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Salivary duct carcinoma (SDC) is a rare malignant tumor of the salivary gland and is most commonly found in the parotid gland, followed by the submandibular gland. Due to its rarity, there is no consensus on its treatment. Surgical resection is currently the only curative treatment. Considering its high degree of malignancy, extensive tumor resection and postoperative adjuvant radiotherapy are recommended. We report a rare case of SDC of the submandibular gland. A 62-year-old man presented to our hospital with complaints of swelling in the right submaxillary area for 4 months, rapidly growing, with pain for 10 days. After admission, fine needle aspiration (FNA) revealed right submandibular gland ductal carcinoma. Considering its aggressiveness, large size, and invasion of parapharyngeal and oral floor soft tissues, the patient received two cycles of neoadjuvant chemotherapy followed by extended surgical resection. Postoperatively, the patient received four cycles of concurrent chemoradiotherapy, followed by afatinib targeted therapy. No recurrence or metastasis was observed in a 45-month follow-up. Thus we present a comprehensive treatment for salivary duct carcinoma combining neoadjuvant chemotherapy with surgery, postoperative concurrent radiotherapy, and chemotherapy followed by afatinib targeted therapy.

Social behavior starts with dynamic approach prior to the final consummation. The flexible processes ensure mutual feedback across social brains to transmit signals. However, how the brain responds to the initial social stimuli precisely to elicit timed behaviors remains elusive. Here, by using real-time calcium recording, we identify the abnormalities of EphB2 mutant with autism-associated Q858X mutation in processing long-range approach and accurate activity of prefrontal cortex (dmPFC). The EphB2-dependent dmPFC activation precedes the behavioral onset and is actively associated with subsequent social action with the partner. Furthermore, we find that partner dmPFC activity is responsive coordinately to the approaching WT mouse rather than Q858X mutant mouse, and the social defects caused by the mutation are rescued by synchro-optogenetic activation in dmPFC of paired social partners. These results thus reveal that EphB2 sustains neuronal activation in the dmPFC that is essential for the proactive modulation of social approach to initial social interaction.

Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer's disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.

Ultra-high resolution computed tomography (UHRCT) has shown great potential for the detection of pulmonary diseases. However, UHRCT scanning generally induces increases in scanning time and radiation exposure. Super resolution is a gradually prosperous application in CT imaging despite higher radiation dose. Recent works have proved that the convolution neural network especially the generative adversarial network (GAN) based model could generate high-resolution CT using phantom images or simulated low resolution data without extra dose. Research that used clinical CT particularly lung images are rare due to the difficulty in collecting paired dataset.To generate clinical Ultra-high resolution computed tomography (UHRCT) in lung from low resolution computed tomography (LRCT) using a GAN model.43 clinical scans with LRCT and UHRCT were collected in this study. Paired patches were selected using the structural similarity index measure (SSIM) and the peak signal-to-noise ratio (PSNR) threshold. A relativistic generative adversarial network (GAN) with gradient guidance was trained to learn the mapping from LRCT to UHRCT. The performance of the proposed method was evaluated using PSNR and SSIM. A reader study with 5-point Likert score (5 for the worst and 1 for the best) is also applied to assess the proposed method in terms of general quality, diagnostic confidence, sharpness and denoise level.Experimental results show that our method got PSNR 32.60 ± 2.92 and SSIM 0.881 ± 0.057 on our clinical CT dataset, outperforming other state-of-the-art methods based on the simulated scenarios. Moreover, reader study shows that our method reached the good clinical performance in terms of general quality (1.14 ± 0.36), diagnostic confidence (1.36 ± 0.49), sharpness (1.07 ± 0.27) and high denoise level (1.29 ± 0.61) compared to other SR methods.This study demonstrated the feasibility of generating UHRCT images from LRCT without longer scanning time or increased radiation dose. This article is protected by copyright. All rights reserved.

Background Ribosomal protein S6 kinase 1 (S6K1) is a serine–threonine kinase that has two main isoforms: p70S6K (70-kDa isoform) and p85S6K (85-kDa isoform). p70S6K, with its upstream mammalian target of rapamycin (mTOR), has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer’s disease (AD). However, the function of p85S6K has long been neglected due to its high similarity to p70S6k. The role of p85S6K in learning and memory is still largely unknown. Methods We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K. Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor. The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence, Western blot, in situ proximity ligation assay, morphological staining and behavioral examination. Further, the expression level of p85S6K was measured in brains from AD patients and AD model mice. Results p85S6K, but not p70S6K, was enriched in the postsynaptic densities. Moreover, knockdown of p85S6K resulted in defective spatial and recognition memory. In addition, p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150. Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in synapses, thus sustaining synaptic function and spine densities. Moreover, p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice. Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice. Conclusions These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1. The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.

Additional file 1. Table S1: Information of brain donors in this study. Fig. S1: The expression pattern of S6K1 in HEK293 cells and neurons. Fig. S2: The quantification of PSD95 and synaptophysin in fractions and the validation of p70S6K antibodies. Fig. S3: Knockdown of p85S6K efficiently reduces p85S6K in PSD-1 and does not affect the locomotor activity and anxiety-like behavior. Fig. S4: p85S6K cannot be immunoprecipitated with GluA1 with little expression of AKAP79 in HEK293 cells. Fig. S5: p85S6K does not interfere with the interaction between GluA1 and PKA. Fig. S6: The immunoblots of p85S6K/p70S6K and phosphorylated form in remaining human temporal cortex samples related to Fig. 5a. Fig. S7: p85S6K expression in P2 pellets of cortex of APP/PS1 mice. Fig. S8: p85S6K expression is decreased in PSD-1 of cortex of 5×FAD mice. Fig. S9: PSD95 expression is not altered in AD brains. Fig. S10: Overexpression of p85S6K does not affect the locomotor activity and anxiety-like behavior. Fig. S11: Upregulation of p85S6K does not enhance the spatial learning and spine density in S845A mice. Fig. S12: The NLS predicted in p85S6K by www.csbio.sjtu.edu.cn/bioinf/INSP/ . Fig. S13: The expression of GluA1 and its phosphorylation at Ser845 are reduced in P2 pellets from fractionation of cortex of 7-month old 5×FAD and 9-month old APP/PS1 mice.

