Publications by authors named "Xiaolin Cheng"

126 Publications

Activated nanoscale actin-binding domain motion in the catenin-cadherin complex revealed by neutron spin echo spectroscopy.

Proc Natl Acad Sci U S A 2021 Mar;118(13)

Department of Chemistry and Biochemistry, City College of New York, City University of New York, New York, NY 10031;

As the core component of the adherens junction in cell-cell adhesion, the cadherin-catenin complex transduces mechanical tension between neighboring cells. Structural studies have shown that the cadherin-catenin complex exists as an ensemble of flexible conformations, with the actin-binding domain (ABD) of α-catenin adopting a variety of configurations. Here, we have determined the nanoscale protein domain dynamics of the cadherin-catenin complex using neutron spin echo spectroscopy (NSE), selective deuteration, and theoretical physics analyses. NSE reveals that, in the cadherin-catenin complex, the motion of the entire ABD becomes activated on nanosecond to submicrosecond timescales. By contrast, in the α-catenin homodimer, only the smaller disordered C-terminal tail of ABD is moving. Molecular dynamics (MD) simulations also show increased mobility of ABD in the cadherin-catenin complex, compared to the α-catenin homodimer. Biased MD simulations further reveal that the applied external forces promote the transition of ABD in the cadherin-catenin complex from an ensemble of diverse conformational states to specific states that resemble the actin-bound structure. The activated motion and an ensemble of flexible configurations of the mechanosensory ABD suggest the formation of an entropic trap in the cadherin-catenin complex, serving as negative allosteric regulation that impedes the complex from binding to actin under zero force. Mechanical tension facilitates the reduction in dynamics and narrows the conformational ensemble of ABD to specific configurations that are well suited to bind F-actin. Our results provide a protein dynamics and entropic explanation for the observed force-sensitive binding behavior of a mechanosensitive protein complex.
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http://dx.doi.org/10.1073/pnas.2025012118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020631PMC
March 2021

Structural Insights into gp16 ATPase in the Bacteriophage ϕ29 DNA Packaging Motor.

Biochemistry 2021 Mar 9;60(11):886-897. Epub 2021 Mar 9.

The Key Laboratory of Innate Immune Biology of Fujian Province, Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, Biomedical Research Center of South China, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China.

Biological motors, ubiquitous in living systems, convert chemical energy into different kinds of mechanical motions critical to cellular functions. Gene product 16 (gp16) in bacteriophage ϕ29 is among the most powerful biomotors known, which adopts a multisubunit ring-shaped structure and hydrolyzes ATP to package double-stranded DNA (dsDNA) into a preformed procapsid. Here we report the crystal structure of the C-terminal domain of gp16 (gp16-CTD). Structure-based alignment and molecular dynamics simulations revealed an essential binding surface of gp16-CTD for prohead RNA, a unique component of the motor complex. Furthermore, our simulations highlighted a dynamic interplay between the N-terminal domain and the CTD of gp16, which may play a role in driving movement of DNA into the procapsid. Lastly, we assembled an atomic structural model of the complete ϕ29 dsDNA packaging motor complex by integrating structural and experimental data from multiple sources. Collectively, our findings provided a refined inchworm-revolution model for dsDNA translocation in bacteriophage ϕ29 and suggested how the individual domains of gp16 work together to power such translocation.
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http://dx.doi.org/10.1021/acs.biochem.0c00935DOI Listing
March 2021

Facilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors.

Nat Commun 2021 02 23;12(1):1248. Epub 2021 Feb 23.

Division of Pharmaceutics & Pharmacology, College of Pharmacy, Ohio State University, Columbus, OH, 43210, USA.

