Publications by authors named "Fa Zhang"

81 Publications

Richer fusion network for breast cancer classification based on multimodal data.

BMC Med Inform Decis Mak 2021 04 22;21(Suppl 1):134. Epub 2021 Apr 22.

Department of Oncology, Peking University International Hospital, Beijing, China.

Background: Deep learning algorithms significantly improve the accuracy of pathological image classification, but the accuracy of breast cancer classification using only single-mode pathological images still cannot meet the needs of clinical practice. Inspired by the real scenario of pathologists reading pathological images for diagnosis, we integrate pathological images and structured data extracted from clinical electronic medical record (EMR) to further improve the accuracy of breast cancer classification.

Methods: In this paper, we propose a new richer fusion network for the classification of benign and malignant breast cancer based on multimodal data. To make pathological image can be integrated more sufficient with structured EMR data, we proposed a method to extract richer multilevel feature representation of the pathological image from multiple convolutional layers. Meanwhile, to minimize the information loss for each modality before data fusion, we use the denoising autoencoder as a way to increase the low-dimensional structured EMR data to high-dimensional, instead of reducing the high-dimensional image data to low-dimensional before data fusion. In addition, denoising autoencoder naturally generalizes our method to make the accurate prediction with partially missing structured EMR data.

Results: The experimental results show that the proposed method is superior to the most advanced method in terms of the average classification accuracy (92.9%). In addition, we have released a dataset containing structured data from 185 patients that were extracted from EMR and 3764 paired pathological images of breast cancer, which can be publicly downloaded from http://ear.ict.ac.cn/?page_id=1663 .

Conclusions: We utilized a new richer fusion network to integrate highly heterogeneous data to leverage the structured EMR data to improve the accuracy of pathological image classification. Therefore, the application of automatic breast cancer classification algorithms in clinical practice becomes possible. Due to the generality of the proposed fusion method, it can be straightforwardly extended to the fusion of other structured data and unstructured data.
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http://dx.doi.org/10.1186/s12911-020-01340-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061018PMC
April 2021

Dilated-DenseNet For Macromolecule Classification In Cryo-electron Tomography.

Bioinform Res Appl 2020 Dec 18;12304:82-94. Epub 2020 Aug 18.

High Performance Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China.

Cryo-electron tomography (cryo-ET) combined with subtomogram averaging (STA) is a unique technique in revealing macromolecule structures in their near-native state. However, due to the macromolecular structural heterogeneity, low signal-to-noise-ratio (SNR) and anisotropic resolution in the tomogram, macromolecule classification, a critical step of STA, remains a great challenge. In this paper, we propose a novel convolution neural network, named 3D-Dilated-DenseNet, to improve the performance of macromolecule classification in STA. The proposed 3D-Dilated-DenseNet is challenged by the synthetic dataset in the SHREC contest and the experimental dataset, and compared with the SHREC-CNN (the state-of-the-art CNN model in the SHREC contest) and the baseline 3D-DenseNet. The results showed that 3D-Dilated-DenseNet significantly outperformed 3D-DenseNet but 3D-DenseNet is well above SHREC-CNN. Moreover, in order to further demonstrate the validity of dilated convolution in the classification task, we visualized the feature map of 3D-Dilated-DenseNet and 3D-DenseNet. Dilated convolution extracts a much more representative feature map.
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http://dx.doi.org/10.1007/978-3-030-57821-3_8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046028PMC
December 2020

Macromolecules Structural Classification with a 3D Dilated Dense Network in Cryo-electron Tomography.

IEEE/ACM Trans Comput Biol Bioinform 2021 Mar 17;PP. Epub 2021 Mar 17.

Cryo-electron tomography, combined with subtomogram averaging (STA), can reveal three-dimensional (3D) macromolecule structures in the near-native state from cells and other biological samples. In STA, to get a high-resolution 3D view of macromolecule structures, diverse macromolecules captured by the cellular tomograms need to be accurately classified. However, due to the poor signal-to-noise-ratio (SNR) and severe ray artifacts in the tomogram, it remains a major challenge to classify macromolecules with high accuracy.
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http://dx.doi.org/10.1109/TCBB.2021.3065986DOI Listing
March 2021

Editorial: Computational Learning Models and Methods Driven by Omics for Precision Medicine.

Front Genet 2020 23;11:620976. Epub 2020 Dec 23.

Faculty of Computing, Engineering and the Built Environment, School of Computing, Engineering and Intelligent Systems, Ulster University, Coleraine, United Kingdom.

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http://dx.doi.org/10.3389/fgene.2020.620976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785880PMC
December 2020

[Relationship between long non-coding RNA MALAT1 and prostate cancer].

Zhonghua Nan Ke Xue 2020 Feb;26(2):174-179

Department of Urology, Lanzhou University First Hospital / The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu 730000, China.

Prostate cancer (PCa), as a malignant tumor originating in the prostate glandular epithelium, has become a global "killer" that threatens the health of elderly men. PCa-related studies have been focusing on the progression mechanisms and treatment strategies of the malignancy, particularly on the role of long non-coding RNA (lncRNA) in recent years. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a key role in the progression and treatment of PCa, as well as in its metastasis and invasion and cell proliferation. lncRNA MALAT1 not only influences the biological characteristics of PCa, but also has a regulatory effect on the medicinal treatment of the disease, its action mechanisms involving ceRNA and AR signaling pathways. This review focuses on the relationship between lncRNA MALAT1 and PCa, aiming to provide a new research direction for the diagnosis and treatment of the malignancy.
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February 2020

Analysis of codon usage patterns in citrus based on coding sequence data.