Background To evaluate clinical performance of deep learning enhanced ultra-fast SPECT/CT bone scan. Methods One hundred and two patients were enrolled in this retrospective study. The probable malignant tumor sites continuously underwent a 20min SPECT/CT and a 3min SPECT scan. A deep learning model was applied to generate algorithm-enhanced images (3min-DL SPECT). Two reviewers evaluated general image quality, 99mTc-MDP distribution, artifacts, and diagnostic confidence independently. The sensitivity, specificity, accuracy, and inter-observer agreement were calculated. Linear regression was analyzed for lesion SUVmax between 3min-DL and 20min SPECT. Peak signal-to-noise ratio (PSNR), image similarity (SSIM) were evaluated. Results The general image quality, 99mTc-MDP distribution, artefact, and diagnostic confidence of 3min-DL images were significantly superior to those of 20min images (P 0.05). The diagnosis results of 20min and 3min-DL images showed a high inter-observer agreement (Kappa = 0.822, 0.732). PSNR and SSIM of 3min-DL images were significantly higher than 3min images (51.44 vs 38.44, 0.863 vs 0.752, P max of 3min-DL and 20min images (r = 0.987; P

Threat and extinction memories are crucial for organisms’ survival in changing environments. These memories are believed to be encoded by separate ensembles of neurons in the brain, but their whereabouts remain elusive. Using an auditory fear-conditioning and extinction paradigm in male mice, here we discovered that two distinct projection neuron subpopulations in physical proximity within the insular cortex (IC), targeting the central amygdala (CeA) and nucleus accumbens (NAc), respectively, to encode fear and extinction memories. Reciprocal intracortical inhibition of these two IC subpopulations gates the emergence of either fear or extinction memory. Using rabies-virus-assisted tracing, we found IC-NAc projection neurons to be preferentially innervated by intercortical inputs from the orbitofrontal cortex (OFC), specifically enhancing extinction to override fear memory. These results demonstrate that IC serves as an operation node harboring distinct projection neurons that decipher fear or extinction memory under the top-down executive control from OFC.

Quantitative susceptibility mapping (QSM) is used to quantify iron deposition in non-human primates in our study. Although QSM has many applications in detecting iron deposits in the human brain, including the distribution of iron deposits in specific brain regions, the change of iron deposition with aging, and the comparison of iron deposits between diseased groups and healthy controls, few studies have applied QSM to non-human primates, while most animal brain experiments focus on biochemical and anatomical results instead of non-invasive experiments. Additionally, brain imaging in children's research is difficult, but can be substituted using young rhesus monkeys, which are very similar to humans, as research animals. Therefore, understanding the relationship between iron deposition and age in rhesus macaques' brains can offer insights into both the developmental trajectory of magnetic susceptibility in the animal model and the correlated evidence in children's research. Twenty-three healthy rhesus macaque monkeys (23 ± 7.85 years, range 2-29 years) were included in this research. Seven regions of interest (ROIs-globus pallidus, substantia nigra, dentate nucleus, caudate nucleus, putamen, thalamus, red nucleus) have been analyzed in terms of QSM and R

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

To evaluate the clinical performance of a deep learning (DL)–based method for brain MRI exams with reduced gadolinium-based contrast agent (GBCA) dose to provide better understanding of the readiness and limitations of this method. Eighty-three consecutive patients (from March 2019 to August 2019) who underwent brain contrast-enhanced (CE) MRI were included. Three 3D T1-weighted images with zero-dose, low-dose (10%), and full-dose (100%) GBCA were collected. The first 30 cases were used to train a DL model to synthesize the full-dose GBCA images from the zero-dose and low-dose image pairs. The remaining 53 cases were used for testing. The enhancement pattern, number, and location of enhancing lesions were recorded. Overall image quality, image signal noise ratio (SNR), lesion conspicuity, and lesion enhancement were assessed. Lesion detection from the DL-synthesized CE-MRI image accurately matched those from the true full-dose CE-MRI images in 48 of 53 cases (90.6%). The DL method identified the lesions in 34 of 36 cases (94.4%) with a single enhanced lesion and all lesions in 3 of 6 cases (50.0%) in cases with multiple enhancing lesions. The agreement between synthesized and true full-dose CE-MRI images were 0.73, 0.63, 0.89, and 0.87 for image quality, image SNR, lesion conspicuity, and lesion enhancement, respectively. The proposed DL method is a feasible way to minimize the dosage of GBCAs in brain MRI without sacrificing the diagnostic information. Missing enhancement of small lesions in patients with multiple lesions was observed, requiring improvements in algorithms or dosage design. • This study evaluated the clinical performance of a DL-based reconstruction method for significant dose reduction in GBCA contrast-enhanced MRI exams. • The proposed DL method has the potential to satisfy the routine radiological diagnosis needs in certain clinical applications.

Deficits in synaptic transmission and plasticity are thought to contribute to the pathophysiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Several brain stimulation techniques are currently available to assess or modulate human neuroplasticity, which could offer clinically useful interventions as well as quantitative diagnostic and prognostic biomarkers. In this review, we discuss several brain stimulation techniques, with a special emphasis on transcranial magnetic stimulation and deep brain stimulation (DBS), and review the results of clinical studies that applied these techniques to examine or modulate impaired neuroplasticity at the local and network levels in patients with AD or PD. The impaired neuroplasticity can be detected in patients at the earlier and later stages of both neurodegenerative diseases. However, current brain stimulation techniques, with a notable exception of DBS for PD treatment, cannot serve as adequate clinical tools to assist in the diagnosis, treatment, or prognosis of individual patients with AD or PD. Targeting the impaired neuroplasticity with improved brain stimulation techniques could offer a powerful novel approach for the treatment of AD and PD.

