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Mashup Score: 1Multivalent Targeting of Blood-Brain Barrier LRP1 for Neurovascular Recovery Therapy for Alzheimer s Disease - 5 hour(s) ago
We have developed a new method for treating Alzheimer’s disease (AD) by targeting the LRP1 receptor at the blood-brain barrier (BBB) using a nanoscopic multivalent scaffold decorated with LRP1 targeting peptides. Our experiments on AD model mice have demonstrated that this treatment significantly reduces amyloid-β (Aβ) deposits and improves cognitive function. This study introduces a new approach to drug design that combines multivalent targeting with controlling membrane trafficking using the same tools for nanocarrier design, creating a novel therapeutic intervention. In doing so, we emphasize the crucial role that the BBB plays in AD pathogenesis, highlighting the vital importance of LRP1-mediated Aβ clearance. ### Competing Interest Statement The authors have declared no competing interest.
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Mashup Score: 0Daily Acute Intermittent Hypoxia Elicits Age & Sex-Dependent Changes in Molecules Regulating Phrenic Motor Plasticity - 5 hour(s) ago
Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (LTF). Repetitive daily AIH (dAIH) exposure enhances phrenic LTF, demonstrating a form of metaplasticity. Two additional factors impacting phrenic LTF are age and sex. For example, moderate AIH-induced phrenic LTF decreases with age in males, but increases in middle-aged females. However, little is known concerning cellular mechanisms of dAIH effects or age-dependent sexual dimorphism in phrenic LTF. Moderate AIH elicits distinct signaling cascades within phrenic motor neurons initiated by 5HT2 receptors (Q pathway) versus adenosine 2A or 5HT7 receptors (S pathway), respectively. The Q and S pathways interact via mutual crosstalk inhibition, a powerful regulator of phrenic LTF. To test the hypothesis that dAIH, age and sex effects on phrenic LTF are associated with differential expression of molecules known to regulate the Q and S pathways, we assessed mRNA of key reg
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Mashup Score: 0
The guidance cue netrin-1 promotes both growth cone attraction and growth cone repulsion. How netrin-1 elicits these diverse axonal responses, beyond engaging the attractive receptor DCC and repulsive receptors of the UNC5 family, remains elusive. Here we demonstrate that murine netrin-1 induces biphasic axonal responses in cortical neurons: attraction at lower concentrations and repulsion at higher concentrations using both a microfluidic-based netrin-1 gradient and bath application of netrin-1. TRIM9 is a brain-enriched E3 ubiquitin ligase previously shown to bind and cluster the attractive receptor DCC at the plasma membrane and regulate netrin-dependent attractive responses. However, whether TRIM9 also regulated repulsive responses to netrin-1 remained to be seen. In this study, we show that TRIM9 localizes and interacts with both the attractive netrin receptor DCC and the repulsive netrin receptor, UNC5C, and that deletion of murine Trim9 alters both attractive and repulsive respo
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Mashup Score: 4Exercising with virtual reality is potentially better for the working memory and positive mood than cycling alone - 5 hour(s) ago
Although virtual reality (VR) exercise has attracted attention as a factor in exercise habituation due to its mood-enhancing effects, its impact on brain function remains unclear. This study, involving 23 healthy university students, used functional magnetic resonance imaging (fMRI) to explore how VR exercise affects working memory, a key executive function, and its underlying neural mechanisms. Our findings indicate that a 10-min VR exercise session improved mood (arousal and vitality level) and working memory task performance (3-back task) more effectively than exercise or rest alone. Furthermore, the results confirmed that increased vitality from exercise and VR exercise interventions was associated with improved 3-back task performance. However, specific brain regions contributing to this enhancement remain unidentified. These results highlight VR exercise as the optimal exercise program for enhancing working memory function by increasing vitality level. These insights underscore V
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Mashup Score: 0
Shape features are crucial for reading. Here we investigate the effect of expertise in reading visual Braille, a script developed for touch that does not share the typical explicit shape information of other alphabets. We compared visual Braille readers and a naive control group and found that individually localized visual word form area VWFA) was selectively activated for visual Braille when compared to scrambled Braille, but only in expert Braille readers. Multivariate analyses showed that linguistic properties can be decoded from Latin in both groups and from Braille in expert readers. Yet, cross-script generalization failed to reveal common representations across Latin and Braille scripts in experts, suggesting script-specific orthographic representations. Primary visual cortex, shape-selective areas (LO), and linguistic areas (l-PosTemp) showed similar multivariate profiles to VWFA, but with cross-script generalization in left Posterior Temporal area only. We conclude that the lin
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Mashup Score: 0The Brain Computes Dynamic Facial Movements for Emotion Categorization Using a Third Pathway - 5 hour(s) ago
Recent theories suggest a new brain pathway dedicated to processing social movement is involved in understanding emotions from biological motion, beyond the well-known ventral and dorsal pathways. However, how this social pathway functions as a network that computes dynamic biological motion signals for perceptual behavior is unchartered. Here, we used a generative model of important facial movements that participants (N = 10) categorized as “happy,” “surprise,” “fear,” “anger,” “disgust,” “sad” while we recorded their MEG brain responses. Using new representational interaction measures (between facial features, MEGt source, and behavioral responses), we reveal per participant a functional social pathway extending from occipital cortex to superior temporal gyrus. Its MEG sources selectively represent, communicate and compose facial movements to disambiguate emotion categorization behavior, while occipital cortex swiftly filters out task-irrelevant identity-defining face shape features.
