Publications by authors named "Guolin Ma"

68 Publications

3D IFPN: Improved Feature Pyramid Network for Automatic Segmentation of Gastric Tumor.

Front Oncol 2021 20;11:618496. Epub 2021 May 20.

School of Biomedical Engineering, Shenzhen University, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Shenzhen, China.

Automatic segmentation of gastric tumor not only provides image-guided clinical diagnosis but also assists radiologists to read images and improve the diagnostic accuracy. However, due to the inhomogeneous intensity distribution of gastric tumors in CT scans, the ambiguous/missing boundaries, and the highly variable shapes of gastric tumors, it is quite challenging to develop an automatic solution. This study designs a novel 3D improved feature pyramidal network (3D IFPN) to automatically segment gastric tumors in computed tomography (CT) images. To meet the challenges of this extremely difficult task, the proposed 3D IFPN makes full use of the complementary information within the low and high layers of deep convolutional neural networks, which is equipped with three types of feature enhancement modules: 3D adaptive spatial feature fusion (ASFF) module, single-level feature refinement (SLFR) module, and multi-level feature refinement (MLFR) module. The 3D ASFF module adaptively suppresses the feature inconsistency in different levels and hence obtains the multi-level features with high feature invariance. Then, the SLFR module combines the adaptive features and previous multi-level features at each level to generate the multi-level refined features by skip connection and attention mechanism. The MLFR module adaptively recalibrates the channel-wise and spatial-wise responses by adding the attention operation, which improves the prediction capability of the network. Furthermore, a stage-wise deep supervision (SDS) mechanism and a hybrid loss function are also embedded to enhance the feature learning ability of the network. CT volumes dataset collected in three Chinese medical centers was used to evaluate the segmentation performance of the proposed 3D IFPN model. Experimental results indicate that our method outperforms state-of-the-art segmentation networks in gastric tumor segmentation. Moreover, to explore the generalization for other segmentation tasks, we also extend the proposed network to liver tumor segmentation in CT images of the MICCAI 2017 Liver Tumor Segmentation Challenge.
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http://dx.doi.org/10.3389/fonc.2021.618496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173118PMC
May 2021

Dual-energy computed tomography could reliably differentiate metastatic from non-metastatic lymph nodes of less than 0.5 cm in patients with papillary thyroid carcinoma.

Quant Imaging Med Surg 2021 Apr;11(4):1354-1367

Department of Radiology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.

Background: Dual-energy computed tomography (DECT) has been widely applied to detect lymph node (LN) and lymph node metastasis (LNM) in various cancers, including papillary thyroid carcinoma (PTC). This study aimed to quantitatively evaluate metastatic cervical lymph nodes (LNs) <0.5 cm in patients with PTC using DECT, which has not been done in previous studies.

Methods: Preoperative DECT data of patients with pathologically confirmed PTC were retrospectively collected and analyzed between May 2016 and June 2018. A total of 359 LNs from 52 patients were included. Diameter, iodine concentration (IC), normalized iodine concentration (NIC), and the slope of the energy spectrum curve (λ) of LNs in the arterial and the venous phases were compared between metastatic and non-metastatic LNs. The optimal parameters were obtained from the receiver operating characteristic (ROC) curves. The generalized estimation equation (GEE) model was used to evaluate independent diagnostic factors for LNM.

Results: A total of 139 metastatic and 220 non-metastatic LNs were analyzed. There were statistical differences of quantitative parameters between the two groups (P value 0.000-0.007). The optimal parameter for diagnosing LNM was IC in the arterial phase, and its area under the curve (AUC), sensitivity, and specificity were 0.775, 71.9%, and 73.6%, respectively. When the three parameters of diameter, IC in the arterial phase, and NIC in the venous phase were combined, the prediction efficiency was better, and the AUC was 0.819. The GEE results showed that LNs located in level VIa [odds ratio (OR) 2.030, 95% confidence interval (CI): 1.134-3.634, P=0.017], VIb (OR 2.836, 95% CI: 1.597-5.038, P=0.000), diameter (OR 2.023, 95% CI: 1.158-3.532, P=0.013), IC in the arterial phase (OR 4.444, 95% CI: 2.808-7.035, P=0.000), and IC in the venous phase (OR 5.387, 95% CI: 3.449-8.413, P=0.000) were independent risk factors for LNM in patients with PTC.

Conclusions: DECT had good diagnostic performance in the differentiation of cervical metastatic LNs <0.5 cm in patients with PTC.
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http://dx.doi.org/10.21037/qims-20-846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930679PMC
April 2021

Multi-U-Net: Residual Module under Multisensory Field and Attention Mechanism Based Optimized U-Net for VHR Image Semantic Segmentation.

Sensors (Basel) 2021 Mar 5;21(5). Epub 2021 Mar 5.

Key Laboratory of Smart City and Environment Modeling of Autonomous Region Universities, College of Resources and Environment Sciences, Xinjiang University, Urumqi 830046, China.

As the acquisition of very high resolution (VHR) images becomes easier, the complex characteristics of VHR images pose new challenges to traditional machine learning semantic segmentation methods. As an excellent convolutional neural network (CNN) structure, U-Net does not require manual intervention, and its high-precision features are widely used in image interpretation. However, as an end-to-end fully convolutional network, U-Net has not explored enough information from the full scale, and there is still room for improvement. In this study, we constructed an effective network module: residual module under a multisensory field (RMMF) to extract multiscale features of target and an attention mechanism to optimize feature information. RMMF uses parallel convolutional layers to learn features of different scales in the network and adds shortcut connections between stacked layers to construct residual blocks, combining low-level detailed information with high-level semantic information. RMMF is universal and extensible. The convolutional layer in the U-Net network is replaced with RMMF to improve the network structure. Additionally, the multiscale convolutional network was tested using RMMF on the Gaofen-2 data set and Potsdam data sets. Experiments show that compared to other technologies, this method has better performance in airborne and spaceborne images.
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http://dx.doi.org/10.3390/s21051794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961556PMC
March 2021

Predicting the Level of Tumor-Infiltrating Lymphocytes in Patients With Breast Cancer: Usefulness of Mammographic Radiomics Features.

Front Oncol 2021 11;11:628577. Epub 2021 Mar 11.

Department of Radiology, China-Japan Friendship Hospital, Beijing, China.

Objectives: This study aimed to investigate whether radiomics classifiers from mammography can help predict tumor-infiltrating lymphocyte (TIL) levels in breast cancer.

