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This study examines the sex-specific effects of gestational exposure (days 6–21) to endocrine-disrupting chemicals such as bisphenol A (BPA), diethylhexyl phthalate (DEHP), or their combination on brain monoamine levels that play an important role in regulating behavior. Pregnant Sprague–Dawley rats were orally administered saline, low doses (5 µg/kg BW/day) of BPA or DEHP, and their combination or a high dose (7.5 mg/kg BW/day) of DEHP alone or in combination with BPA during pregnancy. The offspring were subjected to a behavioral test and sacrificed in adulthood, and the brains were analyzed for neurotransmitter levels. In the paraventricular nucleus, there was a marked reduction in dopamine levels (p < 0.01) in male offspring from the BPA, DEHP, and B + D (HD) groups, which correlated well with their shock probe defensive burying times. Neurotransmitter changes in all brain regions examined were significant in female offspring, with DEHP (HD) females being affected the most, followed by the B + D groups. BPA and/or DEHP (LD) increased monoamine turnover in a region-specific manner in male offspring (p < 0.05). Overall, prenatal exposure to BPA, DEHP, or their combination alters monoamine levels in a brain region-specific, sex-specific, and dose-dependent manner, which could have implications for their behavioral and neuroendocrine effects.

Telehealth presents both the potential to improve access to care and to widen the digital divide contributing to health care disparities and obliging health care systems to standardize approaches to measure and display telehealth disparities. Based on a literature review and the operational experience of clinicians, informaticists, and researchers in the Supporting Pediatric Research on Outcomes and Utilization of Telehealth (SPROUT)–Clinical and Translational Science Awards (CTSA) Network, we outline a strategic framework for health systems to develop and optimally use a telehealth equity dashboard through a 3-phased approach of (1) defining data sources and key equity-related metrics of interest; (2) designing a dynamic and user-friendly dashboard; and (3) deploying the dashboard to maximize engagement among clinical staff, investigators, and administrators.

Characterized by positive symptoms (such as changes in behavior or thoughts, including delusions and hallucinations), negative symptoms (such as apathy, anhedonia, and social withdrawal), and cognitive impairments, schizophrenia is a chronic, severe, and disabling mental disorder with late adolescence or early adulthood onset. Antipsychotics are the most commonly used drugs to treat schizophrenia, but those currently in use do not fully reverse all three types of symptoms characterizing this condition. Schizophrenia is frequently misdiagnosed, resulting in a delay of or inappropriate treatment. Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of schizophrenia. The recent studies reviewed included microRNA profiling in blood- and urine-based materials and nervous tissue materials. From the studies that had validated the preliminary findings, potential candidate biomarkers for schizophrenia in adults could be miR-22-3p, -30e-5p, -92a-3p, -148b-5p, -181a-3p, -181a-5p, -181b-5p, -199b-5p, -137 in whole blood, and miR-130b, -193a-3p in blood plasma. Antipsychotic treatment of schizophrenia patients was found to modulate the expression of certain microRNAs including miR-130b, -193a-3p, -132, -195, -30e, -432 in blood plasma. Further studies are warranted with adolescents and young adults having schizophrenia and consideration should be given to using animal models of the disorder to investigate the effect of suppressing or overexpressing specific microRNAs.

Abstract Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy.

Inappropriate levels of hyperactivity, impulsivity, and inattention characterize attention deficit hyperactivity disorder, a common childhood-onset neuropsychiatric disorder. The cognitive function and learning ability of children with attention deficit hyperactivity disorder are affected, and these symptoms may persist to adulthood if they are not treated. The diagnosis of attention deficit hyperactivity disorder is only based on symptoms and objective tests for attention deficit hyperactivity disorder are missing. Treatments for attention deficit hyperactivity disorder in children include medications, behavior therapy, counseling, and education services which can relieve many of the symptoms of attention deficit hyperactivity disorder but cannot cure it. There is a need for a molecular biomarker to distinguish attention deficit hyperactivity disorder from healthy subjects and other neurological conditions, which would allow for an earlier and more accurate diagnosis and appropriate treatment to be initiated. Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of attention deficit hyperactivity disorder. The recent studies reviewed had performed microRNA profiling in whole blood, white blood cells, blood plasma, and blood serum of children with attention deficit hyperactivity disorder. A large number of microRNAs were dysregulated when compared to healthy controls and with some overlap between individual studies. From the studies that had included a validation set of patients and controls, potential candidate biomarkers for attention deficit hyperactivity disorder in children could be miR-140-3p, let-7g-5p, -30e-5p, -223-3p, -142-5p, -486-5p, -151a-3p, -151a-5p, and -126-5p in total white blood cells, and miR-4516, -6090, -4763-3p, -4281, -4466, -101-3p, -130a-3p, -138-5p, -195-5p, and -106b-5p in blood serum. Further studies are warranted with children and adults with attention deficit hyperactivity disorder, and consideration should be given to utilizing rat models of attention deficit hyperactivity disorder. Animal studies could be used to confirm microRNA findings in human patients and to test the effects of targeting specific microRNAs on disease progression and behavior.

Knowledge of the mechanical properties of brain tissue in vivo is essential to understanding the mechanisms underlying traumatic brain injury (TBI) and to creating accurate computational models of TBI and neurosurgical simulation. Brain white matter, which is composed of aligned, myelinated, axonal fibers, is structurally anisotropic. White matter in vivo also exhibits mechanical anisotropy, as measured by magnetic resonance elastography (MRE), but measurements of anisotropy obtained by mechanical testing of white matter ex vivo have been inconsistent. The minipig has a gyrencephalic brain with similar white matter and gray matter proportions to humans and therefore provides a relevant model for human brain mechanics. In this study, we compare estimates of anisotropic mechanical properties of the minipig brain obtained by identical, non-invasive methods in the live (in vivo) and dead animals (in situ). To do so, we combine wave displacement fields from MRE and fiber directions derived from diffusion tensor imaging (DTI) with a finite element-based, transversely-isotropic nonlinear inversion (TI-NLI) algorithm. Maps of anisotropic mechanical properties in the minipig brain were generated for each animal alive and at specific times post-mortem. These maps show that white matter is stiffer, more dissipative, and more anisotropic than gray matter when the minipig is alive, but that these differences largely disappear post-mortem, with the exception of tensile anisotropy. Overall, brain tissue becomes stiffer, less dissipative, and less mechanically anisotropic post-mortem. These findings emphasize the importance of testing brain tissue properties in vivo. Statement of Significance: In this study, MRE and DTI in the minipig were combined to estimate, for the first time, anisotropic mechanical properties in the living brain and in the same brain after death. Significant differences were observed in the anisotropic behavior of brain tissue post-mortem. These results demonstrate the importance of measuring brain tissue properties in vivo as well as ex vivo, and provide new quantitative data for the development of computational models of brain biomechanics.

Abstract Cortical folding is an important process during brain development, and aberrant folding is linked to disorders such as autism and schizophrenia. Changes in cell numbers, size, and morphology have been proposed to exert forces that control the folding process, but these changes may also influence the mechanical properties of developing brain tissue. Currently, the changes in tissue stiffness during brain folding are unknown. Here, we report stiffness in the developing ferret brain across multiple length scales, emphasizing changes in folding cortical tissue. Using rheometry to measure the bulk properties of brain tissue, we found that overall brain stiffness increases with age over the period of cortical folding. Using atomic force microscopy to target the cortical plate, we found that the occipital cortex increases in stiffness as well as stiffness heterogeneity over the course of development and folding. These findings can help to elucidate the mechanics of the cortical folding process by clarifying the concurrent evolution of tissue properties.

