Publications by authors named "Wenliang Wang"

162 Publications

The feasibility of non-contrast-enhanced zero echo time magnetic resonance angiography for characterization of intracranial atherosclerotic disease.

Quant Imaging Med Surg 2021 Jun;11(6):2442-2452

Department of Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.

Background: Accurate and non-invasive assessment of intracranial atherosclerotic disease (ICAD) is important because of its effect on treatment planning. The aim of this study is to investigate if zero echo time (zTE) magnetic resonance angiography (zTE-MRA) is feasible in the characterization of ICAD.

Methods: A total of 175 patients with ICAD were recruited. ZTE-MRA and time-of-flight (TOF)-MRA sequences were conducted for all participants using a 3T clinical MR system. Forty-one patients also underwent digital subtraction angiography (DSA), and were confirmed to have intracranial arterial stenosis (ICAS). Weighted kappa (κ) statistics were used to assess the inter-observer agreement and diagnostic consistency of both zTE- and TOF-MRA, using DSA as a reference. The Wilcoxon signed-rank test was used to evaluate differences in image quality between zTE- and TOF-MRA images. The nonparametric test of multiple paired samples was used to compare the results of vascular stenosis diagnosis between zTE-, TOF-MRA and DSA.

Results: Supported by high inter-observer agreement (weighted κ=0.78), zTE-MRA generated significantly higher scores than TOF-MRA for susceptibility artifact signal (mean: 3.03±0.98 2.72±1.09; P=0.017) and flow signal in parent artery (mean: 3.63±0.49 3.07±0.82; P<0.001). Additionally, zTE-MRA showed more robust diagnostic performance than TOF-MRA for patients with ICAD and degree of vascular stenosis (P<0.05), and was highly consistent with reference DSA images (weighted κ=0.80).

Conclusions: ZTE-MRA has potential for use as a routine clinical method for patients with ICAD.
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http://dx.doi.org/10.21037/qims-20-696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107310PMC
June 2021

RNAi and chemogenetic reporter co-regulation in primate striatal interneurons.

Gene Ther 2021 May 19. Epub 2021 May 19.

Laboratory of Neuropsychology, NIMH, NIH, Bethesda, MD, USA.

Using genetic tools to study the functional roles of molecularly specified neuronal populations in the primate brain is challenging, primarily because of specificity and verification of virus-mediated targeting. Here, we report a lentivirus-based system that helps improve specificity and verification by (a) targeting a selected molecular mechanism, (b) in vivo reporting of expression, and (c) allowing the option to independently silence all regional neural activity. Specifically, we modulate cholinergic signaling of striatal interneurons by shRNAmir and pair it with hM4Di_CFP, a chemogenetic receptor that can function as an in vivo and in situ reporter. Quantitative analyses by visual and deep-learning assisted methods show an inverse linear relation between hM4Di_CFP and ChAT protein expression for several shRNAmir constructs. This approach successfully applies shRNAmir to modulating gene expression in the primate brain and shows that hM4Di_CFP can act as a readout for this modulation.
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http://dx.doi.org/10.1038/s41434-021-00260-yDOI Listing
May 2021

Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics.

Cell Chem Biol 2021 May 7. Epub 2021 May 7.

Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. Electronic address:

Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.
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http://dx.doi.org/10.1016/j.chembiol.2021.04.014DOI Listing
May 2021

Comparison of Brassica Genomes reveals asymmetrical gene retention between functional groups of genes in recurrent polyploidizations.

Plant Mol Biol 2021 May 19;106(1-2):193-206. Epub 2021 Mar 19.

College of Life Sciences, Wuhan University, Wuhan, 430072, China.

Key Message: We provided a study on homeologous gene evolution of homeologous genes by comparing Brassica genomes. Polyploidy has played fundamental roles during the evolution of plants. Following polyploidization, many duplicated genes are diversified or lost in a process termed diploidization. Understanding the retention and diversification of homeologs after polyploidization will help elucidate the process of diploidization. Here, we investigated the evolution of homeologous genes in Brassica genomes and observed similarly asymmetrical gene retention among different functional groups and consistent retention after recurrent polyploidizations. In the comparative analysis of Brassica diploid genomes, we found that preferentially retained genes show different patterns on sequence and expression divergence: genes with the function of 'biosynthetic process' and 'transport' were under much stronger purifying selection, while transcriptional regulatory genes diverged much faster than other genes. Duplicate pairs of the former two functional groups show conserved high expression patterns, while most of transcriptional regulatory genes are simultaneously lowly expressed. Furthermore, homeologs in diploids and allotetraploids showed similar loss and retention patterns: duplicates in progenitor genomes were more likely to be retained and accumulated fewer substitutions. However, transcriptional regulation is also enriched in the genes that do not have any non-synonymous mutations in the Brassica allotetraploids, indicating that some of these genes were under strong purifying selection. Overall, our study provided insight into the evolution of homeologs genes during diploidization process.
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http://dx.doi.org/10.1007/s11103-021-01137-9DOI Listing
May 2021

Evaluation of the Effectiveness of Lumbar Punctures in Aneurysmal Subarachnoid Hemorrhage Patient with External Ventricular Drainage.

