Ex Vivo method for Rapid Quantification of Post Traumatic Brain Injury Lesion Volumes Using Ultrasound.

BACKGROUND: Studies of traumatic brain injury often involve the quantification of the lesion volume as a major outcome measure. The determination of lesion volume typically employs the cutting and mounting of brain tissue, and the calculation of the cross-sectional area of the lesion within each section of brain after histological staining. This is a time consuming and laborious task often requiring many weeks to determine the lesion volume for an individual brain. METHODS: In this report we present a method for determining the lesion volume within the brain following traumatic brain injury that involves the use of ultrasound imaging. With this process the lesion volume can be determined within a time period of 90minutes per brain rather than weeks and months. Moreover, we have developed a pipeline that will combine the cross-sectional ultrasound images of the brain with the Allen Mouse Brain Atlas to provide the precise anatomical structures that are affected by traumatic injury to the brain. The anatomical detail was lastly paired with behavioral data showing neurological deficits correlated with specific areas of brain injury. RESULTS: The accuracy and precision of this method was shown to be highly consistent with the traditional histological approach. Additionally, the mapping process and behavioral data show that neurological recovery from 1 to 3 weeks post injury is not correlated with gross anatomical recovery of the TBI lesion in our TBI model. CONCLUSION: Together these approaches will enhance the pipeline for processing brain tissue in experimental conditions where the lesion volume is an important outcome parameter and provide more high resolution information about the identity of the damaged regions of the brain.

Cell Transplantation for Repair of the Spinal Cord and Prospects for Generating Region-Specific Exogenic Neuronal Cells.

Spinal cord injury (SCI) is associated with currently irreversible consequences in several functional components of the central nervous system. Despite the severity of injury, there remains no approved treatment to restore function. However, with a growing number of preclinical studies and clinical trials, cell transplantation has gained significant potential as a treatment for SCI. Researchers have identified several cell types as potential candidates for transplantation. To optimize successful functional outcomes after transplantation, one key factor concerns generating neuronal cells with regional and subtype specificity, thus calling on the developmental transcriptome patterning of spinal cord cells. A potential source of spinal cord cells for transplantation is the generation of exogenic neuronal progenitor cells via the emerging technologies of gene editing and blastocyst complementation. This review highlights the use of cell transplantation to treat SCI in the context of relevant developmental gene expression patterns useful for producing regionally specific exogenic spinal cells via in vitro differentiation and blastocyst complementation.

Impact of anesthesia on micromagnetic stimulation (µMS) of the vagus nerve.

To treat diseases associated with vagal nerve control of peripheral organs, it is necessary to selectively activate efferent and afferent fibers in the vagus. As a result of the nerve's complex anatomy, fiber-specific activation proves challenging. Spatially selective neuromodulation using micromagnetic stimulation(µMS) is showing incredible promise. This neuromodulation technique uses microcoils(µcoils) to generate magnetic fields by powering them with a time-varying current. Following the principles of Faraday's law of induction, a highly directional electric field is induced in the nerve from the magnetic field. In this study on rodent cervical vagus, a solenoidalµcoil was oriented at an angle to left and right branches of the nerve. The aim of this study was to measure changes in the mean arterial pressure (MAP) and heart rate (HR) followingµMS of the vagus. Theµcoils were powered by a single-cycle sinusoidal current varying in pulse widths(PW = 100, 500, and 1000µsec) at a frequency of 20 Hz. Under the influence of isoflurane,µMS of the left vagus at 1000µsec PW led to an average drop in MAP of 16.75 mmHg(n = 7). In contrast,µMS of the right vagus under isoflurane resulted in an average drop of 11.93 mmHg in the MAP(n = 7). Surprisingly, there were no changes in HR to either right or left vagalµMS suggesting the drop in MAP associated with vagusµMS was the result of stimulation of afferent, but not efferent fibers. In urethane anesthetized rats, no changes in either MAP or HR were observed uponµMS of the right or left vagus(n = 3). These findings suggest the choice of anesthesia plays a key role in determining the efficacy ofµMS on the vagal nerve. Absence of HR modulation uponµMS could offer alternative treatment options using VNS with fewer heart-related side-effects.