BMC Genomics 2020 Dec 16;21(Suppl 5):234. Epub 2020 Dec 16.

High Performance Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, 100190, China.

Background: Codon usage is an important determinant of gene expression levels that can help us understand codon biology, evolution and mRNA translation of species. The majority of previous codon usage studies have focused on single species analysis, although few studies have focused on the species within the same genus. In this study, we proposed a multispecies codon usage analysis workflow to reveal the genetic features and correlation in citrus.

Results: Our codon usage analysis workflow was based on the GC content, GC plot, and relative synonymous codon usage value of each codon in 8 citrus species. This approach allows for the comparison of codon usage bias of different citrus species. Next, we performed cluster analysis and obtained an overview of the relationship in citrus. However, traditional methods cannot conduct quantitative analysis of the correlation. To further estimate the correlation among the citrus species, we used the frequency profile to construct feature vectors of each species. The Pearson correlation coefficient was used to quantitatively analyze the distance among the citrus species. This result was consistent with the cluster analysis.

Conclusions: Our findings showed that the citrus species are conserved at the genetic level and demonstrated the existing genetic evolutionary relationship in citrus. This work provides new insights into codon biology and the evolution of citrus and other plant species.
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http://dx.doi.org/10.1186/s12864-020-6641-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739459PMC
December 2020

Compressed sensing improved iterative reconstruction-reprojection algorithm for electron tomography.

BMC Bioinformatics 2020 Nov 18;21(Suppl 6):202. Epub 2020 Nov 18.

High Performance Computer Research Center, Institute Of Computing Technology, Chinese Academy of Sciences, Beijing, 100190, China.

Background: Electron tomography (ET) is an important technique for the study of complex biological structures and their functions. Electron tomography reconstructs the interior of a three-dimensional object from its projections at different orientations. However, due to the instrument limitation, the angular tilt range of the projections is limited within +70 to -70. The missing angle range is known as the missing wedge and will cause artifacts.

Results: In this paper, we proposed a novel algorithm, compressed sensing improved iterative reconstruction-reprojection (CSIIRR), which follows the schedule of improved iterative reconstruction-reprojection but further considers the sparsity of the biological ultra-structural content in specimen. The proposed algorithm keeps both the merits of the improved iterative reconstruction-reprojection (IIRR) and compressed sensing, resulting in an estimation of the electron tomography with faster execution speed and better reconstruction result. A comprehensive experiment has been carried out, in which CSIIRR was challenged on both simulated and real-world datasets as well as compared with a number of classical methods. The experimental results prove the effectiveness and efficiency of CSIIRR, and further show its advantages over the other methods.

Conclusions: The proposed algorithm has an obvious advance in the suppression of missing wedge effects and the restoration of missing information, which provides an option to the structural biologist for clear and accurate tomographic reconstruction.
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http://dx.doi.org/10.1186/s12859-020-3529-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672846PMC
November 2020

Live-SIMBA: an ImageJ plug-in for the universal and accelerated single molecule-guided Bayesian localization super resolution microscopy (SIMBA) method.

Biomed Opt Express 2020 Oct 25;11(10):5842-5859. Epub 2020 Sep 25.

High Performance Computer Research Center, Institute of Computing Technology Chinese Academy of Sciences, No. 6 Kexueyuan South Road, Haidian District, Beijing, 100190, China.

Live-cell super-resolution fluorescence microscopy techniques allow biologists to observe subcellular structures, interactions and dynamics at the nanoscale level. Among of them, single molecule-guided Bayesian localization super resolution microscopy (SIMBA) and its derivatives produce an appropriate 50 nm spatial resolution and a 0.1-2s temporal resolution in living cells with simple off-the-shelf total internal reflection fluorescence (TIRF) equipment. However, SIMBA and its derivatives are limited by the requirement for dual-channel dataset or single-channel dataset with special design, the time-consuming calculation for extended field of view and the lack of real-time visualization tool. Here, we propose a universal and accelerated SIMBA ImageJ plug-in, Live-SIMBA, for time-series analysis in living cells. Live-SIMBA circumvents the requirement of dual-channel dataset using intensity-based sampling algorithm and improves the computing speed using multi-core parallel computing technique. Live-SIMBA also better resolves the weak signals inside the specimens with adjustable background estimation and distance-threshold filter. With improved fidelity on reconstructed structures, greatly accelerated computation, and real-time visualization, Live-SIMBA demonstrates its extended capabilities in live-cell super-resolution imaging.
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http://dx.doi.org/10.1364/BOE.404820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587271PMC
October 2020

Efficacy and tolerability of combination therapy with alpha-blockers and phosphodiesterase-5 inhibitors compared with monotherapy for lower urinary tract symptoms: Protocol for a systematic review and network meta-analysis.

Medicine (Baltimore) 2020 Oct;99(43):e22834

Department of Urology, Gansu Provincial Hospital.