The question posed in the title serves as a springboard to examine the interdisciplinary nature of cognitive science and the role philosophy should play. I will argue that philosophy has a clearly defined role to play over and above the contributions made by philosophies specific to the various disciplines engaged in cognitive science. I also point out that by engaging with cognitive science – an endeavor defined by a clear scientific goal – philosophy itself will have to change in ways that are bound to affect the future of philosophizing. In the first part of this paper, I play devil’s advocate, arguing that philosophy should not be amongst the disciplines engaged in cognitive science. In the second part, I discuss how the relationship between philosophy and psychology has been changed by their common participation in cognitive science: psychology is now admittedly philosophical and philosophy has become naturalized. In the third part, I suggest that philosophy is better equipped than psychology to handle the thorny question of representation in cognitive science. In the fourth part and conclusion, I argue that cognitive science will influence both the theory and practice of philosophy: the futures of cognitive science and philosophy are tied together.

Background: Prenatal exposures to endocrine disrupting chemicals (EDCs) are correlated with adverse behavioral outcomes, but the effects of combinations of these chemicals are unclear. The aim of this study was to determine the dose-dependent effects of prenatal exposure to EDCs on male and female behavior.Methods: Pregnant Sprague-Dawley rats were orally dosed with vehicle, bisphenol A (BPA) (5 μg/kg body weight (BW)/day), low-dose (LD) diethylhexyl phthalate (DEHP) (5 μg/kg BW/day), high-dose (HD) DEHP (7.5 mg/kg BW/day), a combination of BPA and LD-DEHP (B + D (LD)), or a combination of BPA and HD-DEHP (B + D (HD)) on gestational days 6–21. Adult offspring were subjected to the Open Field Test (OFT), Elevated Plus Maze (EPM), and Shock Probe Defensive Burying test (SPDB) in adulthood. Body, adrenal gland, and pituitary gland weights were collected at sacrifice. Corticosterone (CORT) was measured in the serum.Results: Female EDC-exposed offspring showed anxiolytic effects in the OFT, while male offspring were unaffected. DEHP (HD) male offspring demonstrated a feminization of behavior in the EPM. Most EDC-exposed male offspring buried less in the SPDB, while their female counterparts showed reduced shock reactivity, indicating sex-specific maladaptive alterations in defensive behaviors. Additionally, DEHP (LD) males and females and B + D (LD) females displayed increased immobility in this test. DEHP (LD) alone and in combination with BPA led to lower adrenal gland weights, but only in male offspring. Finally, females treated with a mixture of B + D (HD) had elevated CORT levels.Conclusion: Prenatal exposure to BPA, DEHP, or a mixture of the two, affects behavior, CORT levels, and adrenal gland weights in a sex- and dose-dependent manner.

Temporal lobe epilepsy is the most common form of focal epilepsy in adults, accounting for one third of all diagnosed epileptic patients, with seizures originating from or involving mesial temporal structures such as the hippocampus, and many of these patients being refractory to treatment with anti-epileptic drugs. Temporal lobe epilepsy is the most common childhood neurological disorder and, compared with adults, the symptoms are greatly affected by age and brain development. Diagnosis of temporal lobe epilepsy relies on clinical examination, patient history, electroencephalographic recordings, and brain imaging. Misdiagnosis or delay in diagnosis is common. A molecular biomarker that could distinguish epilepsy from healthy subjects and other neurological conditions would allow for an earlier and more accurate diagnosis and appropriate treatment to be initiated. Among possible biomarkers of pathological changes as well as potential therapeutic targets in the epileptic brain are microRNAs. Most of the recent studies had performed microRNA profiling in body fluids such as blood plasma and blood serum and brain tissues such as temporal cortex tissue and hippocampal tissue. A large number of microRNAs were dysregulated when compared to healthy controls and with some overlap between individual studies that could serve as potential biomarkers. For example, in adults with temporal lobe epilepsy, possible biomarkers are miR-199a-3p in blood plasma and miR-142-5p in blood plasma and blood serum. In adults with mesial temporal lobe epilepsy, possible biomarkers are miR-153 in blood plasma and miR-145-3p in blood serum. However, in many of the studies involving patients who receive one or several anti-epileptic drugs, the influence of these on microRNA expression in body fluids and brain tissues is largely unknown. Further studies are warranted with children with temporal lobe epilepsy and consideration should be given to utilizing mouse or rat and non-human primate models of temporal lobe epilepsy. The animal models could be used to confirm microRNA findings in human patients and to test the effects of targeting specific microRNAs on disease progression and behavior.

Abstract Background/Objective To compare functional hearing and tinnitus outcomes in treated large (~ 3 cm) vestibular schwannoma (VS) and posterior fossa meningioma cohorts, and construct willingness‐to‐accept profiles for an experimental brain implant to treat unilateral hearing loss. Methods A two‐way MANOVA model with two independent variables (tumor type; time from treatment) and three dependent variables (hearing effort of tumor ear; abbreviated Speech, Spatial, and Qualities of Hearing scale (SSQ12); Tinnitus Functional Index (TFI)) was used to analyze data from VS (N = 32) and meningioma (N = 50) patients who were treated at a tertiary care center between 2010 and 2020. A query to probe acceptance of experimental treatment for hearing loss relative to expected benefit was used to construct willingness‐to‐accept profiles. Results Tumor type was statistically significant on the combined dependent variables analysis (F[3, 76] = 19.172, p 2 years) (p ≤ .017). At the 60% speech understanding level, 77% of respondents would accept an experimental brain implant. Conclusion Hearing outcome is better for posterior fossa meningioma compared to VS. Most patients with hearing loss in the tumor ear would consider a brain implant if the benefit level would be comparable to a cochlear implant. Level of Evidence 2

Objective: Our goal is to investigate if microbiota composition modulates reward signaling and assess the role of the vagus in mediating microbiota to brain communication. Methods: Male germ-free Fisher rats were colonized with gastrointestinal contents from chow (low fat (LF) ConvLF) or HF (ConvHF) fed rats. Results: Following colonization, ConvHF rats consumed significantly more food than ConvLF animals. ConvHF rats displayed lower feeding-induced extracellular DOPAC levels (a metabolite of dopamine) in the Nucleus Accumbens (NAc) as well as reduced motivation for HF foods compared to ConvLF rats. Dopamine receptor 2 (DDR2) expression levels in the NAc were also significantly lower in ConvHF animals. Similar deficits were observed in conventionally raised HF fed rats, showing that diet-driven alteration in reward can be initiated via microbiota. Selective gut to brain deafferentation restored DOPAC levels, DRD2 expression, and motivational drive in ConvHF rats. Conclusions: We concluded from these data that a HF-type microbiota is sufficient to alter appetitive feeding behavior and that bacteria to reward communication is mediated by the vagus nerve.

Efficient removal of apoptotic cells by phagocytosis underlies tissue development, wound repair, host defense and organ homeostasis. Here, authors identify TRPM7 as a regulator of cargo acidification and Ca2+ signaling during apoptotic cell clearance.