Mapping brain networks in MPS I mice and their restoration following gene therapy.

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disorder that causes syndromes characterized by physiological dysfunction in many organs and tissues. Despite the recognizable morphological and behavioral deficits associated with MPS I, neither the underlying alterations in functional neural connectivity nor its restoration following gene therapy have been shown. By employing high-resolution resting-state fMRI (rs-fMRI), we found significant reductions in functional neural connectivity in the limbic areas of the brain that play key roles in learning and memory in MPS I mice, and that adeno-associated virus (AAV)-mediated gene therapy can reestablish most brain connectivity. Using logistic regression in MPS I and treated animals, we identified functional networks with the most alterations. The rs-fMRI and statistical methods should be translatable into clinical evaluation of humans with neurological disorders.

A Technological and Regulatory Review on Human-Animal Chimera Research: The Current Landscape of Biology, Law, and Public Opinion.

Organ transplantation is a highly utilized treatment for many medical conditions, yet the number of patients waiting for organs far exceeds the number available. The challenges and limitations currently associated with organ transplantation and technological advances in gene editing techniques have led scientists to pursue alternate solutions to the donor organ shortage. Growing human organs in animals and harvesting those organs for transplantation into humans is one such solution. These chimeric animals usually have certain genes necessary for a specific organ's development inhibited at an early developmental stage, followed by the addition of cultured pluripotent human cells to fill that developmental niche. The result is a chimeric animal that contains human organs which are available for transplant into a patient, circumventing some of the limitations currently involved in donor organ transplantation. In this review, we will discuss both the current scientific and legal landscape of human-animal chimera (HAC) research. We present an overview of the technological advances that allow for the creation of HACs, the patents that currently exist on these methods, as well as current public attitude and understanding that can influence HAC research policy. We complement our scientific and public attitude discussion with a regulatory overview of chimera research at both the national and state level, while also contrasting current U.S. legislation with regulations in other countries. Overall, we provide a comprehensive analysis of the legal and scientific barriers to conducting research on HACs for the generation of transplantable human organs, as well as provide recommendations for the future.

Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent for the worldwide COVID-19 pandemic, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe disease, and sexual dimorphism in clinical outcomes has been reported in COVID-19. SARS-CoV-2 infection in humans can cause damage to multiple organ systems, including the brain. Neurological symptoms are widely observed in patients with COVID-19, with many survivors suffering from persistent neurological and cognitive impairment, potentially accelerating Alzheimer's disease. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6 mice were inoculated, by intranasal route, with SARS-CoV-2 lineage B.1.351 variant known to infect mice. Older animals and in particular males exhibited a significantly greater weight loss starting at 4 dpi. In addition, male animals exhibited higher viral RNA loads and higher titers of infectious virus in the lung, which was particularly evident in males at 16 months of age. Notably, no viral RNA was detected in the brains of infected mice, regardless of age or sex. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain was increased with viral infection. An unbiased brain RNA-seq/transcriptomic analysis showed that SARS-CoV-2 infection caused significant changes in gene expression profiles in the brain, with innate immunity, defense response to virus, cerebravascular and neuronal functions, as the major molecular networks affected. The data presented in this study show that SARS-CoV-2 infection triggers a neuroinflammatory response despite the lack of detectable virus in the brain. Age and sex have a modifying effect on this pathogenic process. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and supression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.

Nonhematopoietic Umbilical Cord Blood Stem Cell Administration Improves Long-term Neurodevelopment After Periventricular-Intraventricular Hemorrhage in Neonatal Rats.

