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The translation of stem cell therapies has been hindered by low cell survival and retention rates. Injectable hydrogels enable the site-specific delivery of therapeutic cargo, including cells, to overcome these challenges. We hypothesized that delivery of mesenchymal stem cells (MSC) via shear-thinning and injectable hyaluronic acid (HA) hydrogels would mitigate renal damage following ischemia-reperfusion acute kidney injury. Acute kidney injury (AKI) was induced in mice by bilateral or unilateral ischemia-reperfusion kidney injury. Three days later, mice were treated with MSCs either suspended in media injected intravenously via the tail vein, or injected under the capsule of the left kidney, or MSCs suspended in HA injected under the capsule of the left kidney. Serial measurements of serum and urine biomarkers of renal function and injury, as well as transcutaneous glomerular filtration rate (tGFR) were performed. In vivo optical imaging showed that MSCs localized to both kidneys in a sustained manner after bilateral ischemia and remained within the ipsilateral treated kidney after unilateral ischemic AKI. One month after injury, MSC/HA treatment significantly reduced urinary NGAL compared to controls; it did not significantly reduce markers of fibrosis compared to untreated controls. An analysis of kidney proteomes revealed decreased extracellular matrix remodeling and high overlap with sham proteomes in MSC/HA-treated animals. Hydrogel-assisted MSC delivery shows promise as a therapeutic treatment following acute kidney injury.

IntroductionWe present a case series of neonates with anuric ESRD undergoing renal replacement therapy (RRT) and discuss the associated ethical implications of RRT in this population.MethodsWe reviewed patients who initiated RRT within 1 week of life due to anuric ESRD from 2009–2019 at a single tertiary center. Primary outcomes were receipt of renal transplant (RT), one-year survival, and overall survival.ResultsFive patients met the inclusion criteria. Two patients received an RT. One-year survival was 80%, while overall survival was 60% with a median follow-up of 18 months. In the 2 still-living patients who have not undergone RT, they are ineligible, one due to recent malignancy and the other from acquired cardiovascular comorbidities.ConclusionPatients with anuric ESRD requiring RRT undergo multiple treatment challenges with low RT and survival rates. These findings should be shared with families considering intervention for cases of severe renal disease diagnosed prenatally.

PurposeEnhanced recovery after surgery (ERAS) is a perioperative management strategy to hasten postoperative recovery. We examined the effects of a pilot implementation of ERAS for pediatric patients on anesthetic outcomes.MethodsWe performed a prospective case–control study utilizing an ERAS protocol in patients aged < 18 years undergoing urologic reconstruction that included a bowel anastomosis. Protocol elements included: multimodal analgesia, opioid minimization, and routine nausea/vomiting prophylaxis. ERAS patients were propensity-matched with historical controls. Outcomes of interest included maximum PACU pain score, time to first opioid, opioid-free days, and need for opioids on day of discharge.ResultsA total of 13 ERAS patients and 26 historical controls were included, with median ages 9.9 years (IQR 9.1–11) and 10.4 years (IQR 8.0–12.4), respectively. ERAS increased the percentage of patients who did not receive any intraoperative or postoperative opioids (0% vs 15%, p = 0.046 for both) and reduced maximum PACU pain score (3 vs 0, p < 0.001). The use of postoperative supplemental oxygen was decreased in the ERAS group (85% vs 38%, p = 0.013).ConclusionsThe implementation of an ERAS protocol appears to decrease postoperative pain, opioid usage, and positively impact other anesthetic outcomes in children undergoing urologic reconstructive surgery utilizing a bowel anastomosis.

The fruit fly Drosophila melanogaster has emerged as a key model organism in neuroscience, in large part due to the concentration of collaboratively generated molecular, genetic and digital resources available for it. Here we complement the approximately 140,000 neuron FlyWire whole-brain connectome 1 with a systematic and hierarchical annotation of neuronal classes, cell types and developmental units (hemilineages). Of 8,453 annotated cell types, 3,643 were previously proposed in the partial hemibrain connectome 2 , and 4,581 are new types, mostly from brain regions outside the hemibrain subvolume. Although nearly all hemibrain neurons could be matched morphologically in FlyWire, about one-third of cell types proposed for the hemibrain could not be reliably reidentified. We therefore propose a new definition of cell type as groups of cells that are each quantitatively more similar to cells in a different brain than to any other cell in the same brain, and we validate this definition through joint analysis of FlyWire and hemibrain connectomes. Further analysis defined simple heuristics for the reliability of connections between brains, revealed broad stereotypy and occasional variability in neuron count and connectivity, and provided evidence for functional homeostasis in the mushroom body through adjustments of the absolute amount of excitatory input while maintaining the excitation/inhibition ratio. Our work defines a consensus cell type atlas for the fly brain and provides both an intellectual framework and open-source toolchain for brain-scale comparative connectomics. A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

The fruit fly Drosophila melanogasterhas emerged as a key model organism in neuroscience, in large part due to the concentration of collaboratively generated molecular, genetic and digital resources available for it. Here we complement the approximately 140,000 neuron FlyWire whole-brain connectome1 with a systematic and hierarchical annotation of neuronal classes, cell types and developmental units (hemilineages). Of8,453 annotated cell types, 3,643 were previously proposed in the partial hemibrain connectome2, and 4,581 are new types, mostly from brain regions outside the hemibrain subvolume. Although nearly all hemibrain neurons could be matched morphologically in FlyWire, about one-third of cell types proposed for the hemibrain could not be reliably reidentified. We therefore propose a new definition of cell type as groups of cells that are each quantitatively more similar to cells in a different brain than to any other cell in the same brain, and we validate this definition through joint analysis of FlyWire and hemibrain connectomes. Further analysis defined simple heuristics for the reliability of connections between brains, revealed broad stereotypy and occasional variability in neuron count and connectivity, and provided evidence for functional homeostasis in the mushroom body through adjustments of the absolute amount of excitatory input while maintaining the excitation/inhibition ratio. Our work defines a consensus cell type atlas for the fly brain and provides both an intellectual framework and open-source toolchain for brain-scale comparative connectomics.

