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Current methods for bioprinting functional tissue lack appropriate biofabrication techniques to build complex 3D microarchitectures essential for guiding cell growth and promoting tissue maturation1. 3D printing of central nervous system (CNS) structures has not been accomplished, possibly owing to the complexity of CNS architecture. Here, we report the use of a microscale continuous projection printing method (μCPP) to create a complex CNS structure for regenerative medicine applications in the spinal cord. μCPP can print 3D biomimetic hydrogel scaffolds tailored to the dimensions of the rodent spinal cord in 1.6 s and is scalable to human spinal cord sizes and lesion geometries. We tested the ability of µCPP 3D-printed scaffolds loaded with neural progenitor cells (NPCs) to support axon regeneration and form new ‘neural relays’ across sites of complete spinal cord injury in vivo in rodents1,2. We find that injured host axons regenerate into 3D biomimetic scaffolds and synapse onto NPCs implanted into the device and that implanted NPCs in turn extend axons out of the scaffold and into the host spinal cord below the injury to restore synaptic transmission and significantly improve functional outcomes. Thus, 3D biomimetic scaffolds offer a means of enhancing CNS regeneration through precision medicine.Fast scalable 3D bioprinting generates biocompatible and biomimetic scaffolds to precisely fit the geometries of spinal cord lesions, promote axonal regeneration, and support stem cell grafts to promote recovery from spinal cord injury in rodents.

Neural stem cells (NSCs) differentiate into both neurons and glia, and strategies using human NSCs have the potential to restore function following spinal cord injury (SCI). However, the time period of maturation for human NSCs in adult injured CNS is not well defined, posing fundamental questions about the design and implementation of NSC-based therapies. This work assessed human H9 NSCs that were implanted into sites of SCI in immunodeficient rats over a period of 1.5 years. Notably, grafts showed evidence of continued maturation over the entire assessment period. Markers of neuronal maturity were first expressed 3 months after grafting. However, neurogenesis, neuronal pruning, and neuronal enlargement continued over the next year, while total graft size remained stable over time. Axons emerged early from grafts in very high numbers, and half of these projections persisted by 1.5 years. Mature astrocyte markers first appeared after 6 months, while more mature oligodendrocyte markers were not present until 1 year after grafting. Astrocytes slowly migrated from grafts. Notably, functional recovery began more than 1 year after grafting. Thus, human NSCs retain an intrinsic human rate of maturation, despite implantation into the injured rodent spinal cord, yet they support delayed functional recovery, a finding of great importance in planning human clinical trials.

In a nonhuman primate model of spinal cord injury, human neural progenitor cell grafts exhibit long-term survival, differentiation, and anatomical integration with host spinal circuitry. We grafted human spinal cord–derived neural progenitor cells (NPCs) into sites of cervical spinal cord injury in rhesus monkeys ( Macaca mulatta ). Under three-drug immunosuppression, grafts survived at least 9 months postinjury and expressed both neuronal and glial markers. Monkey axons regenerated into grafts and formed synapses. Hundreds of thousands of human axons extended out from grafts through monkey white matter and synapsed in distal gray matter. Grafts gradually matured over 9 months and improved forelimb function beginning several months after grafting. These findings in a 'preclinical trial' support translation of NPC graft therapy to humans with the objective of reconstituting both a neuronal and glial milieu in the site of spinal cord injury.

There are workloads that do not need the total data ordering enforced by the Transmission Control Protocol (TCP). For example, Virtual Network Computing (VNC) has a sequence of pixel-based updates in which the order of rectangles can be relaxed. However, VNC runs over the TCP and can have higher latency due to unnecessary blocking to ensure total ordering. By using Quick UDP Internet Connections (QUIC) as the underlying protocol, we are able to implement a partial order delivery approach, which can be combined with Forward Error Correction (FEC) to reduce data latency. Our earlier work on consistency fences provides a mechanism and semantic foundation for partial ordering. Our new evaluation on the Emulab testbed, with two different synthetic workloads for streaming and non-streaming updates, shows that our partial order and FEC strategy can reduce the blocking time and inter-delivery time of rectangles compared to total delivery. For one workload, partially ordered data with FEC can reduce the 99-percentile message-blocking time to 0.4 ms versus 230 ms with totally ordered data. That workload was with 0.5% packet loss, 100 ms Round-Trip Time (RTT), and 100 Mbps bandwidth. We study the impact of varying the packet-loss rate, RTT, bandwidth, and CCA and demonstrate that partial order and FEC latency improvements grow as we increase packet loss and RTT, especially with the emerging Bottleneck Bandwidth and Round-Trip propagation time (BBR) congestion control algorithm.

