Traumatic brain injury and recovery mechanisms: peptide modulation of periventricular neurogenic regions by the choroid plexus–CSF nexus

In traumatic brain injury (TBI), severe disruptions occur in the choroid plexus (CP)–cerebrospinal fluid (CSF) nexus that destabilize the nearby hippocampal and subventricular neurogenic regions. Following invasive and non-invasive injuries to cortex, several adverse sequelae harm the brain interior: (i) structural damage to CP epithelium that opens the blood–CSF barrier (BCSFB) to protein, (ii) altered CSF dynamics and intracranial pressure (ICP), (iii) augmentation of leukocyte traffic across CP into the CSF–brain, (iv) reduction in CSF sink action and clearance of debris from ventricles, and (v) less efficient provision of micronutritional and hormonal support for the CNS. However, gradual post-TBI restitution of the injured CP epithelium and ependyma, and CSF homeostatic mechanisms, help to restore subventricular/subgranular neurogenesis and the cognitive abilities diminished by CNS damage. Recovery from TBI is faciltated by upregulated choroidal/ependymal growth factors and neurotrophins, and their secretion into ventricular CSF. There, by an endocrine-like mechanism, CSF bulk flow convects the neuropeptides to target cells in injured cortex for aiding repair processes; and to neurogenic niches for enhancing conversion of stem cells to new neurons. In the recovery from TBI and associated ischemia, the modulating neuropeptides include FGF2, EGF, VEGF, NGF, IGF, GDNF, BDNF, and PACAP. Homeostatic correction of TBI-induced neuropathology can be accelerated or amplified by exogenously boosting the CSF concentration of these growth factors and neurotrophins. Such intraventricular supplementation via the CSF route promotes neural restoration through enhanced neurogenesis, angiogenesis, and neuroprotective effects. CSF translational research presents opportunities that involve CP and ependymal manipulations to expedite recovery from TBI

Deep Learning for Predicting Significant Wave Height From Synthetic Aperture Radar

The Sentinel-1 satellites equipped with synthetic aperture radars (SARs) provide near-global coverage of the world's oceans every six days. We curate a data set of collocations between SAR and altimeter satellites and investigate the use of deep learning to predict significant wave height from SAR. While previous models for predicting geophysical quantities from SAR rely heavily on feature-engineering, our approach learns directly from low-level image cross-spectra. Training on collocations from 2015 to 2017, we demonstrate on test data from 2018 that deep learning reduces the state-of-the-art root mean squared error by 50%, from 0.6 to 0.3 m when compared to altimeter data. Furthermore, we isolate the contributions of different features to the model performance

Deep Learning for Predicting Significant Wave Height From Synthetic Aperture Radar

The Sentinel-1 satellites equipped with synthetic aperture radars (SARs) provide near-global coverage of the world’s oceans every six days. We curate a data set of collocations between SAR and altimeter satellites and investigate the use of deep learning to predict significant wave height from SAR. While previous models for predicting geophysical quantities from SAR rely heavily on feature-engineering, our approach learns directly from low-level image cross-spectra. Training on collocations from 2015 to 2017, we demonstrate on test data from 2018 that deep learning reduces the state-of-the-art root mean squared error by 50%, from 0.6 to 0.3 m when compared to altimeter data. Furthermore, we isolate the contributions of different features to the model performance

Noninvasive fractal biomarker of clock neurotransmitter disturbance in humans with dementia

Human motor activity has a robust, intrinsic fractal structure with similar patterns from minutes to hours. The fractal activity patterns appear to be physiologically important because the patterns persist under different environmental conditions but are significantly altered/reduced with aging and Alzheimer's disease (AD). Here, we report that dementia patients, known to have disrupted circadian rhythmicity, also have disrupted fractal activity patterns and that the disruption is more pronounced in patients with more amyloid plaques (a marker of AD severity). Moreover, the degree of fractal activity disruption is strongly associated with vasopressinergic and neurotensinergic neurons (two major circadian neurotransmitters) in postmortem suprachiasmatic nucleus (SCN), and can better predict changes of the two neurotransmitters than traditional circadian measures. These findings suggest that the SCN impacts human activity regulation at multiple time scales and that disrupted fractal activity may serve as a non-invasive biomarker of SCN neurodegeneration in dementia

Targeting the choroid plexus-CSF-brain nexus using peptides identified by phage display.

Drug delivery to the central nervous system requires the use of specific portals to enable drug entry into the brain and, as such, there is a growing need to identify processes that can enable drug transfer across both blood-brain and blood-cerebrospinal fluid barriers. Phage display is a powerful combinatorial technique that identifies specific peptides that can confer new activities to inactive particles. Identification of these peptides is directly dependent on the specific screening strategies used for their selection and retrieval. This chapter describes three selection strategies, which can be used to identify peptides that target the choroid plexus (CP) directly or for drug translocation across the CP and into cerebrospinal fluid

Frequent Infection of Cerebellar Granule Cell Neurons by Polyomavirus JC in Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) occurs most often in immunosuppressed individuals. The lesions of PML result from astrocyte and oligodendrocyte infection by the polyomavirus JC (JCV); JCV has also been shown to infect and destroy cerebellar granule cell neurons (GCNs) in 2 HIV-positive patients. To determine the prevalence and pattern of JCV infection in GCNs we immunostained formalin-fixed, paraffin-embedded cerebellar samples from 40 HIV-positive and 3 HIV-negative PML patients for JCV, glial and neuronal markers. JCV infection was detected in 30 patients (70%); 28 (93%) of these had JCV-infected cells in the granule cell layer (GCL); JCV-infected GCNs were demonstrated in 15/19 (79%) tested cases. JCV regulatory T antigen (T Ag) was expressed more frequently and abundantly in GCNs than JCV VP1 capsid protein. None of 37 HIV-negative controls but 1/35 (3%) HIV-positive subjects without PML had distinct foci of JCV-infected GCNs. Thus, JCV infection of GCNs is frequent in PML patients and may occur in the absence of cerebellar white matter demyelinating lesions. The predominance of T Ag over VP1 expression in GCNs suggests that they may be the site of early or latent central nervous system JCV infection. These results indicate that infection of GCNs is an important, previously overlooked aspect of JCV pathogenesis in immunosuppressed individuals

Targeting choroid plexus epithelia and ventricular ependyma for drug delivery to the central nervous system

Background: Because the choroid plexus (CP) is uniquely suited to control the composition of cerebrospinal fluid (CSF), there may be therapeutic benefits to increasing the levels of biologically active proteins in CSF to modulate central nervous system (CNS) functions. To this end, we sought to identify peptides capable of ligand-mediated targeting to CP epithelial cells reasoning that they could be exploited to deliver drugs, biotherapeutics and genes to the CNS.Methods: A peptide library displayed on M13 bacteriophage was screened for ligands capable of internalizing into CP epithelial cells by incubating phage with CP explants for 2 hours at 37C and recovering particles with targeting capacity.Results: Three peptides, identified after four rounds of screening, were analyzed for specific and dose dependant binding and internalization. Binding was deemed specific because internalization was prevented by co-incubation with cognate synthetic peptides. Furthermore, after i.c.v. injection into rat brains, each peptide was found to target phage to epithelial cells in CP and to ependyma lining the ventricles.Conclusion: These data demonstrate that ligand-mediated targeting can be used as a strategy for drug delivery to the central nervous system and opens the possibility of using the choroid plexus as a portal of entry into the brain