Measurement(s) scientific literature on natural glycans Technology Type(s) annotation of publications Sample Characteristic - Organism Bacteria • Archaea • Viridiplantae • Fungi

Abstract Background 5-Hydroxytryptamine (5-HT) receptors 1B, 1D and 1F have key roles in migraine pharmacotherapy. Selective agonists targeting these receptors, such as triptans and ditans, are effective in aborting acute migraine attacks and inhibit the in vivo release of calcitonin gene-related peptide (CGRP) in human and animal models. The study aimed to examine the localization, genetic expression and functional aspects of 5- HT1B/1D/1F receptors in the trigeminal system in order to further understand the molecular sites of action of triptans (5-HT1B/1D) and ditans (5-HT1F). Methods Utilizing immunohistochemistry, the localization of 5-HT and of 5-HT1B/1D/1F receptors was examined in rat trigeminal ganglion (TG) and combined with quantitative polymerase chain reaction to quantify the level of expression for 5-HT1B/1D/1F receptors in the TG. The functional role of these receptors was examined ex vivo with a capsaicin/potassium induced 5-HT and CGRP release. Results 5-HT immunoreactivity (ir) was observed in a minority of CGRP negative C-fibres, most neuron somas and faintly in A-fibres and Schwann cell neurolemma. 5-HT1B/1D receptors were expressed in the TG, while the 5-HT1F receptor displayed a weak ir. The 5-HT1D receptor co-localized with receptor activity-modifying protein 1 (RAMP1) in Aδ-fibres in the TG, while 5-HT1B-ir was weakly expressed and 5-HT1F-ir was not detected in these fibres. None of the 5-HT1 receptors co-localized with CGRP-ir in C-fibres. 5-HT1D receptor mRNA was the most prominently expressed, followed by the 5-HT1B receptor and lastly the 5-HT1F receptor. The 5-HT1B and 5-HT1D receptor antagonist, GR127935, could reverse the inhibitory effect of Lasmiditan (a selective 5-HT1F receptor agonist) on CGRP release in the soma-rich TG but not in soma-poor TG or dura mater. 5-HT release in the soma-rich TG, and 5-HT content in the baseline samples, negatively correlated with CGRP levels, showing for the first time a physiological role for 5-HT induced inhibition. Conclusion This study reveals the presence of a subgroup of C-fibres that store 5-HT. The data shows high expression of 5-HT1B/1D receptors and suggests that the 5-HT1F receptor is a relatively unlikely target in the rat TG. Furthermore, Lasmiditan works as a partial agonist on 5-HT1B/1D receptors in clinically relevant dose regiments.

Abstract Background Based on the current understanding of the role of neuropeptide signalling in migraine, we explored the therapeutic potential of a specific cannabinoid agonist. The aim of the present study was to examine the effect of the synthetic endocannabinoid (eCB) analogue, arachidonyl-2′-chloroethylamide (ACEA), on calcitonin gene-related peptide (CGRP) release in the dura and trigeminal ganglion (TG), as cannabinoids are known to activate Gi/o-coupled cannabinoid receptors type 1 (CB1), resulting in neuronal inhibition. Methods The experiments were performed using the hemi-skull model and dissected TGs from male Sprague-Dawley rats. CGRP release was induced by either 60 mM K+ (for depolarization-induced stimulation) or 100 nM capsaicin (for transient receptor potential vanilloid 1 (TRPV1) -induced stimulation) and measured using an enzyme-linked immunosorbent assay. The analysis of CGRP release data was combined with immunohistochemistry in order to study the cellular localization of CB1, cannabinoid receptor type 2 (CB2), CGRP and receptor activity modifying protein 1 (RAMP1), a subunit of the functional CGRP receptor, in the TG. Results CB1 was predominantly expressed in neuronal somas in which colocalization with CGRP was observed. Furthermore, CB1 exhibited colocalization with RAMP1 in neuronal Aδ-fibres but was not clearly expressed in the CGRP-immunoreactive C-fibres. CB2 was mainly expressed in satellite glial cells and did not show substantial colocalization with either CGRP or RAMP1. Without stimulation, 140 nM ACEA per se caused a significant increase in CGRP release in the dura but not TG, compared to vehicle. Furthermore, 140 nM ACEA did not significantly modify neither K+- nor capsaicin-induced CGRP release. However, when the TRPV1 blocker AMG9810 (1 mM) was coapplied with ACEA, K+-induced CGRP release was significantly attenuated in the TG and dura. Conclusions Results from the present study indicate that ACEA per se does not exhibit antimigraine potential due to its dual agonistic properties, resulting in activation of both CB1 and TRPV1, and thereby inhibition and stimulation of CGRP release, respectively.

Glaucoma is a neurodegenerative disease in which optic nerve damage and visual field defects occur. It is a leading cause of irreversible blindness. Its pathogenesis is largely unknown although several risk factors have been identified, with an increase in intraocular pressure being the main one. Lowering of intraocular pressure is the only treatment available. Open-angle glaucoma is the most common form of the condition, accounting for ~90% of all cases of glaucoma, with primary open-angle glaucoma and exfoliation glaucoma being the most frequent types. There are strong indications that microRNAs play important roles in the pathogenesis of primary open-angle glaucoma. Most of the recent studies reviewed had performed microRNA profiling in aqueous humor from glaucoma patients compared to controls who were chiefly cataract patients. A very large number of microRNAs were dysregulated but with limited overlap between individual studies. MiRNAs in aqueous humor that could be possible targets for therapeutic intervention are miR-143-3p, miR-125b-5p, and miR-1260b. No overlap of findings occurred within the dysregulated miRNAs for blood plasma, blood serum, peripheral blood mononuclear cells, and tears of primary open-angle glaucoma patients. Several important limitations were identified in these studies. Further studies are warranted of microRNA expression in aqueous humor and blood samples of primary open-angle glaucoma patients in the early stages of the disease so that validated biomarkers can be identified and treatment initiated. In addition, whether modifying the levels of specific microRNAs in aqueous humor or tears has a beneficial effect on intraocular pressure and ophthalmic examination of the eyes should be investigated using suitable animal models of glaucoma.

A review of recent animal models of amyotrophic lateral sclerosis showed a large number of miRNAs had altered levels of expression in the brain and spinal cord, motor neurons of spinal cord and brainstem, and hypoglossal, facial, and red motor nuclei and were mostly upregulated. Among the miRNAs found to be upregulated in two of the studies were miR-21, miR-155, miR-125b, miR-146a, miR-124, miR-9, and miR-19b, while those downregulated in two of the studies included miR-146a, miR-29, miR-9, and miR-125b. A change of direction in miRNA expression occurred in some tissues when compared (e.g., miR-29b-3p in cerebellum and spinal cord of wobbler mice at 40 days), or at different disease stages (e.g., miR-200a in spinal cord of SOD1(G93A) mice at 95 days vs. 108 and 112 days). In the animal models, suppression of miR-129-5p resulted in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and tended to improve motor neuron survival in the SOD1(G93A) mouse model. Suppression of miR-155 was also associated with increased lifespan, while lowering of miR-29a tended to improve lifespan in males and increase muscle strength in SOD1(G93A) mice. Overexpression of members of miR-17~92 cluster improved motor neuron survival in SOD1(G93A) mice. Treatment with an artificial miRNA designed to target hSOD1 increased lifespan and improved muscle strength in SOD1(G93A) animals. Further studies with animal models of amyotrophic lateral sclerosis are warranted to validate these findings and identify specific miRNAs whose suppression or directed against hSOD1 results in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and improved motor neuron survival in SOD1(G93A) animals.