Methods: Data from 121 consecutive patients with pathologically-proven breast cancer who underwent preoperative mammography from February 2018 to May 2019 were retrospectively analyzed. Patients were randomly divided into a training dataset (n = 85) and a validation dataset (n = 36). A total of 612 quantitative radiomics features were extracted from mammograms using the Pyradiomics software. Radiomics feature selection and radiomics classifier were generated through recursive feature elimination and logistic regression analysis model. The relationship between radiomics features and TIL levels in breast cancer patients was explored. The predictive capacity of the radiomics classifiers for the TIL levels was investigated through receiver operating characteristic curves in the training and validation groups. A radiomics score (Rad score) was generated using a logistic regression analysis method to compute the training and validation datasets, and combining the Mann-Whitney U test to evaluate the level of TILs in the low and high groups.

Results: Among the 121 patients, 32 (26.44%) exhibited high TIL levels, and 89 (73.56%) showed low TIL levels. The ER negativity (p = 0.01) and the Ki-67 negative threshold level (p = 0.03) in the low TIL group was higher than that in the high TIL group. Through the radiomics feature selection, six top-class features [Wavelet GLDM low gray-level emphasis (mediolateral oblique, MLO), GLRLM short-run low gray-level emphasis (craniocaudal, CC), LBP2D GLRLM short-run high gray-level emphasis (CC), LBP2D GLDM dependence entropy (MLO), wavelet interquartile range (MLO), and LBP2D median (MLO)] were selected to constitute the radiomics classifiers. The radiomics classifier had an excellent predictive performance for TIL levels both in the training and validation sets [area under the curve (AUC): 0.83, 95% confidence interval (CI), 0.738-0.917, with positive predictive value (PPV) of 0.913; AUC: 0.79, 95% CI, 0.615-0.964, with PPV of 0.889, respectively]. Moreover, the Rad score in the training dataset was higher than that in the validation dataset (p = 0.007 and p = 0.001, respectively).

Conclusion: Radiomics from digital mammograms not only predicts the TIL levels in breast cancer patients, but can also serve as non-invasive biomarkers in precision medicine, allowing for the development of treatment plans.
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http://dx.doi.org/10.3389/fonc.2021.628577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991288PMC
March 2021

Regional brain network and behavioral alterations in EGR3 gene transfected rat model of schizophrenia.

Brain Imaging Behav 2021 Mar 15. Epub 2021 Mar 15.

School of Life Science, Beijing Institute of Technology, No.5 Zhongguancun South Street, Haidian District, Beijing, 100081, China.

Schizophrenia is a severe psychiatric disease while its etiology and effective treatment are not completely clear. A rat model of schizophrenia was previously established by transfecting EGR3 gene into the hippocampus of rats. This study aimed to investigate the behavioral and cerebral alterations of the schizophrenic model rats and the risperidone effects. Twenty-six rats were divided into 3 groups: schizophrenia model group (E group), risperidone treatment group (T group), and healthy control group (H group). Morris water maze and open field test were used as behavioral tests, resting-state functional magnetic resonance imaging (fMRI) was performed after EGR3 gene transfection and risperidone therapy. Graph analyses were used for examining cerebral alterations of the rats. Behavioral tests demonstrated reduced spatial working memory and exploring unfamiliar space ability in schizophrenic model rats. Graph analyses revealed reduced regional architectures in the olfactory bulb, nucleus accumbens, and pineal gland in group E compared to group H (p < 0.05), while group T showed increased regional architecture in pineal gland compared to group E (p < 0.05). Besides, the regional architectures in the olfactory bulb, nucleus accumbens were lower in group T than group H, while the hippocampus showed increased regional architecture in group T compared to group H (p < 0.05). Schizophrenia induced several regional alterations in the cerebrum while risperidone can reverse part of these alterations. This study lends support for future research on the pathology of schizophrenia and provides new insights on the role of risperidone in schizophrenia.
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http://dx.doi.org/10.1007/s11682-021-00462-3DOI Listing
March 2021

Alterations and Associations Between Magnetic Susceptibility of the Basal Ganglia and Diffusion Properties in Alzheimer's Disease.

Front Neurosci 2021 16;15:616163. Epub 2021 Feb 16.

Department of Radiology, China-Japan Friendship Hospital, Beijing, China.

This study adopted diffusion tensor imaging to detect alterations in the diffusion parameters of the white matter fiber in Alzheimer's disease (AD) and used quantitative susceptibility mapping to detect changes in magnetic susceptibility. However, whether the changes of susceptibility values due to excessive iron in the basal ganglia have correlations with the alterations of the diffusion properties of the white matter in patients with AD are still unknown. We aim to investigate the correlations among magnetic susceptibility values of the basal ganglia, diffusion indexes of the white matter, and cognitive function in patients with AD. Thirty patients with AD and nineteen healthy controls (HCs) were recruited. Diffusion indexes of the whole brain were detected using tract-based spatial statistics. The caudate nucleus, putamen, and globus pallidus were selected as regions of interest, and their magnetic susceptibility values were measured. Compared with HCs, patients with AD showed that there were significantly increased axial diffusivity (AxD) in the internal capsule, superior corona radiata (SCR), and right anterior corona radiata (ACR); increased radial diffusivity (RD) in the right anterior limb of the internal capsule, ACR, and genu of the corpus callosum (GCC); and decreased fractional anisotropy (FA) in the right ACR and GCC. The alterations of RD values, FA values, and susceptibility values of the right caudate nucleus in patients with AD were correlated with cognitive scores. Besides, AxD values in the right internal capsule, ACR, and SCR were positively correlated with the magnetic susceptibility values of the right caudate nucleus in patients with AD. Our findings revealed that the magnetic susceptibility of the caudate nucleus may be an MRI-based biomarker of the cognitive dysfunction of AD and abnormal excessive iron distribution in the basal ganglia had adverse effects on the diffusion properties of the white matter.
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http://dx.doi.org/10.3389/fnins.2021.616163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921325PMC
February 2021

3D Multi-Attention Guided Multi-Task Learning Network for Automatic Gastric Tumor Segmentation and Lymph Node Classification.

IEEE Trans Med Imaging 2021 06 1;40(6):1618-1631. Epub 2021 Jun 1.

