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3D printing has emerged as one of the most promising tools to overcome the processing and morphological limitations of traditional tissue engineering scaffold design. However, there is a need for improved minimally invasive, void-filling materials to provide mechanical support, biocompatibility, and surface erosion characteristics to ensure consistent tissue support during the healing process. Herein, soft, elastomeric aliphatic polycarbonate-based materials were designed to undergo photopolymerization into supportive soft tissue engineering scaffolds. The 4D nature of the printed scaffolds is manifested in their shape memory properties, which allows them to fill model soft tissue voids without deforming the surrounding material. In vivo, adipocyte lobules were found to infiltrate the surface-eroding scaffold within 2 months, and neovascularization was observed over the same time. Notably, reduced collagen capsule thickness indicates that these scaffolds are highly promising for adipose tissue engineering and repair. Shape memory scaffolds are needed for minimally invasive tissue repair and void filling. Here the authors report on the development of 4D printed polycarbonate-based scaffolds with surface degradation properties which fill voids without deforming tissue and allow for tissue ingrowth with reduced immune response.

Biocompatible polymers are widely used in tissue engineering and biomedical device applications. However, few biomaterials are suitable for use as long-term implants and these examples usually possess limited property scope, can be difficult to process, and are non-responsive to external stimuli. Here, we report a class of easily processable polyamides with stereocontrolled mechanical properties and high-fidelity shape memory behaviour. We synthesise these materials using the efficient nucleophilic thiol-yne reaction between a dipropiolamide and dithiol to yield an α,β − unsaturated carbonyl moiety along the polymer backbone. By rationally exploiting reaction conditions, the alkene stereochemistry is modulated between 35–82% cis content and the stereochemistry dictates the bulk material properties such as tensile strength, modulus, and glass transition. Further access to materials possessing a broader range of thermal and mechanical properties is accomplished by polymerising a variety of commercially available dithiols with the dipropiolamide monomer. Few biomaterials are suitable for long-term tissue engineering applications and these examples usually possess limited property scope, can be difficult to process, and are non-responsive to external stimuli. Here, the authors overcome these issues by developing a class of easily processable polyamides with stereo-controlled mechanical properties and high-fidelity shape memory behaviour.

Complex mechanisms that detect changes in brainstem parenchymal PCO2/[H+] and trigger adaptive changes in lung ventilation are responsible for central respiratory CO2 chemosensitivity. Previous studies of chemosensory signalling pathways suggest that at the level of the ventral surface of the medulla oblongata (VMS), CO2-induced changes in ventilation are (at least in part) mediated by the release and actions of ATP and/or acetylcholine (ACh). Here we performed simultaneous real-time biosensor recordings of CO2-induced ATP and ACh release from the VMS in vivo and in vitro, to test the hypothesis that central respiratory CO2 chemosensory transduction involves simultaneous recruitment of purinergic and cholinergic signalling pathways. In anaesthetised and artificially ventilated rats, an increase in inspired CO2 triggered ACh release on the VMS with a peak amplitude of ~5 μM. Release of ACh was only detected after the onset of CO2-induced activation of the respiratory activity and was markedly reduced (by ~70%) by ATP receptor blockade. In horizontal slices of the VMS, CO2-induced release of ATP was reliably detected, whereas CO2 or bath application of ATP (100 μM) failed to trigger release of ACh. These results suggest that during hypercapnia locally produced ATP induces or potentiates the release of ACh (likely from the medullary projections of distal groups of cholinergic neurones), which may also contribute to the development and/or maintenance of the ventilatory response to CO2.

