Publications by authors named "Binbin Wang"

290 Publications

A genetically stable Zika virus vaccine candidate protects mice against virus infection and vertical transmission.

NPJ Vaccines 2021 Feb 17;6(1):27. Epub 2021 Feb 17.

Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, USA.

Although live attenuated vaccines (LAVs) have been effective in the control of flavivirus infections, to date they have been excluded from Zika virus (ZIKV) vaccine trials due to safety concerns. We have previously reported two ZIKV mutants, each of which has a single substitution in either envelope (E) glycosylation or nonstructural (NS) 4B P36 and displays a modest reduction in mouse neurovirulence and neuroinvasiveness, respectively. Here, we generated a ZIKV mutant, ZE4B-36, which combines mutations in both E glycosylation and NS4B P36. The ZE4B-36 mutant is stable and attenuated in viral replication. Next-generation sequence analysis showed that the attenuating mutations in the E and NS4B proteins are retained during serial cell culture passages. The mutant exhibits a significant reduction in neuroinvasiveness and neurovirulence and low infectivity in mosquitoes. It induces robust ZIKV-specific memory B cell, antibody, and T cell-mediated immune responses in type I interferon receptor (IFNR) deficient mice. ZIKV-specific T cell immunity remains strong months post-vaccination in wild-type C57BL/6 (B6) mice. Vaccination with ZE4B-36 protects mice from ZIKV-induced diseases and vertical transmission. Our results suggest that combination mutations in E glycosylation and NS4B P36 contribute to a candidate LAV with significantly increased safety but retain strong immunogenicity for prevention and control of ZIKV infection.
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http://dx.doi.org/10.1038/s41541-021-00288-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889622PMC
February 2021

An advanced color tunable persistent luminescent NaCaGeOF:Tb phosphor for multicolor anti-counterfeiting.

Dalton Trans 2021 Feb 12. Epub 2021 Feb 12.

Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province and State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.

Luminescent materials play an important role in anticounterfeiting applications due to their superior properties of visual convenience and high concealment. However, traditional luminescent materials usually exhibit monochromatic emission and are easily counterfeited. Therefore, in this work, we report a multicolor long persistent luminescence (PersL) material, NaCa2GeO4F:Tb3+ (abbreviated as NCGOF:Tb3+), where the color of PersL can be tuned from blue to cyan and bright green by changing the concentration of Tb3+, and the afterglow (concentration) can last for 5.62 h (0.1%), 8.52 h (0.4%) and 7.14 h (0.8%) at the corresponding concentrations of Tb3+, respectively. Investigation revealed that the multicolor PersL is essentially associated with the opportune traps and cross-relaxation effect of Tb3+ in NCGOF. Based on the unique features of PersL, anticounterfeiting devices have been fabricated, and the results indicate that their multicolor features can be easily detected using a portable ultraviolet lamp, and that they are impossible to counterfeit using any substitute so far, meaning that they provide a high level of security for use in practical applications.
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http://dx.doi.org/10.1039/d0dt04231eDOI Listing
February 2021

Systematic characterization of mutations altering protein degradation in human cancers.

Mol Cell 2021 Feb 1. Epub 2021 Feb 1.

Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address:

The ubiquitin-proteasome system (UPS) is the primary route for selective protein degradation in human cells. The UPS is an attractive target for novel cancer therapies, but the precise UPS genes and substrates important for cancer growth are incompletely understood. Leveraging multi-omics data across more than 9,000 human tumors and 33 cancer types, we found that over 19% of all cancer driver genes affect UPS function. We implicate transcription factors as important substrates and show that c-Myc stability is modulated by CUL3. Moreover, we developed a deep learning model (deepDegron) to identify mutations that result in degron loss and experimentally validated the prediction that gain-of-function truncating mutations in GATA3 and PPM1D result in increased protein stability. Last, we identified UPS driver genes associated with prognosis and the tumor microenvironment. This study demonstrates the important role of UPS dysregulation in human cancer and underscores the potential therapeutic utility of targeting the UPS.
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http://dx.doi.org/10.1016/j.molcel.2021.01.020DOI Listing
February 2021

Almonertinib-induced interstitial lung disease: A case report.

Medicine (Baltimore) 2021 Jan;100(3):e24393

Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.

Rationale: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have elicited favorable anti-tumor activity in non-small cell lung cancer especially the lung adenocarcinoma. Interstitial lung disease (ILD) is 1 of the fatal side effects of EGFR-TKIs. However, such type of side effect has not been observed in the follow-up during the treatment of the third-generation EGFR-TKI Almonertinib (also called HS-10296). Here, we first report an Almonertinib-induced ILD in an elderly female patient.

Patient Concerns: A 70-year-old female diagnosed with " lung adenocarcinoma with intracranial metastasis" harboring a mutation of EGFR 19DEL was administrated with Almonertinib 110 mg orally as the first-line treatment. However, she presented with chest tightness, and shortness of breath, accompanying with paroxysmal dry cough 3 months after the initiation of Almonertinib.

Diagnoses: Extensive relevant examinations did not provide conclusive results and the chest computed tomography showed a diffuse ILD in bilateral pulmonary.

Interventions: The patient was diagnosed with Almonertinib-induced ILD in the absence of no other potential causes. She discontinued Almonertinib and was treated with oxygen uptaken and methylprednisolone.

Outcomes: The whole symptoms were eliminated and the chest computed tomography showed ILD got remission after the prescription of methylprednisolone.

Lessons: Almonertinib has potential to cause the rare but severe interstitial lung disease. Clinicians should keep cautious of this when prescribing Almonertinib.
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http://dx.doi.org/10.1097/MD.0000000000024393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837903PMC
January 2021

Optimized production and immunogenicity of an insect virus-based chikungunya virus candidate vaccine in cell culture and animal models.

Emerg Microbes Infect 2021 Dec;10(1):305-316

Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, USA.