Social isolation in adolescence leads to lasting deficits, including emotional and cognitive dysregulation. It remains unclear, however, how social isolation affects certain processes of memory and what molecular mechanisms are involved. In this study, we found that social isolation during the post-weaning period resulted in forgetting of the long-term fear memory, which was attributable to the downregulation of synaptic function in the hippocampal CA1 region mediated by EphB2, a receptor tyrosine kinase which involves in the glutamate receptor multiprotein complex. Viral-mediated EphB2 knockdown in CA1 mimicked the memory defects in group-housed mice, whereas restoration of EphB2 by either viral overexpression or resocialization reversed the memory decline in isolated mice. Taken together, our finding indicates that social isolation gives rise to memory forgetting by disrupting EphB2-mediated synaptic plasticity, which may provide a potential target for preventing memory loss caused by social isolation or loneliness.

Postsynaptic structure assembly and remodeling are crucial for functional synapse formation during the establishment of neural circuits. However, how the specific scaffold proteins regulate this process during the development of the postnatal period is poorly understood. In this study, we find that the deficiency of ligand of Numb protein X 1 (Lnx1) leads to abnormal development of dendritic spines to impair functional synaptic formation. We further demonstrate that loss of Lnx1 promotes the internalization of EphB receptors from the cell surface. Constitutively active EphB2 intracellular signaling rescues synaptogenesis in Lnx1 mutant mice. Our data thus reveal a molecular mechanism whereby the Lnx1-EphB complex controls postsynaptic structure for synapse maturation during the adolescent period.

BackgroundTo generate high-quality bone scan SPECT images from only 1/7 scan time SPECT images using deep learning-based enhancement method.Materials and methodsNormal-dose (925–1110 MBq) clinical technetium 99 m-methyl diphosphonate (99mTc-MDP) SPECT/CT images and corresponding SPECT/CT images with 1/7 scan time from 20 adult patients with bone disease and a phantom were collected to develop a lesion-attention weighted U2-Net (Qin et al. in Pattern Recognit 106:107404, 2020), which produces high-quality SPECT images from fast SPECT/CT images. The quality of synthesized SPECT images from different deep learning models was compared using PSNR and SSIM. Clinic evaluation on 5-point Likert scale (5 = excellent) was performed by two experienced nuclear physicians. Average score and Wilcoxon test were constructed to assess the image quality of 1/7 SPECT, DL-enhanced SPECT and the standard SPECT. SUVmax, SUVmean, SSIM and PSNR from each detectable sphere filled with imaging agent were measured and compared for different images.ResultsU2-Net-based model reached the best PSNR (40.8) and SSIM (0.788) performance compared with other advanced deep learning methods. The clinic evaluation showed the quality of the synthesized SPECT images is much higher than that of fast SPECT images (P P > 0.999), similar detail of 99mTc-MDP (P = 0.125) and the same diagnostic confidence (P = 0.1875). 4, 5 and 6 spheres could be distinguished on 1/7 SPECT, DL-enhanced SPECT and the standard SPECT, respectively. The DL-enhanced phantom image outperformed 1/7 SPECT in SUVmax, SUVmean, SSIM and PSNR in quantitative assessment.ConclusionsOur proposed method can yield significant image quality improvement in the noise level, details of anatomical structure and SUV accuracy, which enabled applications of ultra fast SPECT bone imaging in real clinic settings.

Acid-sensing ion channels (ASICs), the main H+ receptors in the central nervous system, sense extracellular pH fluctuations and mediate cation influx. ASIC1a, the major subunit responsible for acid-activated current, is widely expressed in brain neurons, where it plays pivotal roles in diverse functions including synaptic transmission and plasticity. However, the underlying molecular mechanisms for these functions remain mysterious. Using extracellular epitope tagging and a novel antibody recognizing the hASIC1a ectodomain, we examined the membrane targeting and dynamic trafficking of hASIC1a in cultured cortical neurons. Surface hASIC1a was distributed throughout somata and dendrites, clustered in spine heads, and co-localized with postsynaptic markers. By extracellular pHluorin tagging and fluorescence recovery after photobleaching, we detected movement of hASIC1a in synaptic spine heads. Single-particle tracking along with use of the anti-hASIC1a ectodomain antibody revealed long-distance migration and local movement of surface hASIC1a puncta on dendrites. Importantly, enhancing synaptic activity with brain-derived neurotrophic factor accelerated the trafficking and lateral mobility of hASIC1a. With this newly-developed toolbox, our data demonstrate the synaptic location and high dynamics of functionally-relevant hASIC1a on the surface of excitatory synapses, supporting its involvement in synaptic functions. Electronic supplementary material The online version of this article (10.1007/s12264-020-00581-9) contains supplementary material, which is available to authorized users.

Soil microbial communities and enzyme activities play key roles in soil ecosystems. Both are sensitive to changes in environmental factors, including seasonal temperature, precipitation variations and soil properties. To understand the interactive mechanisms of seasonal changes that affect soil microbial communities and enzyme activities in a subtropical masson pine (Pinus massoniana) forest, we investigated the soil microbial community structure and enzyme activities to identify the effect of seasonal changes on the soil microbial community for two years in Jinyun Mountain National Nature Reserve, Chongqing, China. The soil microbial community structure was investigated using phospholipid fatty acids (PLFAs). The results indicated that a total of 36 different PLFAs were identified, and 16:0 was found in the highest proportions in the four seasons, moreover, the total PLFAs abundance were highest in spring and lowest in winter. Bacteria and actinomycetes were the dominant types in the study area. Seasonal changes also had a significant (P < 0.05) influence on the soil enzyme activity. The maximum and minimum values of the invertase and catalase activities were observed in autumn and winter, respectively. However, the maximum and minimum values of the urease and phosphatase acid enzymatic activities were found in spring and winter, respectively. Canonical correspondence analysis (CCA) analysis revealed that the seasonal shifts in soil community composition and enzyme activities were relatively more sensitive to soil moisture and temperature, but the microbial community structure and enzyme activity were not correlated with soil pH in the study region. This study highlights how the seasonal variations affect the microbial community and function (enzyme activity) to better understand and predict microbial responses to future climate regimes in subtropical area.