The fruit fly combines surprisingly sophisticated behaviour with a highly tractable nervous system. A large part of the fly's success as a model organism in modern neuroscience stems from the concentration of collaboratively generated molecular genetic and digital resources. As presented in our FlyWire companion paper , this now includes the first full brain connectome of an adult animal. Here we report the systematic and hierarchical annotation of this ~130,000-neuron connectome including neuronal classes, cell types and developmental units (hemilineages). This enables any researcher to navigate this huge dataset and find systems and neurons of interest, linked to the literature through the Virtual Fly Brain database . Crucially, this resource includes 4,552 cell types. 3,094 are rigorous consensus validations of cell types previously proposed in the hemibrain connectome . In addition, we propose 1,458 new cell types, arising mostly from the fact that the FlyWire connectome spans the whole brain, whereas the hemibrain derives from a subvolume. Comparison of FlyWire and the hemibrain showed that cell type counts and strong connections were largely stable, but connection weights were surprisingly variable within and across animals. Further analysis defined simple heuristics for connectome interpretation: connections stronger than 10 unitary synapses or providing >1% of the input to a target cell are highly conserved. Some cell types showed increased variability across connectomes: the most common cell type in the mushroom body, required for learning and memory, is almost twice as numerous in FlyWire as the hemibrain. We find evidence for functional homeostasis through adjustments of the absolute amount of excitatory input while maintaining the excitation-inhibition ratio. Finally, and surprisingly, about one third of the cell types proposed in the hemibrain connectome could not yet be reliably identified in the FlyWire connectome. We therefore suggest that cell types should be defined to be robust to inter-individual variation, namely as groups of cells that are quantitatively more similar to cells in a different brain than to any other cell in the same brain. Joint analysis of the FlyWire and hemibrain connectomes demonstrates the viability and utility of this new definition. Our work defines a consensus cell type atlas for the fly brain and provides both an intellectual framework and open source toolchain for brain-scale comparative connectomics.

This journal format thesis presents interdisciplinary research on characterising the biological process of intracellular transport using random walk models. The first two chapters outline the aims of the thesis, summarise the main chapters, and introduce intracellular transport, anomalous diffusion and various random walk models. This includes uncoupled continuous time random walks both in discrete and continuous space with extension to Levy walks, the fractional diffusion equation using the structured density approach, velocity random walks and fractional Brownian motion.The third chapter outlines experimental observations for power-law distributed running times in active intracellular transport. In addition, a mesoscopic Levy walk model is introduced making connections to a previously established microscopic framework involving multiple detachment and attachment rates of motor proteins. This work shows that the Levy walk model is capable of accurately describing intracellular transport and is compatible with the microscopic mechanisms of previously proposed theories. Furthermore, a new persistent random walk model with finite velocities that describe the phenomena of self-reinforcing directionality in the transport of endosomes is presented. Through this model, superdiffusion is exhibited despite exponential running times. Exact analytical expressions for the first and second moments are derived and validated using Monte Carlo simulations.The fourth chapter models the passive intracellular transport of lysosomes using the variable-order fractional diffusion equation. In doing so, the asymptotic representation of the solution of the variable-order fractional diffusion equation is found for an anomalous exponent that monotonically increases with position away from the origin. Furthermore, the asymptotic representation is validated using Monte Carlo simulations and experimental evidence for variable-order fractional diffusion in lysosomes is presented.The final chapter presents a neural network, trained on fractional Brownian motion, which estimates the Hurst exponent of a trajectory using as few as seven data points. This neural network is then applied using a windowed approach to trajectories of GFP-Rab5 tagged endosomes, GFP-SNX1 tagged endosomes and lysosomes. The Hurst exponents estimated locally in time for single experimental trajectories form distinct probability density functions for each different intracellular vesicle and various statistics on the vesicle dynamics are extracted. In doing so, the potential of this new technique is demonstrated.

We formulate a compounded random walk that is physically well defined on both finite and infinite domains, and samples space-dependent forces throughout jumps. The governing evolution equation for the walk limits to a space-fractional Fokker-Planck equation valid on bounded domains, and recovers the well known superdiffusive space-fractional diffusion equation on infinite domains. This compounded random walk, and its associated fractional Fokker-Planck equation, provides a major advance for modelling space-fractional diffusion through potential fields and on finite domains.

Transport phenomena play a vital role in various fields of science and engineering. In this work, exact solutions are derived for advection equations with integer- and fractional-order time derivatives and a constant time-delay in the spatial derivative. Solutions are obtained, for arbitrary separable initial conditions, by incorporating recently introduced delay functions in a separation of variables approach. Examples are provided showing oscillatory and translatory behaviours that are fundamentally different to standard propagating wave solutions.

In this work, exact solutions are derived for an integer- and fractional-order time-delayed diffusion equation with arbitrary initial conditions. The solutions are obtained using Fourier transform methods in conjunction with the known properties of delay functions. It is observed that the solutions do not exhibit infinite speed of propagation for smooth initial conditions that are bounded and positive. Sufficient conditions on the initial condition are also established such that the finite time blowup of the solutions can be explicitly calculated. Examples are provided that highlight the contrasting behaviours of these exact solutions with the known dynamics of solutions to the standard diffusion equation.