attention, and decision confidence. Here we investigate how preparatory alpha in a cued pretarget interval influences performance and phenomenology, by recording simultaneous subjective measures of attention and confidence (experiment 1) or attention and visibility (experiment 2) on a trial-by-trial basis in a visual detection task. Across both experiments, alpha amplitude was negatively and linearly correlated with the intensity of subjective attention. In contrast with this linear relationship, we observed a quadratic relationship between the strength of alpha oscillations and subjective ratings of confidence and visibility. We find that this same quadratic relationship links alpha amplitude with the strength of stimulus-evoked responses. Visibility and confidence judgments also corresponded with the strength of evoked responses, but confidence, uniquely, incorporated information about attentional state. As such, our findings reveal distinct psychological and neural correlates of metacognitive judgments of attentional state, stimulus visibility, and decision confidence when these judgments are preceded by a cued target interval.

Fast and accurate diffusion NMR acquisition in continuous flow.

FlowNMR spectroscopy has become a popular and powerful technique for online reaction monitoring. DOSY NMR is an established technique for obtaining information about diffusion rates and molecular size on static samples. This work extends the FlowNMR toolbox to include FlowDOSY based on convection compensation and use of a low-pulsation pump or flow effect correction, allowing accurate and precise diffusion coefficients to be obtained at flow rates up to 4.0 mL min-1 in less than 5 minutes.

Simultaneous One-Pot Interpenetrating Network Formation to Expand 3D Processing Capabilities.

The incorporation of a secondary network into traditional single-network hydrogels can enhance mechanical properties, such as toughness and loading to failure. These features are important for many applications, including as biomedical materials; however, the processing of interpenetrating polymer network (IPN) hydrogels is often limited by their multistep fabrication procedures. Here, a one-pot scheme for the synthesis of biopolymer IPN hydrogels mediated by the simultaneous crosslinking of two independent networks with light, namely: i) free-radical crosslinking of methacrylate-modified hyaluronic acid (HA) to form the primary network and ii) thiol-ene crosslinking of norbornene-modified HA with thiolated guest-host assemblies of adamantane and ß-cyclodextrin to form the secondary network, is reported. The mechanical properties of the IPN hydrogels are tuned by changing the network composition, with high water content (≈94%) hydrogels exhibiting excellent work of fracture, tensile strength, and low hysteresis. As proof-of-concept, the IPN hydrogels are implemented as low-viscosity Digital Light Processing resins to fabricate complex structures that recover shape upon loading, as well as in microfluidic devices to form deformable microparticles. Further, the IPNs are cytocompatible with cell adhesion dependent on the inclusion of adhesive peptides. Overall, the enhanced processing of these IPN hydrogels will expand their utility across applications.