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes. Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia. Frontotemporal dementia is characterized by progressive impairments in behavior, executive function, and language. There are two main clinical subtypes: behavioral-variant frontotemporal dementia and primary progressive aphasia. The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients. Without validated biomarkers, the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features, but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders. In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies. Measurement of specific miRNAs singly or in combination, or as miRNA pairs (as a ratio) in blood plasma, serum, or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls, Alzheimer’s disease, and amyotrophic lateral sclerosis. Furthermore, upregulation of miR-223-3p and downregulation of miR-15a-5p, which occurred both in blood serum and cerebrospinal fluid, distinguished behavioral-variant frontotemporal dementia from healthy controls. Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia, respectively, from healthy controls. Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p, miR-15a-5p, miR-22-3p in blood serum and cerebrospinal fluid, and miR-124 in cerebrospinal fluid. No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes. Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.

The incidence of neurodegenerative diseases is increasing due to changing age demographics and the incidence of sports-related traumatic brain injury is tending to increase over time. Currently approved medicines for neurodegenerative diseases only temporarily reduce the symptoms but cannot cure or delay disease progression. Cell transplantation strategies offer an alternative approach to facilitating central nervous system repair, but efficacy is limited by low in vivo survival rates of cells that are injected in suspension. Transplanting cells that are attached to or encapsulated within a suitable biomaterial construct has the advantage of enhancing cell survival in vivo. A variety of biomaterials have been used to make constructs in different types that included nanoparticles, nanotubes, microspheres, microscale fibrous scaffolds, as well as scaffolds made of gels and in the form of micro-columns. Among these, Tween 80-methoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid) nanoparticles loaded with rhynchophylline had higher transport across a blood-brain barrier model and decreased cell death in an in vitro model of Alzheimer’s disease than rhynchophylline or untreated nanoparticles with rhynchophylline. In an in vitro model of Parkinson’s disease, trans-activating transcriptor bioconjugated with zwitterionic polymer poly(2-methacryoyloxyethyl phosphorylcholine) and protein-based nanoparticles loaded with non-Fe hemin had a similar protective ability as free non-Fe hemin. A positive effect on neuron survival in several in vivo models of Parkinson’s disease was associated with the use of biomaterial constructs such as trans-activating transcriptor bioconjugated with zwitterionic polymer poly(2-methacryoyloxyethyl phosphorylcholine) and protein-based nanoparticles loaded with non-Fe hemin, carbon nanotubes with olfactory bulb stem cells, poly(lactic-co-glycolic acid) microspheres with attached DI-MIAMI cells, ventral midbrain neurons mixed with short fibers of poly-(L-lactic acid) scaffolds and reacted with xyloglucan with/without glial-derived neurotrophic factor, ventral midbrain neurons mixed with Fmoc-DIKVAV hydrogel with/without glial-derived neurotrophic factor. Further studies with in vivo models of Alzheimer’s disease and Parkinson’s disease are warranted especially using transplantation of cells in agarose micro-columns with an inner lumen filled with an appropriate extracellular matrix material.

In this paper, we present the results of a systematic statistical analysis of the fungal glycome in comparison with the prokaryotic and protistal glycomes as described in the scientific literature and presented in the Carbohydrate Structure Database (CSDB). The monomeric and dimeric compositions of glycans, their non-carbohydrate modifications, glycosidic linkages, sizes of structures, branching degree and net charge are assessed. The obtained information can help elucidating carbohydrate molecular markers for various fungal classes which, in its turn, can be demanded for the development of diagnostic tools and carbohydrate-based vaccines against pathogenic fungi. It can also be useful for revealing specific glycosyltransferases active in a particular fungal species.

BackgroundMigraine is a widespread and prevalent disease with a complex pathophysiology, of which neuroinflammation and increased pain sensitivity have been suggested to be involved. Various studies have investigated the presence of different inflammatory markers in migraineurs and investigated the role of inflammation in inflammatory models with complete Freund's adjuvant (CFA) or inflammatory soup added to the dura mater.ObjectiveThe aim of the current study was to examine whether application of CFA to the dura mater would cause behavioral alterations that are migraine relevant. In addition, we investigated the potential mitigating effects of fremanezumab, a CGRP (calcitonin gene-related peptide) specific antibody, following CFA application.MethodsMale Sprague-Dawley rats were randomly divided into six groups: fresh (n = 7), fresh + carprofen (n = 6), fresh + anti-CGRP (n = 6), sham (n = 7), CFA (n = 16), CFA + anti-CGRP (n = 8). CFA was applied for 15 min on a 3 × 3 mm clearing of the skull exposing the dura mater of male Sprague-Dawley rats. We applied the Light/Dark box and Open Field test, combined with the electronic von Frey test to evaluate outcomes. Finally, we observed CGRP immunoreactivity in the trigeminal ganglion.ResultsNo differences were observed in the Light/Dark box test. The Open Field test detected behavior differences, notably that sham rats spend less time in the central zone, reared less and groomed more than fresh + carprofen rats. The other groups were not significantly different compared to sham rats, indicating that activation of the TGVS is present in sham surgery and cannot be exacerbated by CFA. However, for the allodynia, we observed specific periorbital sensitization, not observed in the sham animals. This could not be mitigated by fremanezumab, although it clearly reduced the amount of CGRP positive fibers.ConclusionCFA surgically administered to the dura causes periorbital allodynia and increases CGRP positive fibers in the trigeminal ganglion. Fremanezumab does not reduce periorbital allodynia even though it reduces CGRP positive fibers in the TG. Further work is needed to investigate whether CFA administered to the dura could be used as a non-CGRP inflammatory migraine model.

The importance of the brain, its location inside the skull, and its soft, delicate, nature pose multiple practical challenges to studying brain mechanics. These challenges have elevated the role of theoretical models and computational studies of brain mechanics for understanding TBI and developing countermeasures, to gain insight into cortical folding and misfolding, and to improve the precision of brain surgery. Ultimately, experimental measurements remain necessary to build accurate computational models and to evaluate these models objectively, so that these models may be used with confidence to inform scientists and clinicians concerned with TBI, brain development, and neurosurgery. This perspective reviews recent progress, unresolved questions, and future challenges in using experimental data to improve computer models of brain mechanics. Statement of significance: Computational models of brain mechanics will play important roles in preventing traumatic brain injury, understanding brain development, and improving brain surgery. Comprehensive experimental measurements remain necessary to build accurate computational models and to evaluate these models objectively. The fragility of the brain and its fundamental importance complicate the questions of what measurements can be made, and how to interpret them. This perspective reviews recent progress, unresolved questions, and future challenges in using experimental data to improve computer models of brain mechanics.