Periventricular-intraventricular hemorrhage (PIVH) is common in extremely low gestational age neonates (ELGAN) and leads to motor and behavioral impairments. Currently there is no effective treatment for PIVH. Whether human nonhematopoietic umbilical cord blood-derived stem cell (nh-UCBSC) administration reduces the severity of brain injury and improves long-term motor and behavioral function was tested in an ELGAN-equivalent neonatal rat model of PIVH. In a collagenase-induced unilateral PIVH on postnatal day (P) 2 model, rat pups received a single dose of nh-UCBSCs at a dose of 1 × 106 cells i.p. on P6 (PIVH + UCBSC group) or were left untreated (Untreated PIVH group). Motor deficit was determined using forelimb placement, edge-push, and elevated body swing tests at 2 months (N = 5-8). Behavior was evaluated using open field exploration and rearing tests at 4 months (N =10-12). Cavity volume and hemispheric volume loss on the PIVH side were determined at 7 months (N = 6-7). Outcomes were compared between the Untreated PIVH and PIVH + UCBSC groups and a Control group. Unilateral motor deficits were present in 60%-100% of rats in the Untreated PIVH group and 12.5% rats in the PIVH + UCBSC group (P = 0.02). Untreated PIVH group exhibited a higher number of quadrant crossings in open field exploration, indicating low emotionality and poor habituation, and had a cavitary lesion and hemispheric volume loss on the PIVH side. Performance in open field exploration correlated with cavity volume (r2 = 0.25; P < 0.05). Compared with the Untreated PIVH group, performance in open field exploration was better (P = 0.0025) and hemispheric volume loss was lower (19.9 ± 4.4% vs 6.1 ± 2.6%, P = 0.018) in the PIVH + UCBSC group. These results suggest that a single dose of nh-UCBSCs administered in the subacute period after PIVH reduces the severity of injury and improves neurodevelopment in neonatal rats.

Micromagnetic Stimulation (µMS) Controls Dopamine Release: An in vivo Study Using WINCS Harmoni.

Objective: Research into the role of neurotransmitters in regulating normal and pathologic brain functions has made significant progress. Yet, clinical trials that aim to improve therapeutic interventions do not take advantage of the in vivo changes in the neurochemistry that occur in real time during disease progression, drug interactions or response to pharmacological, cognitive, behavioral, and neuromodulation therapies. In this work, we used the WINCS Harmoni tool to study the real time in vivo changes in dopamine release in rodent brains for the micromagnetic neuromodulation therapy. Approach: Although still in its infancy, micromagnetic stimulation (µMS) using micro-meter sized coils or microcoils (µcoils) has shown incredible promise in spatially selective, galvanic contact free and highly focal neuromodulation. These µcoils are powered by a time-varying current which generates a magnetic field. As per Faraday's Laws of Electromagnetic Induction, this magnetic field induces an electric field in a conducting medium (here, the brain tissues). We used a solenoidal-shaped µcoil to stimulate the medial forebrain bundle (MFB) of the rodent brain in vivo. The evoked in vivo dopamine releases in the striatum were tracked in real time by carbon fiber microelectrodes (CFM) using fast scan cyclic voltammetry (FSCV). Results: Our experiments report that µcoils can successfully activate the MFB in rodent brains, triggering dopamine release in vivo. We further show that the successful release of dopamine upon micromagnetic stimulation is dependent on the orientation of the µcoil. Furthermore, varied intensities of µMS can control the concentration of dopamine releases in the striatum. Significance: This work helps us better understand the brain and its conditions arising from a new therapeutic intervention, like µMS, at the level of neurotransmitter release. Despite its early stage, this study potentially paves the path for µMS to enter the clinical world as a precisely controlled and optimized neuromodulation therapy.

Transplanting Microglia for Treating CNS Injuries and Neurological Diseases and Disorders, and Prospects for Generating Exogenic Microglia.