Mutations in human equilibrative nucleoside transporter 3 (ENT3) encoded by SLC29A3 results in anemia and erythroid hypoplasia, suggesting that ENT3 may regulate erythropoiesis. Here, we demonstrate that lysosomal ENT3 transport of taurine-conjugated bile acids (TBA) facilitates TBA chemical chaperone function and alleviates endoplasmic reticulum (ER) stress in expanding mouse hematopoietic stem and progenitor cells (HSPCs). Slc29a3 HSPCs accumulate less TBA despite elevated levels of TBA in Slc29a3 mouse plasma and have elevated basal ER stress, reactive oxygen species (ROS), and radiation-induced apoptosis. Reintroduction of ENT3 allows for increased accumulation of TBA into HSPCs, which results in TBA-mediated alleviation of ER stress and erythroid apoptosis. Transplanting TBA-preconditioned HSPCs expressing ENT3 into Slc29a3 mice increase bone marrow repopulation capacity and erythroid pool size and prevent early mortalities. Together, these findings suggest a putative role for a facilitative lysosomal transporter in the bile acid regulation of ER stress in mouse HSPCs which may have implications in erythroid biology, the treatment of anemia observed in ENT3-mutated human genetic disorders, and nucleoside analog drug therapy.
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http://dx.doi.org/10.1038/s41467-021-21451-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902824PMC
February 2021

Adenosquamous carcinoma of the breast: a population-based study.

Breast Cancer 2021 Feb 12. Epub 2021 Feb 12.

Department of Breast Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.

Background: To summarize the clinicopathological characteristics, prognosis, and management of breast adenosquamous carcinoma (ASC).

Methods: A population-based study was performed using retrospectively extracted data from the Surveillance, Epidemiology, and End Results database for breast cancer patients with histological diagnoses of ASC, infiltrating duct carcinoma (IDC) and squamous cell carcinoma (SCC) from 2004 to 2016.

Results: ASC presented similar tumor size but low histological grade and less lymph node metastasis compared to IDC. ASC expressed less positive rate of hormone receptors and barely HER2, which was similar with SCC. ASC patients underwent the similar surgical and systematic treatment as IDC, only with less radiotherapy. Median follow-up data of 78 months showed that the prognosis of IDC patients was better than that of ASC patients (all p < 0.05 for BCSM and OS). ASC was not an independent prognosis factor of breast cancer. After propensity score matching (PSM), no significant difference in BCSM nor OS was observed between ASC and IDC groups. In HR-negative patients, the prognosis of ASC was similar with that of IDC, and both were superior to SCC. In HR-positive patients, the 5-year survival rate of ASC was 63.5%, which was far less than that in ASC of HR-negative (81.0%). Multivariate analysis showed that older age (age > 60) and advanced AJCC-stage were independent factors of poor prognosis in ASC, breast-conserving surgery was also ideally suited for ASC.

Conclusions: ASC has unique clinicopathological characteristics and prognosis. It is imperative to focus on a more precise and personalized treatment management of ASC patients.
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http://dx.doi.org/10.1007/s12282-021-01222-3DOI Listing
February 2021

Preanesthetic nebulized ketamine vs preanesthetic oral ketamine for sedation and postoperative pain management in children for elective surgery: A retrospective analysis for effectiveness and safety.

Medicine (Baltimore) 2021 Feb;100(6):e24605

Department of Anesthesiology, Yichang Central People's Hospital and The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, China.

Abstract: Preoperative anxiety is a major problem in children leading to a poor outcome. Preanesthetic oral ketamine is generally used in children but has less bioavailability due to the first-pass effect. Even ketamine has an unpleasant taste. Preanesthetic inhaled ketamine is also reported effective and safe in children. The objectives of the study were to compare the effectiveness and safety of preanesthetic nebulized ketamine against preanesthetic oral ketamine for sedation and postoperative pain management in children.Children received 10 mg/kg oral ketamine (children received preanesthetic oral ketamine [OK cohort], n = 142), or nebulized with 3 mg/kg ketamine (children were preanesthetic nebulized with ketamine [NK cohort], n = 115), or received apple juice (children suspectable to preoperative ketamine and received apple juice only [OA cohort], n = 126) before anesthesia for elective surgery. Data regarding preoperative hemodynamic parameters, sedation score measurements, postoperative pain management, postoperative nausea and vomiting management, and postoperative complications were collected and analyzed.Preoperative hemodynamic parameters for oral and nebulized ketamine administration were stable. Nebulized ketamine was provided higher sedation than apple juice (P = .002, q = 4.859) and oral ketamine (P = .002, q = 3.526). Children of NK cohort had required fewer fentanyl consumption until discharge than those of OA (55.45 ± 7.19 μG/ child vs 65.15 ± 15.24 μG/ child, P < .0001, q = 9.859) and OK (55.45 ± 7.19 μG/child vs 60.19 ± 8.12 μG/child, P < .0001, q = 4.953) cohorts. Children of the NK cohort had consumed higher ondansetron syrup than those of the OA cohort but fewer than those of the OK cohort until discharge. Gastrointestinal side effects were reported in the OK cohort, and nose irritation and drowsiness were reported in the NK cohort.Like preanesthetic oral ketamine, preanesthetic inhaled ketamine also has safety for children. Preanesthetic inhaled ketamine can provide effective sedation in low doses during operation than preanesthetic oral ketamine.Level of evidence: III.
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http://dx.doi.org/10.1097/MD.0000000000024605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886447PMC
February 2021