Purpose: This study aimed to compare the efficacy and safety of combination therapy consisting of α-blockers and different phosphodiesterase type 5 inhibitors for lower urinary tract symptoms (LUTS) by performing a network meta-analysis.

Method: Relevant articles were retrieved from the Cochrane Library, PubMed, and EMBASE databases. Bayesian network meta-analyses were performed with a random-effect model to compare the efficacy and safety of combination therapy with α-blockers and phosphodiesterase-5 inhibitors for LUTS. The odds ratio (OR), mean difference (MD) and surface under the cumulative ranking curve (SUCRA) were calculated with the GeMTC R package.

Results: Twenty randomized trials with 4131 patients were included in this network meta-analysis. Based on the SUCRA values, vardenafil (10 mg) combined with α-blockers ranked first, first and sixth; sildenafil (25 mg) combined with α-blockers ranked second, third and first; and tadalafil (20 mg) combined with α-blockers ranked third, second and fourth in IPSS, post void residual, and maximum flow rate, respectively.

Conclusions: Combination therapy with α-blockers and phosphodiesterase-5 inhibitors was effective and well tolerated for LUTS. For men who prioritize high efficacy, vardenafil (10 mg) combined with α-blockers seems to be the treatment of choice. For men wishing to optimize minimally invasive treatment, sildenafil (25 mg) and tadalafil (20 mg) combined with α-blockers appears to have a possible advantage in terms of avoiding adverse effects.
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http://dx.doi.org/10.1097/MD.0000000000022834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581165PMC
October 2020

Clinical characteristics of pediatric synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome: the first Chinese case series from a single center.

Clin Rheumatol 2021 Apr 15;40(4):1487-1495. Epub 2020 Sep 15.

Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Introduction: Pediatric SAPHO syndrome is regarded as the equivalent of chronic recurrent multifocal osteomyelitis or chronic non-bacterial osteomyelitis. This study aimed to evaluate the clinical features and treatment options for Chinese pediatric patients with SAPHO syndrome.

Method: We conducted a single-center, retrospective study on a sample of 24 pediatric patients with SAPHO syndrome who were diagnosed at Peking Union Medical College Hospital from April 2014 to August 2018. The demographic, clinical, laboratory, imaging, histological, and therapeutic data were collected and analyzed.

Results: A total of 15 boys and 9 girls were included. The mean age of onset of bone and skin symptoms was 11.7 ± 3.8 and 14.4 ± 2.7 years, respectively. The mean follow-up period was 39.2 months. Seventeen patients had skin manifestations (46% had severe acne, 100% were boys; 21% had palmoplantar pustulosis, 100% were girls). Bone lesions were localized in four of the following major regions: anterior chest wall (42%), mandible (29%), peripheral bones (50%), and spine and sacroiliac joints (21%). Six patients had been treated with non-steroidal anti-inflammatory drugs, 10 with bisphosphonate, 10 with a tumor necrosis factor-α antagonist, and 1 with glucocorticoids, with variable responses. A total of 70% of the patients had complete remission after bisphosphonate or TNF-α antagonist therapy.

Conclusion: Pediatric patients with SAPHO syndrome have different characteristics from other cohorts in the sex ratio, frequency of mandibular involvement, and sex distribution of skin lesions. Bisphosphonate and TNF-α antagonists show a favorable response in pediatric SAPHO syndrome treatment. Key points •Being the first study that describes an Asian pediatric SAPHO case series. •Chinese pediatric patients with SAPHO syndrome have different characteristics from Chinese adult patients and Caucasian pediatric patients.
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http://dx.doi.org/10.1007/s10067-020-05393-wDOI Listing
April 2021

Short Beam Shear Behavior and Failure Characterization of Hybrid 3D Braided Composites Structure with X-ray Micro-Computed Tomography.

Polymers (Basel) 2020 Aug 26;12(9). Epub 2020 Aug 26.

Innovation Platform of Intelligent and Energy-Saving Textiles, School of Textile Science and Engineering, Tiangong University, Tianjin 300387, China.

Three-dimensional braided composite has a unique spatial network structure that exhibits the characteristics of high delamination resistance, damage tolerance, and shear strength. Considering the characteristics of braided structures, two types of high-performance materials, namely, aramid and carbon fibers, were used as reinforcements to prepare braided composites with different hybrid structures. In this study, the longitudinal and transverse shear properties of 3D braided hybrid composites were tested to investigate the influences of hybrid and structural effects. The damage characteristics of 3D braided hybrid composites under short beam shear loading underwent comprehensive morphological analysis via optical microscopy, water-logging ultrasonic scanning, and X-ray micro-computed tomography methods. It is shown that the shear toughness of hybrid braided composite has been improved at certain degrees compared with the pure carbon fiber composite under both transverse and longitudinal directions. The hybrid braided composites with aramid fiber as axial yarn and carbon fiber as braiding yarn exhibited the best shear toughness under transverse shear loading. Meanwhile, the composites with carbon fiber as axial yarn and aramid fiber as braiding yarn demonstrated the best shear toughness in the longitudinal direction. Due to the different distribution of axial and braiding yarns, the transverse shear property of hybrid braided structure excels over the longitudinal shear property. The failure modes of the hybrid braided composite under the two loading directions are considerably different. Under transverse loading, the primary failure mode of the composites is yarn fracture. Under longitudinal loading, the primary failure modes are resin fracture and fiber slip. The extensive interfacial effects and the good deformation capability of the hybrid braided composites can effectively prevent the longitudinal development of internal cracks in the pattern, improving the shear properties of braided composites.
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http://dx.doi.org/10.3390/polym12091931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564245PMC
August 2020

The RNA-Binding Protein HuR in Digestive System Tumors.

