Traumatic brain injury (TBI) is the leading cause of death in young individuals, and is a major health concern that often leads to long-lasting complications. However, the electrophysiological events ...that occur immediately after traumatic brain injury, and may underlie impact outcomes, have not been fully elucidated. To investigate the electrophysiological events that immediately follow traumatic brain injury, a weight-drop model of traumatic brain injury was used in rats pre-implanted with epidural and intracerebral electrodes. Electrophysiological (near-direct current) recordings and simultaneous alternating current recordings of brain activity were started within seconds following impact. Cortical spreading depolarization (SD) and SD-induced spreading depression occurred in approximately 50% of mild and severe impacts. SD was recorded within three minutes after injury in either one or both brain hemispheres. Electrographic seizures were rare. While both TBI- and electrically induced SDs resulted in elevated oxidative stress, TBI-exposed brains showed a reduced antioxidant defense. In severe TBI, brainstem SD could be recorded in addition to cortical SD, but this did not lead to the death of the animals. Severe impact, however, led to immediate death in 24% of animals, and was electrocorticographically characterized by non-spreading depression (NSD) of activity followed by terminal SD in both cortex and brainstem.
Brain microvessels possess the unique properties of a blood–brain barrier (BBB), tightly regulating the passage of molecules from the blood to the brain neuropil and vice versa. In models of brain ...injury, BBB dysfunction and the associated leakage of serum albumin to the neuropil have been shown to induce pathological plasticity, neuronal hyper-excitability, and seizures. The effect of neuronal activity on BBB function and whether it plays a role in plasticity in the healthy brain remain unclear. Here we show that neuronal activity induces modulation of microvascular permeability in the healthy brain and that it has a role in local network reorganization. Combining simultaneous electrophysiological recording and vascular imaging with transcriptomic analysis in rats, and functional and BBB-mapping MRI in human subjects, we show that prolonged stimulation of the limb induces a focal increase in BBB permeability in the corresponding somatosensory cortex that is associated with long-term synaptic plasticity. We further show that the increased microvascular permeability depends on neuronal activity and involves caveolae-mediated transcytosis and transforming growth factor β signaling. Our results reveal a role of BBB modulation in cortical plasticity in the healthy brain, highlighting the importance of neurovascular interactions for sensory experience and learning.
Axons sense molecular cues in their environment to arrive at their post-synaptic targets. While many of the molecular cues have been identified, the mechanisms that regulate their spatiotemporal ...expression remain elusive. We examined here the transcriptional regulation of the guidance gene
slit1
both in vitro and in vivo by specific fibroblast growth factor receptors (Fgfrs). We identified an Fgf-responsive 2.3 kb
slit1
promoter sequence that recapitulates spatiotemporal endogenous expression in the neural tube and eye of
Xenopus
embryos. We found that signaling through Fgfr1 is the main regulator of
slit1
expression both in vitro in A6 kidney epithelial cells, and in the
Xenopus
forebrain, even when other Fgfr subtypes are present in cells. These data argue that a specific signaling pathway downstream of Fgfr1 controls in a cell-autonomous manner
slit1
forebrain expression and are novel in identifying a specific growth factor receptor for in vivo control of the expression of a key embryonic axon guidance cue.
Summary
Lower vertebrates use rapid light‐regulated changes in skin colour for camouflage (background adaptation) or during circadian variation in irradiance levels. Two neuroendocrine systems, the ...eye/alpha‐melanocyte‐stimulating hormone (α‐MSH) and the pineal complex/melatonin circuits, regulate the process through their respective dispersion and aggregation of pigment granules (melanosomes) in skin melanophores. During development, Xenopus laevis tadpoles raised on a black background or in the dark perceive less light sensed by the eye and darken in response to increased α‐MSH secretion. As embryogenesis proceeds, the pineal complex/melatonin circuit becomes the dominant regulator in the dark and induces lightening of the skin of larvae. The eye/α‐MSH circuit continues to mediate darkening of embryos on a black background, but we propose the circuit is shut down in complete darkness in part by melatonin acting on receptors expressed by pituitary cells to inhibit the expression of pomc, the precursor of α‐MSH.
The mechanisms underlying the complications of mild traumatic brain injury, including post-concussion syndrome, post-impact catastrophic death, and delayed neurodegeneration, remain poorly ...understood. This limited pathophysiological understanding has hindered the development of diagnostic and prognostic biomarkers and has prevented the advancement of treatments for the sequelae of mild traumatic brain injury. We aimed to characterize the early electrophysiological and neurovascular alterations following repetitive mild traumatic brain injury and sought to identify new targets for the diagnosis and treatment of individuals at risk of severe post-impact complications. We combined behavioural, electrophysiological, molecular, and neuroimaging techniques in a rodent model of repetitive mild traumatic brain injury. In humans, we used dynamic contrast-enhanced MRI to quantify blood-brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury. Rats could clearly be classified based on their susceptibility to neurological complications, including life-threatening outcomes, following repetitive injury. Susceptible animals showed greater neurological complications and had higher levels of blood-brain barrier dysfunction, transforming growth factor β signaling, and neuroinflammation compared to resilient animals. Cortical spreading depolarizations were the most common electrophysiological events immediately following mild traumatic brain injury and were associated with longer recovery from impact. Triggering cortical spreading depolarizations in mild traumatic brain injured rats (but not in controls) induced blood-brain barrier dysfunction. Treatment with a selective transforming growth factor β receptor inhibitor prevented blood-brain barrier opening and reduced injury complications. Consistent with the rodent model, blood-brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury. We provide evidence that cortical spreading depolarization, blood-brain barrier dysfunction, and pro-inflammatory transforming growth factor β signaling are associated with severe, potentially life-threatening outcomes, following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of transforming growth factor β signaling may be a novel strategy in treating mild traumatic brain injury.