A chimeric Eilat/ Chikungunya virus (EILV/CHIKV) was previously reported to replicate only in mosquito cells but capable of inducing robust adaptive immunity in animals. Here, we initially selected C7/10 cells to optimize the production of the chimeric virus. A two-step procedure produced highly purified virus stocks, which was shown to not cause hypersensitive reactions in a mouse sensitization study. We further optimized the dose and characterized the kinetics of EILV/CHIKV-induced immunity. A single dose of 10 PFU was sufficient for induction of high levels of CHIKV-specific IgM and IgG antibodies, memory B cell and CD8 T cell responses. Compared to the live-attenuated CHIKV vaccine 181/25, EILV/CHIKV induced similar levels of CHIKV-specific memory B cells, but higher CD8 T cell responses at day 28. It also induced stronger CD8, but lower CD4 T cell responses than another live-attenuated CHIKV strain (CHIKV/IRES) at day 55 post-vaccination. Lastly, the purified EILV/CHIKV triggered antiviral cytokine responses and activation of antigen presenting cell (APC)s but did not induce APCs alone upon exposure. Overall, our results demonstrate that the EILV/CHIKV vaccine candidate is safe, inexpensive to produce and a potent inducer of both innate and adaptive immunity in mice.
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http://dx.doi.org/10.1080/22221751.2021.1886598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919884PMC
December 2021

MiR-122-5p Mitigates Inflammation, Reactive Oxygen Species and SH-SY5Y Apoptosis by Targeting CPEB1 After Spinal Cord Injury Via the PI3K/AKT Signaling Pathway.

Neurochem Res 2021 Feb 2. Epub 2021 Feb 2.

Department of Spine Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, People's Republic of China.

Spinal cord injury (SCI) is a threatening disease that lead to severe motor and sensory deficits. Previous research has revealed that miRNAs are involved in the pathogenesis of a variety of diseases. However, whether miR-122-5p was involved in SCI was rarely investigated. In our study, we intended to probe role of miR-122-5p in the regulation of inflammatory response, reactive oxygen species (ROS) and SH-SY5Y apoptosis. We found miR-122-5p was downregulated in SCI mouse model and LPS-induced SH-SY5Y cells. Moreover, miR-122-5p overexpression alleviated inflammatory response, ROS and SH-SY5Y apoptosis in SCI mice. In addition, miR-122-5p elevation also mitigated SCI in LPS-induced SH-SY5Y cells. Additionally, cytoplasmic polyadenylation element binding protein 1 (CPEB1) was verified to be a target of miR-122-5p. CPEB1 expression was upregulated in SCI mouse model and LPS-induced SH-SY5Y cells. CPEB1 expression was negatively related to miR-122-5p expression. Moreover, CPEB1 activated the PI3K/AKT signaling pathway in SH-SY5Y cells. Finally, CPEB1 elevation recovered the suppressive effect on inflammatory response, ROS and SH-SY5Y apoptosis in LPS-treated SH-SY5Y cells mediated by miR-122-5p upregulation and through the PI3K/AKT signaling pathway.
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http://dx.doi.org/10.1007/s11064-021-03232-1DOI Listing
February 2021

Long noncoding RNA ZFAS1 aggravates spinal cord injury by binding with miR-1953 and regulating the PTEN/PI3K/AKT pathway.

Neurochem Int 2021 Jan 29:104977. Epub 2021 Jan 29.

Department of Spine Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China; Department of Spine Surgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, Jiangsu, China. Electronic address:

Multiple evidence has shown that long non-coding RNAs (lncRNAs) are novel modulators in the development of many neurological diseases, including spinal cord injury (SCI). Recently, a novel lncRNA zinc finger antisense 1 (ZFAS1) has been found to facilitate the development of many human diseases. However, the effect of ZFAS1 in SCI has not been explored. In the present study, we used the SCI mouse models and LPS-treated BV-2 cellular models to explore the role of ZFAS1 in SCI. Basso Mouse Scale score was applied to reveal locomotor function. Cresyl violet staining was used to reveal volume of spared myelin around the lesion in the injured cord. RIP and luciferase reporter assay were applied to detect binding capacity among RNAs. Next, ZFAS1 was identified to be upregulated in spinal cord tissues of SCI mice. ZFAS1 knockdown promoted functional recovery and inhibited cell apoptosis and the inflammatory response in SCI mice. ZFAS1 bound with microRNA 1953 (miR-1953), and miR-1953 was downregulated in spinal cord tissues of SCI mice. Furthermore, we confirmed that ZFAS1 promoted SCI progression via binding with miR-1953. In addition, phosphatase and tensin homolog (PTEN) was verified to be a downstream target for miR-1953 in vitro, and PTEN was upregulated in spinal cord tissues of SCI mice. Finally, we illustrated that ZFAS1 inactivated the PI3K/AKT pathway through upregulation of PTEN. In conclusion, our study revealed that ZFAS1 facilitated SCI by binding with miR-1953 and regulating the PTEN/PI3K/AKT pathway, which may provide a potential novel insight for treatment of SCI.
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http://dx.doi.org/10.1016/j.neuint.2021.104977DOI Listing
January 2021

Metagenomic insights into Chinese northeast suancai: Predominance and diversity of genes associated with nitrogen metabolism in traditional household suancai fermentation.

Food Res Int 2021 Jan 28;139:109924. Epub 2020 Nov 28.

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China. Electronic address:

Chinese northeast suancai represents a typical and valuable food product that has been handed down by traditional household procedures over centuries. Nitrite is formed and accumulated during the suancai fermentation process and commonly causes food safety problems. The biogeochemical cycle of nitrite may provide a reference and guidance for the enzymatic degradation of nitrite in fermented food. The potential nitrogen metabolic pathways in the microbially driven suancai fermentation were reasonably inferred through monitoring nitrogen conversions and detecting the genes of different functional enzymes. Complex microbial metabolism is responsible for the unique nitrogen conversions during suancai fermentation. The metagenomic results showed that Pseudomonas with nitrate reductase genes (narG, narH, narI) and nitrite reductase genes (nirB, nirD) contributed the most to both nitrite reduction and nitrate reduction. The majority of the sequences of nitrate reductase and nitrite reductase were derived from the families of Pseudomonadaceae, Erwiniaceae and Yersiniaceae. According to the physicochemical analysis, the nitrite concentration of the fermentation broth reached the peak value (0.48 mM) and gradually decreased to the minimum (0.02 mM). The downward trend of the pH and nitrite concentration were closely associated with the nitrite enzymatic degradation period before the acid degradation period. Our results indicated that nitrite removal in suancai fermentation involved the reduction of nitrite to ammonia and denitrification, which were mainly contributed by the reduction of nitrite to ammonia mediated by the nirB/nirD enzyme (Indentified ECs: 1.7.1.15). This research offers new insights into the metagenome-based bioinformatic roles of the previously unstudied microorganisms in spontaneous suancai fermentation for the enzymatic degradation of nitrite. It provides helpful basis for the detection and even elimination of nitrite in suancai and for improving the safety level of suancai.
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http://dx.doi.org/10.1016/j.foodres.2020.109924DOI Listing
January 2021

Automated interpretation of congenital heart disease from multi-view echocardiograms.