Biomed Res Int 2020 24;2020:9656051. Epub 2020 Jul 24.

Department of Urology, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, Gansu 730050, China.

Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins. This molecule, which was first described in tumors nearly two decades ago, has recently received much attention in tumor-related research because it regulates the expression of many tumor-associated molecules through posttranscriptional regulatory mechanisms, thereby affecting biological characteristics. It is suggested that HuR might be a novel therapeutic target and a marker for therapeutic response and prognostic assessment. Increasing evidence supports that HuR also plays critical roles in the development, therapy, and prognosis of digestive system tumors. Herein, we review the relationships between HuR and digestive system tumors, demonstrating the importance of HuR in digestive system tumor diagnosis.
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http://dx.doi.org/10.1155/2020/9656051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396115PMC
April 2021

A Parallel Cerebrovascular Segmentation Algorithm Based on Focused Multi-Gaussians Model and Heterogeneous Markov Random Field.

IEEE Trans Nanobioscience 2020 07;19(3):538-546

A complete and detailed cerebrovascular image segmented from time-of-flight magnetic resonance angiography (TOF-MRA) data is essential for the diagnosis and therapy of the cerebrovascular diseases. In recent years, three-dimensional cerebrovascular segmentation algorithms based on statistical models have been widely used, but the existed methods always perform poorly on stenotic vessels and are not robust enough. In this paper, we propose a parallel cerebrovascular segmentation algorithm based on focused multi-Gaussians model and heterogeneous Markov random field. Specifically, we present a focused multi-Gaussians (FMG) model with local fitting region to model the vascular tissue more accurately and introduce the chaotic oscillation particle swarm optimization (CO-PSO) algorithm to improve the global optimization capability in the parameter estimation. Furthermore, we design a heterogeneous Markov Random Field (MRF) in the three-dimensional neighborhood system to incorporate precise local character of image. Finally, the algorithm has been performed parallel optimization based on GPUs and obtain about 60 times speedup compared to serial execution. The experiments show that the proposed algorithm can produce more detailed segmentation result in shorter time and performs well on the stenotic vessels robustly.
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http://dx.doi.org/10.1109/TNB.2020.2996604DOI Listing
July 2020

Super-resolution nanoscopy by coherent control on nanoparticle emission.

Sci Adv 2020 Apr 17;6(16):eaaw6579. Epub 2020 Apr 17.

State Key Laboratory for Artificial Microstructure and Mesoscopic Physics, Department of Physics, Peking University, Beijing 100871, China.

Super-resolution nanoscopy based on wide-field microscopic imaging provided high efficiency but limited resolution. Here, we demonstrate a general strategy to push its resolution down to ~50 nm, which is close to the range of single molecular localization microscopy, without sacrificing the wide-field imaging advantage. It is done by actively and simultaneously modulating the characteristic emission of each individual emitter at high density. This method is based on the principle of excited state coherent control on single-particle two-photon fluorescence. In addition, the modulation efficiently suppresses the noise for imaging. The capability of the method is verified both in simulation and in experiments on ZnCdS quantum dot-labeled films and COS7 cells. The principle of coherent control is generally applicable to single-multiphoton imaging and various probes.
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http://dx.doi.org/10.1126/sciadv.aaw6579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164939PMC
April 2020

miRNAs: A Promising Target in the Chemoresistance of Bladder Cancer.

Onco Targets Ther 2019 31;12:11805-11816. Epub 2019 Dec 31.

Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.

Chemotherapy is an important cancer treatment method. Tumor chemotherapy resistance is one of the main factors leading to tumor progression. Like other malignancies, bladder cancer, especially muscle-invasive bladder cancer, is prone to chemotherapy resistance. Additionally, only approximately 50% of muscle-invasive bladder cancer responds to cisplatin-based chemotherapy. miRNAs are a class of small, endogenous, noncoding RNAs that regulate gene expression at the posttranscriptional level, which results in the inhibition of translation or the degradation of mRNA. In the study of miRNAs and cancer, including gastric cancer, prostate cancer, liver cancer, and colorectal cancer, it has been found that miRNAs can regulate the expression of genes related to tumor resistance, thereby promoting the progression of tumors. In bladder cancer, miRNAs are also closely related to chemotherapy resistance, suggesting that miRNAs can be a new therapeutic target for the chemotherapy resistance of bladder cancer. Therefore, understanding the mechanisms of miRNAs in the chemotherapy resistance of bladder cancer is an important foundation for restoring the chemotherapy sensitivity of bladder cancer and improving the efficacy of chemotherapy and patient survival. In this article, we review the role of miRNAs in the development of chemotherapy-resistant bladder cancer and the various resistance mechanisms that involve apoptosis, the cell cycle, epithelial-mesenchymal transition (EMT), and cancer stem cells (CSCs).
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http://dx.doi.org/10.2147/OTT.S231489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997227PMC
December 2019

Standard-tract percutaneous nephrolithotomy for complicated calculi within horseshoe kidneys: A report of one case.