Microglia are associated with a wide range of both neuroprotective and neuroinflammatory functions in the central nervous system (CNS) during development and throughout lifespan. Chronically activated and dysfunctional microglia are found in many diseases and disorders, such as Alzheimer's disease, Parkinson's disease, and CNS-related injuries, and can accelerate or worsen the condition. Transplantation studies designed to replace and supplement dysfunctional microglia with healthy microglia offer a promising strategy for addressing microglia-mediated neuroinflammation and pathologies. This review will cover microglial involvement in neurological diseases and disorders and CNS-related injuries, current microglial transplantation strategies, and different approaches and considerations for generating exogenic microglia.

Micromagnetic stimulation (µMS) dose-response of the rat sciatic nerve.

Objective.The objective of this study was to investigate the effects of micromagnetic stimuli strength and frequency from theMagneticPen(MagPen) on the rat right sciatic nerve. The nerve's response was measured by recording muscle activity and movement of the right hind limb.Approach.The MagPen was custom-built to be stably held over the sciatic nerve. Rat leg muscle twitches were captured on video, and movements were extracted using image processing algorithms. EMG recordings were also used to measure muscle activity.Main results.The MagPen prototype, when driven by an alternating current, generates a time-varying magnetic field, which, according to Faraday's law of electromagnetic induction, induces an electric field for neuromodulation. The orientation-dependent spatial contour maps of the induced electric field from the MagPen prototype have been numerically simulated. Furthermore, in thisin vivowork onµMS, a dose-response relationship has been reported by experimentally studying how varying the amplitude (Range: 25 mVp-pthrough 6Vp-p) and frequency (range: 100 Hz through 5 kHz) of the MagPen stimuli alters hind limb movement. The primary highlight of this dose-response relationship (repeated overnrats, wheren= 7) is that for aµMS stimuli of higher frequency, significantly smaller amplitudes can trigger hind limb muscle twitch. This frequency-dependent activation can be justified by Faraday's Law, which states that the magnitude of the induced electric field is directly proportional to the frequency.Significance.This work reports thatµMS can successfully activate the sciatic nerve in a dose-dependent manner. The impact of this dose-response curve addresses the controversy in this research community about whether the stimulation from theseµcoils arise from a thermal effect or micromagnetic stimulation. MagPen probes do not have a direct electrochemical interface with tissue and therefore do not experience electrode degradation, biofouling, and irreversible redox reactions like traditional direct contact electrodes. Magnetic fields from theµcoils create more precise activation than electrodes because they apply more focused and localized stimulation. Finally, unique features ofµMS, such as the orientation dependence, directionality, and spatial specificity, have been discussed.

Neuronal Transplantation for Alzheimer's Disease and Prospects for Generating Exogenic Neurons as a Source of Cells for Implantation.

Alzheimer's disease (AD) is a devastating neurodegenerative disease with limited therapeutic options. Cellular transplantation of healthy exogenic neurons to replace and restore neuronal cell function has previously been explored in AD animal models, yet most of these transplantation methods have utilized primary cell cultures or donor grafts. Blastocyst complementation offers a novel approach to generate a renewable exogenic source of neurons. These exogenic neurons derived from stem cells would develop with the in vivo context of the inductive cues within a host, thus recapitulating the neuron-specific characteristics and physiology. AD affects many different cell types including hippocampal neurons and limbic projection neurons, cholinergic nucleus basis and medial septal neurons, noradrenergic locus coeruleus neurons, serotonergic raphe neurons, and limbic and cortical interneurons. Blastocyst complementation can be adapted to generate these specific neuronal cells afflicted by AD pathology, by ablating important cell type and brain region-specific developmental genes. This review discusses the current state of neuronal transplantation to replace specific neural cell types affected by AD, and the developmental biology to identify candidate genes for knockout in embryos for creating niches to generate exogenic neurons via blastocyst complementation.

In Silico Stage-Matching of Human, Marmoset, Mouse, and Pig Embryos to Enhance Organ Development Through Interspecies Chimerism.