Automatic gastric tumor segmentation and lymph node (LN) classification not only can assist radiologists in reading images, but also provide image-guided clinical diagnosis and improve diagnosis accuracy. However, due to the inhomogeneous intensity distribution of gastric tumor and LN in CT scans, the ambiguous/missing boundaries, and highly variable shapes of gastric tumor, it is quite challenging to develop an automatic solution. To comprehensively address these challenges, we propose a novel 3D multi-attention guided multi-task learning network for simultaneous gastric tumor segmentation and LN classification, which makes full use of the complementary information extracted from different dimensions, scales, and tasks. Specifically, we tackle task correlation and heterogeneity with the convolutional neural network consisting of scale-aware attention-guided shared feature learning for refined and universal multi-scale features, and task-aware attention-guided feature learning for task-specific discriminative features. This shared feature learning is equipped with two types of scale-aware attention (visual attention and adaptive spatial attention) and two stage-wise deep supervision paths. The task-aware attention-guided feature learning comprises a segmentation-aware attention module and a classification-aware attention module. The proposed 3D multi-task learning network can balance all tasks by combining segmentation and classification loss functions with weight uncertainty. We evaluate our model on an in-house CT images dataset collected from three medical centers. Experimental results demonstrate that our method outperforms the state-of-the-art algorithms, and obtains promising performance for tumor segmentation and LN classification. Moreover, to explore the generalization for other segmentation tasks, we also extend the proposed network to liver tumor segmentation in CT images of the MICCAI 2017 Liver Tumor Segmentation Challenge. Our implementation is released at https://github.com/infinite-tao/MA-MTLN.
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http://dx.doi.org/10.1109/TMI.2021.3062902DOI Listing
June 2021

Anterior Mediastinal Lesion Segmentation Based on Two-Stage 3D ResUNet With Attention Gates and Lung Segmentation.

Front Oncol 2020 8;10:618357. Epub 2021 Feb 8.

Beijing Engineering Research Center of Mixed Reality and Advanced Display, School of Optics and Photonics, Beijing Institute of Technology, Beijing, China.

Objectives: Anterior mediastinal disease is a common disease in the chest. Computed tomography (CT), as an important imaging technology, is widely used in the diagnosis of mediastinal diseases. Doctors find it difficult to distinguish lesions in CT images because of image artifact, intensity inhomogeneity, and their similarity with other tissues. Direct segmentation of lesions can provide doctors a method to better subtract the features of the lesions, thereby improving the accuracy of diagnosis.

Method: As the trend of image processing technology, deep learning is more accurate in image segmentation than traditional methods. We employ a two-stage 3D ResUNet network combined with lung segmentation to segment CT images. Given that the mediastinum is between the two lungs, the original image is clipped through the lung mask to remove some noises that may affect the segmentation of the lesion. To capture the feature of the lesions, we design a two-stage network structure. In the first stage, the features of the lesion are learned from the low-resolution downsampled image, and the segmentation results under a rough scale are obtained. The results are concatenated with the original image and encoded into the second stage to capture more accurate segmentation information from the image. In addition, attention gates are introduced in the upsampling of the network, and these gates can focus on the lesion and play a role in filtering the features. The proposed method has achieved good results in the segmentation of the anterior mediastinal.

Results: The proposed method was verified on 230 patients, and the anterior mediastinal lesions were well segmented. The average Dice coefficient reached 87.73%. Compared with the model without lung segmentation, the model with lung segmentation greatly improved the accuracy of lesion segmentation by approximately 9%. The addition of attention gates slightly improved the segmentation accuracy.

Conclusion: The proposed automatic segmentation method has achieved good results in clinical data. In clinical application, automatic segmentation of lesions can assist doctors in the diagnosis of diseases and may facilitate the automated diagnosis of illnesses in the future.
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http://dx.doi.org/10.3389/fonc.2020.618357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901488PMC
February 2021

Caffeine-Operated Synthetic Modules for Chemogenetic Control of Protein Activities by Life Style.

Adv Sci (Weinh) 2021 Feb 13;8(3):2002148. Epub 2020 Dec 13.

Center for Translational Cancer Research Institute of Biosciences and Technology Texas A&M University Houston TX 77030 USA.

A genetically encoded caffeine-operated synthetic module (COSMO) is introduced herein as a robust chemically induced dimerization (CID) system. COSMO enables chemogenetic manipulation of biological processes by caffeine and its metabolites, as well as caffeinated beverages, including coffee, tea, soda, and energy drinks. This CID tool, evolved from an anti-caffeine nanobody via cell-based high-throughput screening, permits caffeine-inducible gating of calcium channels, tumor killing via necroptosis, growth factors-independent activation of tyrosine receptor kinase signaling, and enhancement of nanobody-mediated antigen recognition for the severe acute respiratory distress coronavirus 2 (SARS-CoV-2) spike protein. Further rationalized engineering of COSMO leads to 34-217-fold enhancement in caffeine sensitivity (EC = 16.9 nanomolar), which makes it among the most potent CID systems like the FK506 binding protein (FKBP)-FKBP rapamycin binding domain (FRB)-rapamycin complex. Furthermore, bivalent COSMO (biCOMSO) connected with a long linker favors intramolecular dimerization and acts as a versatile precision switch when inserted in host proteins to achieve tailored function. Given the modularity and high transferability of COMSO and biCOSMO, these chemical biology tools are anticipated to greatly accelerate the development of therapeutic cells and biologics that can be switched on and off by caffeinated beverages commonly consumed in the daily life.
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http://dx.doi.org/10.1002/advs.202002148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856909PMC
February 2021

Alterations of Iron Level in the Bilateral Basal Ganglia Region in Patients With Middle Cerebral Artery Occlusion.

Front Neurosci 2020 21;14:608058. Epub 2021 Jan 21.

Department of Radiology, China-Japan Friendship Hospital, Beijing, China.

The purpose of this study was to explore the changes of iron level using quantitative susceptibility mapping (QSM) in the bilateral basal ganglia region in middle cerebral artery occlusion (MCAO) patients with long-term ischemia. Twenty-seven healthy controls and nine patients with MCAO were recruited, and their QSM images were obtained. The bilateral caudate nucleus (Cd), putamen (Pt), and globus pallidus (Gp) were selected as the regions of interest (ROIs). Susceptibility values of bilateral ROIs were calculated and compared between the affected side and unaffected side in patients with MCAO and between patients with MCAO and healthy controls. In addition, receiver operating characteristic (ROC) curves were performed to evaluate the diagnostic capability of susceptibility values in differentiating healthy controls and patients with MCAO by the area under the curve (AUC). The susceptibility values of bilateral Cd were asymmetric in healthy controls; however, this asymmetry disappeared in patients with MCAO. In addition, compared with healthy controls, the average susceptibility values of the bilateral Pt in patients with MCAO were increased ( < 0.05), and the average susceptibility value of the bilateral Gp was decreased < 0.05). ROC curves showed that the susceptibility values of the Pt and Gp had a larger AUC (AUC = 0.700 and 0.889, respectively). As measured by QSM, the iron levels of the bilateral basal ganglia region were significantly changed in patients with MCAO. Iron dyshomeostasis in the basal ganglia region might be involved in the pathophysiological process of middle cerebral artery stenosis and occlusion. These findings may provide a novel insight to profoundly address the pathophysiological mechanisms of MCAO.
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http://dx.doi.org/10.3389/fnins.2020.608058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859276PMC
January 2021

Engineering of a bona fide light-operated calcium channel.