Med Image Anal 2021 Apr 26;69:101942. Epub 2020 Dec 26.

Center for Genetics, National Research Institute for Family Planning, Beijing, China. Electronic address:

Congenital heart disease (CHD) is the most common birth defect and the leading cause of neonate death in China. Clinical diagnosis can be based on the selected 2D key-frames from five views. Limited by the availability of multi-view data, most methods have to rely on the insufficient single view analysis. This study proposes to automatically analyze the multi-view echocardiograms with a practical end-to-end framework. We collect the five-view echocardiograms video records of 1308 subjects (including normal controls, ventricular septal defect (VSD) patients and atrial septal defect (ASD) patients) with both disease labels and standard-view key-frame labels. Depthwise separable convolution-based multi-channel networks are adopted to largely reduce the network parameters. We also approach the imbalanced class problem by augmenting the positive training samples. Our 2D key-frame model can diagnose CHD or negative samples with an accuracy of 95.4%, and in negative, VSD or ASD classification with an accuracy of 92.3%. To further alleviate the work of key-frame selection in real-world implementation, we propose an adaptive soft attention scheme to directly explore the raw video data. Four kinds of neural aggregation methods are systematically investigated to fuse the information of an arbitrary number of frames in a video. Moreover, with a view detection module, the system can work without the view records. Our video-based model can diagnose with an accuracy of 93.9% (binary classification), and 92.1% (3-class classification) in a collected 2D video testing set, which does not need key-frame selection and view annotation in testing. The detailed ablation study and the interpretability analysis are provided. The presented model has high diagnostic rates for VSD and ASD that can be potentially applied to the clinical practice in the future. The short-term automated machine learning process can partially replace and promote the long-term professional training of primary doctors, improving the primary diagnosis rate of CHD in China, and laying the foundation for early diagnosis and timely treatment of children with CHD.
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http://dx.doi.org/10.1016/j.media.2020.101942DOI Listing
April 2021

Corticosteroid therapy in critically ill patients with COVID-19: a multicenter, retrospective study.

Crit Care 2020 12 18;24(1):698. Epub 2020 Dec 18.

Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.

Background: Corticoid therapy has been recommended in the treatment of critically ill patients with COVID-19, yet its efficacy is currently still under evaluation. We investigated the effect of corticosteroid treatment on 90-day mortality and SARS-CoV-2 RNA clearance in severe patients with COVID-19.

Methods: 294 critically ill patients with COVID-19 were recruited between December 30, 2019 and February 19, 2020. Logistic regression, Cox proportional-hazards model and marginal structural modeling (MSM) were applied to evaluate the associations between corticosteroid use and corresponding outcome variables.

Results: Out of the 294 critically ill patients affected by COVID-19, 183 (62.2%) received corticosteroids, with methylprednisolone as the most frequently administered corticosteroid (175 accounting for 96%). Of those treated with corticosteroids, 69.4% received corticosteroid prior to ICU admission. When adjustments and subgroup analysis were not performed, no significant associations between corticosteroids use and 90-day mortality or SARS-CoV-2 RNA clearance were found. However, when stratified analysis based on corticosteroid initiation time was performed, there was a significant correlation between corticosteroid use (≤ 3 day after ICU admission) and 90-day mortality (logistic regression adjusted for baseline: OR 4.49, 95% CI 1.17-17.25, p = 0.025; Cox adjusted for baseline and time varying variables: HR 3.89, 95% CI 1.94-7.82, p < 0.001; MSM adjusted for baseline and time-dependent variants: OR 2.32, 95% CI 1.16-4.65, p = 0.017). No association was found between corticosteroid use and SARS-CoV-2 RNA clearance even after stratification by initiation time of corticosteroids and adjustments for confounding factors (corticosteroids use ≤ 3 days initiation vs no corticosteroids use) using MSM were performed.

Conclusions: Early initiation of corticosteroid use (≤ 3 days after ICU admission) was associated with an increased 90-day mortality. Early use of methylprednisolone in the ICU is therefore not recommended in patients with severe COVID-19.
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http://dx.doi.org/10.1186/s13054-020-03429-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747001PMC
December 2020

Surgical treatment for basilar invagination with irreducible atlantoaxial dislocation: transoral atlantoaxial reduction plate fixation vs occipitocervical fixation.

BMC Musculoskelet Disord 2020 Dec 8;21(1):825. Epub 2020 Dec 8.

The First School of Clinical Medicine, Southern Medical University, No.1838 North of Guangzhou Road, Guangzhou, 510515, People's Republic of China.

Background: Transoral atlantoaxial reduction plate (TARP) fixation or occipitocervical fixation (OF) is an effective treatment for basilar invagination (BI) with irreducible atlantoaxial dislocation (IAAD). But, all current clinical studies involved a single surgical procedure. The clinical effects of TARP and OF operation for BI with IAAD have yet to be compared. We therefore present this report to compare the treatment of TARP and OF procedure for BI with IAAD.

Methods: Fifty-six patients with BI with IAAD who underwent TARP or OF operation from June 2011 to June 2017 were retrospectively analyzed. Among these, 35 patients underwent TARP operation (TARP group), and 21 patients underwent OF operation (OF group). We compared the difference of clinical, radiological, and surgical outcomes between the TARP and OF groups postoperatively.