Listeria monocytogenes upregulates mitochondrial calcium signalling to inhibit LC3-associated phagocytosis as a survival strategy.

Nat Microbiol 2021 03 18;6(3):366-379. Epub 2021 Jan 18.

Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA.

Mitochondria are believed to have originated ~2.5 billion years ago. As well as energy generation in cells, mitochondria have a role in defence against bacterial pathogens. Despite profound changes in mitochondrial morphology and functions following bacterial challenge, whether intracellular bacteria can hijack mitochondria to promote their survival remains elusive. We report that Listeria monocytogenes-an intracellular bacterial pathogen-suppresses LC3-associated phagocytosis (LAP) by modulation of mitochondrial Ca (mtCa) signalling in order to survive inside cells. Invasion of macrophages by L. monocytogenes induced mtCa uptake through the mtCa uniporter (MCU), which in turn increased acetyl-coenzyme A (acetyl-CoA) production by pyruvate dehydrogenase. Acetylation of the LAP effector Rubicon with acetyl-CoA decreased LAP formation. Genetic ablation of MCU attenuated intracellular bacterial growth due to increased LAP formation. Our data show that modulation of mtCa signalling can increase bacterial survival inside cells, and highlight the importance of mitochondrial metabolism in host-microbial interactions.
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http://dx.doi.org/10.1038/s41564-020-00843-2DOI Listing
March 2021

Computational and Experimental Approaches to Investigate Lipid Nanoparticles as Drug and Gene Delivery Systems.

Curr Top Med Chem 2021 ;21(2):92-114

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.

Lipid nanoparticles (LNPs) have been widely applied in drug and gene delivery. More than twenty years ago, Doxil was the first LNPs-based drug approved by the US Food and Drug Administration (FDA). Since then, with decades of research and development, more and more LNP-based therapeutics have been used to treat diverse diseases, which often offer the benefits of reduced toxicity and/or enhanced efficacy compared to the active ingredients alone. Here, we provide a review of recent advances in the development of efficient and robust LNPs for drug/gene delivery. We emphasize the importance of rationally combining experimental and computational approaches, especially those providing multiscale structural and functional information of LNPs, to the design of novel and powerful LNP-based delivery systems.
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http://dx.doi.org/10.2174/1568026620666201126162945DOI Listing
January 2021

Investigation of the Psychological disorders in the healthcare nurses during a coronavirus disease 2019 outbreak in China.

Medicine (Baltimore) 2020 Aug;99(34):e21662

Department of Orthopedic, the First College of Clinical Medical Science, China Three Gorges University and Yichang Central People's Hospital, Yichang, Hubei, China.

The first case of atypical pneumonia caused by coronavirus disease 2019 (COVID-19) was reported in Wuhan, China in December 2019. Since then, cases of novel coronavirus-infected pneumonia (NCIP) have been reported throughout China as well as in 25 other countries. With the rapid growth of this global outbreak, psychological disorders or impact among the healthcare nurses caused by the COVID-19 pandemic is of great importance and worth to be evaluated. Here, we aimed to determine the levels of stress and psychological disorders of nurses who provided nursing care during the COVID-19 outbreak. A total of 159 nurses who provided healthcare work for COVID-19 patients were enrolled in our study. The psychological disorders and stress level were assessed via a questionnaire implemented by the mobile app. The results showed that the nurses who worked in the non-critical care ward (general ward in which the invasive medical procedure such as mechanical ventilation is absent) scored significantly higher on the traumatization condition (P < .05) and stress level (P < .01) as well as the impact of event scale -revised level (P < .01) compared with those worked in the critical care ward. In contrast to the previous report, our findings revealed that the future intervention for preventing the mental crisis among the healthcare nurses needs to be focusing on the individuals in the non-critical care ward instead of those in the critical care ward under the spreading of COVID-19.
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http://dx.doi.org/10.1097/MD.0000000000021662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447415PMC
August 2020