The majority of human brain folding occurs during the third trimester of gestation. Although many studies have investigated the physical mechanisms of brain folding, a comprehensive understanding of this complex process has not yet been achieved. In mechanical terms, the “differential growth hypothesis” suggests that the formation of folds results from a difference in expansion rates between cortical and subcortical layers, which eventually leads to mechanical instability akin to buckling. It has also been observed that axons, a substantial component of subcortical tissue, can elongate or shrink under tensile or compressive stress, respectively. Previous work has proposed that this cell-scale behavior in aggregate can produce stress-dependent growth in the subcortical layers. The current study investigates the potential role of stress-dependent growth on cortical surface morphology, in particular the variations in folding direction and curvature over the course of development. Evolution of sulcal direction and mid-cortical surface curvature were calculated from finite element simulations of three-dimensional folding in four different initial geometries: (i) sphere; (ii) axisymmetric oblate spheroid; (iii) axisymmetric prolate spheroid; and (iv) triaxial spheroid. The results were compared to mid-cortical surface reconstructions from four preterm human infants, imaged and analyzed at four time points during the period of brain folding. Results indicate that models incorporating subcortical stress-dependent growth predict folding patterns that more closely resemble those in the developing human brain. Statement of Significance: Cortical folding is a critical process in human brain development. Aberrant folding is associated with disorders such as autism and schizophrenia, yet our understanding of the physical mechanism of folding remains limited. Ultimately mechanical forces must shape the brain. An important question is whether mechanical forces simply deform tissue elastically, or whether stresses in the tissue modulate growth. Evidence from this paper, consisting of quantitative comparisons between patterns of folding in the developing human brain and corresponding patterns in simulations, supports a key role for stress-dependent growth in cortical folding.

Abstract The progestin-based hormonal contraceptive Depot Medroxyprogesterone Acetate (DMPA) is widely used in sub-Saharan Africa, where HIV-1 is endemic. Meta-analyses have shown that women using DMPA are 40% more likely than women not using hormonal contraceptives to acquire Human Immunodeficiency Virus (HIV-1). Therefore understanding how DMPA increases susceptibility to HIV-1 is an important public health issue. Using C57BL/6 mice and our previously optimized humanized mouse model (NOD-Rag1 tm1Mom Il2rg tm1Wjl transplanted with hCD34-enriched hematopoietic stem cells; Hu-mice) where peripheral blood and tissues are reconstituted by human immune cells, we assessed how DMPA affected mucosal barrier function, HIV-1 susceptibility, viral titres, and target cells compared to mice in the diestrus phase of the estrous cycle, when endogenous progesterone is highest. We found that DMPA enhanced FITC-dextran dye leakage from the vaginal tract into the systemic circulation, enhanced target cells (hCD68+ macrophages, hCD4+ T cells) in the vaginal tract and peripheral blood (hCD45+hCD3+hCD4+hCCR5+ T cells), increased the rate of intravaginal HIV-1 infection, extended the window of vulnerability, and lowered vaginal viral titres following infection. These findings suggest DMPA may enhance susceptibility to HIV-1 in Hu-mice by impairing the vaginal epithelial barrier, increasing vaginal target cells (including macrophages), and extending the period of time during which Hu-mice are susceptible to infection; mechanisms that might also affect HIV-1 susceptibility in women.

A review of recent animal models of Huntington’s disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex, and which were mostly downregulated. Among the altered microRNAs were miR-9/9*, miR-29b, miR-124a, miR-132, miR-128, miR-139, miR-122, miR-138, miR-23b, miR-135b, miR-181 (all downregulated) and miR-448 (upregulated), and similar changes had been previously found in Huntington’s disease patients. In the animal cell studies, the altered microRNAs included miR-9, miR-9*, miR-135b, miR-222 (all downregulated) and miR-214 (upregulated). In the animal models, overexpression of miR-155 and miR-196a caused a decrease in mutant huntingtin mRNA and protein level, lowered the mutant huntingtin aggregates in striatum and cortex, and improved performance in behavioral tests. Improved performance in behavioral tests also occurred with overexpression of miR-132 and miR-124. In the animal cell models, overexpression of miR-22 increased the viability of rat primary cortical and striatal neurons infected with mutant huntingtin and decreased huntingtin -enriched foci of ≥ 2 µm. Also, overexpression of miR-22 enhanced the survival of rat primary striatal neurons treated with 3-nitropropionic acid. Exogenous expression of miR-214, miR-146a, miR-150, and miR-125b decreased endogenous expression of huntingtin mRNA and protein in HdhQ111/HdhQ111 cells. Further studies with animal models of Huntington’s disease are warranted to validate these findings and identify specific microRNAs whose overexpression inhibits the production of mutant huntingtin protein and other harmful processes and may provide a more effective means of treating Huntington’s disease in patients and slowing its progression.

Choroidal neovascularization characterizes wet age-related macular degeneration. Choroidal neovascularization formation involves a primarily angiogenic process that is combined with both inflammation and proteolysis. A primary cause of choroidal neovascularization pathogenesis is alterations in pro- and anti-angiogenic factors derived from the retinal pigment epithelium, with vascular endothelium growth factor being mainly responsible for both clinical and experimental choroidal neovascularization. MicroRNAs (miRNAs) which are short, non-coding, endogenous RNA molecules have a major role in regulating various pathological processes, including inflammation and angiogenesis. A review of recent studies with the mouse laser-induced choroidal neovascularization model has shown alterations in miRNA expression in choroidal neovascularization tissues and could be potential therapeutic targets for wet age-related macular degeneration. Upregulation of miR-505 (days 1 and 3 post-laser), miR-155 (day 14) occurred in retina; miR-342-5p (days 3 and 7), miR-126-3p (day 14) in choroid; miR-23a, miR-24, miR-27a (day 7) in retina/choroid; miR-505 (days 1 and 3) in retinal pigment epithelium/choroid; downregulation of miR-155 (days 1 and 3), miR-29a, miR-29b, miR-29c (day 5), miR-93 (day 14), miR-126 (day 14) occurred in retinal pigment epithelium/choroid. Therapies using miRNA mimics or inhibitors were found to decrease choroidal neovascularization lesions. Choroidal neovascularization development was reduced by overexpression of miR-155, miR-188-5p, miR-(5,B,7), miR-126-3p, miR-342-5p, miR-93, miR-126, miR-195a-3p, miR-24, miR-21, miR-31, miR-150, and miR-184, or suppression of miR-505, miR-126-3p, miR-155, and miR-23/27. Further studies are warranted to determine miRNA expression in mouse laser-induced choroidal neovascularization models in order to validate and extend the reported findings. Important experimental variables need to be standardized; these include the strain and age of animals, gender, number and position of laser burns to the eye, laser parameters to induce choroidal neovascularization lesions including wavelength, power, spot size, and duration.

A main cause of vision loss in the elderly is age-related macular degeneration (AMD). Among the cellular, biochemical, and molecular changes linked to this disease, inflammation and angiogenesis appear as being crucial in AMD pathogenesis and progression. There are two forms of the disease: dry AMD, accounting for 80–90% of cases, and wet AMD. The disease usually begins as dry AMD associated with retinal pigment epithelium and photoreceptor degeneration, whereas wet AMD is associated with choroidal neovascularization resulting in severe vision impairment. The new vessels are largely malformed, leading to blood and fluid leakage within the disrupted tissue, which provokes inflammation and scar formation and results in retinal damage and detachment. MicroRNAs are dysregulated in AMD and may facilitate the early detection of the disease and monitoring disease progression. Two recent reviews of microRNAs in AMD had indicated weaknesses or limitations in four earlier investigations. Studies in the last three years have shown considerable progress in overcoming some of these concerns and identifying specific microRNAs as biomarkers for AMD. Further large-scale studies are warranted using appropriate statistical methods to take into account gender and age disparity in the study populations and confounding factors such as smoking status.