Currently, there is a significant shortage of transplantable organs for patients in need. Interspecies chimerism and blastocyst complementation are alternatives for generating transplantable human organs in host animals such as pigs to meet this shortage. While successful interspecies chimerism and organ generation have been observed between evolutionarily close species such as rat and mouse, barriers still exist for more distant species pairs such as human-mouse, marmoset-mouse, human-pig, and others. One of the proposed barriers to chimerism is the difference in developmental stages between the donor cells and the host embryo at the time the cells are introduced into the host embryo. Hence, there is a logical effort to stage-match the donor cells with the host embryos for enhancing interspecies chimerism. In this study, we used an in silico approach to simultaneously stage-match the early developing embryos of four species, including human, marmoset, mouse, and pig based on transcriptome similarities. We used an unsupervised clustering algorithm to simultaneously stage-match all four species as well as Spearman's correlation analyses to stage-match pairs of donor-host species. From our stage-matching analyses, we found that the four stages that best matched with each other are the human blastocyst (E6/E7), the gastrulating mouse embryo (E6-E6.75), the marmoset late inner cell mass, and the pig late blastocyst. We further demonstrated that human pluripotent stem cells best matched with the mouse post-implantation stages. We also performed ontology analysis of the genes upregulated and commonly expressed between donor-host species pairs at their best matched stages. The stage-matching results predicted by this study will inform in vivo and in vitro interspecies chimerism and blastocyst complementation studies and can be used to match donor cells with host embryos between multiple species pairs to enhance chimerism for organogenesis.

Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome.

Hunter syndrome is a rare x-linked recessive genetic disorder that affects lysosomal metabolism due to deficiency of iduronate-2-sulfatase (IDS), with subsequent accumulation of glycosaminoglycans heparan and dermatan sulfates (GAG). Enzyme replacement therapy is the only FDA-approved remedy and is an expensive life-time treatment that alleviates some symptoms of the disease without neurocognitive benefit. We previously reported successful treatment in a mouse model of mucopolysaccharidosis type II (MPS II) using adeno-associated viral vector serotype 9 encoding human IDS (AAV9.hIDS) via intracerebroventricular injection. As a less invasive and more straightforward procedure, here we report intravenously administered AAV9.hIDS in a mouse model of MPS II. In animals administered 1.5 × 1012 vg of AAV9.hIDS at 2 months of age, we observed supraphysiological levels of IDS enzyme activity in the circulation (up to 9100-fold higher than wild-type), in the tested peripheral organs (up to 560-fold higher than wild-type), but only 4% to 50% of wild type levels in the CNS. GAG levels were normalized on both sides of the blood-brain-barrier (BBB) in most of tissues tested. Despite low levels of the IDS observed in the CNS, this treatment prevented neurocognitive decline as shown by testing in the Barnes maze and by fear conditioning. This study demonstrates that a single dose of IV-administered AAV9.hIDS may be an effective and non-invasive procedure to treat MPS II that benefits both sides of the BBB, with implications for potential use of IV-administered AAV9 for other neuronopathic lysosomal diseases.

Cell Reprogramming for Regeneration and Repair of the Nervous System.

A persistent barrier to the cure and treatment of neurological diseases is the limited ability of the central and peripheral nervous systems to undergo neuroregeneration and repair. Recent efforts have turned to regeneration of various cell types through cellular reprogramming of native cells as a promising therapy to replenish lost or diminished cell populations in various neurological diseases. This review provides an in-depth analysis of the current viral vectors, genes of interest, and target cellular populations that have been studied, as well as the challenges and future directions of these novel therapies. Furthermore, the mechanisms by which cellular reprogramming could be optimized as treatment in neurological diseases and a review of the most recent cellular reprogramming in vitro and in vivo studies will also be discussed.

Interspecies Chimeric Barriers for Generating Exogenic Organs and Cells for Transplantation.