A computational study of effects on membrane recruitment of the polar linkers in Vitamin E derivatives.

Biochim Biophys Acta Gen Subj 2020 10 11;1864(10):129655. Epub 2020 Jun 11.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

Background: Previous studies found that Vitamin E (VE) could recruit protein kinase B (Akt1) to the membrane by targeting its unconventional lipid-binding site, which led to the dephosphorylation of Akt1 at Ser473, eventually deactivating the enzyme.

Methods: A series of VE-like compounds with varying types and lengths of the linker groups are designed to study the VE-driven membrane recruitment of Akt1 using a combined molecular docking and molecular dynamics (MD) simulation approach.

Results: We find that the linker groups with only one methylene linker and multiple hydrogen bond donors are optimal for achieving a balance between binding to the protein and partitioning into the membrane to form a stable protein-ligand-membrane ternary complex. These polar linkers are found to form stable hydrogen bonds with the lipid head groups during the MD simulations, which turns out critical for ensuring that the chromanol ring of the VE-like compounds resides above the membrane surface to fully engage in the protein.

Conclusions: Our results reveal the molecular determinants of the linker groups for VE derivatives' ability to anchor Akt1 to the membrane.

General Significance: These findings will facilitate the design of membrane interfacial compounds to recruit specific proteins to the membrane to modulate the protein function.
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http://dx.doi.org/10.1016/j.bbagen.2020.129655DOI Listing
October 2020

Carotenoids promote lateral packing and condensation of lipid membranes.

Phys Chem Chem Phys 2020 Jun 20;22(21):12281-12293. Epub 2020 May 20.

Center for Molecular Biophysics, Oak Ridge National Lab, Oak Ridge, TN 37830, USA.

Carotenoids are pigment molecules that protect biomembranes against degradation and may be involved in the formation of functional bacterial membrane microdomains. Little is known on whether different types of carotenoids have different effects on the membrane or if there is any concentration dependence of these effects. In this work, we present results from molecular dynamics simulations of phospholipid bilayers containing different amounts of either β-carotene or zeaxanthin. Both β-carotene and zeaxanthin show the ability to laterally condense the membrane lipids and reduce their inter-leaflet interactions. With increasing concentrations, both carotenoids increase the bilayer thickness and rigidity. The results reveal that carotenoids have similar effects to cholesterol on regulating the behavior of fluid-phase membranes, suggesting that they could function as sterol substitutes and confirming their potential role in the formation of functional membrane domains.
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http://dx.doi.org/10.1039/d0cp01031fDOI Listing
June 2020

SCNrank: spectral clustering for network-based ranking to reveal potential drug targets and its application in pancreatic ductal adenocarcinoma.

BMC Med Genomics 2020 04 3;13(Suppl 5):50. Epub 2020 Apr 3.

Department of Biomedical informatics, College of medicine, the Ohio State University, Columbus, OH, 43210, USA.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy. Due to its wide heterogeneity, PDAC acts aggressively and responds poorly to most chemotherapies, causing an urgent need for the development of new therapeutic strategies. Cell lines have been used as the foundation for drug development and disease modeling. CRISPR-Cas9 plays a key role in every step-in drug discovery: from target identification and validation to preclinical cancer cell testing. Using cell-line models and CRISPR-Cas9 technology together make drug target prediction feasible. However, there is still a large gap between predicted results and actionable targets in real tumors. Biological network models provide great modus to mimic genetic interactions in real biological systems, which can benefit gene perturbation studies and potential target identification for treating PDAC. Nevertheless, building a network model that takes cell-line data and CRISPR-Cas9 data as input to accurately predict potential targets that will respond well on real tissue remains unsolved.