Recently, based on functional differences, we subdivided neurons juxtaposed to the facial nucleus into two distinct populations, the parafacial ventral and lateral regions, i.e., pFV and pFL. Little is known about the composition of these regions, i.e., are they homogenous or heterogeneous populations? Here, we manipulated their excitability in spontaneously breathing vagotomized urethane anesthetized adult rats to further characterize their role in breathing. In the pFL, disinhibition or excitation decreased breathing frequency (f) with a concomitant increase of tidal volume (VT), and induced active expiration; in contrast, reducing excitation had no effect. This result is congruent with pFL neurons constituting a conditional expiratory oscillator comprised of a functionally homogeneous set of excitatory neurons that are tonically suppressed at rest. In the pFV, disinhibition increased f with a presumptive reflexive decrease in VT; excitation increased f, VT and sigh rate; reducing excitation decreased VT with a presumptive reflexive increase in f. Therefore, the pFV, has multiple functional roles that require further parcellation. Interestingly, while hyperpolarization of the pFV reduces ongoing expiratory activity, no perturbation of pFV excitability induced active expiration. Thus, while the pFV can affect ongoing expiratory activity, presumably generated by the pFL, it does not appear capable of directly inducing active expiration. We conclude that the pFL contains neurons that can initiate, modulate, and sustain active expiration, whereas the pFV contains subpopulations of neurons that differentially affect various aspects of breathing pattern, including but not limited to modulation of ongoing expiratory activity.

Neuronal cell groups residing within the retrotrapezoid nucleus (RTN) and C1 area of the rostral ventrolateral medulla oblongata contribute to the maintenance of resting respiratory activity and arterial blood pressure, and play an important role in the development of cardiorespiratory responses to metabolic challenges (such as hypercapnia and hypoxia). In rats, acute silencing of neurons within the parafacial region which includes the RTN and the rostral aspect of the C1 circuit (pF RTN/C1 ), transduced to express HM 4 D (G i -coupled) receptors, was found to dramatically reduce exercise capacity (by 60%), determined by an intensity controlled treadmill running test. In a model of simulated exercise (electrical stimulation of the sciatic or femoral nerve in urethane anaesthetised spontaneously breathing rats) silencing of the pF RTN/C1 neurons had no effect on cardiovascular changes, but significantly reduced the respiratory response during steady state exercise. These results identify a neuronal cell group in the lower brainstem which is critically important for the development of the respiratory response to exercise and, determines exercise capacity.

Breathing in mammals is hypothesized to result from the interaction of two distinct oscillators: the preBötzinger Complex (preBötC) driving inspiration and the lateral parafacial region (pFL) driving active expiration. To understand the interactions between these oscillators, we independently altered their excitability in spontaneously breathing vagotomized urethane-anesthetized adult rats. Hyperpolarizing preBötC neurons decreased inspiratory activity and initiated active expiration, ultimately progressing to apnea, i.e., cessation of both inspiration and active expiration. Depolarizing pFL neurons produced active expiration at rest, but not when inspiratory activity was suppressed by hyperpolarizing preBötC neurons. We conclude that in anesthetized adult rats active expiration is driven by the pFL but requires an additional form of network excitation, i.e., ongoing rhythmic preBötC activity sufficient to drive inspiratory motor output or increased chemosensory drive. The organization of this coupled oscillator system, which is essential for life, may have implications for other neural networks that contain multiple rhythm/pattern generators. Mammals breathe air into and out of their lungs to absorb oxygen into the body and to remove carbon dioxide. The rhythm of breathing is most likely controlled by two groups of neurons in a part of the brain called the brain stem. One group called the preBötzinger Complex drives breathing in (inspiration), and normally, breathing out (expiration) occurs when the muscles responsible for inspiration relax. The other group of neurons – known as the lateral parafacial region – controls extra muscles that allow us to increase our breathing when we need to, such as during exercise. Huckstepp et al. set out to determine how these two groups of neurons interact with one another in anesthetized rats to produce a reliable and efficient pattern of breathing. The experiments provide further evidence that inspiration is mainly driven by the preBötzinger Complex. Whilst activity from the lateral parafacial region is needed to cause the rats to breathe out more forcefully than normal, a second low level of activity from another source is also required. This source could either be the preBötzinger Complex, or some unknown neurons that change their activity in response to the levels of oxygen and carbon dioxide in the blood or fluid of the brain. Further investigation is required to identify how these interactions go awry in diseases that affect breathing, such as sleep apneas.