Neural progenitor cell (NPC) transplantation has high therapeutic potential in neurological disorders. Functional restoration may depend on the formation of reciprocal connections between host and graft. While it has been reported that axons extending out of neural grafts in the brain form contacts onto phenotypically appropriate host target regions, it is not known whether adult, injured host axons regenerating into NPC grafts also form appropriate connections. We report that spinal cord NPCs grafted into the injured adult rat spinal cord self-assemble organotypic, dorsal horn-like domains. These clusters are extensively innervated by regenerating adult host sensory axons and are avoided by corticospinal axons. Moreover, host axon regeneration into grafts increases significantly after enrichment with appropriate neuronal targets. Together, these findings demonstrate that injured adult axons retain the ability to recognize appropriate targets and avoid inappropriate targets within neural progenitor grafts, suggesting that restoration of complex circuitry after SCI may be achievable. Understanding how transplanted cells interact with the host nervous system will be important for cell based neural regeneration approaches. Here, the authors study the sensory fate of neural progenitor cell grafts transplanted to the injured spinal cord, and show that host axons retain the ability to distinguish appropriate and inappropriate graft targets.

Spinal cord injury (SCI) leads to irreversible functional impairment caused by neuronal loss and the disruption of neuronal connections across the injury site. While several experimental strategies have been used to minimize tissue damage and to enhance axonal growth and regeneration, the corticospinal projection, which is the most important voluntary motor system in humans, remains largely refractory to regenerative therapeutic interventions. To date, one of the most promising pre-clinical therapeutic strategies has been neural stem cell (NSC) therapy for SCI. Over the last decade we have found that host axons regenerate into spinal NSC grafts placed into sites of SCI. These regenerating axons form synapses with the graft, and the graft in turn extends very large numbers of new axons from the injury site over long distances into the distal spinal cord. Here we discuss the pathophysiology of SCI that makes the spinal cord refractory to spontaneous regeneration, the most recent findings of neural stem cell therapy for SCI, how it has impacted motor systems including the corticospinal tract and the implications for sensory feedback.

Background:The prevalence of global health in graduate medical education in the United States (US) has soared over the past two decades. The majority of US internal medicine and pediatric residency programs now offer global health electives abroad. Despite the prevalence of global health electives among US graduate medical programs today, challenges exist that may impact the experience for visiting trainees and/or host institutions. Previous reviews have predominately focused on experiences of undergraduate medical students and have primarily described positive outcomes.Objectives:The aim of this study was to summarize the overall impact of global health electives on US internal medicine, medicine-pediatric, and pediatric residents, paying specific attention to any negative themes reported in the literature.Methods:An Ovid MEDLINE and Ovid EMBASE literature search was conducted to identify studies that evaluated the effects of global health electives on US internal medicine, medicine-pediatric, and pediatric residents.Findings:Ten studies were included. Four positive themes emerged: (1) improvement of medical knowledge, physical examination, and procedural skills, (2) improvement in resourcefulness and cost-effectiveness, (3) improvement in cultural and interpersonal competence, and (4) professional and career development. Two negative themes were identified: (1) health risks and (2) safety risks.Conclusions:Global health electives provide a number of perceived benefits for US medical trainees; however, we importantly highlight health and safety concerns described while abroad. Global health educators should recognize the host of unique challenges experienced during a global health elective and investigate how to best mitigate these concerns. Incorporation of mandatory pre-, intra-, and post-elective training programs and establishment of universally adopted global health best practice guidelines may serve to address some the challenges visiting trainees encounter while abroad.

The game of checkers has roughly 500 billion billion possible positions (5 x 10²⁰). The task of solving the game, determining the final result in a game with no mistakes made by either player, is daunting. Since 1989, almost continuously, dozens of computers have been working on solving checkers, applying state-of-the-art artificial intelligence techniques to the proving process. This paper announces that checkers is now solved: Perfect play by both sides leads to a draw. This is the most challenging popular game to be solved to date, roughly one million times as complex as Connect Four. Artificial intelligence technology has been used to generate strong heuristic-based game-playing programs, such as Deep Blue for chess. Solving a game takes this to the next level by replacing the heuristics with perfection.

Direct reprogramming of somatic cells into neurons or neural stem cells is one of the most important frontier fields in current neuroscience research. Without undergoing the pluripotency stage, induced neurons or induced neural stem cells are a safer and timelier manner resource in comparison to those derived from induced pluripotent stem cells. In this prospective, we review the recent advances in generation of induced neurons and induced neural stem cells in vitro and in vivo and their potential treatments of neurological disorders.

We introduce optimization through protocol selection (OPS) as a technique to improve bulk-data transfer on shared wide-area networks (WANs). Instead of just fine-tuning the parameters of a network protocol, our empirical results show that the selection of the protocol itself can result in up to four times higher throughput in some key cases. However, OPS for the foreground traffic (e.g., TCP CUBIC, TCP BBR, UDT) depends on knowledge about the network protocols used by the background traffic (i.e., other users). Therefore, we build and empirically evaluate several machine-learned (ML) classifiers, trained on local round-trip time (RTT) time-series data gathered using active probing, to recognize the mix of network protocols in the background with an accuracy of up to 0.96.