The molecular components of the postsynaptic density (PSD) in excitatory synapses of the brain are currently being investigated as one of the major etiologies of neurodevelopmental disorders such as ...schizophrenia (SCZ) and autism. Postsynaptic density protein-95 (PSD-95) is a major regulator of synaptic maturation by interacting, stabilizing and trafficking N-methyl-d-aspartic acid receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPARs) to the postsynaptic membrane. Recently, there has been overwhelming evidence that associates PSD-95 disruption with cognitive and learning deficits observed in SCZ and autism. For instance, recent genomic and sequencing studies of psychiatric patients highlight the aberrations at the PSD of glutamatergic synapses that include PSD-95 dysfunction. In animal studies, PSD-95 deficiency shows alterations in NMDA and AMPA-receptor composition and function in specific brain regions that may contribute to phenotypes observed in neuropsychiatric pathologies. In this review, we describe the role of PSD-95 as an essential scaffolding protein during synaptogenesis and neurodevelopment. More specifically, we discuss its interactions with NMDA receptor subunits that potentially affect glutamate transmission, and the formation of silent synapses during critical time points of neurodevelopment. Furthermore, we describe how PSD-95 may alter dendritic spine morphologies, thus regulating synaptic function that influences behavioral phenotypes in SCZ versus autism. Understanding the role of PSD-95 in the neuropathologies of SCZ and autism will give an insight of the cellular and molecular attributes in the disorders, thus providing treatment options in patients affected.
•PSD-95 mediates NMDA and AMPA receptor clustering and function.•Genetic implications of PSD-95 deficiency in schizophrenia•PSD-95 & NMDAR dysregulation in schizophrenia•PSD-95 regulates spine density involved in schizophrenia.•PSD-95 is associated with NMDAR dysregulation and spine change in autism.
Myocardial native T1 and extracellular volume fraction (ECV) mapping have emerged as cardiac magnetic resonance biomarkers providing unique insight into cardiac pathophysiology. Single breath-hold ...acquisition techniques, available on clinical scanners across multiple vendor platforms, have made clinical T1 and ECV mapping a reality. Although the relationship between changes in native T1 and alterations in cardiac microstructure is complex, an understanding of how edema, blood volume, myocyte and interstitial expansion, lipids, and paramagnetic substances affect T1 and ECV can provide insight into how and why these parameters change in various cardiac pathologies. The goals of this state-of-the-art review will be to review factors influencing native T1 and ECV, to describe how native T1 and ECV are measured, to discuss potential challenges and pitfalls in clinical practice, and to describe new T1 mapping techniques on the horizon.
Endothelial nitric oxide (NO) is generated by constitutively active endothelial nitric oxide synthase (eNOS), an essential enzyme responsible for cardiovascular homeostasis. Historically, endothelial ...NO was first recognized as a major vasodilator involved in control of vasomotor function and local blood flow. In this review, our attention is focused on the emerging role of endothelial NO in linking cerebrovascular function with cognition. We will discuss the recognized ability of endothelial NO to modulate processing of amyloid precursor protein (APP), influence functional status of microglia, and affect cognitive function. Existing evidence suggests that the loss of NO in cultured human cerebrovascular endothelium causes increased expression of APP and β-site APP-cleaving enzyme 1 (BACE1) thereby resulting in increased secretion of amyloid β peptides (Aβ1-40 and Aβ1-42). Furthermore, increased expression of APP and BACE1 as well as increased production of Aβ peptides was detected in the cerebral microvasculature and brain tissue of eNOS-deficient mice. Since Aβ peptides are considered major cytotoxic molecules responsible for the pathogenesis of Alzheimer's disease, these observations support the concept that a loss of endothelial NO might significantly contribute to the initiation and progression of cognitive decline. In addition, genetic inactivation of eNOS causes activation of microglia and promotes a pro-inflammatory phenotype in the brain. Behavioural analysis revealed that eNOS-deficient mice exhibit impaired cognitive performance thereby indicating that selective loss of endothelial NO has a detrimental effect on the function of neuronal cells. Together with findings from prior studies demonstrating the ability of endothelial NO to affect synaptic plasticity, mitochondrial biogenesis, and function of neuronal progenitor cells, it is becoming apparent that the role of endothelial NO in the control of central nervous system function is very complex. We propose that endothelial NO represents the key molecule linking cerebrovascular and neuronal function.