Background
Neonatal hypoxic‐ischemic encephalopathy arises from a reduction of oxygen and blood supply to the infant brain and can lead to severe brain damage and life‐long disability. The damage is ...greatest at the irreversibly injured necrotic core, whereas the penumbra is the surrounding, potentially salvageable tissue populated with a mix of alive and dying cells. To date, there exists no method for targeting drugs to the brain damage.
Methods and Major Results
Bacteriophages are viruses that propagate in bacteria but are biocompatible in humans and also amenable to genetic and chemical modification in a manner distinctive from conventional therapeutic nanoparticles. Here, a library of M13 bacteriophage was administered into a rat model of hypoxic‐ischemic encephalopathy, and unique bacteriophage clones were confirmed to localize in healthy brain tissue versus the core and penumbra zones of injury.
Conclusions
For the first time, there is a potential to directly deliver therapeutics to different regions of the neonatal brain injury.
Graphical and Lay Summary
A library of M13 bacteriophage tagged with unique 12‐mer peptide sequences on the order of 109 diversity was injected into newborn rats following the induction of hypoxic‐ischemic brain injury. After three iterations of bacteriophage recovery from the injured site of the cerebral cortex, re‐injection into the animal model, and DNA sequencing, we identified the enrichment of specific bacteriophage clones in the lesion
.
Self-assembling peptides are a promising class of biomaterials with desirable biocompatibility and versatility. In particular, the oligopeptide (RADA)₄, consisting of arginine (R), alanine (A), and ...aspartic acid (D), self-assembles into nanofibers that develop into a three-dimensional hydrogel of up to 99.5% (w/v) water; yet, the organization of water within the hydrogel matrix is poorly understood. Importantly, peptide concentration and polarity are hypothesized to control the internal water structure. Using variable temperature deuterium solid-state nuclear magnetic resonance (²H NMR) spectroscopy, we measured the amount of bound water in (RADA)₄-based hydrogels, quantified as the non-frozen water content. To investigate how peptide polarity affects water structure, five lysine (K) moieties were appended to (RADA)₄ to generate (RADA)₄K₅. Hydrogels at 1 and 5% total peptide concentration were prepared from a 75:25 (w/w) blend of (RADA)₄:(RADA)₄K₅ and similarly analyzed by ²H NMR. Interestingly, at 5% peptide concentration, there was lower mobile water content in the lysinated versus the pristine (RADA)₄ hydrogel. Regardless of the presence of lysine, the 5% peptide concentration had higher non-frozen water content at temperatures as low as 217 ± 1.0 K, suggesting that bound water increases with peptide concentration. The bound water, though non-frozen, may be strongly bound to the charged lysine moiety to appear as immobilized water. Further understanding of the factors controlling water structure within hydrogels is important for tuning the transport properties of bioactive solutes in the hydrogel matrix when designing for biomedical applications.
•Males and females have distinct genetic, hormonal, and pharmacokinetic mechanisms.•Biomolecular corona on nanomaterial surface influences interactions with living cells.•Nanomaterials may induce ...endocytosis, inflammation, and toxicity with a sexual bias.•Females are underrepresented in drug trials, more susceptible to adverse drug events.•Biomedical nanomaterials may have sex-specific therapeutic potentials.
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Nanomaterials are found in a wide range of industries from additives in consumer products, drug delivery vehicles, as well as environmental hazards. There is a growing body of evidence that suggests biological sex affects the host response to these nanomaterials. Given that male and female tissues do have distinct profiles of secreted factors, it is reasonable to expect that these adsorb to the surface of nanomaterials. These differences in the composition of the adsorbed biomolecular corona may induce different cellular responses based upon their biological sex. A sexual bias has been observed in the tissue-specific accumulation of nanomaterials, the extent of inflammation, and epigenetic modification induced by nanomaterials. While most of these studies involved exposure to environmental nanomaterials, there were limited examples that evaluated sexual biases related to nanomaterials for drug delivery, especially to the brain. A patient’s sex may influence the therapeutic or general host response to nanomaterials commonly used for biomedical applications. Herein, we begin with a description of the biomolecular corona as the effective interface between nanomaterials and biological systems. Then, the molecular aspects of sexual differentiation are presented regarding genetic factors, hormonal regulation, and mechanisms of processing xenobiotics, as the foundation from which to explore the sex-specific effects of nanomaterials.
Based on the views from HEIs administrators, teachers, and students about online learning during the pandemic in Sri Lanka, this study examines the existing gaps in HEIs that might hinder the ...inclusivity and quality of online learning, and the role of HEIs to drive and support online learning. This study adopts the institutional framework for online and blended learning by Lim et al. (2019) to analyse the enabling factors and challenges faced by HEIs in Sri Lanka to drive and support inclusive and quality online learning, and suggests how their capacity could be built to engage all students in quality online learning. The study highlights that most HEIs in Sri Lanka are in the initial stages towards inclusive and quality online learning. The HEIs in Sri Lanka need to pay more attention to formulating online learning-related policies at the university level, investing in infrastructure and hardware to enhance the access to quality online teaching and learning, sustaining partnerships to support the quality enhancement of online teaching and learning, offering pedagogically-oriented professional development opportunities for teachers, and providing student learning support. Besides these dimensions, two other dimensions, namely curriculum development and reforms and research and evaluation of online learning, have to be taken into consideration. The study suggests a more systematic and holistic approach would be crucial to guide HEIs as they strive toward inclusive and quality online learning in the medium and long run.
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