Results: Compared with OF group, the operative time and blood loss in TARP group were lower. There was no statistical difference in the atlantodental interval (ADI), clivus canal angle (CCA), cervicomedullary angle (CMA), distance between the top of the odontoid process and the Chamberlain line (CL) and Japanese Orthopaedic Association (JOA) score between the TARP and OF groups preoperatively, but the improvements of these parameters in the TARP group were superior to those in the OF group postoperatively. The fusion rates were higher in the TARP group than those in the OF group at the early stage postoperatively.

Conclusions: TARP and OF operations are effective surgical treatment for BI with IAAD, but the performance of reduction and decompression and earlier bone fusion rates of TARP procedure are superior to those of OF.
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http://dx.doi.org/10.1186/s12891-020-03838-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724810PMC
December 2020

Transoral intraarticular cage distraction and C-JAWS fixation for revision of basilar invagination with irreducible atlantoaxial dislocation.

BMC Musculoskelet Disord 2020 Nov 20;21(1):766. Epub 2020 Nov 20.

The First School of Clinical Medicine, Southern Medical University, No.1838 North of Guangzhou Road, Guangzhou, 510515, People's Republic of China.

Background: The revision surgery of basilar invagination (BI) with irreducible atlantoaxial dislocation (IAAD) after a previous occipitocervical fusion (OCF) is challenging. Transoral revision surgery has more advantages than a combined anterior and posterior approach in addressing this pathology. The C-JAWS is a cervical compressive staple that has been used in the lower cervical spine with many advantages. Up to now, there is no report on the application of C-JAWS in the atlantoaxial joint. We therefore present this report to investigate the clinical outcomes of transoral intraarticular cage distraction and C-JAWS fixation for revision of BI with IAAD.

Methods: From June 2011 to June 2015, 9 patients with BI and IAAD were revised by this technique after previous posterior OCF in our department. Plain cervical radiographs, computed tomographic scans and magnetic resonance imaging were obtained pre- and postoperatively to assess the degree of atlantoaxial dislocation and compression of the cervical cord. The Japanese Orthopedic Association (JOA) score was used to evaluate the neurological function.

Results: The revision surgeries were successfully performed in all patients. The average follow-up duration was 18.9 ± 7.3 months (range 9-30 months). The postoperative atlas-dens interval (ADI), cervicomedullary angle (CMA), distance between the top of the odontoid process and the Chamberlain line (CL) and JOA score were significantly improved in all patients (P < 0.05). Bony fusion was achieved after 3-9 months in all cases. No patients developed recurrent atlantoaxial instability.

Conclusions: Transoral revision surgery by intraarticular cage distraction and C-JAWS fixation could provide a satisfactory outcome for BI with IAAD after a previous unsuccessful posterior operation.
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http://dx.doi.org/10.1186/s12891-020-03792-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679985PMC
November 2020

Climatic factors determine the yield and quality of Honghe flue-cured tobacco.

Sci Rep 2020 11 16;10(1):19868. Epub 2020 Nov 16.

College of Agricultural and Life Sciences, Kunming University, Kunming, 650214, Yunnan, China.

Flue-cured tobacco (Nicotiana tabacum L.) is a major cash crop in Yunnan, China, and the yield, chemical components, and their proportions decide the quality of tobacco leaves. To understand the effects of environmental factors (soil and climatic factors) on the yield and quality of flue-cured tobacco and determine the main regulating factors, we selected three flue-cured tobacco cultivars [K326, Yunyan87 (Yun87), and Honghuadajinyuan (Hongda)] grown in the Honghe Tobacco Zone. Indices related to yield and economic traits, chemical component properties, soil physical and chemical properties, and climatic factors at different planting sites, were evaluated. We used variance analysis, correlation analysis, and redundancy analysis (RDA) in this study. The results showed that the yield and chemical component properties of flue-cured tobacco, except for the number of left leaves and plant total sugar (PTS) content, were significantly correlated with climatic factors. Particularly, the yield increased in drier and sunnier weather. In terms of the carbon supply capacity, PTS, petroleum ether (PPE), and starch contents (PS) were higher under high-altitude and high-latitude climatic conditions, whereas for the nitrogen supply capacity, plant nitrogen (PTN) and nicotine (PN) contents improved under low-altitude and low-latitude climatic conditions. PTS, reducing sugar (PRS), potassium (PTK), chlorine (PCL), and PPE contents were negatively related to soil clay content, soil pH, and soil organic matter, whereas PRS and PTK contents were positively correlated with alkali-hydrolyzed nitrogen (AN). According to RDA, the soil clay, AN, available phosphorus (AP), and soil chlorine content (SCL) strongly affected the quality of flue-cured tobacco. The quality of the K326 and Yun87 cultivars was mostly influenced by moisture, whereas the quality of the Hongda cultivar was mostly affected by temperature. In conclusion, compared with soil properties, climatic factors more significantly affect the yield and quality of Honghe flue-cured tobacco leaves.
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http://dx.doi.org/10.1038/s41598-020-76919-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669845PMC
November 2020

TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment.

Nucleic Acids Res 2021 01;49(D1):D1420-D1430

Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200060, China.

Cancer immunotherapy targeting co-inhibitory pathways by checkpoint blockade shows remarkable efficacy in a variety of cancer types. However, only a minority of patients respond to treatment due to the stochastic heterogeneity of tumor microenvironment (TME). Recent advances in single-cell RNA-seq technologies enabled comprehensive characterization of the immune system heterogeneity in tumors but posed computational challenges on integrating and utilizing the massive published datasets to inform immunotherapy. Here, we present Tumor Immune Single Cell Hub (TISCH, http://tisch.comp-genomics.org), a large-scale curated database that integrates single-cell transcriptomic profiles of nearly 2 million cells from 76 high-quality tumor datasets across 27 cancer types. All the data were uniformly processed with a standardized workflow, including quality control, batch effect removal, clustering, cell-type annotation, malignant cell classification, differential expression analysis and functional enrichment analysis. TISCH provides interactive gene expression visualization across multiple datasets at the single-cell level or cluster level, allowing systematic comparison between different cell-types, patients, tissue origins, treatment and response groups, and even different cancer-types. In summary, TISCH provides a user-friendly interface for systematically visualizing, searching and downloading gene expression atlas in the TME from multiple cancer types, enabling fast, flexible and comprehensive exploration of the TME.
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http://dx.doi.org/10.1093/nar/gkaa1020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778907PMC
January 2021

Resveratrol attenuates TLR-4 mediated inflammation and elicits therapeutic potential in models of sepsis.