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A 1 receptors (A 1 Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A 1 R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A 1 Rs arises from BnOCPA’s unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A 1 R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism. Wall et al. describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.

Sleep apnoea is a highly prevalent disease that often goes undetected and is associated with poor clinical prognoses especially when its combined with many different disease states. However, most animal models of sleep apnoea (e.g., intermittent hypoxia) have recently been dispelled as physiologically unrealistic and are often unduly severe. Due to a lack of appropriate models, little is known about the causative link between sleep apnoea and its co-morbidities. To overcome these problems, we have created a more realistic animal model of sleep apnoea of a moderate phenotype by reducing the excitability of the respiratory network. This has been achieved through controlled genetically mediated lesions to the preBötzinger Complex (preBötC), the inspiratory oscillator. This novel model shows increases in sleep disordered breathing with alterations in breathing during wakefulness (decreased frequency and increased tidal volume) as observed clinically. The increase in apnoea episodes leads to a reduction in REM sleep, with all lost active sleep being spent in an awake state. The increase in hypoxic and hypercapnia insults leads to both systemic and neural inflammation. Alterations in neurophysiology, an inhibition of hippocampal long-term potentiation (LTP), reflect deficits in both long- and short-term spatial memory. This improved model of moderate sleep apnoea may be the key to understanding why sleep apnoea has such far reaching and often fatal effects on end organ function.

Regulation of systemic PCO 2 is a life-preserving homeostatic mechanism. In the medulla oblongata, the retrotrapezoid nucleus (RTN) and rostral medullary Raphe are proposed as CO 2 chemosensory nuclei mediating adaptive respiratory changes. Hypercapnia also induces active expiration, an adaptive change thought to be controlled by the lateral parafacial region (pF L ). Here, we use GCaMP6 expression and head-mounted mini-microscopes to image Ca 2+ activity in these nuclei in awake adult mice during hypercapnia. Activity in the pF L supports its role as a homogenous neuronal population that drives active expiration. Our data show that chemosensory responses in the RTN and Raphe differ in their temporal characteristics and sensitivity to CO 2 , raising the possibility these nuclei act in a coordinated way to generate adaptive ventilatory responses to hypercapnia. Our analysis revises the understanding of chemosensory control in awake adult mouse and paves the way to understanding how breathing is coordinated with complex non-ventilatory behaviours.

Complex mechanisms that detect changes in brainstem parenchymal PCO.sub.2 /[H.sup.+ ] and trigger adaptive changes in lung ventilation are responsible for central respiratory CO.sub.2 chemosensitivity. Previous studies of chemosensory signalling pathways suggest that at the level of the ventral surface of the medulla oblongata (VMS), CO.sub.2 -induced changes in ventilation are (at least in part) mediated by the release and actions of ATP and/or acetylcholine (ACh). Here we performed simultaneous real-time biosensor recordings of CO.sub.2 -induced ATP and ACh release from the VMS in vivo and in vitro, to test the hypothesis that central respiratory CO.sub.2 chemosensory transduction involves simultaneous recruitment of purinergic and cholinergic signalling pathways. In anaesthetised and artificially ventilated rats, an increase in inspired CO.sub.2 triggered ACh release on the VMS with a peak amplitude of ~5 [mu]M. Release of ACh was only detected after the onset of CO.sub.2 -induced activation of the respiratory activity and was markedly reduced (by ~70%) by ATP receptor blockade. In horizontal slices of the VMS, CO.sub.2 -induced release of ATP was reliably detected, whereas CO.sub.2 or bath application of ATP (100 [mu]M) failed to trigger release of ACh. These results suggest that during hypercapnia locally produced ATP induces or potentiates the release of ACh (likely from the medullary projections of distal groups of cholinergic neurones), which may also contribute to the development and/or maintenance of the ventilatory response to CO.sub.2.