Methods: We developed a novel algorithm 'Spectral Clustering for Network-based target Ranking' (SCNrank) that systematically integrates three types of data: expression profiles from tumor tissue, normal tissue and cell-line PDAC; protein-protein interaction network (PPI); and CRISPR-Cas9 data to prioritize potential drug targets for PDAC. The whole algorithm can be classified into three steps: 1. using STRING PPI network skeleton, SCNrank constructs tissue-specific networks with PDAC tumor and normal pancreas tissues from expression profiles; 2. With the same network skeleton, SCNrank constructs cell-line-specific networks using the cell-line PDAC expression profiles and CRISPR-Cas 9 data from pancreatic cancer cell-lines; 3. SCNrank applies a novel spectral clustering approach to reduce data dimension and generate gene clusters that carry common features from both networks. Finally, SCNrank applies a scoring scheme called 'Target Influence score' (TI), which estimates a given target's influence towards the cluster it belongs to, for scoring and ranking each drug target.

Results: We applied SCNrank to analyze 263 expression profiles, CRPSPR-Cas9 data from 22 different pancreatic cancer cell-lines and the STRING protein-protein interaction (PPI) network. With SCNrank, we successfully constructed an integrated tissue PDAC network and an integrated cell-line PDAC network, both of which contain 4414 selected genes that are overexpressed in tumor tissue samples. After clustering, 4414 genes are distributed into 198 clusters, which include 367 targets of FDA approved drugs. These drug targets are all scored and ranked by their TI scores, which we defined to measure their influence towards the network. We validated top-ranked targets in three aspects: Firstly, mapping them onto the existing clinical drug targets of PDAC to measure the concordance. Secondly, we performed enrichment analysis to these drug targets and the clusters there are within, to reveal functional associations between clusters and PDAC; Thirdly, we performed survival analysis for the top-ranked targets to connect targets with clinical outcomes. Survival analysis reveals that overexpression of three top-ranked genes, PGK1, HMMR and POLE2, significantly increases the risk of death in PDAC patients.

Conclusion: SCNrank is an unbiased algorithm that systematically integrates multiple types of omics data to do potential drug target selection and ranking. SCNrank shows great capability in predicting drug targets for PDAC. Pancreatic cancer-associated gene candidates predicted by our SCNrank approach have the potential to guide genetics-based anti-pancreatic drug discovery.
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http://dx.doi.org/10.1186/s12920-020-0681-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7119297PMC
April 2020

Rational Design of Small Molecules to Enhance Genome Editing Efficiency by Selectively Targeting Distinct Functional States of CRISPR-Cas12a.

Bioconjug Chem 2020 03 6;31(3):542-546. Epub 2020 Mar 6.

Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.

CRISPR-Cas12a, a type-V CRISPR-Cas endonuclease, is an effective genome editing platform. To improve the gene editing efficiency of Cas12a, we rationally designed small molecule enhancers through a combined computational approach. First, we used extensive molecular dynamics (MD) simulations to explore the conformational landscape of Cas12a from (AsCas12a), revealing distinct conformational states that could be targeted by small molecules to modulate its genome editing function. We then identified 57 compounds that showed different binding behavior and stabilizing effects on these distinct conformational states using molecular docking. After experimental testing 6 of these 57 compounds, compound , quinazoline-2,4(1,3)-dione, was found particularly promising in enhancing the AsCas12a-mediated genome editing efficiency in human cells. Compound was shown to act like a molecular "glue" at the interface between AsCas12a and crRNA near the 5'-handle region, thus specifically stabilizing the enzyme-crRNA complex. These results provide a new paradigm for future design of small molecules to modulate the genome editing of the CRISPR-Cas systems.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00062DOI Listing
March 2020

Semi-synthetic cinnamodial analogues: Structural insights into the insecticidal and antifeedant activities of drimane sesquiterpenes against the mosquito Aedes aegypti.

PLoS Negl Trop Dis 2020 02 26;14(2):e0008073. Epub 2020 Feb 26.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America.