Background Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy, and irritability occur in prodromal phases of clinical Alzheimer’s disease (AD), which might be an increased risk for later developing AD. Here we treated young APP/PS1 AD model mice prophylactically with serotonin-selective re-uptake inhibitor (SSRI) paroxetine and investigated the protective role of anti-depressant agent in emotional abnormalities and cognitive defects during disease progress. Methods To investigate the protective role of paroxetine in emotional abnormalities and cognitive defects during disease progress, we performed emotional behaviors of 3 months old APP/PS1 mouse following oral administration of paroxetine prophylactically starting at 1 month of age. Next, we tested the cognitive, biochemical and pathological, effects of long term administration of paroxetine at 6 months old. Results Our results showed that AD mice displayed emotional dysfunction in the early stage. Prophylactic administration of paroxetine ameliorated the initial emotional abnormalities and preserved the eventual memory function in AD mice. Conclusion Our data indicate that prophylactic administration of paroxetine ameliorates the emotional dysfunction and memory deficit in AD mice. These neuroprotective effects are attributable to functional restoration of glutamate receptor (GluN2A) in AD mice.

In this work, a series of Cu(II)-doped Bi2WO6 nanomaterials with good photo-response properties were facile synthesized and used to obtain efficient peroxymonosulfate (PMS) activation activity for norfloxacin (NOF) removal under visible LED light irradiation. It was found that Cu–Bi2WO6 presents superior catalytic performance for NOF degradation in comparison with pristine Bi2WO6, attributed to the partial substitution of Bi3+ by Cu ions. Moreover, the effects of experimental conditions were carefully investigated, including PMS concentration, catalyst dosage and initial pH, and the experimental data fitted well with the pseudo-first-order model. Experimental results implied that there was a synergic effect of visible LED light energy and the sulfate radical (SR)-Fenton reaction. Additionally, the 5Cu–Bi2WO6 nanomaterial presented the best degradation efficiency of 89.27% and exhibited high NOF degradation in 5 cycles with limited Cu leaching. Furthermore, EPR and radical quenching experiments were performed to identify the reactive oxygen species presented in the SR-photo-Fenton reaction. Finally, the major degradation intermediates of NOF were detected, and a possible degradation pathway was given. Thus, a mechanism of the significant photocatalytic activity enhancement by copper doping of the Bi2WO6 catalyst was proposed.

Social interaction and communication are evolutionary conserved behaviours that are developed in mammals to establish partner cognition. Deficit in sociability has been represented in human patients and animal models of neurodevelopmental disorders, which are connected with genetic variants of synaptic glutamate receptors and associated PDZ-binding proteins. However, it remains elusive how these key proteins are specialized in the cellular level for the initial social behaviour during postnatal developmental stage. Here we identify a hippocampal CA3 specifically expressed PDZ scaffold protein Lnx1 required for initial social behaviour. Through gene targeting we find that Lnx1 deficiency led to a hippocampal subregional disorder in neuronal activity and social memory impairments for partner discrimination observed in juvenile mice which also show cognitive defects in adult stage. We further demonstrate that Lnx1 deletion causes NMDA receptor (NMDAR) hypofunction and this is attributable to decreased GluN2B expression in PSD compartment and disruption of the Lnx1–NMDAR–EphB2 complex. Specific restoration of Lnx1 or EphB2 protein in the CA3 area of Lnx1−/− mice rescues the defective synaptic function and social memory. These findings thus reveal crucial roles of postsynaptic NMDAR multiprotein complex that regulates the formation of initial social memory during the adolescent period.

The epigenetic clock is defined by the DNA methylation (DNAm) level and has been extensively applied to distinguish biological age from chronological age. Aging-related neurodegeneration is associated with epigenetic alteration, which determines the status of diseases. In recent years, extensive research has shown that physical exercise (PE) can affect the DNAm level, implying a reversal of the epigenetic clock in neurodegeneration. PE also regulates brain plasticity, neuroinflammation, and molecular signaling cascades associated with epigenetics. This review summarizes the effects of PE on neurodegenerative diseases via both general and disease-specific DNAm mechanisms, and discusses epigenetic modifications that alleviate the pathological symptoms of these diseases. This may lead to probing of the underpinnings of neurodegenerative disorders and provide valuable therapeutic references for cognitive and motor dysfunction.

Purpose A method named DECOMPOSE-QSM is developed to decompose bulk susceptibility measured with QSM into sub-voxel paramagnetic and diamagnetic components based on a three-pool complex signal model. Methods Multi-echo gradient echo signal is modeled as a summation of three weighted exponentials corresponding to three types of susceptibility sources: reference susceptibility, diamagnetic and paramagnetic susceptibility relative to the reference. Paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS) maps are constructed to represent the sub-voxel compartments by solving for linear and nonlinear parameters in the model. Results Numerical forward simulation and phantom validation confirmed the ability of DECOMPOSE-QSM to separate the mixture of paramagnetic and diamagnetic components. The PCS obtained from temperature-variant brainstem imaging follows the Curie's Law, which further validated the model and the solver. Initial in vivo investigation of human brain images showed the ability to extract sub-voxel PCS and DCS sources that produce visually enhanced contrast between brain structures comparing to threshold QSM.