World Neurosurg 2021 Mar 15. Epub 2021 Mar 15.

Department of Neurosurgery, Union Hospital, Tongji Medical College, Wuhan, China. Electronic address:

Background: For aSAH patients with external ventricular drainage (EVD) because of hydrocephalus, the consensus on application of CSF drainage from the lumbar cistern is mixed owing to concerns about its safety and questionable effectiveness. This study evaluated the additional effectiveness of CSF drainage from the lumbar cistern in aSAH patients with EVD.

Methods: This was a retrospective and observational study of adult patients with aSAH who were admitted to the intensive care unit at the Wuhan Union Hospital between June 2018 and June 2019. Three aSAH patients with EVD and serial lumbar punctures (LPs) were selected for comparison of CSF components. Four more aSAH patients who underwent divergent CSF drainage were selected to profile the additional effectiveness of lumbar cistern drainage in aSAH patients with EVD.

Results: Cases 1-3 with EVD and serial LPs showed dramatically higher red blood cell (RBC) and leukocyte counts with steeper changing curve in the lumbar cistern CSF than in the ventricle CSF. Case 5 had EVD alone and showed a slower clearing rate of blood clot in subarachnoid space compared with case 1. Case 4, with serial LPs alone, showed a steep changing curve of both RBC and leukocyte counts in the lumbar cistern CSF. Cases 6 and 7, with EVD and follow-up LPs, showed dramatically higher RBC and leukocyte counts in the lumbar cistern CSF than in the ventricle CSF after almost 2 weeks of EVD.

Conclusions: For aSAH patients with EVD, serial LPs can accelerate clearance of toxic products from the subarachnoid space.
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http://dx.doi.org/10.1016/j.wneu.2021.02.025DOI Listing
March 2021

Cellulose-based electrospun nanofiber membrane with core-sheath structure and robust photocatalytic activity for simultaneous and efficient oil emulsions separation, dye degradation and Cr(VI) reduction.

Carbohydr Polym 2021 Apr 22;258:117676. Epub 2021 Jan 22.

Shaanxi Provincial Key Laboratory of Papermaking Technology and Specialty Paper Development, National Demonstration Center for Experimental Light Chemistry Engineering Education, Shaanxi University of Science and Technology, Xi'an, 710021, China; Limerick Pulp and Paper Centre, University of New Brunswick, Fredericton, New Brunswick, E3B 5A3, Canada.

Electrospun nanofiber membrane (ENM) shows great advantage and potential in wastewater treatment due to its unique properties. However, exploring a green and efficient ENM for remediation of complex wastewater, such as simultaneous containing oils, dyes and heavy metal ion, remains challenging. In this work, a cellulose-based photocatalytic ENM, is constructed for this purpose. The hybrid ENM is prepared via electrospinning deacetylated cellulose acetate/polyvinyl pyrrolidone (CeP) nanofibers as skeleton cores and in-situ synthesis of beta hydroxyl oxidize iron decorated iron-based MOF (β[email protected](Fe)) heterojunctions as photocatalytic sheaths. The core-sheath structured ENM has ultrahigh MIL-100(Fe) loading (78 wt%), large surface areas (1105 m/g) and well-dispersed β-FeOOH nanorods. Thanks to these porous and hydrophilic MIL-100(Fe), along with a robust photocatalysis-Fenton synergy from β[email protected](Fe), the as-prepared ENM shows outstanding performances with simultaneous high removal efficiency for oils (99.5 %), dyes (99.4 %) and chromium ion (Cr(VI)) (99.7 %). Additionally, the photocatalytic ENM can achieve a long-term reuse owing to its inherent self-cleaning function.
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http://dx.doi.org/10.1016/j.carbpol.2021.117676DOI Listing
April 2021

Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML).

Eur J Pharmacol 2021 Apr 11;897:173944. Epub 2021 Feb 11.

Anhui Province Key Laboratory of Medical Physics and Technology; CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, PR China. Electronic address:

As the critical driving force for chronic myeloid leukemia (CML), BCR gene fused ABL kinase has been extensively explored as a validated target of drug discovery. Although imatinib has achieved tremendous success as the first-line treatment for CML, the long-term application ultimately leads to resistance, primarily via various acquired mutations occurring in the BCR-ABL kinase. Although dasatinib and nilotinib have been approved as second-line therapies that could overcome some of these mutants, the most prevalent gatekeeper T315I mutant remains unconquered. Here, we report a novel type II kinase inhibitor, CHMFL-48, that potently inhibits the wild-type BCR-ABL (wt) kinase as well as a panel of imatinib-resistant mutants, including T315I, F317L, E255K, Y253F, and M351T. CHMFL-48 displayed great inhibitory activity against ABL wt (IC: 1 nM, 70-fold better than imatinib) and the ABL T315I mutant (IC: 0.8 nM, over 10,000-fold better than imatinib) in a biochemical assay and potently blocked the autophosphorylation of BCR-ABL wt and BCR-ABL mutants in a cellular context, which further affected downstream signalling mediators, including signal transducer and activator of transcription 5 (STAT5) and CRK like proto-oncogene (CRKL), and led to the cell cycle progression blockage as well as apoptosis induction. CHMFL-48 also exhibited great anti-leukemic efficacies in vivo in K562 cells and p210-T315I-transformed BaF3 cell-inoculated murine models. This discovery extended the pharmacological diversity of BCR-ABL kinase inhibitors and provided more potential options for anti-CML therapies.
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http://dx.doi.org/10.1016/j.ejphar.2021.173944DOI Listing
April 2021

Redox-Responsive Multifunctional Polypeptides Conjugated with Au Nanoparticles for Tumor-Targeting Gene Therapy and Their 1 + 1 > 2 Synergistic Effects.