Sci Rep 2020 11 2;10(1):18837. Epub 2020 Nov 2.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.

Sepsis is a potentially fatal condition triggered by systemic inflammatory response to infection. Due to the heightened immune reactivity and multi-organ pathology, treatment options are limited and several clinical trials have not produced the desired outcome, hence the interest in the discovery of novel therapeutic strategies. The polyphenol resveratrol (RSV) has shown promise against several pathological states, including acute and chronic inflammation. In this study, we evaluated its therapeutic potential in a murine model of sepsis and in patients undergoing transrectal ultrasound biopsy. RSV was able to inhibit lipopolysaccharide (LPS) stimulated inflammatory responses through blocking Phospholipase D (PLD) and its downstream signaling molecules SphK1, ERK1/2 and NF-κB. In addition, RSV treatment resulted in the downregulation of MyD88, an adaptor molecule in the TLR4 signaling pathway, and this effect at least in part, involved RSV-induced autophagy. Notably, RSV protected mice against polymicrobial septic shock induced upon cecal ligation and puncture, and inhibited pro-inflammatory cytokine production by human monocytes from transrectal ultrasound (TRUS) biopsy patients. Together, these findings demonstrate the immune regulatory activity of RSV and highlight its therapeutic potential in the management of sepsis.
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http://dx.doi.org/10.1038/s41598-020-74578-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608666PMC
November 2020

Long Non-Coding RNA NRAD1 and LINC00152 are Highly Expressed and Associated with Prognosis in Patients with Hepatocellular Carcinoma.

Onco Targets Ther 2020 14;13:10409-10416. Epub 2020 Oct 14.

Department of Hepatology, Qingdao Sixth People's Hospital, Qingdao, People's Republic of China.

Background: Hepatocellular carcinoma (HCC) is prevalent throughout the world. The aim of this study is to explore new long non-coding RNAs (lncRNAs) associated with hepatocellular carcinoma and detect their expression levels in hepatocellular carcinoma cell lines and tissues. These results will provide new clues on further function and biomarker studies of HCC-related lncRNAs.

Patients And Methods: All patients were diagnosed as HCC between 30th, March, 2015 and 30th, July, 2018. LncRNA human gene expression microarray was applied to the profiling of lncRNAs in four cancerous tissues and the paired paracancerous tissues.

Results: We retrospectively reviewed 63 patients with primary HCC who underwent a curative liver resection at the Department of Hepatology, Qingdao Sixth People's Hospital. The expression level of lncRNA NRAD1 and LINC00152 was detected by real-time PCR. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazards models. By microarray profiling of lncRNAs, 256 lncRNAs were found to be differentially expressed, including 162 upregulated and 94 downregulated (P<0.05, fold change>2). Two candidate lncRNAs were determined as the targets in this study, which were NRAD1 (upregulated by 6.35 fold), LINC00152 (upregulated by 4.53 fold). NRAD1 and LINC00152 were downregulated in the normal liver cell lines Chang liver, HL7702, THLE-2, THLE-3, FL62891 and AML12, which were significantly lower than HCC cell lines SMMC-7721, Hep3B, HuH7, MHCC-97H, HCC-LM and SK-Hep-1 (<0.05). Overexpression of lncRNA NRAD1 and LINC00152 was associated with decreasing OS rates, respectively (P=0.0263 and P=0.0285). Meanwhile, overexpression of NRAD1 and LINC00152 was associated with decreasing PFS rates, respectively (P=0.0174 and P=0.0041). After adjusting for competing risk factors, we identified that microvascular invasion (P=0.014), tumor size (P=0.026), lncRNA NRAD1 (P=0.001) and LINC00152P9 (P=0.036) expression levels were independent prognostic factors associated with prognosis of patients with HCC.

Conclusion: We found lncRNA NRAD1 and LINC00152 expressed significantly higher in HCC tissues compared with non-tumorous tissues. Overexpression of lncRNA NRAD1 and LINC00152 were independent risk factors associated with the prognosis of patients with HCC.
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http://dx.doi.org/10.2147/OTT.S251231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569076PMC
October 2020

Analysis of CNVs of CFTR gene in Chinese Han population with CBAVD.

Mol Genet Genomic Med 2020 11 19;8(11):e1506. Epub 2020 Sep 19.

Graduate School of Peking Union Medical College, Beijing, P. R. China.

Background: Congenital bilateral absence of vas deferens (CBAVD) is an important disease of male infertility, which affects 1%-2% of infertile population. In addition to common mutations of CFTR, copy number variants (CNVs) have also been implicated as one of the pathogenesis of CBAVD. The present study aimed to investigate the genetic contribution of CFTR CNVs in Chinese Han population with CBAVD.

Methods: Two hundred and sixty-three CBAVD patients were recruited. Genomic DNA was extracted from peripheral blood samples. The Multiplex Ligation-dependent Probe Amplification assay was performed which targets the region of the CFTR gene.

Results: Among 263 Chinese men affected with CBAVD in this study, 5 (1.90%) patients were detected for copy number variants in the region of CFTR gene (4 of them carried partial deletions and 1 of them carried partial duplication of CFTR gene).

Conclusions: The study showed that the rate of CFTR CNVs in Chinese population with CBAVD were basically consistent with the previous reports. And the study first revealed genetic risk of CNVs of CFTR on a large sample size of CBAVD patients in Chinese Han population, which prompted that it was necessary to detect CNVs of CFTR in Chinese Han people with CBAVD.
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http://dx.doi.org/10.1002/mgg3.1506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667304PMC
November 2020

Transport and fate of human expiratory droplets-A modeling approach.