Nat Commun 2021 01 11;12(1):164. Epub 2021 Jan 11.

Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.

The current optogenetic toolkit lacks a robust single-component Ca-selective ion channel tailored for remote control of Ca signaling in mammals. Existing tools are either derived from engineered channelrhodopsin variants without strict Ca selectivity or based on the stromal interaction molecule 1 (STIM1) that might crosstalk with other targets. Here, we describe the design of a light-operated Ca channel (designated LOCa) by inserting a plant-derived photosensory module into the intracellular loop of an engineered ORAI1 channel. LOCa displays biophysical features reminiscent of the ORAI1 channel, which enables precise optical control over Ca signals and hallmark Ca-dependent physiological responses. Furthermore, we demonstrate the use of LOCa to modulate aberrant hematopoietic stem cell self-renewal, transcriptional programming, cell suicide, as well as neurodegeneration in a Drosophila model of amyloidosis.
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http://dx.doi.org/10.1038/s41467-020-20425-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801460PMC
January 2021

Microwave-Induced Thermal Lesion Detection via Ultrasonic Scatterer Center Frequency Analysis with Autoregressive Cepstrum.

Crit Rev Biomed Eng 2020 ;48(2):85-93

Department of Radiology, China-Japan Friendship Hospital, Beijing, China.

We proposed a new method for microwave-induced thermal lesion detection using the autoregressive spectrum analysis of ultrasonic backscattered signals in this paper. Eighteen cases of microwave ablation experiments and twenty cases of water bath heating experiments were conducted. Ultrasonic radiofrequency data of normal and coagulated porcine liver tissues were collected through these two experiments. Then, autoregressive spectrum analysis was performed; the mean frequency of the dominant peak in the autoregressive spectrum was computed based on water bath experiments; and a method for recognizing normal and solidified tissues was obtained by comparing the difference of the dominant peak in the autoregressive spectrum. Two bandpass finite impulse response filters, whose passbands corresponded respectively to the dominant peak in the autoregressive spectrum of normal and coagulated tissues, were used to compute the power spectral integration for the microwave-induced experiments. Microwave-induced thermal lesions were detected based on the differences between the power spectral integrations from the two filters. Compared to the caliper-measured area, the power spectral integration detected area had an error of (10.25 ± 3.59). Experimental results indicated that the proposed method may be used in preliminary detection of microwave-induced thermal lesions.
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http://dx.doi.org/10.1615/CritRevBiomedEng.2020033670DOI Listing
January 2020

Anisotropy of Anomalous Diffusion Improves the Accuracy of Differentiating and Grading Alzheimer's Disease Using Novel Fractional Motion Model.

Front Aging Neurosci 2020 19;12:602510. Epub 2020 Nov 19.

Beijing City Key Lab for Medical Physics and Engineering, Institute of Heavy Ion Physics, School of Physics, Peking University, Beijing, China.

Recent evidence shows that the fractional motion (FM) model may be a more appropriate model for describing the complex diffusion process of water in brain tissue and has shown to be beneficial in clinical applications of Alzheimer's disease (AD). However, the FM model averaged the anomalous diffusion parameter values, which omitted the impacts of anisotropy. This study aimed to investigate the potential feasibility of anisotropy of anomalous diffusion using the FM model for distinguishing and grading AD patients. Twenty-four patients with AD and 11 matched healthy controls were recruited, diffusion MRI was obtained from all participants and analyzed using the FM model. Generalized fractional anisotropy (gFA), an anisotropy metric, was introduced and the gFA values of FM-related parameters, Noah exponent (α) and the Hurst exponent (), were calculated and compared between the healthy group and AD group and between the mild AD group and moderate AD group. The receiver-operating characteristic (ROC) analysis and the multivariate logistic regression analysis were used to assess the diagnostic performances of the anisotropy values and the directionally averaged values. The gFA(α) and gFA() values of the moderate AD group were higher than those of the mild AD group in left hippocampus. The gFA(α) value of the moderate AD group was significantly higher than that of the healthy control group in both the left and right hippocampus. The gFA(ADC) values of the moderate AD group were significantly lower than those of the mild AD group and healthy control group in the right hippocampus. Compared with the gFA(α), gFA(), α, and , the ROC analysis showed larger areas under the curves for combination of α + gFA(α) and the combination of + gFA() in differentiating the mild AD and moderate AD groups, and larger area under the curves for combination of α + gFA(α) in differentiating the healthy controls and AD groups. The anisotropy of anomalous diffusion could significantly differentiate and grade patients with AD, and the diagnostic performance was improved when the anisotropy metric was combined with commonly used directionally averaged values. The utility of anisotropic anomalous diffusion may provide novel insights to profoundly understand the neuropathology of AD.
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http://dx.doi.org/10.3389/fnagi.2020.602510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710869PMC
November 2020

Influence of EGR3 Transfection on Imaging and Behavior in Rats and Therapeutic Effect of Risperidone in Schizophrenia Model.

Front Psychiatry 2020 24;11:00787. Epub 2020 Sep 24.

Department of Radiology, China-Japan Friendship Hospital, Beijing, China.

Schizophrenia is a type of neurodevelopmental psychiatric disorder. However, to date, scientists have not discovered the etiology and effective treatment of this condition. We injected the early growth response gene (EGR3) into the bilateral hippocampus to build a schizophrenia rat model. Behavioral phenotyping and resting-state functional magnetic resonance imaging (rs-fMRI) were used to analyze the behavioral and cerebral alterations in the schizophrenia rat model. The efficacy of risperidone therapy was also evaluated. We divided 34 rats into four groups: schizophrenia model group (E group), sham-operation group (FE group), healthy control group (H group), and risperidone therapy group (T group). Open field test and Morris water maze were conducted as behavioral experiments. Next, we performed rs-fMRI after four weeks of EGR3 transfection and risperidone treatment and analyzed imaging data using regional homogeneity (ReHo), the amplitude of low-frequency fluctuations (ALFF), and functional connectivity (FC). We examined the difference in behavioral and neural activation among the four groups and considered the correlations between behavior and imaging results. EGR3 gene transfection decreased the total moved distance in the open field test and the duration in the Q5 zone of the Morris water maze. Risperidone treatment reversed the trend and improved the performance of rats in these behavioral tests. Schizophrenia induced several neural alterations in ALFF and ReHo metrics of the rat brain, and risperidone could partly reverse these alterations. The results suggest that similar research is required for schizophrenia and that risperidone may be a novel treatment for dysregulated neural activation in schizophrenia.
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http://dx.doi.org/10.3389/fpsyt.2020.00787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542223PMC
September 2020

Optogenetic approaches to control Ca-modulated physiological processes.