ACS Biomater Sci Eng 2020 01 10;6(1):463-473. Epub 2019 Dec 10.

Laboratory of Polymer Composites Engineering, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.

Gene therapy is regarded as one of the most potential technologies for tumor therapy. Gene delivery systems with high specificity and good biocompatibility are urgently demanded. Hence, in this research, we designed and synthesized a series of tumor targeting and redox-responsive gold nanoparticles conjugated with three kinds of functional polypeptides (AuNPPs) that consisted of targeting peptide GE11, cell-penetrating peptide octaarginine (R8), and polyhistidine. All the AuNPPs exhibited superior cancer cellular internalization ability and targeting gene transfection efficiency compared with commercial agent BPEI 25K. It is interesting to find that different relative positions of GE11 and R8 can cause the change of target ability and gene transfection efficiency, and the suitable relative position of R8 and GE11 can not only endow the gene vector with functions that peptides previously own but also bring the synergistic effects. The best-performed AuNPP6-1 was chosen to transport the epidermal growth factor receptor (EGFR)-shRNA into A549 tumor-bearing BALB/c nude mice, and in vivo fluorescence imaging showed AuNPP6-1 mainly accumulated in tumor sites and achieved a great targeting therapy effect. These results provide significantly important information on understanding and constructing the tumor-targeting gene vector.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01581DOI Listing
January 2020

Highly Efficient InGaN Nanorods Photoelectrode by Constructing Z-scheme Charge Transfer System for Unbiased Water Splitting.

Small 2021 Jan 22;17(3):e2006666. Epub 2020 Dec 22.

State Key Laboratory of Luminescent Materials and Devices, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510640, China.

Unbiased photoelectrochemical water splitting for the promising InGaN nanorods photoelectrode is highly desirable, but it is practically hindered by the serious recombination of charge carrier in bulk and surface of InGaN nanorods. Herein, an unbiased Z-scheme InGaN nanorods/Cu O nanoparticles heterostructured system with boosted interfacial charge transfer is constructed for the first time. The introduced Cu O nanoparticles pose double-sided effect on photoelectrochemical (PEC) performance of InGaN nanorods, which enables a robust hybrid structure and induces weakened light absorption capability simultaneously. As a result, the optimized InGaN/Cu O-1.5C photoelectrode with the uniform morphology exhibits an enhanced photocurrent density of ≈170 µA cm at 0 V versus Pt, with 8.5-fold enhancement compared with pure InGaN nanorods. Comprehensive investigations into experimental results and theoretical calculations reveal that the electrons accumulation and holes depletion of Cu O facilitate to form a typical Z-scheme band alignment, thus providing a large photovoltage to drive unbiased water splitting and enhancing the stability of Cu O. This work provides a novel and facile strategy to achieve InGaN nanorods and other catalyst-based PEC water splitting without external bias, and to relieve the bottlenecks of charge transfer dynamics at the electrode bulk and electrode/electrolyte interface by constructing Z-scheme heterostructure.
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http://dx.doi.org/10.1002/smll.202006666DOI Listing
January 2021

Dinuclear gold catalysis.

Chem Soc Rev 2021 Feb;50(3):1874-1912

State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. and Advanced Catalytic Engineering Research Center of the Ministry of Education, Hunan University, Changsha 410082, China.

Gold chemistry has developed extensively in the past decade, and a dozen good reviews have been presented discussing this progress. Few however have paid close attention to the progress in organic synthesis of dinuclear gold-catalysis. A dinuclear gold catalyst is defined here as a gold complex with two gold centers linked by a bidentate ligand. With theoretical analysis and some representative studies in recent years, this comprehensive review highlights the particular properties of dinuclear gold-complexes, especially aurophilic interactions, and systematically summarizes the recent achievements of dinuclear gold-catalyzed coupling reactions, asymmetric catalysis, and photocatalysis, where dinuclear gold catalysts tend to show a greater advantage than the mononuclear gold catalysts.
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http://dx.doi.org/10.1039/d0cs00254bDOI Listing
February 2021

Extraction, modification, and property characterization of dietary fiber from .

Food Sci Nutr 2020 Nov 27;8(11):6131-6143. Epub 2020 Sep 27.

Institute of Agro-Food Science and Technology Shandong Academy of Agricultural Sciences Jinan Shandong PR China.