The Aedes aegypti mosquito serves as a major vector for viral diseases, such as dengue, chikungunya, and Zika, which are spreading across the globe and threatening public health. In addition to increased vector transmission, the prevalence of insecticide-resistant mosquitoes is also on the rise, thus solidifying the need for new, safe and effective insecticides to control mosquito populations. We recently discovered that cinnamodial, a unique drimane sesquiterpene dialdehyde of the Malagasy medicinal plant Cinnamosma fragrans, exhibited significant larval and adult toxicity to Ae. aegypti and was more efficacious than DEET-the gold standard for insect repellents-at repelling adult female Ae. aegypti from blood feeding. In this study several semi-synthetic analogues of cinnamodial were prepared to probe the structure-activity relationship (SAR) for larvicidal, adulticidal and antifeedant activity against Ae. aegypti. Initial efforts were focused on modification of the dialdehyde functionality to produce more stable active analogues and to understand the importance of the 1,4-dialdehyde and the α,ß-unsaturated carbonyl in the observed bioactivity of cinnamodial against mosquitoes. This study represents the first investigation into the SAR of cinnamodial as an insecticide and antifeedant against the medically important Ae. aegypti mosquito.
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http://dx.doi.org/10.1371/journal.pntd.0008073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062286PMC
February 2020

Na/K-ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives.

J Nat Prod 2020 03 25;83(3):638-648. Epub 2020 Feb 25.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.

(+)-Digoxin () is a well-known cardiac glycoside long used to treat congestive heart failure and found more recently to show anticancer activity. Several known cardenolides (-) and two new analogues, (+)-8(9)-β-anhydrodigoxigenin () and (+)-17--20,22-dihydro-21α-hydroxydigoxin (), were synthesized from and evaluated for their cytotoxicity toward a small panel of human cancer cell lines. A preliminary structure-activity relationship investigation conducted indicated that the C-12 and C-14 hydroxy groups and the C-17 unsaturated lactone unit are important for to mediate its cytotoxicity toward human cancer cells, but the C-3 glycosyl residue seems to be less critical for such an effect. Molecular docking profiles showed that the cytotoxic and the noncytotoxic derivative bind differentially to Na/K-ATPase. The HO-12β, HO-14β, and HO-3'aα hydroxy groups of (+)-digoxin () may form hydrogen bonds with the side-chains of Asp121 and Asn122, Thr797, and Arg880 of Na/K-ATPase, respectively, but the altered lactone unit of results in a rotation of its steroid core, which depotentiates the binding between this compound and Na/K-ATPase. Thus, was found to inhibit Na/K-ATPase, but did not. In addition, the cytotoxic did not affect glucose uptake in human cancer cells, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na/K-ATPase but not by interacting with glucose transporters.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243443PMC
March 2020

The structures of polyunsaturated lipid bilayers by joint refinement of neutron and X-ray scattering data.

Chem Phys Lipids 2020 07 12;229:104892. Epub 2020 Feb 12.

Department of Physics, Brock University, St. Catharines, ON, Canada; The Bredesen Center, University of Tennessee, Knoxville, TN, USA; Shull Wollan Center, Oak Ridge National Laboratory, Oak Ridge, TN, USA; Large Scale Structures Group, Neutron Sciences Directorate, Oak Ridge National Laboratory, Oak Ridge, TN, USA; Department of Physics and Astronomy, University of Tennessee, Knoxville, TN, USA. Electronic address:

We present the detailed structural analysis of polyunsaturated fatty acid-containing phospholipids namely, 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (PDPC) and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (SDPC). A newly developed molecular dynamics (MD) simulation parsing scheme for lipids containing fatty acids with multiple double bonds was implemented into the scattering density profile (SDP) model to simultaneously refine differently contrasted neutron and X-ray scattering data. SDP analyses of scattering data at 30 °C yielded lipid areas of 71.1 Å and 70.4 Å for PDPC and SDPC bilayers, respectively, and a model free analysis of PDPC at 30 °C resulted in a lipid area of 72 Å. In addition to bilayer structural parameters, using area-constrained MD simulations we determined the area compressibility modulus, K, to be 246.4 mN/m, a value similar to other neutral phospholipids.
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http://dx.doi.org/10.1016/j.chemphyslip.2020.104892DOI Listing
July 2020

Real-time surgical instrument detection in robot-assisted surgery using a convolutional neural network cascade.