Phys Fluids (1994) 2020 Aug;32(8):083307

Department of Civil and Environmental Engineering, University of Missouri, Columbia, Missouri 65211, USA.

The transport and fate of human expiratory droplets play a key role in the transmission of respiratory infectious diseases. In this paper, we present a modeling approach to understand the fundamental dynamics of exhaled droplets in human respiratory activities. The model solves a series of governing equations of droplets and uses a continuous random walk model to simulate turbulent fluctuations in violent expiratory events. The validation of the model shows the improvement in the prediction of dispersion of median-sized droplets. We show that these droplets are sensitive to environmental conditions, including temperature, humidity, and ambient flows. Applying the model to a set of idealized conditions such as free-fall and continuous jets, we demonstrate significantly different impacts of environmental parameters on droplets with different sizes. Using a realistic droplet size distribution and cough duration, we quantify the transport and fate of droplets in the near field of source and the potential influences by ambient conditions. The model we developed from this study could be applied to study the mechanisms for airborne pathogens, e.g., influenza virus and new coronavirus.
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http://dx.doi.org/10.1063/5.0021280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437951PMC
August 2020

Motion-preserving treatment of unstable atlas fracture: transoral anterior C1-ring osteosynthesis using a laminoplasty plate.

BMC Musculoskelet Disord 2020 Aug 12;21(1):538. Epub 2020 Aug 12.

The First School of Clinical Medicine, Southern Medical University, No.1838 North of Guangzhou Road, Guangzhou, 510515, People's Republic of China.

Background: C1-ring osteosynthesis is a valid alternative to posterior C1-C2 or C0-C2 fusion to preserve important C1-C2 motion in the treatment of unstable atlas fractures. Nevertheless, the fixation instruments used in current studies for transoral anterior C1-ring osteosynthesis were not suitable for anterior anatomy of the atlas or did not have reduction mechanism. We therefore present this report to investigate preliminary clinical effects of transoral anterior C1-ring osteosynthesis using a laminoplasty plate in unstable atlas fractures.

Methods: From January 2014 to December 2017, 13 patients with unstable atlas fractures were retrospectively reviewed. All patients were treated with transoral anterior C1-ring osteosynthesis using a laminoplasty plate. Pre- and postoperative images were obtained to assess reduction of the fracture, internal fixation placement, and bone union. Neurological function, range of motion, and pain levels were evaluated clinically on follow-up.

Results: The surgeries were successfully performed in all cases. The average follow-up duration was 16.6 ± 4.4 months (range 12-24 months). One patient suffered screw loosening after operation and underwent replacement operation subsequently. Satisfactory clinical outcomes were achieved in all patients with ideal fracture reduction, reliable plate placement, well-preserved range of motion, and neck pain alleviation. All patients achieved bone union of fractures without loss of reduction or implant failure or C1-C2 instability during the follow-up. No vascular or neurological complication was noted during the operation and follow-up.

Conclusions: Transoral anterior C1-ring osteosynthesis using a laminoplasty plate is a effective surgical treatment for unstable atlas fractures. This technique has a ingenious reduction mechanism, and can provide satisfactory bone union and preservation of C1-C2 motion.
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http://dx.doi.org/10.1186/s12891-020-03575-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425063PMC
August 2020

Variability of a natural hydrocarbon seep and its connection to the ocean surface.

Sci Rep 2020 07 28;10(1):12654. Epub 2020 Jul 28.

Lamont Doherty Earth Observatory, Columbia University, Palisades, NY, USA.

Natural hydrocarbon seeps are ubiquitous along continental margins. Despite their significance, we lack a basic understanding of the long-term temporal variability of seep dynamics, including bubble size, rise velocity, composition, and upwelling and entrainment processes. The shortcoming makes it difficult to constrain the global estimates of oil and gas entering the marine environment. Here we report on a multi-method approach based on optical, acoustic, satellite remote sensing, and simulations, to connect the characteristics of a hydrocarbon seep in the Gulf of Mexico to its footprint on the sea surface. Using an in-situ camera, bubble dynamics at the source were measured every 6 h over 153 days and the integrated total hydrocarbon release volume was estimated as 53 m. The vertical velocity was acoustically measured at 20 m above bed (mab) and found to be approximately 40% less than the dispersed-phase at the source, indicating that the measured values are reflecting the plume continuous-phase flow. Numerical simulations predict that the oily bubbles with diameters larger than 8 mm reach the surface with a small footprint, i.e. forming an oil slick origin, deflection of which with wind and surface current leads to the formation of an oil slick on the surface. Nineteen SAR images are used to estimate the oil seepage rate from GC600 for 2017 giving an average discharge of 14.4 cm/s.
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http://dx.doi.org/10.1038/s41598-020-68807-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387546PMC
July 2020

Long Non-Coding RNA THOR Enhances the Stem Cell-Like Traits of Triple-Negative Breast Cancer Cells Through Activating β-Catenin Signaling.

Med Sci Monit 2020 Jul 14;26:e923507. Epub 2020 Jul 14.

Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, Hubei, China (mainland).

BACKGROUND The oncogenic roles of lncRNA THOR have been revealed in several tumors, however, its functions in breast cancer are still unclear. MATERIAL AND METHODS Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect THOR expression in clinical samples and the expression of stemness regulatory factors. ALDH1 assay and sphere-formation analysis were constructed to examine the stemness of cells. Cell viability assay was constructed to determine the cell proliferation capacity. In vitro RNA-RNA interaction and messenger RNA (mRNA) stability assays were performed to explore the mechanisms. RESULTS THOR was overexpressed in triple-negative breast cancer (TNBC) compared to that in luminal A- and B-type breast cancer. THOR silencing reduced TNBC cell stemness, which was evident by the decreased sphere-formation ability, stemness marker expression and ALDH1 activity. Mechanistically, THOR directly bound to ß-catenin mRNA, enhanced ß-catenin mRNA stability and thus increased its expression. Furthermore, overexpression of ß-catenin partially diminished THOR silencing-mediated inhibition on TNBC cell stemness. CONCLUSIONS This work proposes that THOR facilitates TNBC cell stemness through activating ß-catenin signaling.
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http://dx.doi.org/10.12659/MSM.923507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366791PMC
July 2020

Quantifying the evaporation amounts of 75 high-elevation large dimictic lakes on the Tibetan Plateau.