A growing need for organs and novel cell-based therapies has provided a niche for approaches like interspecies chimeras. To generate organs from one donor species in another host species requires techniques such as blastocyst complementation and gene editing to successfully create an embryo that has cells from both the donor and the host. However, the task of developing highly efficacious and competent interspecies chimeras is met by many challenges. These interspecies chimeric barriers impede the formation of chimeras, often leading to lower levels of chimeric competency. The barriers that need to be addressed include the evolutionary distance between species, stage-matching, temporal and spatial synchronization of developmental timing, interspecies cell competition and the survival of pluripotent stem cells and embryos, compatibility of ligand-receptor signaling between species, and the ethical concerns of forming such models. By overcoming the interspecies chimera barriers and creating highly competent chimeras, the technology of organ and cellular generation can be honed and refined to develop fully functioning exogenic organs, tissues, and cells for transplantation.

Orientation selective DBS of entorhinal cortex and medial septal nucleus modulates activity of rat brain areas involved in memory and cognition.

The recently introduced orientation selective deep brain stimulation (OS-DBS) technique freely controls the direction of the electric field's spatial gradient by using multiple contacts with independent current sources within a multielectrode array. The goal of OS-DBS is to align the electrical field along the axonal track of interest passing through the stimulation site. Here we utilized OS-DBS with a planar 3-channel electrode for stimulating the rat entorhinal cortex (EC) and medial septal nucleus (MSN), two promising areas for DBS treatment of Alzheimer's disease. The brain responses to OS-DBS were monitored by whole brain functional magnetic resonance imaging (fMRI) at 9.4 T with Multi-Band Sweep Imaging with Fourier Transformation (MB-SWIFT). Varying the in-plane OS-DBS stimulation angle in the EC resulted in activity modulation of multiple downstream brain areas involved in memory and cognition. Contrary to that, no angle dependence of brain activations was observed when stimulating the MSN, consistent with predictions based on the electrode configuration and on the main axonal directions of the targets derived from diffusion MRI tractography and histology. We conclude that tuning the OS-DBS stimulation angle modulates the activation of brain areas relevant to Alzheimer's disease, thus holding great promise in the DBS treatment of the disease.

Strength-frequency curve for micromagnetic neurostimulation through excitatory postsynaptic potentials (EPSPs) on rat hippocampal neurons and numerical modeling of magnetic microcoil (µcoil).

Objective.The objective of this study was to measure the effect of micromagnetic stimulation (µMS) on hippocampal neurons, by using single microcoil (µcoil) prototype, magnetic pen (MagPen). MagPen will be used to stimulate the CA3 region magnetically and excitatory post synaptic potential (EPSP) response measurements will be made from the CA1 region. The threshold for micromagnetic neurostimulation as a function of stimulation frequency of the current driving theµcoil will be demonstrated. Finally, the optimal stimulation frequency of the current driving theµcoil to minimize power will be estimated.Approach.A biocompatible, watertight, non-corrosive prototype, MagPen was built, and customized such that it is easy to adjust the orientation of theµcoil and its distance over the hippocampal tissue in anin vitrorecording setting. Finite element modeling of theµcoil design was performed to estimate the spatial profiles of the magnetic flux density (in T) and the induced electric fields (in V m-1). The induced electric field profiles generated at different values of current applied to theµcoil can elicit a neuronal response, which was validated by numerical modeling. The modeling settings for theµcoil were replicated in experiments on rat hippocampal neurons.Main results.The preferred orientation of MagPen over the Schaffer Collateral fibers was demonstrated such that they elicit a neuron response. The recorded EPSPs from CA1 region due toµMS at CA3 region were validated by applying tetrodotoxin (TTX). Application of TTX to the hippocampal slice blocked the EPSPs fromµMS while after prolonged TTX washout, a partial recovery of the EPSP fromµMS was observed. Finally, it was interpreted through numerical analysis that increasing frequency of the current driving theµcoil, led to a decrease in the current amplitude threshold for micromagnetic neurostimulation.Significance.This work reports that micromagnetic neurostimulation can be used to evoke population EPSP responses in the CA1 region of the hippocampus. It demonstrates the strength-frequency curve forµMS and its unique features related to orientation dependence of theµcoils, spatial selectivity and stimulation threshold related to distance dependence. Finally, the challenges related toµMS experiments were studied including ways to overcome them.

ssDNA nanotubes for selective targeting of glioblastoma and delivery of doxorubicin for enhanced survival.