Healthc Technol Lett 2019 Dec 26;6(6):275-279. Epub 2019 Nov 26.

Laboratory of Laparoscopic Technique and Engineering, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.

Surgical instrument detection in robot-assisted surgery videos is an import vision component for these systems. Most of the current deep learning methods focus on single-tool detection and suffer from low detection speed. To address this, the authors propose a novel frame-by-frame detection method using a cascading convolutional neural network (CNN) which consists of two different CNNs for real-time multi-tool detection. An hourglass network and a modified visual geometry group (VGG) network are applied to jointly predict the localisation. The former CNN outputs detection heatmaps representing the location of tool tip areas, and the latter performs bounding-box regression for tool tip areas on these heatmaps stacked with input RGB image frames. The authors' method is tested on the publicly available dataset and the dataset. The experimental results show that their method achieves better performance than mainstream detection methods in terms of detection accuracy and speed.
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http://dx.doi.org/10.1049/htl.2019.0064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952255PMC
December 2019

Rational design, synthesis, and evaluation of uncharged, "smart" bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase.

J Biol Chem 2020 03 4;295(13):4079-4092. Epub 2020 Feb 4.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0751. Electronic address:

Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime-based therapies whose success rates are currently limited. The pyridinium cation hampers uptake of OPs into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are nonproductive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)-inhibited human AChE, here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved reactivation of diverse OP-human AChE conjugates. Oxime group reorientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, "smart" accelerated antidotes against OP toxicity.
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http://dx.doi.org/10.1074/jbc.RA119.012400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105318PMC
March 2020

Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper.

Bioorg Med Chem 2020 02 7;28(4):115301. Epub 2020 Jan 7.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

A new non-cytotoxic [(+)-17β-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na/K-ATPase. Compound 3 docks deeply in the Na/K-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na/K-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na/K-ATPase. Thus, 3 was found to inhibit Na/K-ATPase, but 1 did not. In addition, the cytotoxic and Na/K-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na/K-ATPase but not by interacting with glucose transporters.
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http://dx.doi.org/10.1016/j.bmc.2019.115301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029422PMC
February 2020

Insecticidal and Antifeedant Activities of Malagasy Medicinal Plant ( sp.) Extracts and Drimane-Type Sesquiterpenes against Mosquitoes.

Insects 2019 Oct 25;10(11). Epub 2019 Oct 25.

Department of Entomology, The Ohio State University, Ohio Agricultural Research and Development Center, Wooster, OH 44691, USA.

The overuse of insecticides with limited modes of action has led to resistance in mosquito vectors. Thus, insecticides with novel modes of action are needed. Secondary metabolites in Madagascan plants of the genus (Canellaceae) are commonly used in traditional remedies and known to elicit antifeedant and toxic effects in insect pests. Here we test the hypothesis that extracts of sp. enriched in drimane sesquiterpenes are toxic and/or antifeedant to the yellow fever mosquito . We show that the bark and root extracts, which contain a higher abundance of drimane sesquiterpenes compared to leaves, were the most efficacious. Screening isolated compounds revealed cinnamodial to be the primary driver of adulticidal activity, whereas cinnamodial, polygodial, cinnafragrin A, and capsicodendrin contributed to the larvicidal activity. Moreover, an abundant lactone (cinnamosmolide) in the root extract synergized the larvicidal effects of cinnamodial. The antifeedant activity of the extracts was primarily contributed to cinnamodial, polygodial, and cinnamolide. Parallel experiments with warburganal isolated from (Canellaceae) revealed that aldehydes are critical for-and a hydroxyl modulates-insecticidal activity. Our results indicate that plant drimane sesquiterpenes provide valuable chemical platforms for developing insecticides and repellents to control mosquito vectors.
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http://dx.doi.org/10.3390/insects10110373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920793PMC
October 2019

Computationally Guided Discovery and Experimental Validation of Indole-3-acetic Acid Synthesis Pathways.

ACS Chem Biol 2019 12 18;14(12):2867-2875. Epub 2019 Nov 18.