Postsynaptic density protein-95 (PSD-95) is a major regulator in the maturation of excitatory synapses by interacting and trafficking N-methyl-D-aspartic acid receptors (NMDAR) and ...α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPAR) to the postsynaptic membrane. PSD-95 disruption has recently been associated with neuropsychiatric disorders such as schizophrenia and autism. However, the effects of PSD-95 deficiency on the prefrontal cortex (PFC)-associated functions, including cognition, working memory, and sociability, has yet to be investigated. Using a PSD-95 knockout mouse model (PSD-95
), we examined how PSD-95 deficiency affects NMDAR and AMPAR expression and function in the medial prefrontal cortex (mPFC) during juvenile and adolescent periods of development. We found significant increases in total protein levels of NMDAR subunits GluN1, and GluN2B, accompanied by decreases in AMPAR subunit GluA1 during adolescence. Correspondingly, there is a significant increase in NMDAR/AMPAR-mediated current amplitude ratio that progresses from juvenile-to-adolescence. Behaviorally, PSD-95
mice exhibit a lack of sociability, as well as learning and working memory deficits. Together, our data indicate that PSD-95 deficiency disrupts mPFC synaptic function and related behavior at a critical age of development. This study highlights the importance of PSD-95 during neurodevelopment in the mPFC and its potential link in the pathogenesis associated with schizophrenia and/or autism.
The pioneering work done in South Africa in developing radio communications technology for use underground in mines is summarised. Propagation took place, in the main, directly through the rock ...strata with incidental coupling into power cables, pipes, rails and other conductors. The research established the optimum frequencies for communications as well as the most appropriate antennas. Specialised radio equipment was developed for this task as constrained by the technology of the time. Size and weight were major constraints; ultimately, handheld equipment, using single-sideband modulation, was produced that functioned exceptionally well in numerous situations underground.
Trophic cascades occur in many ecosystems, but the factors regulating them are still elusive. We suggest that an overlooked factor is that trophic interactions (TIs) are often scale-dependent and ...possibly interact across spatial scales. To explore the role of spatial scale for trophic cascades, and particularly the occurrence of cross-scale interactions (CSIs), we collected and analysed food-web data from 139 stations across 32 bays in the Baltic Sea. We found evidence of a four-level trophic cascade linking TIs across two spatial scales: at bay scale, piscivores (perch and pike) controlled mesopredators (three-spined stickleback), which in turn negatively affected epifaunal grazers. At station scale (within bays), grazers on average suppressed epiphytic algae, and indirectly benefitted habitat-forming vegetation. Moreover, the direction and strength of the grazer–algae relationship at station scale depended on the piscivore biomass at bay scale, indicating a cross-scale interaction effect, potentially caused by a shift in grazer assemblage composition. In summary, the trophic cascade from piscivores to algae appears to involve TIs that occur at, but also interact across, different spatial scales. Considering scale-dependence in general, and CSIs in particular, could therefore enhance our understanding of trophic cascades.
Despite significant effort, cancer still remains a leading cause of death worldwide. In order to reduce its burden, the development and improvement of noninvasive strategies for early detection and ...diagnosis of cancer are urgently needed. Raman spectroscopy, an optical technique that relies on inelastic light scattering arising from molecular vibrations, is one such strategy, as it can noninvasively probe cancerous markers using only endogenous contrast. In this review, spontaneous, coherent and surface enhanced Raman spectroscopies and imaging, as well as the fundamental principles governing the successful use of these techniques, are discussed. Methods for spectral data analysis are also highlighted. Utilization of the discussed Raman techniques for the detection and diagnosis of cancer in vitro, ex vivo and in vivo is described. The review concludes with a discussion of the future directions of Raman technologies, with particular emphasis on their clinical translation.
Nanotechnology is a rapidly growing area of research in part due to its integration into many biomedical applications. Within nanotechnology, gold and silver nanostructures are some of the most ...heavily utilized nanomaterial due to their unique optical, photothermal, and facile surface chemical properties. In this review, common colloid synthesis methods and biofunctionalization strategies of gold and silver nanostructures are highlighted. Their unique properties are also discussed in terms of their use in biodiagnostic, imaging, therapeutic, and drug delivery applications. Furthermore, relevant clinical applications utilizing gold and silver nanostructures are also presented. We also provide a table with reviews covering related topics.
In this work a physically-based model is developed to address slip in polycrystalline metals and alloys subjected to very high rates of deformation (10
4–10
8
s
−1). Constitutive relations are ...provided for the kinematics, kinetics, and substructure of fcc metals with micron-scale grains. The main innovative feature of this work is the treatment of the dislocation substructure in the weak shock loading regime. Here, the mobile and immobile dislocation densities are assigned as internal state variables and path-dependent differential equations are formulated for their evolution. This enables physical descriptions of slip resistance and the plastic flow rate. The constitutive model is applied to 6061-T6 Al alloy and the viscoplastic relations are employed in steady plastic wave calculations that enable comparison of the model to experiments. For shock stress amplitudes of 2–10
GPa the model accurately reproduces direct measurements of material velocity and indirect measurements of the macroscopic shear stress and plastic rate of deformation in the shock front. Model results are also in agreement with measurements of material strength on the Hugoniot for shock stresses up to ∼15
GPa. The accuracy of calculations in the weak shock loading regime indicates the proposed constitutive model may be useful in simulating high-strain-phenomena in a variety of technical applications, including dynamic material responses at small length scales. An improvement to the constitutive model is suggested to bring the model into better agreement with experiments at higher shock stresses.
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