Curr Opin Physiol 2020 Oct 16;17:187-196. Epub 2020 Aug 16.

Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA.

As a versatile intracellular second messenger, calcium ion (Ca) regulates a plethora of physiological processes. To achieve precise control over Ca signals in living cells and organisms, a set of optogenetic tools have recently been crafted by engineering photosensitive domains into intracellular signaling proteins, G-protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), and Ca channels. We highlight herein the optogenetic engineering strategies, kinetic properties, advantages and limitations of these genetically-encoded Ca channel actuators (GECAs) and modulators. In parallel, we present exemplary applications in both excitable and non-excitable cells and tissues. Furthermore, we briefly discuss potential solutions for wireless optogenetics to accelerate the applications of GECAs under physiological conditions, with an emphasis on integrating near-infrared (NIR) light-excitable upconversion nanoparticles (UCNPs) and bioluminescence with optogenetics.
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http://dx.doi.org/10.1016/j.cophys.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654839PMC
October 2020

Medical Imaging Engineering and Technology Branch of the Chinese Society of Biomedical Engineering expert consensus on the application of Emergency Mobile Cabin CT.

Quant Imaging Med Surg 2020 Nov;10(11):2191-2207

The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Started during December 2019, following the emergence of several COVID-19 cases in Wuhan City, Hubei Province, there was a rapid surge and spread of new COVID-19 cases throughout China. The disease has since been included in the Class B infectious diseases category, as stipulated in the Law of the People's Republic of China on the Prevention and Treatment of Infectious Diseases and shall be managed according to Class A infectious diseases. During the early phases of COVID-19 infection, no specific pulmonary imaging features may be evident, or features overlapping with other pneumonia may be observed. Although CT is not the gold standard for the diagnosis of COVID-19, it nonetheless is a convenient and fast method, and its application can be deployed in community hospitals. Furthermore, CT can be used to render a suggestive diagnosis and evaluate the severity as well as the effects of therapeutic interventions for typical cases of COVID-19. The mobile emergency special CT device described in this document (also known as Emergency Mobile Cabin CT) has several unique characteristics, including its mobility, flexibility, and networking capabilities. Furthermore, it adopts a fully independent isolation design to avoid cross-infection between patients and medical staff. It can play an important role in screening suspected cases presenting with imaging features of COVID-19 in hospitals of various levels that provide care to suspected or confirmed COVID-19 patients as part of the first line procedures of epidemic prevention and control.
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http://dx.doi.org/10.21037/qims-20-980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547255PMC
November 2020

Identification and Classification of Alzheimer's Disease Patients Using Novel Fractional Motion Model.

Front Neurosci 2020 17;14:767. Epub 2020 Sep 17.

Department of Radiology, China-Japan Friendship Hospital, Beijing, China.

Most diffusion magnetic resonance imaging (dMRI) techniques use the mono-exponential model to describe the diffusion process of water in the brain. However, the observed dMRI signal decay curve deviates from the mono-exponential form. To solve this problem, the fractional motion (FM) model has been developed, which is regarded as a more appropriate model for describing the complex diffusion process in brain tissue. It is still unclear in the identification and classification of Alzheimer's disease (AD) patients using the FM model. The purpose of this study was to investigate the potential feasibility of FM model for differentiating AD patients from healthy controls and grading patients with AD. Twenty-four patients with AD and 11 healthy controls were included. The left and right hippocampus were selected as regions of interest (ROIs). The apparent diffusion coefficient (ADC) values and FM-related parameters, including the Noah exponent (α), the Hurst exponent (), and the memory parameter (=-1/), were calculated and compared between AD patients and healthy controls and between mild AD and moderate AD patients using a two-sample -test. The correlations between FM-related parameters α, , μ, and ADC values and the cognitive functions assessed by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) scales were investigated using Pearson partial correlation analysis in patients with AD. The receiver-operating characteristic analysis was used to assess the differential performance. We found that the FM-related parameter α could be used to distinguish AD patients from healthy controls ( < 0.05) with greater sensitivity and specificity (left ROI, 0.917 and 0.636; right ROI, 0.917 and 0.727) and grade AD patients ( < 0.05) showed higher sensitivity and specificity (right ROI, 0.917, 0.75). The α was found to be positively correlated with MMSE ( < 0.05) and MoCA ( < 0.05) scores in patients with AD, indicating that the α values in the bilateral hippocampus were a potential MRI-based biomarker of disease severity in AD patients. This novel diffusion model may be useful for further understanding neuropathologic changes in patients with AD.
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http://dx.doi.org/10.3389/fnins.2020.00767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533574PMC
September 2020

Altered brain language network in idiopathic peripheral facial paralysis patients with dysarthria.

Ann Transl Med 2020 Jun;8(11):699

Department of Radiology, China-Japan Friendship Hospital, Beijing, China.

Background: Dysarthria is one of the common symptoms of facial paralysis (FP). This study aimed to investigate functional alterations in the brain language network in early idiopathic peripheral FP patients with dysarthria using resting-state functional magnetic resonance imaging (fMRI).

Methods: A total of 45 cases of FP (left 22, right 23) and 34 cases of healthy control (HC) were recruited into this study. The data of patients with left-side FP and matched controls (17 cases) were flipped from left to right, and the brain regions were defined as ipsilateral and contralateral regions. The FC of 16 ROIs in classical language centers and regions that may be involved in language function were calculated. After identifying the differences of FC between the two groups, the correlation analysis between altered FC and TFGS score of oral muscle movement in FP group were analyzed.

Results: The FC between bilateral language regions has a significantly decreased trend in FP group compared with HC group (P<0.05). The ipsilateral inferior frontal gyrus, superior temporal gyrus, and middle temporal gyrus exhibited significantly decreased FC with multiple brain regions. In addition, we found that thalamus and cerebellum also with a significant alteration in FC in FP patients indicating that these two regions may also be involved in the mechanism of dysarthria in FP. The correlation analysis results indicated that the decrease of FC was positively correlated with the severity of oral paralysis.