Objectives To probe microstructural changes that are associated with subconcussive head impact exposure in deep and cortical gray matter of high school football players over a single season. Methods Players underwent diffusion kurtosis imaging (DKI) and quantitative susceptibility mapping (QSM) scans. Head impact data was recorded. Association between parametric changes and frequency of frontal head impact was assessed. Results In deep gray matter, significant decreases in mean kurtosis (MK) and increases in mean diffusivity (MD) over the season were observed in the thalamus and putamen. Correlations between changes in DKI metrics and frequency of frontal impacts were observed in the putamen and caudate. In cortical gray matter, decreases in MK were observed in regions including the pars triangularis and inferior parietal. In addition, increases in MD were observed in the rostral middle frontal cortices. Negative correlations between MK and frequency of frontal impacts were observed in the posterior part of the brain including the pericalcarine, lingual and middle temporal cortices. Magnetic susceptibility values exhibited no significant difference or correlation, suggesting these diffusion changes common within the group may not be associated with iron-related mechanisms. Conclusion Microstructural alterations over the season and correlations with head impacts were captured by DKI metrics, which suggested that DKI imaging of gray matter may yield valuable biomarkers for evaluating brain injuries associated with subconcussive head impact. Findings of associations between frontal impacts and changes in posterior cortical gray matter also indicated that contrecoup injury rather than coup injury might be the dominant mechanism underlying the observed microstructural alterations. Advances in knowledge Significant microstructural changes, as reflected by DKI metrics, in cortical gray matter such as the rostral middle frontal cortices, and in deep gray matter such as the thalamus were observed in high school football players over the course of a single season without clinically diagnosed concussion. QSM showed no evidence of iron-related changes in the observed subconcussive brain injuries. The detected microstructural changes in cortical and deep gray matter correlated with frequency of subconcussive head impacts. Implications for patient care DKI may yield valuable biomarkers for evaluating the severity of brain injuries associated with subconcussive head impacts in contact sport athletes.

Synaptic associativity, a feature of Hebbian plasticity wherein coactivation of two inputs onto the same neuron produces synergistic actions on postsynaptic activity, is a primary cellular correlate of associative learning. However, whether and how synaptic associativity are implemented into context-dependent relapse of extinguished memory (i.e. fear renewal) is unknown. Here, using an auditory fear conditioning paradigm in mice, we show that fear renewal is determined by the associativity between convergent inputs from the auditory cortex (ACx) and ventral hippocampus (vHPC) onto the lateral amygdala (LA) that reactivate ensembles engaged during learning. Fear renewal enhances synaptic strengths of both ACx to LA and the previously unknown vHPC to LA monosynaptic inputs. While inactivating either of the afferents abolishes fear renewal, optogenetic activation of their input associativity in the LA recapitulates fear renewal. Thus, input associativity underlies fear memory renewal.

ObjectiveTo improve the assessment of primary tumor heterogeneity in magnetic resonance imaging (MRI) of non-small cell lung cancer (NSCLC), we proposed a method using basic measurements from T1- and T2-weighted MRI.MethodsOne hundred and four NSCLC patients with different T stages were studied. Fifty-two patients were analyzed as training group and another 52 as testing group. The ratios of standard deviation (SD)/mean signal value of primary tumor from T1-weighted (T1WI), T1-enhanced (T1C), T2-weighted (T2WI), and T2 fat suppression (T2fs) images were calculated. In the training group, correlation analyses were performed between the ratios and T stages. Then an ordinal regression model was built to generate the tumor heterogeneous index (THI) for evaluating the heterogeneity of tumor. The model was validated in the testing group.ResultsThere were 11, 32, 40, and 21 patients with T1, T2, T3, and T4 disease, respectively. In the training group, the median SD/mean on T1WI, T1C, T2WI, and T2fs sequences was 0.11, 0.19, 0.16, and 0.15 respectively. The SD/mean on T1C (p=0.003), T2WI (p=0.000), and T2fs sequences (p=0.002) correlated significantly with T stages. Patients with more advanced T stage showed higher SD/mean on T2-weighted, T2fs, and T1C sequences. The median THI in the training group was 2.15. THI correlated with T stage significantly (p=0.000). In the testing group, THI was also significantly related to T stages (p=0.001). Higher THI had relevance to more advanced T stage.ConclusionsThe proposed ratio measurements and THI based on MRI can serve as functional radiomic markers that correlated with T stages for evaluating heterogeneity of lung tumors.

To evaluate the clinical performance of a deep learning (DL)-based method for brain MRI exams with reduced gadolinium-based contrast agent (GBCA) dose to provide better understanding of the readiness and limitations of this method.Eighty-three consecutive patients (from March 2019 to August 2019) who underwent brain contrast-enhanced (CE) MRI were included. Three 3D T1-weighted images with zero-dose, low-dose (10%), and full-dose (100%) GBCA were collected. The first 30 cases were used to train a DL model to synthesize the full-dose GBCA images from the zero-dose and low-dose image pairs. The remaining 53 cases were used for testing. The enhancement pattern, number, and location of enhancing lesions were recorded. Overall image quality, image signal noise ratio (SNR), lesion conspicuity, and lesion enhancement were assessed.Lesion detection from the DL-synthesized CE-MRI image accurately matched those from the true full-dose CE-MRI images in 48 of 53 cases (90.6%). The DL method identified the lesions in 34 of 36 cases (94.4%) with a single enhanced lesion and all lesions in 3 of 6 cases (50.0%) in cases with multiple enhancing lesions. The agreement between synthesized and true full-dose CE-MRI images were 0.73, 0.63, 0.89, and 0.87 for image quality, image SNR, lesion conspicuity, and lesion enhancement, respectively.The proposed DL method is a feasible way to minimize the dosage of GBCAs in brain MRI without sacrificing the diagnostic information. Missing enhancement of small lesions in patients with multiple lesions was observed, requiring improvements in algorithms or dosage design.• This study evaluated the clinical performance of a DL-based reconstruction method for significant dose reduction in GBCA contrast-enhanced MRI exams. • The proposed DL method has the potential to satisfy the routine radiological diagnosis needs in certain clinical applications.