Urol Case Rep 2020 May 13;30:101117. Epub 2020 Jan 13.

Gansu Provincial Hospital, Gansu, 730000, China.

A 48-year-old man was presented in the local hospitalized where he lived because of lower back pain one month ago. Then he came to our hospital for kidney stones on the right side within horseshoe kidneys and hydronephrosis diagnosed by imaging and abdominal ultrasound. After we proceeded single standard percutaneous nephrolithotomy with holmium laser combined EMS, his stones were totally removed with little intraoperative bleeding. No eventful post-operative complications occurred and the curative effect was very satisfied by KUB after stay in bed for 3 days reviewed. And a long-term follow up showed his recovery was quite well.
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http://dx.doi.org/10.1016/j.eucr.2020.101117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000816PMC
May 2020

Lung function and blood gas abnormalities in patients with acromegaly.

J Clin Neurosci 2020 Mar 10;73:130-135. Epub 2020 Jan 10.

Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China. Electronic address:

Objective: Respiratory disorders are common complications of acromegaly patients. We conducted a large-scale survey in the patients with acromegaly and demonstrated the characteristics of their lung function and blood gas.

Methods: A prospective cohort study was conducted with 115 patients with active acromegaly and 56 patients with nonfunctioning pituitary adenomas. All patients underwent clinical, biological, radiological, lung functional and blood gas assessments.

Results: Acromegaly patients had a higher lung volume than those with nonfunctioning adenomas (forced vital capacity value (FVC) and FVC% predicted: p < 0.001). The small airway was less obstructive in acromegaly patients (higher FEV1% predicted, PEF% predicted, MEF75% predicted, MEF50% predicted, MEF25% predicted: p ≤ 0.001 for all analyses, FEV1/FVC: p = 0.151). The average partial pressure of carbon dioxide in acromegaly patients was higher (p < 0.001), but there was no significant difference in the average partial pressure of oxygen or oxygen saturation between the two groups (p > 0.05). In acromegaly patients, the average age of patients with small airway obstruction was higher than that of patients with normal lung function (p < 0.05), but no significant difference in GH or IGF-1 levels between the two groups were found (p > 0.05).

Conclusion: The acromegaly patients in this cohort had increased lung volume. However, there was no evidence demonstrating hypoxemia in acromegaly patients. The small airway was less obstructive in acromegaly patents. Small airway obstruction was observed in elderly patients with acromegaly.
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http://dx.doi.org/10.1016/j.jocn.2020.01.003DOI Listing
March 2020

A Consensus Framework of Distributed Multiple-Tilt Reconstruction in Electron Tomography.

J Comput Biol 2019 Dec 2. Epub 2019 Dec 2.

High Performance Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China.

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http://dx.doi.org/10.1089/cmb.2019.0287DOI Listing
December 2019

Structural and Biochemical Insight into the Recruitment of Acyl Carrier Protein-Linked Extender Units in Ansamitocin Biosynthesis.

Chembiochem 2020 05 10;21(9):1309-1314. Epub 2020 Jan 10.

State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, 200240, Shanghai, P. R. China.

A few acyltransferase (AT) domains of modular polyketide synthases (PKSs) recruit acyl carrier protein (ACP)-linked extender units with unusual C2 substituents to confer functionalities that are not available in coenzyme A (CoA)-linked ones. In this study, an AT specific for methoxymalonyl (MOM)-ACP in the third module of the ansamitocin PKS was structurally and biochemically characterized. The AT uses a conserved tryptophan residue at the entrance of the substrate binding tunnel to discriminate between different carriers. A W275R mutation switches its carrier specificity from the ACP to the CoA molecule. The acyl-AT complex structures clearly show that the MOM-ACP accepted by the AT has the 2S instead of the opposite 2R stereochemistry that is predicted according to the biosynthetic derivation from a d-glycolytic intermediate. Together, these results reveal the structural basis of ATs recognizing ACP-linked extender units in polyketide biosynthesis.
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http://dx.doi.org/10.1002/cbic.201900628DOI Listing
May 2020

Mechanical Respond and Failure Mode of Large Size Honeycomb Sandwiched Composites under In-Plane Shear Load.

Molecules 2019 Nov 21;24(23). Epub 2019 Nov 21.

Beijing Key Laboratory of Civil Aircraft Structures and Composite Materials, Beijing Aeronautical Science & Technology Research Institute of COMAC, Beijing 102211, China.