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Mashup Score: 1Cadherin 4 assembles a family of color-selective retinal circuits that respond to light offset. - 5 hour(s) ago
Retinal interneurons and projection neurons (retinal ganglion cells, RGCs) connect in specific combinations in a specialized neuropil called the inner plexiform layer (IPL). The IPL is divided into multiple sublaminae, with neurites of each neuronal type confined to one or a few layers. This laminar specificity is a major determinant of circuit specificity and circuit function. Using a combination of approaches we show that RGCs targeting IPL sublamina 1 and 3a express the adhesion molecule cadherin 4 (Cdh4). Using calcium imaging and iterative immunostaining, we classified Cdh4-RGCs into 9 types that each encode unique aspects of dark visual stimuli. Cdh4 loss selectively disrupted the layer-targeting of these RGCs, reduced their synaptic inputs from interneurons, and severely altered their visual responses. Overexpression of Cdh4 in other retinal neurons directed their neurites to s1-3a through homophilic interactions. Taken together, these results demonstrate that Cdh4 is a novel la
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Mashup Score: 0Resting state brain network segregation is associated with walking speed and working memory in older adults - 5 hour(s) ago
Older adults exhibit larger individual differences in walking ability and cognitive function than young adults. Characterizing intrinsic brain connectivity differences in older adults across a wide walking performance spectrum may provide insight into the mechanisms of functional decline in some older adults and resilience in others. Thus, the objectives of this study were to: (1) determine whether young adults and high- and low-functioning older adults show group differences in brain network segregation, and (2) determine whether network segregation is associated with working memory and walking function in these groups. The analysis included 21 young adults and 81 older adults. Older adults were further categorized according to their physical function using a standardized assessment; 54 older adults had low physical function while 27 were considered high functioning. Structural and functional resting state magnetic resonance images were collected using a Siemens Prisma 3T scanner. Wor
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Mashup Score: 1Hierarchical model of human brain oscillations - 5 hour(s) ago
Whole-brain computational modelling of emergent brain dynamics has become an increasingly important tool for understanding the systems-level mechanisms that govern large-scale brain activity in health and disease. Neuronal synchronization and brain criticality are key candidates of such mechanisms both for healthy cognitive functions and in constituting mechanistic biomarkers for several brain disorders. Despite significant advances, there is not an abundance of modeling approaches that yield both in-vivo-like critical synchronization dynamics and observables that directly match those obtainable with multi-modal neuroimaging. Here, we advance a framework for hierarchical Kuramoto models where the simplest two-layer model comprises a network of pairwise coupled nodes which each contain a large number of oscillators. Already at two levels of hierarchy, this enables explicit representation of local and inter-areal coupling and observations of emergent multi-scale synchronization dynamics.
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Mashup Score: 0Reorganisation of circadian activity and the pacemaker circuit under novel light regimes - 5 hour(s) ago
Many environmental features are cyclic, with predictable daily and yearly changes which vary across latitudes. Organisms cope with such change using internal timekeepers or circadian clocks which have evolved remarkable flexibility. This flexibility is evident in the waveforms of behavioural and underlying molecular rhythms. In today’s world, many ecosystems experience artificial light at night, leading to unusual photoperiodic conditions. Additionally, occupational demands expose many humans to unconventional light cycles. Yet, practical means of manipulating activity waveforms for beneficial purposes are lacking. This requires an understanding of principles and factors governing waveform plasticity of activity rhythms. Even though waveform plasticity remains underexplored, few recent studies have used novel light regimes, inspired by shift work schedules, with alternating bright light and dim light (LDimLDim) to manipulate the activity waveform of nocturnal rodents. We undertook this
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Multivalent Targeting of Blood-Brain Barrier LRP1 for Neurovascular Recovery Therapy for Alzheimer s Disease https://t.co/Eb0FoH2GmG #bioRxiv