In this work, a series of Cu(ii)-doped Bi

Purpose To probe cerebral microstructural abnormalities and assess changes of neuronal density in Disrupted-in-Schizophrenia-1 (DISC1) mice using non-Gaussian diffusion and quantitative susceptibility mapping (QSM). Materials and methods Brain specimens of transgenic DISC1 mice (n = 8) and control mice (n = 7) were scanned. Metrics of neurite orientation dispersion and density imaging (NODDI) and diffusion kurtosis imaging (DKI), as well as QSM, were acquired. Cell counting was performed on Nissl-stained sections. Group differences of imaging metrics and cell density were assessed. Pearson correlations between imaging metrics and cell densities were also examined. Results Significant increases of neuronal density were observed in the hippocampus of DISC1 mice. DKI metrics such as mean kurtosis exhibited significant group differences in the caudate putamen (P = 0.015), cerebral cortex (P = 0.021), and hippocampus (P = 0.011). However, DKI metrics did not correlate with cell density. In contrast, significant positive correlation between density of neurons and the neurite density index of NODDI in the hippocampus was observed (r = 0.783, P = 0.007). Significant correlation between density of neurons and susceptibility (r = 0.657, P = 0.039), as well as between density of neuroglia and susceptibility (r = 0.750, P = 0.013), was also observed in the hippocampus. Conclusion The imaging metrics derived from DKI were not sensitive specifically to cell density, while NODDI could provide diffusion metrics sensitive to density of neurons. The magnetic susceptibility values derived from the QSM method can serve as a sensitive biomarker for quantifying neuronal density.

Astrocytes are fundamental for maintaining brain homeostasis and are commonly involved in the progression of neurodegenerative diseases including Alzheimer's disease (AD). In response to injury or toxic material, astrocytes undergo activation that results in hypertrophy and process ramification. Although numerous studies have shown that reactive astrocytes are intimately related to the pathogenesis of AD, their characteristic features including morphological and molecular alterations that occur during different stages of AD progression remain to be elucidated. Here, we crossed astrocyte-specific reporter mice hGFAP-CreERT2;Rosa-tdTomato with APP/PS1 mice, and then used genetic tracing to characterize the morphological profiles and expression of molecular biomarkers associated with progressive β-amyloid deposits in the cortical region of AD mice. Expression of glutamine synthetase (GS) was lower in cortical reactive astrocytes, in contrast to the higher expression of glial fibrillary acidic protein, of APP/PS1 mice and AD patients relative to that in cortical astrocytes of wild-type mice and age-matched controls, respectively. GS activity was also decreased obviously in the cortex of APP/PS1 mice at 6 and 12 months of age relative to that in the wild-type mice of the same ages. Furthermore, cortical reactive astrocytes in APP/PS1 mice and AD patients did not undergo proliferation. Finally, based on RNA-sequencing analysis, we identified differentially expressed transcripts of signal transduction molecules involved in early induction of reactive astrocytes in the cortex of APP/PS1 mice. These findings provide a morphological and molecular basis with which to understand the function and mechanism of reactive astrocytes in the progression of AD.

Alkali-activated slag materials are known for their high chloride penetration resistance. This makes them potentially applicable as repair systems for damaged steel-reinforced concrete structures, which are exposed to chloride attack. For this purpose, the influence of the activator composition, i.e. the SiO2and Na2O concentration of the alkaline solution on a) the compressive strength, b) shrinkage and mass change and c) the resistance against chloride penetration of four alkali-activated slag mortars (AASM) were studied. An ordinary Portland cement-based mortar was used as the reference sample. Increasing SiO2and Na2O concentrations increased the strength, shrinkage and mass loss of the AASMs. The resistance of the mortars against chloride penetration was evaluated using the non-steady-state migration coefficient Dnssmobtained from NT BUILD 492. The results indicate that the Dnssmis related to differences in the pore solution of the AASMs rather than to differences in their microstructure. An upcoming study of the authors is going to evaluate this hypothesis by the accelerated chloride penetration (diffusion) test.

One aim of this study is to use non-Gaussian diffusion kurtosis imaging (DKI) for capturing microstructural abnormalities in gray matter of Alzheimer's disease (AD). The other aim is to compare DKI metrics against thickness of cortical gray matter and volume of deep gray matter, respectively. A cohort of 18 patients with AD, 18 patients with amnestic mild cognitive impairment (MCI), and 18 normal controls underwent morphological and DKI MR imaging. Images were investigated using regions-of-interest-based analyses for deep gray matter and vertex-wise analyses for cortical gray matter. In deep gray matter, more regions showed DKI parametric abnormalities than atrophies at the early MCI stage. Mean kurtosis (MK) exhibited the largest number of significant abnormalities among all DKI metrics. At the later AD stage, diffusional abnormalities were observed in fewer regions than atrophies. In cortical gray matter, abnormalities in thickness were mainly in the medial and lateral temporal lobes, which fit the locations of known early pathological changes. Microstructural abnormalities were predominantly in the parietal and even frontal lobes, which fit the locations of known late pathological changes. In conclusion, MK can complement conventional diffusion metrics for detecting microstructural changes, especially in deep gray matter. This study also provides evidence supporting the notion that microstructural changes predate morphological changes. Hum Brain Mapp 38:2495-2508, 2017. © 2017 Wiley Periodicals, Inc.

Introduction Alzheimer's disease (AD) is an age‐related neurodegenerative disorder. One of the pathological features of AD is neuronal loss in brain regions associated with cognition, particularly the hippocampus. An enriched environment (EE) can facilitate neuronal plasticity and improve behaviors such as emotion, motor function, and cognition in AD. Methods After APP/PS1 mice were exposed to EE at an early stage (2 months of age), elevated plus maze performance and contextual fear conditioning were tested, and neurogenesis and the extent of activation in the hippocampus were observed. Results The results showed that, compared with that in the mice that experienced a standard environment, the cognition of the mice exposed to EE, as measured by contextual fear conditioning, was not statistically significant. However, based on their performance in the elevated plus maze, the index was increased in the mice, especially the APP/PS1 mice, exposed to EE. Consistent with the behavioral changes, the APP/PS1 mice exposed to EE showed an increased number of c‐Fos‐positive neurons and elevated neurogenesis in the dentate gyrus (DG) area. In addition, the activation of newborn neurons did not occur in the other three groups. Conclusions These results indicate that the activation of newborn neurons may participate in the improvement of behavioral performance in APP/PS1 mice after EE.