En esta historia intelectual de la aparición de la estética musical global, trato del nacimiento de la estética como un campo filosófico moderno y la expansión de la historiografía musical hasta incluir el mundo entero. Estos momentos musicológicos globales son muy evidentes en los primeros escritos de Johann Gottfried Herder (1744-1803), quien canalizaría y mantendría esa confluencia a lo largo de su vasta obra publicada. El título de este artículo procede de Herder, específicamente de los volúmenes que llamó Volkslieder (Canciones populares, 1778/79), en los que conecta sus escritos fundacionales sobre estética, Kritische Wälder (Selvas críticas), con el primer concepto integral de estética musical global. La historia de la recepción de Herder es en sí un hilo conductor crítico en la historia intelectual de la estética musical que conecta el siglo XVIII con el XXI. Sigo este hilo conductor hasta el sur de Asia en el siglo XVIII a la búsqueda de una moderna estética musical hindú fundacional, particularmente en el género clásico kriti, del sur de la India, y el vasto dominio estético de la teoría de los rāga, que también dio un giro hacia lo moderno a finales del siglo XVIII. El artículo concluye volviendo al presente con ejemplos de principios estéticos de Herder aplicados a interpretaciones musicales en la actual crisis migratoria global. Es esa historia intelectual, con ejemplos del pasado y del presente, de la Ilustración en Europa y en el sur de Asia, especialmente sus dimensiones globales, la que da forma a la teoría de momentos musicológicos globales que constituye el núcleo de este artículo.

Meningiomas are heterogeneous tumours. Here, the authors analysed genetic, epigenetic, and transcriptomic features across spatially-distinct meningioma samples to identify molecular programs underlying tumorigenesis that can be detected preoperatively using magnetic resonance imaging.

Existing fingerprint-based indoor localization uses either fine-grained channel state information (CSI) from the physical layer or coarse-grained received signal strength indicator (RSSI) measurements. In this paper, we propose to use a mid-grained intermediate-level channel measurement - spatial beam signal-to-noise ratios (SNRs) that are inherently available and defined in the IEEE 802.11ad/ay standards - to construct the fingerprinting database. These intermediate channel measurements are further utilized by a deep learning approach for multiple purposes: 1) location-only classification; 2) simultaneous location-and-orientation classification; and 3) direct coordinate estimation. Furthermore, the effectiveness of the framework is thoroughly validated by an in-house experimental platform consisting of 3 access points using commercial-off-the-shelf millimeter-wave WiFi routers. The results show a 100% accuracy if the location is only interested, about 99% for simultaneous location-and-orientations classification, and an averaged root mean-square error (RMSE) of 11.1 cm and an average median error of 9.5 cm for direct coordinate estimate, greater than 2-fold improvements over the RMSE of 28.7 cm and median error of 23.6 cm for RSSI-like single SNR-based localization.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. The disability caused by inflammatory demyelination clinically dominates the early stages of relapsing-remitting MS and is reversible. Once there is considerable loss of axons, MS patients enter a secondary progressive stage. Disease-modifying drugs currently in use for MS suppress the immune system and reduce relapse rates but are not effective in the progressive stage. Various animal models of MS (mostly mouse and rat) have been established and proved useful in studying the disease process and response to therapy. The experimental autoimmune encephalomyelitis animal studies reviewed here showed that a chronic progressive disease can be induced by immunization with appropriate amounts of myelin oligodendrocyte glycoprotein together with mycobacterium tuberculosis and pertussis toxin in Freund’s adjuvant. The clinical manifestations of autoimmune encephalomyelitis disease were prevented or reduced by treatment with certain pharmacological agents given prior to, at, or after peak disease, and the agents had protective effects as shown by inhibiting demyelination and damage to neurons, axons and oligodendrocytes. In the cuprizone-induced toxicity animal studies, the pharmacological agents tested were able to promote remyelination and increase the number of oligodendrocytes when administered therapeutically or prophylactically. A monoclonal IgM antibody protected axons in the spinal cord and preserved motor function in animals inoculated with Theiler’s murine encephalomyelitis virus. In all these studies the pharmacological agents were administered singly. A combination therapy may be more effective, especially using agents that target neuroinflammation and neurodegeneration, as they may exert synergistic actions.

Multiple sclerosis is a chronic autoimmune disease of the central nervous system. It is the main cause of non-traumatic neurological disability in young adults. Multiple sclerosis mostly affects people aged 20–50 years; however, it can occur in young children and much older adults. Factors identified in the distribution of MS include age, gender, genetics, environment, and ethnic background. Multiple sclerosis is usually associated with progressive degrees of disability. The disease involves demyelination of axons of the central nervous system and causes brain and spinal cord neuronal loss and atrophy. Diagnosing multiple sclerosis is based on a patient’s medical history including symptoms, physical examination, and various tests such as magnetic resonance imaging, cerebrospinal fluid and blood tests, and electrophysiology. The disease course of multiple sclerosis is not well correlated with the biomarkers presently used in clinical practice. Blood-derived biomarkers that can detect and distinguish the different phenotypes in multiple sclerosis may be advantageous in personalized treatment with disease-modifying drugs and to predict response to treatment. The studies reviewed have shown that the expression levels of a large number of miRNAs in peripheral blood, serum, exosomes isolated from serum, and cerebrospinal fluid are altered in multiple sclerosis and can distinguish the disease phenotypes from each other. Further studies are warranted to independently validate these findings so that individual or pairs of miRNAs in serum or cerebrospinal fluid can be used as potential diagnostic markers for adult and pediatric multiple sclerosis and for monitoring disease progression and response to therapy.

Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain, spinal cord and optic nerve leading to demyelination. Focal demyelination is associated with relapsing-remitting multiple sclerosis, while progressive forms of the disease show axonal degeneration and neuronal loss. The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity. MicroRNAs (miRNAs) are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases. A review of recent studies with the experimental autoimmune encephalomyelitis animal model (mostly female mice 6–12 weeks of age) has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset (asymptomatic) stage when assessed in blood plasma and urine exosomes, and spinal cord tissue. The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes, brain and spinal cord tissue, and at the post-peak (chronic) stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue. Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease. Interestingly, experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a, miR-23b, miR-497, miR-26a, and miR-20b, or by suppression of miR-182, miR-181c, miR-223, miR-155, and miR-873. Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course. Additionally, studies should be performed with male mice of a similar age, and with aged male and female mice.