Conclusions: Idiopathic peripheral FP with dysarthria induces several FC alterations in the brain language network. The severity of oral paralysis is associated with these functional alterations.
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http://dx.doi.org/10.21037/atm.2020.03.133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327355PMC
June 2020

A STIMulating journey into optogenetic engineering.

Cell Calcium 2020 May 4;88:102197. Epub 2020 May 4.

Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA. Electronic address:

Genetically-encoded calcium actuators (GECAs) stemmed from STIM1 have enabled optical activation of endogenous ORAI1 channels in both excitable and non-excitable tissues. These GECAs offer new non-invasive means to probe the structure-function relations of calcium channels and wirelessly control the behavior of awake mice.
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http://dx.doi.org/10.1016/j.ceca.2020.102197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609480PMC
May 2020

Correlation Between Mammographic Radiomics Features and the Level of Tumor-Infiltrating Lymphocytes in Patients With Triple-Negative Breast Cancer.

Front Oncol 2020 15;10:412. Epub 2020 Apr 15.

Beijing Engineering Research Center of Mixed Reality and Advanced Display, School of Optics and Photonics, Beijing Institute of Technology, Beijing, China.

Tumor-infiltrating lymphocytes (TILs) have been identified as a significant prognostic indicator of response to neoadjuvant therapy and immunotherapy for triple-negative breast cancer (TNBC) patients. Herein, we aim to assess the association between TIL levels and mammographic features in TNBC patients. Forty-three patients with surgically proven TNBC who underwent preoperative mammography from January 2018 to December 2018 were recruited. Pyradiomics software was used to extract 204 quantitative radiomics features, including morphologic, grayscale, and textural features, from the segmented lesion areas. The correlation between radiological characteristics and TIL levels was evaluated by screening the most statistically significant radiological features using Mann-Whitney -test and Pearson correlation coefficient. The patients were divided into two groups based on tumor TIL levels: patients with TIL levels <50% and those with TIL levels ≥50%. The correlation between TIL levels and clinicopathological characteristics was assessed using the chi-square test or Fisher's exact test. Mann-Whitney -test and Pearson correlation coefficient were used to analyze the statistical significance and Pearson correlation coefficient of clinical pathological features, age, and radiological features. Of 43 patients, 32 (74.4%) had low TIL levels and 11 (25.6%) had high TIL levels. The histological grade of the low TIL group was higher than that of the high TIL group ( = 0.043). The high TIL group had a more negative threshold Ki-67 level (<14%) than the low TIL group ( = 0.017). The six most important radiomics features [uniformity, variance, grayscale symbiosis matrix (GLCM) correlation, GLCM autocorrelation, gray level difference matrix (GLDM) low gray level emphasis, and neighborhood gray-tone difference matrix (NGTDM) contrast], representing qualitative mammographic image characteristics, were statistically different ( < 0.05) among the low and high TIL groups. Tumors in the high TIL group had a more non-uniform density and a smoother gradient of the tumor pattern than the low TIL group. The changes in Ki-67, age, epidermal growth factor receptor, radiomic characteristics, and Pearson correlation coefficient were statistically significant ( < 0.05). Mammography features not only distinguish high and low TIL levels in TNBC patients but also can act as imaging biomarkers to enhance diagnosis and the response of patients to neoadjuvant therapies and immunotherapies.
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http://dx.doi.org/10.3389/fonc.2020.00412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174560PMC
April 2020

Optical Control of CRAC Channels Using Photoswitchable Azopyrazoles.

J Am Chem Soc 2020 05 6;142(20):9460-9470. Epub 2020 May 6.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.

The Ca release-activated Ca (CRAC) channels control many Ca-modulated physiological processes in mammals. Hyperactivating CRAC channels are known to cause several human diseases, including Stormorken syndrome. Here, we show the design of azopyrazole-derived photoswitchable CRAC channel inhibitors (designated ), which enable optical inhibition of store-operated Ca influx and downstream signaling. Moreover, has been applied to alleviate thrombocytopenia and hemorrhage in a zebrafish model of Stormorken syndrome in a light-dependent manner.
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http://dx.doi.org/10.1021/jacs.0c02949DOI Listing
May 2020

Sulfenic Acid-Mediated on-Site-Specific Immobilization of Mitochondrial-Targeted NIR Fluorescent Probe for Prolonged Tumor Imaging.

Anal Chem 2020 05 1;92(10):6977-6983. Epub 2020 May 1.

State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China.

Mitochondria plays pivotal roles in energy production and apoptotic pathways. Mitochondria-targeting strategy has been recognized as a promising way for cancer theranostics. Thus, spatiotemporally manipulating the prolonged retention of theranostic agents within mitochondria is considerably significant in cancer diagnosis and therapy. Herein, as a proof-of concept, we for the first time report a sulfenic acid-responsive platform on controlled immobilization of probes within mitochondria for prolonged tumor imaging. A novel near-infrared (NIR) probe DATC constructed with a NIR dye (Cy5) as signal unit, a cationic triphenylphosphonium (TPP) for mitochondria targeting, and a sulfenic acid-reactive group (1,3-cyclohexanedione) for mitochondrial fixation was rationally designed and synthesized. This probe displayed good target ability to mitochondria and could act as a promising fluorescent probe for specific visualization of endogenous protein sulfenic acids expressed in the mitochondria. Moreover, the probe could be spontaneously fixed on site through the specific reaction and covalent binding to the sulfenic acids of oxidized proteins under oxidative stress, resulting in enhanced intracellular uptake and prolonged retention. We thus believe that this mitochondria-targeted and locational immobilization strategy may offer a new insight for long-term tumor imaging and effective therapy.
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http://dx.doi.org/10.1021/acs.analchem.9b05855DOI Listing
May 2020

Optogenetic engineering to probe the molecular choreography of STIM1-mediated cell signaling.

Nat Commun 2020 02 25;11(1):1039. Epub 2020 Feb 25.

Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA.

Genetically encoded photoswitches have enabled spatial and temporal control of cellular events to achieve tailored functions in living cells, but their applications to probe the structure-function relations of signaling proteins are still underexplored. We illustrate herein the incorporation of various blue light-responsive photoreceptors into modular domains of the stromal interaction molecule 1 (STIM1) to manipulate protein activity and faithfully recapitulate STIM1-mediated signaling events. Capitalizing on these optogenetic tools, we identify the molecular determinants required to mediate protein oligomerization, intramolecular conformational switch, and protein-target interactions. In parallel, we have applied these synthetic devices to enable light-inducible gating of calcium channels, conformational switch, dynamic protein-microtubule interactions and assembly of membrane contact sites in a reversible manner. Our optogenetic engineering approach can be broadly applied to aid the mechanistic dissection of cell signaling, as well as non-invasive interrogation of physiological processes with high precision.
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http://dx.doi.org/10.1038/s41467-020-14841-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042325PMC
February 2020

Relationship Between Computed Tomography Imaging Features and Clinical Characteristics, Masaoka-Koga Stages, and World Health Organization Histological Classifications of Thymoma.