Excitatory hippocampal granule cells regulate activation and transition of quiescent neural stem cells during voluntary exercise., The quiescence of radial neural stem cells (rNSCs) in adult brain is regulated by environmental stimuli. However, little is known about how the neurogenic niche couples the external signal to regulate activation and transition of quiescent rNSCs. Here, we reveal that long-term excitation of hippocampal dentate granule cells (GCs) upon voluntary running leads to activation of adult rNSCs in the subgranular zone and thereby generation of newborn neurons. Unexpectedly, the role of these excited GC neurons in NSCs depends on direct GC-rNSC interaction in the local niche, which is through down-regulated ephrin-B3, a GC membrane–bound ligand, and attenuated transcellular EphB2 kinase–dependent signaling in the adjacent rNSCs. Furthermore, constitutively active EphB2 kinase sustains the quiescence of rNSCs during running. These findings thus elucidate the physiological significance of GC excitability on adult rNSCs under external environments and indicate a key-lock switch regulation via cell-cell contact for functional transition of rNSCs.

Journal of synchrotron radiation 26(2), 393 - 405 (2019). doi:10.1107/S1600577519001267, MXCuBE2 is the second-generation evolution of the MXCuBE beamline control software, initially developed and used at ESRF – the European Synchrotron. MXCuBE2 extends, in an intuitive graphical user interface (GUI), the functionalities and data collection methods available to users while keeping all previously available features and allowing for the straightforward incorporation of ongoing and future developments. MXCuBE2 introduces an extended abstraction layer that allows easy interfacing of any kind of macromolecular crystallography (MX) hardware component, whether this is a diffractometer, sample changer, detector or optical element. MXCuBE2 also works in strong synergy with the ISPyB Laboratory Information Management System, accessing the list of samples available for a particular experimental session and associating, either from instructions contained in ISPyB or from user input via the MXCuBE2 GUI, different data collection types to them. The development of MXCuBE2 forms the core of a fruitful collaboration which brings together several European synchrotrons and a software development factory and, as such, defines a new paradigm for the development of beamline control platforms for the European MX user community., Published by Wiley-Blackwell, [S.l.]

Cancer often arises by the constitutive activation of mitogenic pathways by mutations in stem cells. Eph receptors are unusual in that although they regulate the proliferation of stem/progenitor cells in many adult organs, they typically fail to transform cells. Multiple ephrins and Eph receptors are often co-expressed and are thought to be redundant, but we here describe an unexpected dichotomy with two homologous ligands, ephrin-B1 and ephrin-B2, regulating specifically migration or proliferation in the intestinal stem cell niche. We demonstrate that the combined activity of two different coexpressed Eph receptors of the A and B class assembled into common signaling clusters in response to ephrin-B2 is required for mitogenic signaling. The requirement of two different Eph receptors to convey mitogenic signals identifies a new type of cooperation within this receptor family and helps explain why constitutive activation of a single receptor fails to transform cells.

Learning to extinguish traumatic memory depends on fine-tuning of hippocampal-prefrontal connections via the ASIC1a channel., Extinction of conditioned fear necessitates the dynamic involvement of hippocampus, medial prefrontal cortex (mPFC), and basolateral amygdala (BLA), but key molecular players that regulate these circuits to achieve fear extinction remain largely unknown. Here, we report that acid-sensing ion channel 1a (ASIC1a) is a crucial molecular regulator of fear extinction, and that this function requires ASIC1a in ventral hippocampus (vHPC), but not dorsal hippocampus, mPFC, or BLA. While genetic disruption or pharmacological inhibition of ASIC1a in vHPC attenuated the extinction of conditioned fear, overexpression of the channel in this area promoted fear extinction. Channelrhodopsin-2–assisted circuit mapping revealed that fear extinction involved an ASIC1a-dependent modification of the long-range hippocampal-prefrontal correlates in a projection-specific manner. Gene expression profiling analysis and validating experiments identified several neuronal activity–regulated and memory-related genes, including Fos, Npas4, and Bdnf, as the potential mediators of ASIC1a regulation of fear extinction. Mechanistically, genetic overexpression of brain-derived neurotrophic factor (BDNF) in vHPC or supplement of BDNF protein in mPFC both rescued the deficiency in fear extinction and the deficits on extinction-driven adaptations of hippocampal-prefrontal correlates caused by the Asic1a gene inactivation in vHPC. Together, these results establish ASIC1a as a critical constituent in fear extinction circuits and thus a promising target for managing adaptive behaviors.

Acid-sensing ion channel 1a (ASIC1a) is abundant in multiple brain regions, including the striatum, which serves as the input nucleus of the basal ganglia and is critically involved in procedural learning and motor memory. We investigated the functional role of ASIC1a in striatal neurons. We found that ASIC1a was critical for striatum-dependent motor coordination and procedural learning by regulating the synaptic plasticity of striatal medium spiny neurons. Global deletion of Asic1a in mice led to increased dendritic spine density but impaired spine morphology and postsynaptic architecture, which were accompanied by the decreased function of N-methyl-D-aspartate (NMDA) receptors at excitatory synapses. These structural and functional changes caused by the loss of ASIC1a were largely mediated by reduced activation (phosphorylation) of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal–regulated protein kinases (ERKs). Consequently, Asic1a null mice exhibited poor performance on multiple motor tasks, which was rescued by striatal-specific expression of either ASIC1a or CaMKII. Together, our data reveal a previously unknown mechanism mediated by ASIC1a that promotes the excitatory synaptic function underlying striatum-related procedural learning and memory.