The present work focuses on the in-plane shear respond and failure mode of large size honeycomb sandwich composites which consist of plain weave carbon fabric laminate skins and aramid paper core. A special size specimen based on a typical element of aircraft fuselage was designed and manufactured. A modified in-plane shear test method and the corresponding fixture was developed. Three large size specimens were tested. The distributed strain gauges were used to monitor the mechanical response and ultimate bearing capacity. The results show that a linear respond of displacement and strain appears with the increase of the load. The average shear failure load reaches 205.68 kN with the shear failure occurring on the face sheet, and the maximum shear strain monitored on the composite plate is up to 16,115 με. A combination of theoretical analysis and finite element method (FEM) was conducted to predict the shear field distribution and the overall buckling load. The out-of-plane displacement field distribution and in-plane shear strain field distribution under the pure shear loading were revealed. The theoretical analysis method was deduced to obtain the variation rule of the shear buckling load. A good agreement was achieved among the experiment, theoretical analysis, and FEM results. It can be concluded that the theoretical analysis method is relatively conservative, and the FEM is more accurate in case of deformation and strain. The results predicted by h element and p element methods are very close. The results of the study could provide data support for the comprehensive promotion of the design and application of honeycomb sandwich composites.
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http://dx.doi.org/10.3390/molecules24234248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930483PMC
November 2019

A novel constrained reconstruction model towards high-resolution sub-tomogram averaging.

Bioinformatics 2019 Oct 16. Epub 2019 Oct 16.

King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, Thuwal, Saudi Arabia.

Motivation: Electron tomography (ET) offers a unique capacity to image biological structures in situ. However, the resolution of ET reconstructed tomograms is not comparable to that of the single-particle cryo-EM. If many copies of the object of interest are present in the tomograms, their structures can be reconstructed in the tomogram, picked, aligned and averaged to increase the signal-to-noise ratio and improve the resolution, which is known as the subtomogram averaging (STA). To date, the resolution improvement of the subtomogram averaging is still limited because each reconstructed subtomogram is of low reconstruction quality due to the missing wedge issue.% issue in the tilt series images.

Results: In this paper, we propose a novel computational model, the constrained reconstruction model (CRM), to better recover the information from the multiple subtomograms and compensate for the missing wedge issue in each of them. CRM is supposed to produce a refined reconstruction in the final turn of subtomogram averaging after alignment, instead of directly taking the average. We first formulate the averaging method and our CRM as linear systems, and prove that the solution space of CRM is no larger, and in practice much smaller, than that of the averaging method. We then propose a sparse Kaczmarz algorithm to solve the formulated CRM, and further extend the solution to the simultaneous algebraic reconstruction technique (SART). Experimental results demonstrate that CRM can significantly alleviate the missing wedge issue and improve the final reconstruction quality. In addition, our model is robust to the number of images in each tilt series, the tilt range, and the noise level.

Availability: The codes of CRM-SIRT and CRM-SART are available at https://github.com/icthrm/CRM.
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http://dx.doi.org/10.1093/bioinformatics/btz787DOI Listing
October 2019

Fast Super-Resolution Imaging Technique and Immediate Early Nanostructure Capturing by a Photoconvertible Fluorescent Protein.

Nano Lett 2020 04 7;20(4):2197-2208. Epub 2019 Oct 7.

Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.

Low temporal resolution and limited photocontrollable fluorescent protein probes have restricted the widespread application of single-molecule localization microscopy (SMLM). In the current study, we developed a new photoconvertible fluorescent protein (PCFP), pcStar, and quick single molecule-guided Bayesian localization microscopy (Quick-SIMBA). The combination of pcStar and Quick-SIMBA achieved the highest temporal resolution (0.1-0.25 s) with large field-of-view (76 × 9.4 μm -76 × 31.4 μm) among the SMLM methods, which enabled the dynamic movements of the endoplasmic reticulum dense tubular matrix to be resolved. Moreover, pcStar extended the application of SMLM to imaging the immediate early nanostructures in embryos and revealed a specific "parallel three-pillar" structure in the neuronal-glial cell junction, helping to elucidate glial cell "locking" and support of neurons during embryogenesis.
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http://dx.doi.org/10.1021/acs.nanolett.9b02855DOI Listing
April 2020

A joint method for marker-free alignment of tilt series in electron tomography.

Bioinformatics 2019 07;35(14):i249-i259

Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

Motivation: Electron tomography (ET) is a widely used technology for 3D macro-molecular structure reconstruction. To obtain a satisfiable tomogram reconstruction, several key processes are involved, one of which is the calibration of projection parameters of the tilt series. Although fiducial marker-based alignment for tilt series has been well studied, marker-free alignment remains a challenge, which requires identifying and tracking the identical objects (landmarks) through different projections. However, the tracking of these landmarks is usually affected by the pixel density (intensity) change caused by the geometry difference in different views. The tracked landmarks will be used to determine the projection parameters. Meanwhile, different projection parameters will also affect the localization of landmarks. Currently, there is no alignment method that takes interrelationship between the projection parameters and the landmarks.

Results: Here, we propose a novel, joint method for marker-free alignment of tilt series in ET, by utilizing the information underlying the interrelationship between the projection model and the landmarks. The proposed method is the first joint solution that combines the extrinsic (track-based) alignment and the intrinsic (intensity-based) alignment, in which the localization of landmarks and projection parameters keep refining each other until convergence. This iterative approach makes our solution robust to different initial parameters and extreme geometric changes, which ensures a better reconstruction for marker-free ET. Comprehensive experimental results on three real datasets show that our new method achieved a significant improvement in alignment accuracy and reconstruction quality, compared to the state-of-the-art methods.

Availability And Implementation: The main program is available at https://github.com/icthrm/joint-marker-free-alignment.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612841PMC
July 2019

Hepatic and renal functions and blood cell counts in brain tumor patients during the perioperative period.