Dietary fiber (DF) has gained a great attention owing to its potential health benefits. is an edible fungus with high protein and low fat contents, which is also an enriched source of DF. However, limited study has been conducted on optimizing the conditions of . -derived DF extraction and modification as well as characterizing its properties. In this study, ultrasound-assisted enzymatic method for DF extraction was optimized as the following conditions: liquid material ratio of 29 ml/g, α-amylase concentration of 1.50%, protamex concentration of 1.20%, and ultrasonic power of 150 W, which improved the DF extraction yield to 37.70%. Moreover, high temperature modification (HTM) and cellulase modification (CEM) were applied to modify . -derived DF. The results showed that HTM had more potential capacity in converting insoluble DF into soluble DF, and DF with HTM exhibited more advantages in its physicochemical properties than DF with CEM. The DF with both HTM and CEM showed antioxidant activities, reflected by the increased reducing power as well as DPPH radical, hydroxyl radical, and ABTS scavenging capabilities in vitro. These findings could offer a reference for the extraction, modification, and characterizing various properties of DF from . , which would establish the foundation for the comprehensive application of fungi-derived DF.
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http://dx.doi.org/10.1002/fsn3.1905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684601PMC
November 2020

Combination of Gas and Increasing Density in the Dural Venous Sinus After Blunt Head Trauma Contributes to Early Diagnosis of Dural Venous Sinus Thrombosis.

World Neurosurg 2021 02 30;146:274-276. Epub 2020 Nov 30.

Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: Dural venous sinus thrombosis (DVST) after blunt head trauma is not rare; however, its clinical manifestations are vague, which impedes early diagnosis that is vital for its management. Prior studies have demonstrated that the presence of gas in the dural venous sinus (DVS) after blunt head trauma increases the likelihood of DVST. On nonenhanced computed tomography (CT), hyperdensity in the DVS is considered a direct sign of thrombosis, which can enable early diagnosis of traumatic DVST with high specificity but low sensitivity. We describe a case of traumatic DVST, which was diagnosed early based on the findings of gas and increasing density in the DVS on regular nonenhanced CT.

Case Description: A 41-year-old man was admitted to our hospital after he landed on his head in a car accident. The initial CT (each slice 5.0 mm thick), taken 40 minutes after the injury, indicated right occipital skull fracture and gas in the right sigmoid sinus. Next, 16 hours after the injury, the patient underwent another head CT (each slice 1.25 mm thick). The image showed increasing density (>65 Hounsfield units) in the right sigmoid sinus and the area of intrasinus gas, which is an indication of traumatic DVST, and the bone window revealed right occipital skull fracture that extended to the right sigmoid sinus. Anticoagulant therapy was immediately started after subsequent computed tomographic venography confirmed nonocclusive venous thrombi in the right transverse sinus, the right sigmoid sinus, and the right internal jugular vein on the level of the second cervical vertebra. Three weeks after the injury, computed tomographic venography re-examination showed that the thrombi had resolved dramatically.

Conclusions: Traumatic DVST was diagnosed early through findings of gas and increasing density in DVS on different nonenhanced CTs. Finding this combination is a practical, sensitive method for early diagnosis of traumatic DVST, especially in patients with hidden skull fractures involving DVS and patients with hypocythemia.
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http://dx.doi.org/10.1016/j.wneu.2020.11.084DOI Listing
February 2021

SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 Are Expressed in the Microvasculature and Ducts of Human Pancreas but Are Not Enriched in β Cells.

Cell Metab 2020 12 13;32(6):1028-1040.e4. Epub 2020 Nov 13.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address:

Isolated reports of new-onset diabetes in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into β cells via co-expression of its canonical cell entry factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2); however, their expression in human pancreas has not been clearly defined. We analyzed six transcriptional datasets of primary human islet cells and found that ACE2 and TMPRSS2 were not co-expressed in single β cells. In pancreatic sections, ACE2 and TMPRSS2 protein was not detected in β cells from donors with and without diabetes. Instead, ACE2 protein was expressed in islet and exocrine tissue microvasculature and in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. These findings reduce the likelihood that SARS-CoV-2 directly infects β cells in vivo through ACE2 and TMPRSS2.
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http://dx.doi.org/10.1016/j.cmet.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664344PMC
December 2020

Discovery of ()-2-(1-(4-Amino-3-(3-fluoro-4-methoxyphenyl)-1-pyrazolo[3,4-]pyrimidin-1-yl)propyl)-3-cyclopropyl-5-fluoroquinazolin-4(3)-one (IHMT-PI3Kδ-372) as a Potent and Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.

J Med Chem 2020 11 12;63(22):13973-13993. Epub 2020 Nov 12.

Anhui Province Key Laboratory of Medical Physics and Technology; CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.