The soil microbial community and soil enzyme activity are important parts of soil ecosystem,and they are sensitive to the ecological environment.In this study,citrus plantation in Mt.Jinyun was chosen as the research object.The phospholipid fatty acid (PLFAs) combined with principal component analysis method was used to study the effect of season changes on soil microbial quantity,community structure characteristics and soil enzyme activity at 0-20 cm soil layer under citrus forest.The results obtained from this study were as follows:① The season changes had a significant impact on soil microbes (

Synapse formation relies on the coordination of dynamic pre- and postsynaptic structures during brain development. Liu et al. reveal that presynaptic terminal maturation of mossy fiber axons is retrogradely regulated by postsynaptic scaffold protein Lnx1 via stabilizing EphB receptor kinases., Neuronal connections are initiated by axon targeting to form synapses. However, how the maturation of axon terminals is modulated through interacting with postsynaptic elements remains elusive. In this study, we find that ligand of Numb protein X 1 (Lnx1), a postsynaptic PDZ protein expressed in hippocampal CA3 pyramidal neurons, is essential for mossy fiber (MF) axon targeting during the postnatal period. Lnx1 deletion causes defective synaptic arrangement that leads to aberrant presynaptic terminals. We further identify EphB receptors as novel Lnx1-binding proteins to form a multiprotein complex that is stabilized on the CA3 neuron membrane through preventing proteasome activity. EphB1 and EphB2 are independently required to transduce distinct signals controlling MF pruning and targeting for precise DG-CA3 synapse formation. Furthermore, constitutively active EphB2 kinase rescues structure of the wired MF terminals in Lnx1 mutant mice. Our data thus define a retrograde trans-synaptic regulation required for integration of post- and presynaptic structure that participates in building hippocampal neural circuits during the adolescence period., Graphical Abstract

The BioMAX beamline at MAX IV is devoted to macromolecular crystallography and will achieve a high level of experimental automation when its full potential is reached due to the usage of high end instrumentation and comprehensive software environment. The control system is based on Tango and Sardana for managing the main elements of the beamline. Data acquisition and experiment control is done through MXCuBE v3, which interfaces with the control layer. Currently, the most critical elements such as the detector and diffractometer are already integrated into the control system, whereas the integration of the sample changer has already started. BioMAX has received its first users, who successfully collected diffraction data and provided feedback on the general performance of the control system and its usability. The present work describes the main features of the control system and its operation, as well as the next instrument integration plans, Proceedings of the 16th Int. Conf. on Accelerator and Large Experimental Control Systems, ICALEPCS2017, Barcelona, Spain

Axonal outgrowth and guidance require numerous extracellular cues and intracellular mediators that transduce signals in the growth cone to regulate cytoskeletal dynamics. However, the way in which cytoskeletal effectors respond to these signals remains elusive. Here, we demonstrate that Porf-2, a neuron-expressed RhoGTPase-activating protein, plays an essential role in the inhibition of initial axon growth by restricting the expansion of the growth cone in a cell-autonomous manner. Furthermore, the EphB1 receptor is identified as an upstream controller that binds and regulates Porf-2 specifically upon extracellular ephrin-B stimulation. The activated EphB forward signal deactivates Rac1 through the GAP domain of Porf-2, which inhibits growth cone formation and brakes axon growth. Our results therefore provide a novel GAP that regulates axon growth and braking sequentially through Eph receptor-independent and Eph receptor-dependent pathways.

The purpose of this work was to investigate the effects of hemispheric location, gender and age on susceptibility value, as well as the association between susceptibility value and diffusional metrics, in deep gray matter. Iron content was estimated in vivo using quantitative susceptibility mapping. Microstructure was probed using diffusional kurtosis imaging. Regional susceptibility and diffusional metrics were measured for the putamen, caudate nucleus, globus pallidus, thalamus, substantia nigra and red nucleus in 42 healthy adults (age range 25-78 years). Susceptibility value was significantly higher in the left than the right side of the caudate nucleus (P = 0.043) and substantia nigra (P < 0.001). Women exhibited lower susceptibility values than men in the thalamus (P < 0.001) and red nucleus (P = 0.032). Significant age-related increases of susceptibility were observed in the putamen (P < 0.001), red nucleus (P < 0.001), substantia nigra (P = 0.004), caudate nucleus (P < 0.001) and globus pallidus (P = 0.017). The putamen exhibited the highest rate of iron accumulation with aging (slope of linear regression = 0.73 × 10(-3) ppm/year), which was nearly twice those in substantia nigra (slope = 0.40 × 10(-3) ppm/year) and caudate nucleus (slope = 0.39 × 10(-3) ppm/year). Significant positive correlations between the susceptibility value and diffusion measurements were observed for fractional anisotropy (P = 0.045) and mean kurtosis (P = 0.048) in the putamen without controlling for age. Neither correlation was significant after controlling for age. Hemisphere, gender and age-related differences in iron measurements were observed in deep gray matter. Notably, the putamen exhibited the highest rate of increase in susceptibility with aging. Correlations between susceptibility value and microstructural measurements were inconclusive. These findings could provide new clues for unveiling mechanisms underlying iron-related neurodegenerative diseases.

With the rapid development of china railway, ZPW-2000A track circuit has been widely used. Tuning area, which is an important part of the ZPW-2000A track circuit, is not only the relationship between the signal transmission quality, and determine the effect of electrical insulation between adjacent sections. Therefore, the study of fault diagnosis aspects for tuning area is urgent and significant. In this paper, using the theory of transmission line a model of track circuit is built, the comparison of the actual data and experimental data of the track surface voltage envelope curve shows the correctness of this model. Owning to the good time-frequency characteristics of wavelet and the nonlinear mapping features of neural network, a fault diagnosis of ZPW-2000A tuning area based on the wavelet neural network(WNN) is proposed. Combined with the practical failure situation of railway site, the fault diagnosis method in this paper can accurately identify failure modes of tuning area.