J Clin Neurosci 2019 Nov 10;69:190-197. Epub 2019 Aug 10.

Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China. Electronic address:

We aimed to investigate the correlations between biochemical and hematological markers and the clinical conditions of brain tumor patients before and after craniotomy. A retrospective study was conducted in 90 brain tumor patients. Age, gender, underlying diseases, tumor size and intraoperative blood loss were recorded. Red blood cell counts and hepatic and renal markers were analyzed preoperatively and postoperatively. Albumin decreased by 5.6 g/L after surgery (p < 0.001). Older patients (>52 years) and females had lower albumin levels than younger patients and males did. Red blood cell counts and hemoglobin levels decreased significantly on the 1st and increased on the 3rd postoperative day. The blood glucose level increased on the 1st postoperative day and then decreased. Older patients had higher blood glucose levels than younger patients did (p < 0.05). The postoperative serum sodium, potassium and calcium levels were within the normal ranges; 37 patients had hypocalcemia (41.1%) and patients with hypokalemia and hyponatremia increased postoperatively. Albumin and hemoglobin levels were linearly correlated (correlation coefficient 0.559, p < 0.001). Intraoperative blood loss was correlated with tumor size (p < 0.05) but did not affect the decrease in hematological markers. In brain tumor patients, red blood cell counts and hemoglobin and serum albumin levels were significantly decreased after craniotomy; these effects were influenced by gender and age instead of intraoperative blood loss. The postoperative blood glucose level peaked and then decreased; it was affected by age and diabetes mellitus. Electrolytes remained relatively stable. These findings have implications for patient management and postoperative complication prevention.
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http://dx.doi.org/10.1016/j.jocn.2019.07.067DOI Listing
November 2019

Improve the Resolution and Parallel Performance of the Three-Dimensional Refine Algorithm in RELION Using CUDA and MPI.

IEEE/ACM Trans Comput Biol Bioinform 2021 Mar-Apr;18(2):583-595. Epub 2021 Apr 8.

In cryo-electron microscopy, RELION is a powerful tool for high-resolution reconstruction. Due to the complicated imaging procedure and the heterogeneity of particles, some of the selected particle images offer more disturbing information than others. However, in the current RELION, all these particle images are treated equally. In our work, we extend RELION's model with one scalar parameter to score the contribution of a particle depending on the error between the experimental particle and the corresponding reprojection. This scores down weight potentially poor particles, hence accelerating the convergence. Besides, by now there is no sophisticated memory management system for RELION, fragmentation on GPU will increase with iterations, eventually crashing the program. In our work, we designed the stack-based memory management system to guarantee the stability of RELION and to optimize the memory usage condition. Also, to reduce memory usage, we developed a customized compressed data structure for the memory-demanding weight array. In addition, to speed up the GPU version of RELION, we proposed two highly efficient parallel algorithms for weight calculation algorithm and weight selection algorithm. Experiments show that compared with RELION, the optimized three-dimensional refine algorithm can speed up the converge procedure, the memory system can avoid memory fragmentation, and a better speed-up ratio can be obtained.
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http://dx.doi.org/10.1109/TCBB.2019.2929171DOI Listing
April 2021

Breast cancer histopathological image classification using a hybrid deep neural network.

Methods 2020 02 15;173:52-60. Epub 2019 Jun 15.

High Performance Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China. Electronic address:

Even with the rapid advances in medical sciences, histopathological diagnosis is still considered the gold standard in diagnosing cancer. However, the complexity of histopathological images and the dramatic increase in workload make this task time consuming, and the results may be subject to pathologist subjectivity. Therefore, the development of automatic and precise histopathological image analysis methods is essential for the field. In this paper, we propose a new hybrid convolutional and recurrent deep neural network for breast cancer histopathological image classification. Based on the richer multilevel feature representation of the histopathological image patches, our method integrates the advantages of convolutional and recurrent neural networks, and the short-term and long-term spatial correlations between patches are preserved. The experimental results show that our method outperforms the state-of-the-art method with an obtained average accuracy of 91.3% for the 4-class classification task. We also release a dataset with 3771 breast cancer histopathological images to the scientific community that is now publicly available at http://ear.ict.ac.cn/?page_id=1616. Our dataset is not only the largest publicly released dataset for breast cancer histopathological image classification, but it covers as many different subclasses spanning different age groups as possible, thus providing enough data diversity to alleviate the problem of relatively low classification accuracy of benign images.
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http://dx.doi.org/10.1016/j.ymeth.2019.06.014DOI Listing
February 2020

Structural Insights into the Substrate Specificity of Acyltransferases from Salinomycin Polyketide Synthase.

Biochemistry 2019 07 19;58(27):2978-2986. Epub 2019 Jun 19.

State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology , Shanghai Jiao Tong University , Shanghai 200240 , China.

