Macromorphological and microstructural changes of gray matter (GM) happen during brain normal aging. However, the mechanism of macro-microstructure association is still unclear, which is of guidance for understanding many neurodegenerative diseases. In this study, adopting structural magnetic resonance imaging (sMRI) and diffusion kurtosis imaging (DKI), GM aging pattern was characterized and its macro-microstructure associations were revealed. For 60 subjects between the ages of 47-79, the DKI and T1-weighted images were investigated with voxel-based analysis. The results demonstrated three age-related overlap patterns between morphological and microstructural changes during normal aging. First, morphological changes and MD metric abnormalities obviously overlapped in the following regions, bilateral frontal lobe, temporal lobe, insula and thalamus. Besides, compared to GM atrophies, MD abnormalities were observed in more regions, cingulate gyrus, parietal lobe and occipital lobe. What's more, in left temporal pole and amygdala, only GM volume changes were detected, and the changes of MD were not found. What important is that intrinsic associations between macrostructure and microstructure were found. Age-independent intrinsic associations revealed the potential mechanisms in the process of aging. The physiological mechanism may be associated with the elimination of neurons and synapses and the shrinkage of large neurons. Understanding the associations of GM volume changes and microstructural changes can account for the underlying mechanisms of aging and age-related neurodegenerative diseases.
Abstract Background Defining reliable brain markers for the prediction of abnormal behavioral outcomes remains an urgent but extremely challenging task in neuroscience research. This is particularly important for infant studies given the most dramatic brain and behavioral growth during infancy. Methods In this study, we proposed a novel prediction scheme through abstracting individual newborn's whole‐brain functional connectivity pattern to three outlier measures (Triple O) and tested the hypothesis that neonates identified as “brain outliers” based on Triple O were more likely to develop as IQ outliers at 4 years of age. Without need for training with behavioral data, Triple O represents a novel proof‐of‐concept approach to predict later IQ outcomes based on neonatal brain data. Results Triple O correctly identified 42.1% true IQ outliers among a mixed cohort of 175 newborns with different term, twin, and maternal disorder statuses. Triple O also reached a high level of specificity (96.2%) and overall accuracy (90.3%). Further incorporating a demographic information indicator, the enhanced Triple O+ could further differentiate between high and low 4YR IQ outliers. Validation tests against seven independent reference samples revealed highly consistent results and a minimum sample size of ~50 for robust performance. Conclusions Considering that postnatal brain growth and various environmental factors likely also contribute to 4YR IQ, the fact that Triple O, based purely on neonatal functional connectivity data, could identify >40% of 4YR IQ outliers is striking. Together with the very high level of specificity, each outlier predicted by Triple O represents a meaningful risk but future efforts are needed to explore ways to identify the rest of outliers. Overall, with no need for training, a high level of robustness, and a minimal requirement on sample size, the proposed Triple O approach demonstrates great potential to predict later outlying IQ performances using neonatal functional connectivity data.
W/CuCrZr alloy composite panels are promising plasma-facing components for use in future nuclear-fusion reactors. However, the intrinsic immiscibility of W and Cu makes joining them difficult. In this study, we developed a vacuum diffusion bonding method that involves sandblasting of the W substrate surface, Cu electroplating and annealing, and subsequent vacuum diffusion bonding to realize W/CuCrZr joints with high bond strength. The morphologies and structures of the W and W/CuCrZr joints were investigated by scanning electron microscopy, X-ray diffraction, and high-resolution transmission electron microscopy. Sandblasting was found to induce the plastic deformation, roughening, and grain refinement of the W substrate surface. During Cu plating on the surface of the sandblasted W (and subsequent annealing), the Cu layer was embedded in micron-scale irregular pits on the sandblasted W surface, creating a tight bond. The shear bond strength (184 MPa) and bonding quality of a W/CuCrZr joint obtained with the sandblasting/Cu interlayer method was superior to those of a W/CuCrZr joint prepared by conventional vacuum diffusion bonding. The structural origins of this superior W/CuCrZr joint were related to a region of W and Cu interdiffusion with a thickness of approximately 30 nm. This improved vacuum diffusion bonding method for W and CuCrZr can facilitate the development of plasma-facing components for future nuclear-fusion devices.
Shewanella oneidensis MR-1 is a platform microorganism for understanding extracellular electron transfer (EET) with a fully sequenced and annotated genome. In comparison to other model microorganisms such as Escherichia coli, the available plasmid parts (such as promoters and replicons) are not sufficient to conveniently and quickly fine-tune the expression of multiple genes in S. oneidensis MR-1. Here, we constructed and characterized a plasmid toolkit that contains a set of expression vectors with a combination of promoters, replicons, antibiotic resistance genes, and an RK2 origin of transfer (oriT) cassette, in which each element can be easily changed by fixed restriction enzyme sites. The expression cassette is also compatible with BioBrick synthetic biology standards. Using green fluorescent protein (GFP) as a reporter, we tested and quantified the strength of promoters. The copy number of different replicons was also measured by real-time quantitative PCR. We further transformed two compatible plasmids with different antibiotic resistance genes into the recombinant S. oneidensis MR-1, enabling control over the expression of two different fluorescent proteins. This plasmid toolkit was further used for overexpression of the MtrCAB porin-c-type cytochrome complex in the S. oneidensis ΔmtrA strain. Tungsten trioxide (WO3) reduction and microbial fuel cell (MFC) assays revealed that the EET efficiency was improved most significantly when MtrCAB was expressed at a moderate level, thus demonstrating the utility of the plasmid toolkit in the EET regulation in S. oneidensis. The plasmid toolkit developed in this study is useful for rapid and convenient fine-tuning of gene expression and enhances the ability to genetically manipulate S. oneidensis MR-1.