Front Oncol 2019 11;9:1041. Epub 2019 Oct 11.

Department of Radiology, China-Japan Friendship Hospital, Beijing, China.

Computed tomography (CT) is an important technique for evaluating the condition and prognosis of patients with thymomas, and it provides guidance regarding treatment strategies. However, the correlation between CT imaging features, described using standard report terms, and clinical characteristics, Masaoka-Koga stages, and World Health Organization (WHO) classifications of patients with thymomas has not been described in detail nor has risk factor analysis been conducted. Overall, 159 patients with thymomas who underwent preoperative contrast-enhanced CT between September 2011 and December 2018 were retrospectively reviewed. We assessed the clinical information, CT imaging features, and pathological findings for each patient. A total of 89 patients were specially used to evaluate postoperative recurrence or metastasis between September 2011 and December 2015 to obtain an appropriate observation period. The relationship between CT imaging features and clinical characteristics, Masaoka-Koga stage, and WHO histological classification were analyzed, and related risk factors based on CT imaging features were identified. CT imaging features did not significantly differ based on sex or age. Some imaging features demonstrated significant differences between the groups with and without related clinical characteristics. Contour (odds ratio [OR] = 3.711, = 0.005), abutment ≥50% (OR = 4.277, = 0.02), and adjacent lung abnormalities (OR = 3.916 = 0.031) were independent risk factors for relapse or metastasis. Among all imaging features, there were significant differences between stage I/II and III/IV lesions in tumor size, calcification, infiltration of surrounding fat, vascular invasion, pleural nodules, elevated hemidiaphragm, and pulmonary nodules. Tumor size (odds ratio = 1.261, = 0.014), vascular invasion (OR = 2.526, = 0.023), pleural nodules (OR = 2.22, = 0.048), and pulmonary nodules (OR = 3.106, = 0.006) were identified as independent risk factors. Tumor size, contour, internal density, infiltration of surrounding fat, and pleural effusion significantly differed between low- and high-risk thymomas. Tumor size (OR = 1.183, = 0.048), contour (OR = 2.288, = 0.003), internal density (OR = 2.192, = 0.024), and infiltration of surrounding fat (OR = 2.811 = 0.005) were independent risk factors. Some CT imaging features demonstrated significant correlations with clinical characteristics, Masaoka-Koga clinical stages, and WHO histological classifications in patients with thymomas. Familiarity with CT features identified as independent risk factors for these related clinical characteristics can facilitate preoperative evaluation and treatment management for the patients with thymoma.
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http://dx.doi.org/10.3389/fonc.2019.01041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798238PMC
October 2019

Cuprous binding promotes interaction of copper transport protein hCTR1 with cell membranes.

Chem Commun (Camb) 2019 Sep 28;55(74):11107-11110. Epub 2019 Aug 28.

CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei Anhui, 230026, China.

Cu(i) binds to the N-terminal metal binding domain (MBD) of hCTR1 and induces its conformational change, which promotes the interaction of the MBD with cell membranes. The membrane interaction was confirmed in living cells. This process could be the first step to initiate the cellular uptake of copper ions by hCTR1.
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http://dx.doi.org/10.1039/c9cc04859fDOI Listing
September 2019

Differences in functional brain alterations driven by right or left facial nerve efferent dysfunction: Evidence from early Bell's palsy.

Quant Imaging Med Surg 2019 Mar;9(3):427-439

Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China.

Background: Bell's palsy is defined as idiopathic unilateral facial nerve palsy. Early Bell's palsy is characterized by emerging asymmetric motor conduction of the facial nerve and obvious imbalance of facial muscle movement, which can result in a substantial psychological impact on patients and trigger brain cortical functional reorganization. However, the differences between the brain functional alterations were driven by right or left facial nerve efferent dysfunction in patients with early Bell's palsy are not fully understood. The neuroimage study in patients with different-sided Bell's palsy in the early stage will help to understand the different mechanisms involved in functional integration driven by unilateral facial efferent nerve dysfunction and to provide the theoretical foundation for the choice of suitable treatment strategy.

Methods: Sixty-seven patients and 37 age- and sex-matched healthy controls were recruited to undergo resting-state functional magnetic resonance imaging (R-fMRI). Regional brain activity was analyzed by comparing the fractional amplitude of low-frequency fluctuations (fALFF) between right palsy and healthy control, left palsy and healthy control, and right and left palsy groups. The altered brain regions were further selected as seeds in subsequent functional connectivity (FC) analysis, and the correlations between the Toronto Facial Grading System (TFGS) scores and the connectivity alterations were also analyzed.

Results: The right and left Bell's palsy groups showed fALFF alterations compared with the healthy control group, and several brain regions with different fALFF values between the right and left palsy groups were identified. In the right palsy group, overall inter-regional FC increased in the right supramarginal gyrus (SMG), bilateral superior frontal gyrus (SFG), and left precentral gyrus (PreCG), compared with the left palsy group. Furthermore, the brain region pairs with higher FC in the right palsy group were left temporal pole of the superior temporal gyrus (TPOsup) and right SMG, left TPOsup and middle cingulate cortex (MCC), left TPOsup and left PreCG, right SMG and SFG, MCC and left PreCG, left and right SFG, and right SFG and left PreCG. In the right palsy group, the left TPOsup and PreCG showed a negative correlation with the TFGS score, while the right SFG and left PreCG showed a positive correlation with the TFGS scores. In the left palsy group, the left TPOsup and right SMG, and the right SMG and SFG region pairs showed a negative correlation with the TFGS score.

Conclusions: The fALFF and FC analyses revealed the remodeling of different brain functional networks driven by right or left facial nerve efferent dysfunction in patients with early Bell's palsy. The reintegration mechanisms differed between patients with right and left Bell's palsy. Additionally, the severity of the disease showed different associations with altered FC.
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http://dx.doi.org/10.21037/qims.2019.02.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462577PMC
March 2019

Altered Brain Fraction Amplitude of Low Frequency Fluctuation at Resting State in Patients With Early Left and Right Bell's Palsy: Do They Have Differences?