Magnetic resonance elastography (MRE) is an MRI technique for imaging the mechanical properties of brain in vivo, and has shown differences in properties between neuroanatomical regions and sensitivity to aging, neurological disorders, and normal brain function. Past MRE studies investigating these properties have typically assumed the brain is mechanically isotropic, though the aligned fibers of white matter suggest an anisotropic material model should be considered for more accurate parameter estimation. Here we used a transversely isotropic, nonlinear inversion algorithm (TI-NLI) and multi-excitation MRE to estimate the anisotropic material parameters of individual white matter tracts in healthy young adults. We found significant differences between individual tracts for three recovered anisotropic parameters: substrate shear stiffness, μ (range: 2.57 – 3.02 kPa), shear anisotropy, φ (range: -0.026 – 0.164), and tensile anisotropy, ζ (range: 0.559 – 1.049). Additionally, we demonstrated the repeatability of these parameter estimates in terms of lower variability of repeated measures in a single subject relative to variability in our sample population. Further, we observed significant differences in anisotropic mechanical properties between segments of the corpus callosum (genu, body, and splenium), which is expected based on differences in axonal microstructure. This study shows the ability of MRE with TI-NLI to estimate anisotropic mechanical properties of white matter and presents reference properties for tracts throughout the healthy brain. Statement of significance: In this study we use magnetic resonance elastography to determine the mechanical properties of white matter, which can be useful in characterizing neurological conditions such as multiple sclerosis and traumatic brain injury. However, due to its fibrous nature, accurate estimation of mechanical properties of white matter requires an anisotropic material model. In this work, we use a transversely isotropic inversion algorithm with data from multi-excitation MRE to determine the anisotropic mechanical properties of white matter in a healthy young population based upon an anisotropic material model. We display the ability of MRE to capture structural differences between different white matter tracts and sub-regions of these tracts, which are expected to reflect differences such as average axon thickness and myelin density. This robust estimation of white matter anisotropic properties in a young, healthy population provides an avenue for future studies to implement these methods to examine brain development, aging, and pathology.

We present a genome assembly from an individual female Streptopelia turtur (the European turtle dove; Chordata; Aves; Columbidae). The genome sequence is 1.18 gigabases in span. The majority of the assembly is scaffolded into 35 chromosomal pseudomolecules, with the W and Z sex chromosomes assembled.

Purpose: The incidence of brain metastases is increasing as a result of more routine diagnostic imaging and improved extracranial systemic treatment strategies. As noted in recent consensus guidelines, postoperative stereotactic radiosurgery (SRS) to the resection cavity has lower rates of local control than whole brain radiation therapy but improved cognitive outcomes. Further analyses are needed to improve local control and minimize toxicity. Methods and materials: Patients receiving SRS to a resection cavity between 2006 and 2016 were retrospectively analyzed. Presurgical variables, including tumor location, diameter, dural/meningeal contact, and histology, were collected, as were SRS treatment parameters. Patients had routine follow-up with magnetic resonance imaging, and those noted to have local failure were further assessed for the recurrence location, distance from the target volume, and dosimetric characteristics. Results: Overall, 82 patients and 85 resection cavities underwent postoperative SRS during the study period. Of these, 58 patients with 60 resection cavities with available follow-up magnetic resonance imaging scans were included in this analysis. With a median follow-up of 19.8 months, local recurrence occurred in 12 of the resection cavities for a 15% 1-year and 18% 2-year local recurrence rate. Pretreatment tumor volume contacted the dura/meninges in 100% of cavities with recurrence versus 67% of controlled cavities (P = .025). A total of 5 infield, 5 marginal, and 4 out-of-field recurrences were found, with a median distance to the centroid from the target volume of 3 mm. The addition of a 10-mm dural margin increased the target volume overlap with the recurrence contours for 10 of the 14 recurrences. Conclusions: Dural contact was associated with an increased rate of recurrence for patients who received SRS to a surgical cavity, and the median distance of marginal recurrences from the target volume was 3 mm. These results provide evidence in support of recent consensus guidelines suggesting that additional dural margin on SRS volumes may benefit local control.

Diabetes mellitus, together with its complications, has been increasing in prevalence worldwide. Its complications include cardiovascular disease (e.g., myocardial infarction, stroke), neuropathy, nephropathy, and eye complications (e.g., glaucoma, cataracts, retinopathy, and macular edema). In patients with either type 1 or type 2 diabetes mellitus, diabetic retinopathy is the leading cause of visual impairment or blindness. It is characterized by progressive changes in the retinal microvasculature. The progression from nonproliferative diabetic retinopathy to a more advanced stage of moderate to severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy occurs very quickly after diagnosis of mild nonproliferative diabetic retinopathy. The etiology of diabetic retinopathy is unclear, and present treatments have limited effectiveness. Currently diabetic retinopathy can only be diagnosed by a trained specialist, which reduces the population that can be examined. A screening biomarker of diabetic retinopathy with high sensitivity and specificity would aid considerably in identifying those individuals in need of clinical assessment and treatment. The majority of the studies reviewed identified specific microRNAs in blood serum/plasma able to distinguish diabetic patients with retinopathy from those without retinopathy and for the progresion of the disease from nonproliferative diabetic retinopathy to proliferative diabetic retinopathy. In addition, certain microRNAs in vitreous humor were dysregulated in proliferative diabetic retinopathy compared to controls. A very high percentage of patients with diabetic retinopathy develop Alzheimer’s disease. Thus, identifying diabetic retinopathy by measurement of suitable biomarkers would also enable better screening and treatment of those individuals at risk of Alzheimer’s disease.

The most common age-related neurodegenerative disease is Alzheimer’s disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation.

Alzheimer’s disease (AD) is the most common age-related, progressive neurodegenerative disease. It is characterized by memory loss and cognitive decline and responsible for most cases of dementia in the elderly. Late-onset or sporadic AD accounts for > 95% of cases, with age at onset > 65 years. Currently there are no drugs or other therapeutic agents available to prevent or delay the progression of AD. The cellular and molecular changes occurring in the brains of individuals with AD include accumulation of β-amyloid peptide and hyperphosphorylated tau protein, decrease of acetylcholine neurotransmitter, inflammation, and oxidative stress. Aggregation of β-amyloid peptide in extracellular plaques and the hyperphosphorylated tau protein in intracellular neurofibrillary tangles are characteristic of AD. A major challenge is identifying molecular biomarkers of the early-stage AD in patients as most studies have been performed with blood or brain tissue samples (postmortem) at late-stage AD. Subjects with mild cognitive impairment almost always have the neuropathologic features of AD with about 50% of mild cognitive impairment patients progressing to AD. They could provide important information about AD pathomechanism and potentially also highlight minimally or noninvasive, easy-to-access biomarkers. MicroRNAs are dysregulated in AD, and may facilitate the early detection of the disease and potentially the continual monitoring of disease progression and allow therapeutic interventions to be evaluated. Four recent reviews have been published of microRNAs in AD, each of which identified areas of weakness or limitations in the reported studies. Importantly, studies in the last three years have shown considerable progress in overcoming some of these limitations and identifying specific microRNAs as biomarkers for AD and mild cognitive impairment. Further large-scale human studies are warranted with less disparity in the study populations, and using an appropriate method to validate the findings.

Paenibacillus spp. exopolysaccharides (EPSs) have become a growing interest recently as a source of biomaterials. In this study, we characterized Paenibacillus polymyxa 2020 strain, which produces a large quantity of EPS (up to 68 g/L),and was isolated from wasp honeycombs. Here we report its complete genome sequence and full methylome analysis detected by Pacific Biosciences SMRT sequencing. Moreover, bioinformatic analysis identified a putative levan synthetic operon. SacC and sacB genes have been cloned and their products identified as glycoside hydrolase and levansucrase respectively. The Fourier transform infrared (FT-IR) and nuclear magnetic resonance (NMR) spectra demonstrated that the EPS is a linear β-(2→6)-linked fructan (levan). The structure and properties of levan polymer produced from sucrose and molasses were analyzed by FT-IR, NMR, scanning electron microscopy (SEM), high performance size exclusion chromatography (HPSEC), thermogravimetric analysis (TGA), cytotoxicity tests and showed low toxicity and high biocompatibility. Thus, P. polymyxa 2020 could be an exceptional cost-effective source for the industrial production of levan-type EPSs and to obtain functional biomaterials based on it for a broad range of applications, including bioengineering.