Salinomycin with antibacterial and anticoccidial activities is a commercial polyether polyketide widely used in animal husbandry as a food additive. Malonyl-CoA (MCoA), methylmalonyl-CoA (MMCoA), and ethylmalonyl-CoA (EMCoA) are used as extension units in its biosynthesis. To understand how the salinomycin modular polyketide synthase (PKS) strictly discriminates among these extension units, the acyltransferase (AT) domains selecting MCoA, MMCoA, and EMCoA were structurally characterized. Molecular dynamics simulations of the AT structures helped to reveal the key interactions involved in enzyme-substrate recognitions, which enabled the engineering of AT mutants with switched specificity. The catalytic efficiencies ( k/ K) of these AT mutants are comparable with those of the wild-type AT domains. These results set the stage for engineering the AT substrate specificity of modular PKSs.
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http://dx.doi.org/10.1021/acs.biochem.9b00305DOI Listing
July 2019

Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity Through a Melanocortin-Dependent Pathway.

Diabetes 2019 06 1;68(6):1329-1340. Epub 2019 Apr 1.

Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides synergized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT-induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy.
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http://dx.doi.org/10.2337/db18-1009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610020PMC
June 2019

Efficacy of bisphosphonates in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a prospective open study.

Clin Exp Rheumatol 2019 Jul-Aug;37(4):663-669. Epub 2019 Feb 7.

Medical Research Ctr.of Orthopaedics, Chinese Academy of Medical Sciences; Beijing Key Lab. for Genetic Res.of Skeletal Deformity; Dept.of Central Laboratory, Peking Union Medical College Hosp., Peking Union Med. College and Chinese Academy of Med.Science.

Objectives: To evaluate the clinical efficacy of bisphosphonates treatment for spinal bone marrow oedema (BME) in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.

Methods: SAPHO syndrome patients presenting to Peking Union Medical College Hospital from 2015 to 2016 were recruited. Patients were administered pamidronate disodium 1 mg/kg/d intravenously, for 3 days, at baseline and 3 months later. The symptoms were evaluated using the Visual Analog Score (VAS) for pain, and other clinical measures including, spinal BME scores, β-crosslaps, osteocalcin, and inflammatory factors, were collected.

Results: A total of 30 patients (20 women and 10 men) with a median age of 47.2 (interquartile range 8.8) years were recruited. In a short time, the patients showed a significant decrease in VAS (before vs. after; first treatment: 5.70±1.62 vs. 2.30±1.29 cm, second treatment: 4.03±1.88 vs. 2.17±1.23 cm) and β-crosslaps (first treatment: 0.4441±0.1923 vs. 0.0859±0.0374 pg/ml, second treatment: 0.2891±0.1983 vs. 0.0962±0.0324 pg/ml) (all p<0.05). At 12-month follow-up, compared with the baseline, we noticed a significant drop in the VAS (5.70±1.62 vs. 2.43±1.25 cm), erythrocyte sedimentation rate (28.87±25.26 vs. 18.00±18.65 mm/h), high-sensitivity C-reactive protein level (11.76±10.19 vs. 5.84±5.88 mg/L), osteocalcin (2.30±1.27 vs. 1.65±0.80 ng/ml), and BME (30.50±24.09 vs. 22.13±27.79) (all p<0.05). No one had serious adverse events.

Conclusions: Bisphosphonates can significantly and rapidly relieve symptoms in patients with SAPHO syndrome and have a long-term effect on inflammation and spinal BME. We suggest that bisphosphonates could be used as the first-line therapeutic drug for SAPHO syndrome, especially in patients with spinal BME.
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July 2019

PIXER: an automated particle-selection method based on segmentation using a deep neural network.

BMC Bioinformatics 2019 Jan 18;20(1):41. Epub 2019 Jan 18.

High Performance Computer Research Center, Institute of Computing Technology Chinese Academy of Sciences, No. 6 Kexueyuan South Road, Haidian District, Beijing, 100190, China.

Background: Cryo-electron microscopy (cryo-EM) has become a widely used tool for determining the structures of proteins and macromolecular complexes. To acquire the input for single-particle cryo-EM reconstruction, researchers must select hundreds of thousands of particles from micrographs. As the signal-to-noise ratio (SNR) of micrographs is extremely low, the performance of automated particle-selection methods is still unable to meet research requirements. To free researchers from this laborious work and to acquire a large number of high-quality particles, we propose an automated particle-selection method (PIXER) based on the idea of segmentation using a deep neural network.

Results: First, to accommodate low-SNR conditions, we convert micrographs into probability density maps using a segmentation network. These probability density maps indicate the likelihood that each pixel of a micrograph is part of a particle instead of just background noise. Particles selected from density maps have a more robust signal than do those directly selected from the original noisy micrographs. Second, at present, there is no segmentation-training dataset for cryo-EM. To enable our plan, we present an automated method to generate a training dataset for segmentation using real-world data. Third, we propose a grid-based, local-maximum method to locate the particles from the probability density maps. We tested our method on simulated and real-world experimental datasets and compared PIXER with the mainstream methods RELION, DeepEM and DeepPicker to demonstrate its performance. The results indicate that, as a fully automated method, PIXER can acquire results as good as the semi-automated methods RELION and DeepEM.

Conclusion: To our knowledge, our work is the first to address the particle-selection problem using the segmentation network concept. As a fully automated particle-selection method, PIXER can free researchers from laborious particle-selection work. Based on the results of experiments, PIXER can acquire accurate results under low-SNR conditions within minutes.
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http://dx.doi.org/10.1186/s12859-019-2614-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339297PMC
January 2019