Front Neurosci 2018 2;12:797. Epub 2018 Nov 2.

Department of Radiology, China-Japan Friendship Hospital, Beijing, China.

Bell's palsy refers to acute idiopathic unilateral facial nerve palsy. It is a common disorder of the main motor pathway to the facial muscles. This study aimed to investigate the abnormal fraction amplitude of low frequency fluctuation (fALFF) of the brain in patients with early left and right Bell's palsy. Sixty-seven patients (left 33, right 34) and 37 age- and sex-matched healthy controls underwent resting-state functional magnetic resonance imaging (R-fMRI) examination. The fALFF values were measured from all subjects and were compared among the left palsy, right palsy, and control groups. Then, correlations between the Toronto Facial Grading System (TFGS) scores of the patients and the fALFF values of abnormal brain regions were analyzed. Significant group differences in fALFF values among the three groups were observed mainly in the cerebral cortical, subcortical, and deep gray matter regions. Compared with the right Bell's palsy group, the left Bell's palsy group showed significantly decreased fALFF values in the left temporal pole of the superior temporal gyrus (TPOsup), right supramarginal, left and right middle cingulate cortex (MCC), left superior frontal gyrus (SFG), and left precentral gyrus (PreCG), and increased fALFF values were observed in the right SFG and PreCG. Furthermore, altered fALFF values correlated positively with the TFGS scores in the left superior TPO, bilateral MCC, and right PreCG, and correlated negatively with the TFGS scores in the right SFG of the left Bell's palsy group. Altered fALFF values correlated positively with the TFGS scores in the bilateral MCC and right PreCG and correlated negatively with the TFGS scores in the left superior TPO and SFG of the right Bell's palsy group. Regulatory mechanisms seem to differ between patients with left and right early Bell's palsy. The severity of the disease is associated with these functional alterations.
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http://dx.doi.org/10.3389/fnins.2018.00797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225791PMC
November 2018

Identification of molecular determinants that govern distinct STIM2 activation dynamics.

PLoS Biol 2018 11 16;16(11):e2006898. Epub 2018 Nov 16.

Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, P. R. China.

The endoplasmic reticulum (ER) Ca2+ sensors stromal interaction molecule 1 (STIM1) and STIM2, which connect ER Ca2+ depletion with extracellular Ca2+ influx, are crucial for the maintenance of Ca2+ homeostasis in mammalian cells. Despite the recent progress in unraveling the role of STIM2 in Ca2+ signaling, the mechanistic underpinnings of its activation remain underexplored. We use an engineering approach to direct ER-resident STIMs to the plasma membrane (PM) while maintaining their correct membrane topology, as well as Förster resonance energy transfer (FRET) sensors that enabled in cellulo real-time monitoring of STIM activities. This allowed us to determine the calcium affinities of STIM1 and STIM2 both in cellulo and in situ, explaining the current discrepancies in the literature. We also identified the key structural determinants, especially the corresponding G residue in STIM1, which define the distinct activation dynamics of STIM2. The chimeric E470G mutation could switch STIM2 from a slow and weak Orai channel activator into a fast and potent one like STIM1 and vice versa. The systemic dissection of STIM2 activation by protein engineering sets the stage for the elucidation of the regulation and function of STIM2-mediated signaling in mammals.
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http://dx.doi.org/10.1371/journal.pbio.2006898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267984PMC
November 2018

Digitoxin Suppresses Store Operated Calcium Entry by Modulating Phosphorylation and the Pore Region of Orai1.

Curr Mol Med 2018 ;18(6):392-399

Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.

Background: Store-operated calcium entry (SOCE), primarily mediated by Orai1 and stromal interaction molecule 1 (STIM1), is a major Ca2+ influx pathway that has been linked to human diseases including myopathy, epilepsy, immunodeficiency, and cancer. Despite of the recent rapid progress of dissecting molecular mechanisms underlying SOCE activation, the development of therapies against dysfunctional SOCE significantly lags behind, partly due to the lack of more specific pharmacological tools and poor understanding of currently available SOCE modifiers, including the a newly identified SOCE inhibitor, digitoxin.

Objective And Methods: Capitalizing on Ca2+ imaging and pharmacological tools, we aimed to systemically delineate the mechanism of action of digitoxin by defining how it impinges on Orai1 to exert its suppressive effect on SOCE.

Results: The SOCE-suppressive function of digitoxin is dependent on S27-S30 residues of wild-type Orai1. With 8h-incubation of digitoxin with STIM1-prebound Orai1 or a constitutively active mutant Orai1-ANSGA, its inhibition was no longer dependent on S27-S30 residues. Instead, the inhibition may involve the pore region of Orai1 channels, as V102C mutant at the pore region would greatly diminish or abolish the inhibition on pre-activated Orai1.

Conclusions: Our study identified two regions that are critical for the inhibition on Orai1 channels, providing valuable hotspots for future design of SOCE inhibitors.
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http://dx.doi.org/10.2174/1566524018666181113111316DOI Listing
September 2019

TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10.

PLoS Biol 2018 11 8;16(11):e3000051. Epub 2018 Nov 8.

Center for Translational Cancer Research, Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas, United States of America.

Cancer cells adopt various modes of migration during metastasis. How the ubiquitination machinery contributes to cancer cell motility remains underexplored. Here, we report that tripartite motif (TRIM) 59 is frequently up-regulated in metastatic breast cancer, which is correlated with advanced clinical stages and reduced survival among breast cancer patients. TRIM59 knockdown (KD) promoted apoptosis and inhibited tumor growth, while TRIM59 overexpression led to the opposite effects. Importantly, we uncovered TRIM59 as a key regulator of cell contractility and adhesion to control the plasticity of metastatic tumor cells. At the molecular level, we identified programmed cell death protein 10 (PDCD10) as a target of TRIM59. TRIM59 stabilized PDCD10 by suppressing RING finger and transmembrane domain-containing protein 1 (RNFT1)-induced lysine 63 (K63) ubiquitination and subsequent phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa (p62)-selective autophagic degradation. TRIM59 promoted PDCD10-mediated suppression of Ras homolog family member A (RhoA)-Rho-associated coiled-coil kinase (ROCK) 1 signaling to control the transition between amoeboid and mesenchymal invasiveness. PDCD10 overexpression or administration of a ROCK inhibitor reversed TRIM59 loss-induced contractile phenotypes, thereby accelerating cell migration, invasion, and tumor formation. These findings establish the rationale for targeting deregulated TRIM59/PDCD10 to treat breast cancer.
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http://dx.doi.org/10.1371/journal.pbio.3000051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245796PMC
November 2018
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