Accumulated pieces of evidence have shown that PI3Kδ plays a critical role in chronic obstructive pulmonary disease (COPD). Using a fragment-hybrid approach, we discovered a potent and selective PI3Kδ inhibitor . In the biochemical assay, inhibits PI3Kδ (IC = 14 nM) with high selectivity over other class I PI3Ks (56∼83 fold). also achieves good selectivity over other protein kinases in the kinome (-score (35) = 0.015). In the cell, selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308 but not other class I PI3K-mediated signaling. Additionally, exhibits no apparent inhibitory effect on CYP isoforms except for a moderate effect on CYP2C9. Furthermore, it shows no apparent inhibitory activity against hERG (IC > 10 μM). In vivo, displays favorable PK properties for inhaled delivery and improves lung function in a rodent model of pulmonary inflammation. These results suggest that might be a new potential therapeutic candidate for COPD.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01544DOI Listing
November 2020

SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells.

bioRxiv 2020 Oct 20. Epub 2020 Oct 20.

Reports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into host β cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. and transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet β cells through these cell entry proteins.
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http://dx.doi.org/10.1101/2020.08.31.275719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587777PMC
October 2020

GPAHex-A synthetic biology platform for Type IV-V glycopeptide antibiotic production and discovery.

Nat Commun 2020 10 16;11(1):5232. Epub 2020 Oct 16.

David Braley Center for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.

Glycopeptide antibiotics (GPAs) are essential for the treatment of severe infectious diseases caused by Gram-positive bacteria. The emergence and spread of GPA resistance have propelled the search for more effective GPAs. Given their structural complexity, genetic intractability, and low titer, expansion of GPA chemical diversity using synthetic or medicinal chemistry remains challenging. Here we describe a synthetic biology platform, GPAHex (GPA Heterologous expression), which exploits the genes required for the specialized GPA building blocks, regulation, antibiotic transport, and resistance for the heterologous production of GPAs. Application of the GPAHex platform results in: (1) a 19-fold increase of corbomycin titer compared to the parental strain, (2) the discovery of a teicoplanin-class GPA from an Amycolatopsis isolate, and (3) the overproduction and characterization of a cryptic nonapeptide GPA. GPAHex provides a platform for GPA production and mining of uncharacterized GPAs and provides a blueprint for chassis design for other natural product classes.
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http://dx.doi.org/10.1038/s41467-020-19138-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567792PMC
October 2020

Vertically aligned GaN nanorod arrays/p-Si heterojunction self-powered UV photodetector with ultrahigh photoresponsivity.

Opt Lett 2020 Sep;45(17):4843-4846

Self-powered photodetectors have demonstrated potential for developing future wireless and implantable devices. Herein, we present a self-powered UV photodetector with an ultrahigh photoresponse based on vertically oriented and high crystalline quality -type GaN nanorod arrays: poly(methyl methacrylate)/p-Si heterojunction. Benefiting from the highly efficient separation and transport of photoexcited electron-hole pairs, significant improvements in photoresponsivity are experimentally obtained. In a zero-biased self-powered detection mode, a 6.7 responsivity and 2.68×10 Jones detectivity are achieved under 355 nm light illumination, and the response time is as low as 0.29/3.07 ms (rise/fall times).
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http://dx.doi.org/10.1364/OL.402454DOI Listing
September 2020

A self-cleaning and photocatalytic cellulose-fiber- supported "[email protected]@MOF- cloth'' membrane for complex wastewater remediation.

Carbohydr Polym 2020 Nov 25;247:116691. Epub 2020 Jun 25.

National Demonstration Center for Experimental Light Chemistry Engineering Education, College of Bioresources Chemical and Materials Engineering, Shaanxi Provincial Key Laboratory of Papermaking Technology and Specialty Paper Development, Shaanxi University of Science and Technology, Xi'an, 710021, China; Department of Chemical Engineering, University of New Brunswick, Fredericton, New Brunswick E3B 5A3, Canada.

Membrane technology is one of the most promising technologies for wastewater remedy. However, it remains challenging to prepare high-performance membrane matrix for complex pollutants, e.g. containing both oil and organic dye. In this work, we facilely fabricate a cellulose-fiber-supported MOF photocatalytic membrane, namely [email protected]@MIL-100(Fe)/CCF, which was prepared via carboxymethylation of cotton fabric (CCF) as scaffold and in-situ synthesis of MOF derivative as photocatalyst. The carboxymethylation significantly improves the hydrophilicity of cotton fabric and the deposition amount of MIL-100(Fe). The high hydrophilicity of modified CCF and porous MIL-100(Fe) further enable the membrane with an efficient adsorption capacity of dyes and underwater oleophobicity against oils. The photocatalysts [email protected] nanoparticles anchored onto MIL-100(Fe) promote the photocatalytic activity. As a result, the membrane shows simultaneous high removal efficiency towards dyes (97.3 %) and oils (99.64 %). Additionally, thanks to the good photocatalytic activity against organic pollutants, the membrane exhibits excellent self-cleaning and a long-term reuse capacity.
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http://dx.doi.org/10.1016/j.carbpol.2020.116691DOI Listing
November 2020

D-dimer in the diagnosis of periprosthetic joint infection: a systematic review and meta-analysis.

J Orthop Surg Res 2020 Jul 16;15(1):265. Epub 2020 Jul 16.

Department of Orthopedics, Characteristic Medical Center of PAP, Tianjin, 300162, China.