Sci Adv 2020 Jun 26;6(26):eaay8558. Epub 2020 Jun 26.

Key Laboratory of Tibetan Environment Changes and Land Surface Processes, Institute of Tibetan Plateau Research, Chinese Academy of Sciences, Beijing 100101, China.

Lake evaporation can influence basin-wide hydrological cycles and is an important factor in loss of water resources in endorheic lakes of the Tibetan Plateau. Because of the scarcity of data, published lake evaporation values are inconsistent, and their spatial distribution has never been reported. Presenting a plausible hypothesis of energy balance during the ice-free seasons, we explored the multiyear (2003-2016) average ice phenology and evaporation amounts of 75 large dimictic lakes by using a combination of meteorological and satellite data. Evaporation amounts show large variability in spatial distribution, with a pattern of higher values in the south. Lakes with higher elevation, smaller area, and higher latitude are generally associated with a shorter ice-free season and lower evaporation. The total evaporated water amounts have values of approximately 29.4 ± 1.2 km year for the 75 studied lakes and 51.7 ± 2.1 km year for all plateau lakes included.
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http://dx.doi.org/10.1126/sciadv.aay8558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319769PMC
June 2020

Effects of various levels of dietary fiber on carcass traits, meat quality and myosin heavy chain I, IIa, IIx and IIb expression in muscles in Erhualian and Large White pigs.

Meat Sci 2020 Nov 24;169:108160. Epub 2020 Apr 24.

Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China. Electronic address:

This study evaluated the effects of bran fiber levels on carcass traits, meat quality and expression of myosin heavy chain isoform genes in muscles in Erhualian (Er-HL) and Large White pig (LW). Our results showed that fiber level did not affect carcass weight of Er-HL, while carcass weight of LW decreased with the increase of fiber level. Fiber level did not influence meat quality traits of LW, whereas increased fiber level led to an increase in pH of Er-HL, and Er-HL fed 7% bran fiber (BRC) increased redness of meat compared with control diet (CON). We observed a decreased MyHCIIb and MyHCIIx mRNAs and protein levels in Er-HL fed 7% BRC compared with those in other groups, accompanying with a tendency for increased mRNA abundance of MyHCI. The slow-twitch oxidative fiber (MyHCI) is rich in myoglobin and mitochondrial oxidative metabolic enzymes, and the increased expression of MyHCI fiber in pork has resulted in higher redness value. In summary, bran fiber had no adverse effect on the meat quality of LW and appropriate fiber level addition in diets could improve meat quality of Er-HL through regulation the expression of myofiber types.
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http://dx.doi.org/10.1016/j.meatsci.2020.108160DOI Listing
November 2020

The activation of antiviral RNA interference not only exists in neural progenitor cells but also in somatic cells in mammals.

Emerg Microbes Infect 2020 Dec;9(1):1580-1589

State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.

The RNA interference (RNAi) pathway directs an important antiviral immunity mechanism in plants and invertebrates. Recently, we and others have demonstrated that the antiviral RNAi response is also conserved in mammals, at least to five distinct RNA viruses, including Zika virus (ZIKV). ZIKV may preferentially infect neuronal progenitor cells (NPCs) in the developing foetal brain. ZIKV infection induces RNAi-mediated antiviral response in human NPCs, but not in the more differentiated NPCs or somatic cells. However, litter is known about the property or function of the virus-derived small-interfering RNAs (vsiRNAs) targeting ZIKV. Here we report a surprising observation: different from observations, viral small RNAs (vsRNAs) targeting ZIKV were produced upon infection in both central neuron system (CNS) and muscle tissues. In addition, our findings demonstrate the production of canonical vsiRNAs in murine CNS upon antiviral RNAi activation by Sindbis virus (SINV), suggesting the possibility of antiviral immune strategy applied by mammals in the CNS.
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http://dx.doi.org/10.1080/22221751.2020.1787798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473182PMC
December 2020

Peli1 signaling blockade attenuates congenital zika syndrome.

PLoS Pathog 2020 06 16;16(6):e1008538. Epub 2020 Jun 16.

Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, United States of America.

Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of lethal encephalitis by facilitating the replication of West Nile virus (WNV), a closely related flavivirus. Here, we found that Peli1 expression was induced on ZIKV-infected human monocytic cells, peripheral blood mononuclear cells, human first-trimester placental trophoblasts, and neural stem cell (hNSC)s. Peli1 mediates ZIKV cell attachment, entry and viral translation and its expression is confined to the endoplasmic reticulum. Moreover, Peli1 mediated inflammatory cytokine and chemokine responses and induced cell death in placental trophoblasts and hNSCs. ZIKV-infected pregnant mice lacking Peli1 signaling had reduced placental inflammation and tissue damage, which resulted in attenuated congenital abnormalities. Smaducin-6, a membrane-tethered Smad6-derived peptide, blocked Peli1-mediated NF-κB activation but did not have direct effects on ZIKV infection. Smaducin-6 reduced inflammatory responses and cell death in placental trophoblasts and hNSCs, and diminished placental inflammation and damage, leading to attenuated congenital malformations in mice. Collectively, our results reveal a novel role of Peli1 in flavivirus pathogenesis and suggest that Peli1 promotes ZIKV vertical transmission and neuronal loss by mediating inflammatory cytokine responses and induction of cell death. Our results also identify Smaducin-6 as a potential therapeutic candidate for treatment of CZS.
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http://dx.doi.org/10.1371/journal.ppat.1008538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297310PMC
June 2020

Effect of Mutation on Growth and Carcass Performance in Duroc x Meishan Hybrid Population.

Animals (Basel) 2020 May 28;10(6). Epub 2020 May 28.

Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.