Advances in brain imaging and computational methods have facilitated the creation of subject-specific computational brain models that aid researchers in investigating brain trauma using simulated impacts. The emergence of magnetic resonance elastography (MRE) as a non-invasive mechanical neuroimaging tool has enabled in vivo estimation of material properties at low-strain, harmonic loading. An open question in the field has been how this data can be integrated into computational models. The goals of this study were to use a novel MRI dataset acquired in human volunteers to generate models with subject-specific anatomy and material properties, and then to compare simulated brain deformations to subject-specific brain deformation data under non-injurious loading. Models of five subjects were simulated with linear viscoelastic (LVE) material properties estimated directly from MRE data. Model predictions were compared to experimental brain deformation acquired in the same subjects using tagged MRI. Outcomes from the models matched the spatial distribution and magnitude of the measured peak strain components as well as the 95th percentile in-plane peak strains within 0.005 mm/mm and maximum principal strain within 0.012 mm/mm. Sensitivity to material heterogeneity was also investigated. Simulated brain deformations from a model with homogenous brain properties and a model with brain properties discretized with up to ten regions were very similar (a mean absolute difference less than 0.0015 mm/mm in peak strains). Incorporating material properties directly from MRE into a biofidelic subject-specific model is an important step toward future investigations of higher-order model features and simulations under more severe loading conditions. Statement of Significance: The study presents a method to calibrate and evaluate subject-specific finite element brain models using a combination of advanced magnetic resonance imaging (MRI) data. The imaging data is acquired in human volunteers and includes anatomical MRI, magnetic resonance elastography (MRE), and tagged MRI to generate subject-specific geometry, calibrate subject-specific material properties, and evaluate simulation response using subject-specific brain deformation. This dataset of MRE and tagged MRI allows for a unique evaluation of whether material properties from MRE can be used to create biofidelic computational models of the human brain. The study develops a calibration procedure to readily calculate linear viscoelastic material parameters from MRE data and then provides a sensitivity study of the effect of mechanical heterogeneity of the brain on simulation response. The calibrated computational models are used to simulate each subject's tagged MRI experiment; the results show good agreement between the simulated and experimental strain fields. The presented study and results will be informative in guiding the calibration of subject-specific computational brain model from experimental MRE data. The processed MRI, MRE, and tagged MRI data are publicly available at https://www.nitrc.org/projects/bbir/.

Herpes simplex virus-1 (HSV-1) establishes a latent infection in neurons and periodically reactivates to cause disease. The stimuli that trigger HSV-1 reactivation have not been fully elucidated. We demonstrate HSV-1 reactivation from latently infected mouse neurons induced by forskolin requires neuronal excitation. Stimuli that directly induce neurons to become hyperexcitable also induced HSV-1 reactivation. Forskolin-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and included an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1β is released under conditions of stress, fever and UV exposure of the epidermis; all known triggers of clinical HSV reactivation. We found that IL-1β induced histone phosphorylation and increased the excitation in sympathetic neurons. Importantly, IL-1β triggered HSV-1 reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV-1 co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation.

The rapid deformation of brain tissue in response to head impact can lead to traumatic brain injury. In vivo measurements of brain deformation during non-injurious head impacts are necessary to understand the underlying mechanisms of traumatic brain injury and compare to computational models of brain biomechanics. Using tagged magnetic resonance imaging (MRI), we obtained measurements of three-dimensional strain tensors that resulted from a mild head impact after neck rotation or neck extension. Measurements of maximum principal strain (MPS) peaked shortly after impact, with maximal values of 0.019–0.053 that correlated strongly with peak angular velocity. Subject-specific patterns of MPS were spatially heterogeneous and consistent across subjects for the same motion, though regions of high deformation differed between motions. The largest MPS values were seen in the cortical gray matter and cerebral white matter for neck rotation and the brainstem and cerebellum for neck extension. Axonal fiber strain (Ef) was estimated by combining the strain tensor with diffusion tensor imaging data. As with MPS, patterns of Ef varied spatially within subjects, were similar across subjects within each motion, and showed group differences between motions. Values were highest and most strongly correlated with peak angular velocity in the corpus callosum for neck rotation and in the brainstem for neck extension. The different patterns of brain deformation between head motions highlight potential areas of greater risk of injury between motions at higher loading conditions. Additionally, these experimental measurements can be directly compared to predictions of generic or subject-specific computational models of traumatic brain injury. Statement of Significance: Traumatic brain injury can result from the rapid acceleration of the skull, leading to deformation of brain tissue and elongation of axonal fibers. Because treatment options and prognostic models for patients are lacking, a better understanding of injury mechanisms is needed. Here, we use tagged magnetic resonance imaging to measure deformation throughout the live, human brain during non-injurious head accelerations. We present the first in vivo measurements of axonal stretch and compare MPS and axonal stretch experienced during neck rotation and neck extension. These results are important to elucidate brain regions at risk for injury. Additionally, they can be directly used to evaluate computational models of brain injury, which are used to predict risk of concussion during head impacts and design protective equipment.

Parkinson’s disease (PD) is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons. The cell bodies of these neurons are present in the substantia nigra, with the nerve terminals being in the striatum. Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these. Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway. Characteristic of neuroinflammation is the activation of brain glial cells, principally microglia and astrocytes that release various soluble factors. Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons. Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD. All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and, when measured, preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-hydroxydopamine, rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals. Some of these agents were shown to exert an anti-inflammatory action, decrease oxidative stress, and reduce lipid peroxidation products. Activation of microglia and astrocytes was also decreased, as well as infiltration of T cells into the substantia nigra. Pretreatment with fingolimod, tanshinoine I, dimethyl fumarate, thalidomide, or cocaine- and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals. Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk, including genetic factors.

Most of all strokes are ischemic due to occlusion of a vessel, and comprise two main types, thrombotic and embolic. Inflammation and immune response play an important role in the outcome of ischemic stroke. Pharmaceutical and cell-based therapies with immunomodulatory properties could be of benefit in treating ischemic stroke. Possible changes in microRNAs brought about by immunomodulatory treatments may be important. The pharmaceutical studies described in this review have identified several differentially regulated miRNAs associated with disregulation of mRNA targets or the upregulation of several neuroprotective genes, thereby highlighting the potential neuroprotective roles of specific miRNAs such as miR-762, -1892, -200a, -145. MiR-124, -711, -145 are the strongly associated miRNAs predicted to mediate anti-inflammatory pathways and microglia/macrophage M2-like activation phenotype. The cell-based therapy studies reviewed have mainly utilized mesenchymal stem cells or human umbilical cord blood cells and shown to improve functional and neurological outcomes in stroke animals. MiR-145 and miR-133b were implicated in nerve cell remodeling and functional recovery after stroke. Human umbilical cord blood cells decreased proinflammatory factors and promoted M2 macrophage polarization in stroke diabetic animals.