Background: D-dimer, a coagulation-related indicator, has recently been used as a tool for the diagnosis of periprosthetic joint infection (PJI), but its reliability is uncertain. The purpose of this systematic review and meta-analysis was to explore the accuracy of D-dimer in the diagnosis of PJI after joint arthroplasty.

Methods: We systematically searched the MEDLINE, EMBASE, and Cochrane databases for relevant literature about D-dimer in the diagnosis of PJI. QUADAS-2 was used to assess the risk of bias and clinical applicability of each included study. We used the bivariate meta-analysis framework to pool the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the SROC curve (AUC). Univariate meta-regression and subgroup analyses were performed to explore the sources of heterogeneity.

Results: We included 8 eligible studies. The pooled diagnostic sensitivity and specificity were 0.82 (95% CI, 0.70-0.89) and 0.70 (95% CI, 0.55-0.82), respectively. The pooled PLR, NLR, and DOR were 2.7 (95% CI, 1.7-4.4), 0.26 (95% CI, 0.15-0.46), and 10 (95% CI, 4-25), respectively. The AUC was 0.83 (95% CI, 0.8-0.86). Serum D-dimer might have higher diagnostic accuracy than plasma D-dimer for PJI (pooled sensitivity: 0.88 vs 0.67; pooled specificity: 0.76 vs 0.61).

Conclusions: D-dimer has limited performance for the diagnosis of PJI.
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http://dx.doi.org/10.1186/s13018-020-01761-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364596PMC
July 2020

Hydrogen bond, ring tension and π-conjugation effects: methyl and vinyl substitutions dramatically change the photodynamics of Criegee intermediates.

Phys Chem Chem Phys 2020 Jul 3;22(27):15295-15302. Epub 2020 Jul 3.

Key Laboratory for Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an, Shaanxi 710062, P. R. China.

The substitution effect in chemistry is a concept that is probably too common to mention, while for a molecule with an elusive electronic structure, substitution can introduce an unusual effect that dramatically tunes the chemical process. To reveal the substitution effects on the photodynamics of Criegee Intermediates (CIs), we carried out the multireference CASSCF trajectory surface-hopping (TSH) molecular dynamics and CASPT2 electronic-structure calculations for a methyl-substituted CI (MCI) and a vinyl-substituted CI (VCI). The results show that for different substituents, the hydrogen bond, ring tension and π-conjugation not only alter the relative stabilities of the conformers/configurations, but also dramatically change the photo-induced channel of CIs. For an anti-MCI, the dominant channel starting from the S state is the ring-closure process leading to dioxirane, while in the syn configuration, the intramolecular CHO hydrogen bond hinders the rotation around the C-O bond and thus leads to a high yield of in-plane O-O dissociation towards acetaldehyde (XA') and the O(D) atom. In a VCI with an unsaturated substituent, the π-conjugation greatly strengthens the O-O bond and therefore no O-O dissociation is observed in all configurations. In addition, the CHO hydrogen bond in the syn-VCI further stabilizes the S-state intermediates and makes them less reactive; in contrast, isomerization to dioxirane becomes the globally dominant channel in the anti-VCI. The dramatic substitution effects by saturated and unsaturated substituents on CIs found here will deepen the understanding of Criegee-intermediate chemistry.
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http://dx.doi.org/10.1039/d0cp01873bDOI Listing
July 2020

Highly Tough, Stretchable, Self-Adhesive and Strain-Sensitive DNA-Inspired Hydrogels for Monitoring Human Motion.

Chemistry 2020 Sep 7;26(50):11604-11613. Epub 2020 Aug 7.

Laboratory of Polymer Composites Engineering, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China.

Hydrogels used as strain sensors often rely on splicing tapes to attach them to surfaces, which causes much inconvenience. Therefore, to develop strain sensor hydrogels that possess both good mechanical properties and self-adhesion is still a great challenge. Inspired by the multiple hydrogen bonding interactions of nucleobases in DNA, we designed and synthesized a series of hydrogels PAAm-GO-Aba/Tba/Aba+Tba comprising polyacrylamide (PAAm), graphene oxide (GO), acrylated adenine and thymine (Aba and Tba). The introduction of nucleobases helps hydrogels to adhere to various substrates through multiple hydrogen-bonding interactions. It has also been found that the adhesive strength of hydrogels with nucleobases for hogskin increased to 2.5 times that of those without nucleobases. Meanwhile, these hydrogels exhibited good dynamic mechanical and self-recovery properties. They can be directly attached to human skin as strain sensors to monitor the motions of finger, wrist, and elbow. Electrical tests indicate that they give precise real-time monitoring data and exhibit good strain sensitivity and electrical stability. This work provides a promising basis from which to explore the fabrication of tough, self-adhesive, and strain-sensitive hydrogels as strain sensors for applications in wearable devices and healthcare monitoring.
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http://dx.doi.org/10.1002/chem.202002244DOI Listing
September 2020

Network-based analysis with primary cells reveals drug response landscape of acute myeloid leukemia.

Exp Cell Res 2020 08 4;393(1):112054. Epub 2020 May 4.