The Meishan pig is a traditional Chinese native breed, known for its excellent reproduction performance that is widely used in commercial pig production through two-way or three-way crossbreeding systems. However, the lean meat yield of Meishan crossbred pigs is still very low and cannot meet the market demand. To evaluate the lean meat yield of Meishan crossbred pigs, six wild-type Meishan sows were artificially inseminated by using the Duroc boar semen in this experiment. Some reproductive performance-related traits of Meishan sows were recorded to ensure that semen from knockout Duroc boar did not affect offspring production, including total births, live births, sex, and litter weight. In total, 73 piglets were obtained and 63 were alive. Male to female ratio was close to 1: 1. because of factors such as disease, only 43 pigs were utilized, including 28 mutant pigs () and 15 homozygous pigs (). We compared the growth performance and carcass performance of these full or half-sib populations and found that there were no differences between and genotypes for live animal measures including average daily gain (ADG), body dimensions, or ultrasonic measurement of fat thickness when pigs were harvested after 120 days of feeding. Conversely, the pigs had higher dressing percentage and lean meat percentage, lower level of carcass fat, larger longissimus muscle area, less percentage of skin and skeleton, thinner average backfat thickness, and lower intramuscular fat (IMF) content than pigs. In conclusion, the production of mutant progeny from Meishan females resulted in improved carcass composition, providing a feasible solution to improve the lean meat yield of Chinese local fat-type pig breeds.
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http://dx.doi.org/10.3390/ani10060932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341510PMC
May 2020

Investigation of the Role of Rare-Earth Elements in Spin-Hall Topological Hall Effect in Pt/Ferrimagnetic-Garnet Bilayers.

Nano Lett 2020 Jun 29;20(6):4667-4672. Epub 2020 May 29.

Department of Physics, The Ohio State University, Columbus, Ohio 43210, United States.

Topological magnetic textures such as skyrmions are being extensively studied for their potential application in spintronic devices. Recently, low-damping ferrimagnetic insulators (FMI) such as TmFeO have attracted significant interest as potential candidates for hosting skyrmions. Here, we report the detection of the spin-Hall topological Hall effect (SH-THE) in Pt/TmFeO and Pt/YFeO bilayers grown on various orientations of GdGaO substrates as well as on epitaxial buffer layers of YScAlO, which separates the FMI from the substrate without sacrificing the crystal quality. The presence of SH-THE in all of the bilayers and trilayers provides evidence that rare-earth ions in either the FMI or substrate may not be critical for inducing an interfacial Dzyaloshinskii-Moriya interaction that is necessary to stabilize magnetic textures. Additionally, the use of substrates with various crystal orientations alters the magnetic anisotropy, which shifts the temperatures and strength of the SH-THE.
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http://dx.doi.org/10.1021/acs.nanolett.0c01620DOI Listing
June 2020

Serum Metabolic Profiling Analysis of Gout Patients Treated with Traditional Chinese Medicine Tongfengtai Granules Based on Gas Chromatography-Mass Spectrometry.

Evid Based Complement Alternat Med 2020 26;2020:7404983. Epub 2020 Apr 26.

Graduate School, Peking Union Medical College, Beijing, China.

Gout has become a public health problem that seriously threatens human health. Traditional Chinese medicines (TCMs) have a long history of treating gout and have some advantages compared with the conventional medicines. Compound TCM Tongfengtai granules are gradually being used for clinical treatment of gout, but its mechanism is still unclear. The purpose of this study was to explore the metabolic profiling of serum from gout patients before and after treatment with Tongfengtai granules and identify the differential metabolites and related metabolic pathways. A total of 40 gout patients hospitalized in Shenzhen Traditional Chinese Medicine Hospital from 2018 to March 2019 were recruited in the current study, and serum samples from these patients before and after treatment with Tongfengtai granules were collected. Gas chromatography-mass spectrometry (GC-MS) assay was used to identify serum metabolites. The OPLS-DA VIP method was used to screen for potential metabolic biomarkers, and MetaboAnalyst 4.0 was used to identify related metabolic pathways. The result showed that there was a significant difference in the concentrations of six metabolites in the serum after treatment: D-galactose, lactic acid, 3-hydroxybutyric acid, D-pyran (type) glucose, alanine, and L-isoleucine. Except D-pyran (type) glucose, the serum concentrations of the other five metabolites were all significantly reduced. Besides, pathway enrichment analysis found that these potential metabolic biomarkers were mainly involved in lactose degradation and the glucose-alanine cycle. Thus, the serum metabolic profiling of gout patients treated with Tongfengtai granules changed, and the differential metabolites and related metabolic pathways might provide clues for understanding the mechanism of Tongfengtai granules.
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http://dx.doi.org/10.1155/2020/7404983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201437PMC
April 2020

Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer.

Mol Cell 2020 06 15;78(6):1096-1113.e8. Epub 2020 May 15.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA. Electronic address:

BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents. We also uncovered functional similarities and differences among BRD2, BRD4, and BRD7. Although deletion of BRD2 enhances sensitivity to BBDIs, BRD7 loss leads to gain of TEAD-YAP chromatin binding and luminal features associated with BBDI resistance. Single-cell RNA-seq, ATAC-seq, and cellular barcoding analysis of BBDI responses in sensitive and resistant cell lines highlight significant heterogeneity among samples and demonstrate that BBDI resistance can be pre-existing or acquired.
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http://dx.doi.org/10.1016/j.molcel.2020.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306005PMC
June 2020

CRISPR Screens Identify Essential Cell Growth Mediators in BRAF Inhibitor-resistant Melanoma.

Genomics Proteomics Bioinformatics 2020 02 13;18(1):26-40. Epub 2020 May 13.

Department of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address:

BRAF is a serine/threonine kinase that harbors activating mutations in ∼7% of human malignancies and ∼60% of melanomas. Despite initial clinical responses to BRAF inhibitors, patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAF inhibitor resistant melanoma, we conduct CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAF inhibitors. To investigate the mechanisms and pathways enabling resistance to BRAF inhibitors in melanomas, we integrate expression, ATAC-seq, and CRISPR screen data. We identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6, which together enable resistance to BRAF inhibitors in melanoma cells. Our findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720, providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.
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http://dx.doi.org/10.1016/j.gpb.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393575PMC
February 2020