In contrast to the adult mammalian central nervous system (CNS), the neurons in the peripheral nervous system (PNS) can regenerate their axons. However, the underlying mechanism dictating the regeneration program after PNS injuries remains poorly understood. Combining chemical inhibitor screening with gain- and loss-of-function analyses, we identified p90 ribosomal S6 kinase 1 (RSK1) as a crucial regulator of axon regeneration in dorsal root ganglion (DRG) neurons after sciatic nerve injury (SNI). Mechanistically, RSK1 was found to preferentially regulate the synthesis of regeneration-related proteins using ribosomal profiling. Interestingly, RSK1 expression was up-regulated in injured DRG neurons, but not retinal ganglion cells (RGCs). Additionally, RSK1 overexpression enhanced phosphatase and tensin homolog (PTEN) deletion-induced axon regeneration in RGCs in the adult CNS. Our findings reveal a critical mechanism in inducing protein synthesis that promotes axon regeneration and further suggest RSK1 as a possible therapeutic target for neuronal injury repair.
Abstract Repeated opioids abuse may produce long‐lasting and complicated cognitive deficits in individuals. Naloxone is a typical mu‐opioid receptor antagonist widely used in clinical treatment for opioid overdose and opioid abuse. However, it remains unclear whether naloxone affects morphine‐induced cognitive deficits. Using the 5‐choice serial reaction time task (5‐CSRTT), the present study investigated cognitive profiles including attention, impulsivity, compulsivity, and processing speed in repeated morphine‐treated mice. Repeated morphine administration (10 mg/kg, i.p.) induced complex cognitive changes including decreased attention and increased impulsivity, compulsivity, processing speed. Systemic naloxone administration (5 mg/kg, i.p.) reversed these cognitive changes under the heavy perceptual load in 5‐CSRTT. Using the novel object recognition (NOR), Y‐maze and open‐field test (OFT), the present study investigated the memory ability and locomotor activity. Naloxone reversed the effect of morphine on recognition memory and locomotion but had no effect on working memory. In addition, repeated morphine administration decreased the expression of postsynaptic density protein 95 (PSD95) and cAMP response element binding protein (CREB) phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP), and these effects were significantly reversed by naloxone in PFC. Our study suggests that repeated exposure to morphine affects multiple cognitive aspects and impairs synaptic functions. Systemic naloxone treatment reverses the mu‐opioids‐induced cognitive changes, especially under the heavy perceptual load, possibly by restoring the synaptic dysfunctions.
Abstract This study aimed to investigate structural synaptic plasticity in the medial prefrontal cortex of rats under treadmill exercise pretreatment or naive conditions in a vascular dementia model, followed by recognition memory performance in a novel object recognition task. In this study, 24 Sprague–Dawley rats were obtained and randomly assigned into 4 groups as follows: control group (Con group, n = 6), vascular dementia (VD group, n = 6), exercise and vascular dementia group (Exe + VD group, n = 6), and exercise group (Exe group, n = 6). Initially, 4 weeks of treadmill exercise intervention was administered to the rats in the Exe + VD and Exe groups. Then, to establish the vascular dementia model, the rats both in the VD and Exe + VD groups were subjected to bilateral common carotids arteries surgery. One week later, open-field task and novel recognition memory task were adopted to evaluate anxiety-like behavior and recognition memory in each group. Then, immunofluorescence and Golgi staining were used to evaluate neuronal number and spine density in the rat medial prefrontal cortex. Transmission electron microscopy was used to observe the synaptic ultrastructure. Finally, microdialysis coupled with high-performance liquid chromatography was used to assess the levels of 5-HT and dopamine in the medial prefrontal cortex. The behavior results showed that 4 weeks of treadmill exercise pretreatment significantly alleviated recognition memory impairment and anxiety-like behavior in VD rats ( P < 0.01), while the rats in VD group exhibited impaired recognition memory and anxiety-like behavior when compared with the Con group ( P < 0.001). Additionally, NeuN immunostaining results revealed a significant decrease of NeuN-marked neuron in the VD group compared to Con group ( P < 0.01), but a significantly increase in this molecular marker was found in the Exe + VD group compared to the Con group ( P < 0.01). Golgi staining results showed that the medial prefrontal cortex neurons in the VD group displayed fewer dendritic spines than those in the Con group ( P < 0.01), and there were more spines on the dendrites of medial prefrontal cortex cells in Exe + VD rats than in VD rats ( P < 0.01). Transmission electron microscopy further revealed that there was a significant reduction of synapses intensity in the medial prefrontal cortex of rats in the VD group when compared with the Con group( P < 0.01), but physical exercise was found to significantly increased synapses intensity in the VD model ( P < 0.01). Lastly, the levels of dopamine and 5-HT in the medial prefrontal cortex of rats in the VD group was significantly lower compared to the Con group ( P < 0.01), and treadmill exercise was shown to significantly increased the levels of dopamine and 5-HT in the VD rats ( P < 0.05). Treadmill exercise pretreatment ameliorated structural synaptic plasticity impairments of medial prefrontal cortex in VD rat and improved recognition memory.
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