High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230036, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, PR China; Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, PR China. Electronic address:

Acute myeloid leukemia (AML) is one of the most common, complex, and heterogeneous hematological malignancies in adults. Despite progresses in understanding the pathology of AML, the 5-year survival rates still remain low compared with CML, CLL, etc. The relationship between genomic features and drug responses is critical for precision medication. Herein, we depicted a picture for response of 145 drugs against 33 primary cell samples derived from AML patients with full spectrum of genomic features assessed by whole exon sequencing and RNA sequencing. In general, most of the samples were much more sensitive to the combinatorial chemotherapy regimens than the single chemotherapy drugs. Overall, these samples were moderately sensitive to the Traditional Chinese Medicine (TCM) and the targeted drugs. In the weighted gene coexpression network analysis (WGCNA), the TCM and targeted therapies displayed similar genetic signatures in the gene module correlation. Meanwhile, the expression of miRNAs, lncRNAs, and mRNAs did not display apparent gene module correlations among those different types of therapies. In addition, the combinatorial chemotherapy bear more module correlations than the single drugs. Interestingly, we found that the gene mutations and drug response were not enriched in any WGCNA module analysis. Most of the sensitive drug response biomarkers were enriched in the ribosome, endocytosis, cell cycle, and p53 associated signaling pathways. This study showed that gene expression modules might show better correlation than gene mutations for drug efficacy predictions.
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http://dx.doi.org/10.1016/j.yexcr.2020.112054DOI Listing
August 2020

Atmospheric Chemistry of Enols: The Formation Mechanisms of Formic and Peroxyformic Acids in Ozonolysis of Vinyl Alcohol.

J Phys Chem A 2020 May 18;124(21):4271-4279. Epub 2020 May 18.

Key Laboratory for Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an 710119, Shaanxi, China.

Vinyl alcohol (VA), for a long time, is thought to be a missing source of formic acid (FA) in the atmospheric models. However, a recent study has shown that FA is just a byproduct in the OH-initiated oxidation of VA, which stimulates investigation on the other sinks of VA in the atmosphere. In this study, the detailed ozonolysis mechanism of VA was investigated theoretically for the first time. The results show that two primary ozonides (- and -POZ) can be formed in the ozonolysis of VA and that FA coupled with the simplest Criegee intermediate (CHOO) can be produced as the main nascent products. Thus, the ozonolysis of VA is predicted to be a more efficient process to produce FA in the atmosphere compared with its OH-initiated oxidation. Moreover, it is found that the -POZ can directly decompose to peroxyformic acid plus formaldehyde, breaking the known "Criegee mechanism" to form carbonyl oxide with carbonyl compound. This special mechanism by providing a new source of peroxy acids in the atmosphere enriches the atmospheric chemistry of enols. The atmospheric lifetime of VA by ozonolysis is predicted to be 30 h, comparable with its prevalent reaction with the OH radical. Therefore, the obtained theoretical results can be usefully incorporated into a future modeling study of enols.
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http://dx.doi.org/10.1021/acs.jpca.0c01480DOI Listing
May 2020

Aza-crown ether locked on polyethyleneimine: solving the contradiction between transfection efficiency and safety during in vivo gene delivery.

Chem Commun (Camb) 2020 May 16;56(41):5552-5555. Epub 2020 Apr 16.

Laboratory of Polymer Composites Engineering, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.

We proposed a method using an aza-crown ether derivative to lock a hyperbranched polyethyleneimine, which endows the PEI with tumor targeting ability, anti-serum ability and extended circulation in the blood meanwhile retaining the high gene complexation and high transfection efficiency. The method we proposed here simultaneously endows cationic materials with high transfection efficiency and high safety, which greatly pushed the cationic materials to be applied in in vivo gene delivery.
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http://dx.doi.org/10.1039/c9cc10041eDOI Listing
May 2020

Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent.

Acta Pharm Sin B 2020 Mar 18;10(3):488-497. Epub 2019 Oct 18.

High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.

Angiogenesis is an essential process in tumor growth, invasion and metastasis. VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment. However, most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration. Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view. Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002), which exhibited high selectivity among structurally closed kinases including PDGFRs, FGFRs, CSF1R, etc. CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC = 66 nmol/L) and VEGFR2 autophosphorylation in cells (ECs ∼100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy and exhibited good PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zebrafish and mouse models without apparent toxicity. These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.
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http://dx.doi.org/10.1016/j.apsb.2019.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049616PMC
March 2020

Joint profiling of chromatin accessibility and CAR-T integration site analysis at population and single-cell levels.

Proc Natl Acad Sci U S A 2020 03 24;117(10):5442-5452. Epub 2020 Feb 24.

Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;

Chimeric antigen receptor (CAR)-T immunotherapy has yielded impressive results in several B cell malignancies, establishing itself as a powerful means to redirect the natural properties of T lymphocytes. In this strategy, the T cell genome is modified by the integration of lentiviral vectors encoding CAR that direct tumor cell killing. However, this therapeutic approach is often limited by the extent of CAR-T cell expansion in vivo. A major outstanding question is whether or not CAR-T integration itself enhances the proliferative competence of individual T cells by rewiring their regulatory landscape. To address this question, it is critical to define the identity of an individual CAR-T cell and simultaneously chart where the CAR-T vector integrates into the genome. Here, we report the development of a method called EpiVIA (https://github.com/VahediLab/epiVIA) for the joint profiling of the chromatin accessibility and lentiviral integration site analysis at the population and single-cell levels. We validate our technique in clonal cells with previously defined integration sites and further demonstrate the ability to measure lentiviral integration sites and chromatin accessibility of host and viral genomes at the single-cell resolution in CAR-T cells. We anticipate that EpiVIA will enable the single-cell deconstruction of gene regulation during CAR-T therapy, leading to the discovery of cellular factors associated with durable treatment.
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http://dx.doi.org/10.1073/pnas.1919259117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071901PMC
March 2020

Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling.

Nature 2020 02 12;578(7796):582-587. Epub 2020 Feb 12.

M. G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.

Addressing the ongoing antibiotic crisis requires the discovery of compounds with novel mechanisms of action that are capable of treating drug-resistant infections. Many antibiotics are sourced from specialized metabolites produced by bacteria, particularly those of the Actinomycetes family. Although actinomycete extracts have traditionally been screened using activity-based platforms, this approach has become unfavourable owing to the frequent rediscovery of known compounds. Genome sequencing of actinomycetes reveals an untapped reservoir of biosynthetic gene clusters, but prioritization is required to predict which gene clusters may yield promising new chemical matter. Here we make use of the phylogeny of biosynthetic genes along with the lack of known resistance determinants to predict divergent members of the glycopeptide family of antibiotics that are likely to possess new biological activities. Using these predictions, we uncovered two members of a new functional class of glycopeptide antibiotics-the known glycopeptide antibiotic complestatin and a newly discovered compound we call corbomycin-that have a novel mode of action. We show that by binding to peptidoglycan, complestatin and corbomycin block the action of autolysins-essential peptidoglycan hydrolases that are required for remodelling of the cell wall during growth. Corbomycin and complestatin have low levels of resistance development and are effective in reducing bacterial burden in a mouse model of skin MRSA infection.
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http://dx.doi.org/10.1038/s41586-020-1990-9DOI Listing
February 2020

The draft genome of mandrill (Mandrillus sphinx): An Old World monkey.

Sci Rep 2020 02 12;10(1):2431. Epub 2020 Feb 12.

Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, 2100, Denmark.

Mandrill (Mandrillus sphinx) is a primate species, which belongs to the Old World monkey (Cercopithecidae) family. It is closely related to human, serving as a model for human health related research. However, the genetic studies on and genomic resources of mandrill are limited, especially in comparison to other primate species. Here we produced 284 Gb data, providing 96-fold coverage (considering the estimated genome size of 2.9 Gb), to construct a reference genome for the mandrill. The assembled draft genome was 2.79 Gb with contig N50 of 20.48 Kb and scaffold N50 of 3.56 Mb. We annotated the mandrill genome to find 43.83% repeat elements, as well as 21,906 protein-coding genes. The draft genome was of good quality with 98% gene annotation coverage by Benchmarking Universal Single-Copy Orthologs (BUSCO). Based on comparative genomic analyses of  the Major Histocompatibility Complex (MHC) of the immune system in mandrill and human, we found that 17 genes in the mandrill that have been associated with disease phenotypes in human such as Lung cancer, cranial volume and asthma, barbored amino acids changing mutations. Gene family analyses revealed expansion of several genes, and several genes associated with stress environmental adaptation and innate immunity responses exhibited signatures of positive selection. In summary, we established the first draft genome of  the mandrill of value for studies on evolution and human health.
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http://dx.doi.org/10.1038/s41598-020-59110-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016171PMC
February 2020

Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression.

Immunity 2020 02 11;52(2):257-274.e11. Epub 2020 Feb 11.

Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Human Pancreas Analysis Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA, https://hpap.pmacs.upenn.edu/. Electronic address:

Genetics is a major determinant of susceptibility to autoimmune disorders. Here, we examined whether genome organization provides resilience or susceptibility to sequence variations, and how this would contribute to the molecular etiology of an autoimmune disease. We generated high-resolution maps of linear and 3D genome organization in thymocytes of NOD mice, a model of type 1 diabetes (T1D), and the diabetes-resistant C57BL/6 mice. Multi-enhancer interactions formed at genomic regions harboring genes with prominent roles in T cell development in both strains. However, diabetes risk-conferring loci coalesced enhancers and promoters in NOD, but not C57BL/6 thymocytes. 3D genome mapping of NODxC57BL/6 F1 thymocytes revealed that genomic misfolding in NOD mice is mediated in cis. Moreover, immune cells infiltrating the pancreas of humans with T1D exhibited increased expression of genes located on misfolded loci in mice. Thus, genetic variation leads to altered 3D chromatin architecture and associated changes in gene expression that may underlie autoimmune pathology.
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http://dx.doi.org/10.1016/j.immuni.2020.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152927PMC
February 2020