Explore the vast range of titles available.

Background Paediatric kidney transplantation has an increased risk of surgical and vascular complications, with intensive care monitoring required postoperatively. This study aimed to determine if perioperative management affects early graft function in living donor paediatric kidney transplantation. Methods Clinical data was extracted from the electronic medical record for living donor kidney transplants at two paediatric centres covering the state of New South Wales (NSW), Australia from 2009 to 2021. Estimated glomerular filtration rate (eGFR) of 7 days and 1-month post-transplant were calculated as measures of early graft function. Results Thirty-nine eligible patients (female n (%) 13 (33%)) with a median (IQR) age of 6 (3–9) years and pre-transplant eGFR of 7 (6–10) mL/min/1.73 m 2 were analysed. Mean (SD) central venous pressure (CVP) after revascularisation was 11 (4) mmHg. Intraoperatively, mean volume of fluid administered was 84 (39) mL/kg, and 34 (87%) patients received vasoactive agents. Average systolic blood pressure (BP) in the first 24-h post-transplant was 117 (12) mmHg. Postoperatively, median volume of fluid administered in the first 24 h was 224 (159–313) mL/kg, and 17 (44%) patients received vasoactive agents. Median eGFR 7 days and 1-month post-transplant were 115 (79–148) and 103 (83–115) mL/min/1.73 m 2 , respectively. Linear regression analyses demonstrated that after adjusting for age, the average CVP after revascularisation and average systolic BP in the first 24-h post-transplant were not associated with eGFR in the first month post-transplant. Conclusions Targeted intraoperative and postoperative fluid and haemodynamic characteristics were achieved but did not correlate with early graft function. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information .

Group 3 innate lymphoid cell (ILC3)-mediated production of the cytokine interleukin-22 (IL-22) is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we find that the function of ILC3s is not constant across the day, but instead oscillates between active phases and resting phases. Coordinate responsiveness of ILC3s in the intestine depended on the food-induced expression of the neuropeptide vasoactive intestinal peptide (VIP). Intestinal ILC3s had high expression of the G protein-coupled receptor vasoactive intestinal peptide receptor 2 (VIPR2), and activation by VIP markedly enhanced the production of IL-22 and the barrier function of the epithelium. Conversely, deficiency in signaling through VIPR2 led to impaired production of IL-22 by ILC3s and increased susceptibility to inflammation-induced gut injury. Thus, intrinsic cellular rhythms acted in synergy with the cyclic patterns of food intake to drive the production of IL-22 and synchronize protection of the intestinal epithelium through a VIP–VIPR2 pathway in ILC3s. Belz and colleagues show that the enteric neuron-derived neuropeptide VIP signals though its receptor VIPR on ILC3s to regulate the cyclic production of IL-22 in response to food intake.

The glymphatic movement of fluid through the brain removes metabolic waste 1 – 4 . Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer’s disease 5 – 8 . Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer’s disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid. Audio and visual stimulation at 40 Hz promote cerebrospinal and interstitial fluid flux in mouse brain and result in amyloid clearance via the glymphatic system in a mouse model of Alzheimer’s disease.

Significance Group 3 innate lymphoid cells enriched in the gut mediate host resistance against intestinal pathogens. Their function and development can be regulated by diverse factors, including neuropeptides secreted by the enteric nervous system. We show that the neuropeptide vasoactive intestinal peptide (VIP) promotes the recruitment of these innate lymphoid cells and other immune cells to the gut through a receptor. Mice lacking VIP or its receptor were highly susceptible to an enteric pathogen infection. Replenishing the innate lymphoid cells or their secreted products into these mice was able to partially or fully restore host resistance to the infection. Thus, the enteric nervous system, through VIP, regulates the recruitment of innate lymphoid cells to the gut, offering protection against enteric pathogens.

The intestinal mucosa serves both as a conduit for the uptake of food-derived nutrients and microbiome-derived metabolites, and as a barrier that prevents tissue invasion by microorganisms and tempers inflammatory responses to the myriad contents of the lumen. How the intestine coordinates physiological and immune responses to food consumption to optimize nutrient uptake while maintaining barrier functions remains unclear. Here we show in mice how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses that are controlled by type-3 innate lymphoid cells (ILC3) 1 – 3 . Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP) 4 . Projections of VIP-producing neurons (VIPergic neurons) in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2; also known as VPAC2). Production of interleukin (IL)-22 by ILC3, which is upregulated by the presence of commensal microorganisms such as segmented filamentous bacteria 5 – 7 , is inhibited upon engagement of VIPR2. As a consequence, levels of antimicrobial peptide derived from epithelial cells are reduced but the expression of lipid-binding proteins and transporters is increased 8 . During food consumption, the activation of VIPergic neurons thus enhances the growth of segmented filamentous bacteria associated with the epithelium, and increases lipid absorption. Our results reveal a feeding- and circadian-regulated dynamic neuroimmune circuit in the intestine that promotes a trade-off between innate immune protection mediated by IL-22 and the efficiency of nutrient absorption. Modulation of this pathway may therefore be effective for enhancing resistance to enteropathogens 2 , 3 , 9 and for the treatment of metabolic diseases. Feeding controls a neuroimmune circuit comprising VIP-producing neurons and type-3 innate lymphoid cells that helps to regulate the efficiency of nutrient uptake and IL-22-mediated immune protection in the intestine.

Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes. Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of inflammatory diseases. Here authors report a cryoelectron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, which provides insights into PACAP27 binding and VIP receptor activation.

Using calcium imaging and optogenetic manipulation in mice performing a working memory task, the authors show that delay activity in prefrontal cortex pyramidal neurons is crucial for task performance. Optogenetic activation of VIP interneurons enhances the neuronal representation of task-relevant information and improves the animal's memory retention. Memory-guided behavior requires maintenance of task-relevant information without sensory input, but the underlying circuit mechanism remains unclear. Calcium imaging in mice performing a delayed Go or No-Go task revealed robust delay activity in dorsomedial prefrontal cortex, with different pyramidal neurons signaling Go and No-Go action plans. Inhibiting pyramidal neurons by optogenetically activating somatostatin- or parvalbumin-positive interneurons, even transiently during the delay, impaired task performance, primarily by increasing inappropriate Go responses. In contrast, activating vasoactive intestinal peptide (VIP)-positive interneurons enhanced behavioral performance and neuronal action plan representation. Furthermore, while endogenous activity of somatostatin and parvalbumin neurons was strongly biased toward Go trials, VIP neurons were similarly active in Go and No-Go trials. Somatostatin or VIP neuron activation also impaired or enhanced performance, respectively, in a delayed two-alternative forced-choice task. Thus, dorsomedial prefrontal cortex is a crucial component of the short-term memory network, and activation of its VIP neurons improves memory retention.

The management of sepsis has substantially improved over the past 15 years. In this study, early, goal-directed therapy, which focuses on the initial resuscitation efforts, was compared with usual care for the management of severe sepsis in the United Kingdom. The incidence of severe sepsis and septic shock in adults is estimated to range from 56 to 91 per 100,000 population per year. 1 Affected patients have high rates of death, complications, and resource utilization. 2 – 5 Since 2002, the Surviving Sepsis Campaign (SSC) has promoted best practice, including early recognition, source control, appropriate and timely antibiotic administration, and resuscitation with intravenous fluids and vasoactive drugs. 6 – 8 Resuscitation guidance is largely based on a 2001 single-center, proof-of-concept study by Rivers et al., which indicated that protocolized delivery of 6 hours of early, goal-directed therapy (EGDT) to patients presenting to the emergency department . . .

Recent success in identifying gene-regulatory elements in the context of recombinant adeno-associated virus vectors has enabled cell-type-restricted gene expression. However, within the cerebral cortex these tools are largely limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple new enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we discovered enhancers selective for parvalbumin (PV) and vasoactive intestinal peptide-expressing interneurons. Demonstrating the functional utility of these elements, we show that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across vertebrate species, including humans. Finally, we demonstrate that our selection method is generalizable and characterizes additional PV-specific enhancers with exquisite specificity within distinct brain regions. Altogether, these viral tools can be used for cell-type-specific circuit manipulation and hold considerable promise for use in therapeutic interventions.This study describes a series of new gene-regulatory sequences that restrict expression of viral transgenes to specific interneuron subtypes, allowing for selective monitoring and manipulation of their activity from mice to humans.

How learning enhances neural representations for behaviorally relevant stimuli via activity changes of cortical cell types remains unclear. We simultaneously imaged responses of pyramidal cells (PYR) along with parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) inhibitory interneurons in primary visual cortex while mice learned to discriminate visual patterns. Learning increased selectivity for task-relevant stimuli of PYR, PV and SOM subsets but not VIP cells. Strikingly, PV neurons became as selective as PYR cells, and their functional interactions reorganized, leading to the emergence of stimulus-selective PYR–PV ensembles. Conversely, SOM activity became strongly decorrelated from the network, and PYR–SOM coupling before learning predicted selectivity increases in individual PYR cells. Thus, learning differentially shapes the activity and interactions of multiple cell classes: while SOM inhibition may gate selectivity changes, PV interneurons become recruited into stimulus-specific ensembles and provide more selective inhibition as the network becomes better at discriminating behaviorally relevant stimuli.