Effective treatment of glioblastoma remains a daunting challenge. One of the major hurdles in the development of therapeutics is their inability to cross the blood-brain tumor barrier (BBTB). Local delivery is an alternative approach that can still suffer from toxicity in the absence of target selectivity. Here, we show that nanotubes formed from self-assembly of ssDNA-amphiphiles are stable in serum and nucleases. After bilateral brain injections, nanotubes show preferential retention by tumors compared to normal brain and are taken up by glioblastoma cells through scavenger receptor binding and macropinocytosis. After intravenous injection, they cross the BBTB and internalize in glioblastoma cells. In a minimal residual disease model, local delivery of doxorubicin showed signs of toxicity in the spleen and liver. In contrast, delivery of doxorubicin by the nanotubes resulted in no systemic toxicity and enhanced mouse survival. Our results demonstrate that ssDNA nanotubes are a promising drug delivery vehicle to glioblastoma.

Microglia and Macrophages in Neuroprotection, Neurogenesis, and Emerging Therapies for Stroke.

Stroke remains the number one cause of morbidity in the United States. Within weeks to months after an ischemic event, there is a resolution of inflammation and evidence of neurogenesis; however, years following a stroke, there is evidence of chronic inflammation in the central nervous system, possibly by the persistence of an autoimmune response to brain antigens as a result of ischemia. The mechanisms underlying the involvement of macrophage and microglial activation after stroke are widely acknowledged as having a role in ischemic stroke pathology; thus, modulating inflammation and neurological recovery is a hopeful strategy for treating the long-term outcomes after ischemic injury. Current treatments fail to provide neuroprotective or neurorestorative benefits after stroke; therefore, to ameliorate brain injury-induced deficits, therapies must alter both the initial response to injury and the subsequent inflammatory process. This review will address differences in macrophage and microglia nomenclature and summarize recent work in elucidating the mechanisms of macrophage and microglial participation in antigen presentation, neuroprotection, angiogenesis, neurogenesis, synaptic remodeling, and immune modulating strategies for treating the long-term outcomes after ischemic injury.

Machine Learning-Enabled High-Resolution Dynamic Deuterium MR Spectroscopic Imaging.

Deuterium magnetic resonance spectroscopic imaging (DMRSI) has recently been recognized as a potentially powerful tool for noninvasive imaging of brain energy metabolism and tumor. However, the low sensitivity of DMRSI has significantly limited its utility for both research and clinical applications. This work presents a novel machine learning-based method to address this limitation. The proposed method synergistically integrates physics-based subspace modeling and data-driven deep learning for effective denoising, making high-resolution dynamic DMRSI possible. Specifically, a novel subspace model was used to represent the dynamic DMRSI signals; deep neural networks were trained to capture the low-dimensional manifolds of the spectral and temporal distributions of practical dynamic DMRSI data. The learned subspace and manifold structures were integrated via a regularization formulation to remove measurement noise. Theoretical analysis, computer simulations, and in vivo experiments have been conducted to demonstrate the denoising efficacy of the proposed method which enabled high-resolution imaging capability. The translational potential was demonstrated in tumor-bearing rats, where the Warburg effect associated with cancer metabolism and tumor heterogeneity were successfully captured. The new method may not only provide an effective tool to enhance the sensitivity of DMRSI for basic research and clinical applications but also provide a framework for denoising other spatiospectral data.