Biological and Nanoscale Systems Group , Biosciences Division Oak Ridge National Laboratory , Oak Ridge , Tennessee 37831 , United States.

Elucidating the interaction networks associated with secondary metabolite production in microorganisms is an ongoing challenge made all the more daunting by the rate at which DNA sequencing technology reveals new genes and potential pathways. Developing the culturing methods, expression conditions, and genetic systems needed for validating pathways in newly discovered microorganisms is often not possible. Therefore, new tools and techniques are needed for defining complex metabolic pathways. Here, we describe an computationally assisted pathway description approach that employs bioinformatic searches of genome databases, protein structural modeling, and protein-ligand-docking simulations to predict the gene products most likely to be involved in a particular secondary metabolite production pathway. This information is then used to direct reconstructions of the pathway and subsequent confirmation of pathway activity using crude enzyme preparations. As a test system, we elucidated the pathway for biosynthesis of indole-3-acetic acid (IAA) in the plant-associated microbe sp. YR343. This organism is capable of metabolizing tryptophan into the plant phytohormone IAA. BLAST analyses identified a likely three-step pathway involving an amino transferase, an indole pyruvate decarboxylase, and a dehydrogenase. However, multiple candidate enzymes were identified at each step, resulting in a large number of potential pathway reconstructions (32 different enzyme combinations). Our approach shows the effectiveness of crude extracts to rapidly elucidate enzymes leading to functional pathways. Results are compared to affinity purified enzymes for select combinations and found to yield similar relative activities. Further, testing of the pathway reconstructions revealed the "underground" nature of IAA metabolism in sp. YR343 and the various mechanisms used to produce IAA. Importantly, our experiments illustrate the scalable integration of computational tools and cell-free enzymatic reactions to identify and validate metabolic pathways in a broadly applicable manner.
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http://dx.doi.org/10.1021/acschembio.9b00725DOI Listing
December 2019

Structurally Modified Cyclopenta[]benzofuran Analogues Isolated from .

J Nat Prod 2019 10 17;82(10):2870-2877. Epub 2019 Oct 17.

Institute of Ecology and Biological Resources , Vietnamese Academy of Science and Technology , Hanoi , Vietnam.

Four new cyclopenta[]benzofuran derivatives based on an unprecedented carbon skeleton (-), with a dihydrofuran ring fused to dioxanyl and aryl rings, along with a new structural analogue () of 5‴-episilvestrol (episilvestrol, ), were isolated from an aqueous extract of a large-scale re-collection of the roots of collected in Vietnam. Compound demonstrated mutarotation in solution due to the presence of a hydroxy group at C-2‴, leading to the isolation of a racemic mixture, despite being purified on a chiral-phase HPLC column. Silvestrol () and episilvestrol () were isolated from the most potently cytotoxic chloroform subfraction of the roots. All new structures were elucidated using 1D and 2D NMR, HRESIMS, IR, UV, and ECD spectroscopic data. Of the five newly isolated compounds, only compound exhibited cytotoxic activity against a human colon cancer (HT-29) and human prostate cancer cell line (PC-3), with IC values of 2.3 μM in both cases. The isolated compounds (-) double the number of dioxanyl ring-containing rocaglate analogues reported to date from species and present additional information on the structural requirements for cancer cell line cytotoxicity within this compound class.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819999PMC
October 2019

STarFish: A Stacked Ensemble Target Fishing Approach and its Application to Natural Products.

J Chem Inf Model 2019 11 24;59(11):4906-4920. Epub 2019 Oct 24.

Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy , The Ohio State University , Columbus , Ohio 43210 , United States.

Target fishing is the process of identifying the protein target of a bioactive small molecule. To do so experimentally requires a significant investment of time and resources, which can be expedited with a reliable computational target fishing model. The development of computational target fishing models using machine learning has become very popular over the last several years because of the increased availability of large amounts of public bioactivity data. Unfortunately, the applicability and performance of such models for natural products has not yet been comprehensively assessed. This is, in part, due to the relative lack of bioactivity data available for natural products compared to synthetic compounds. Moreover, the databases commonly used to train such models do not annotate which compounds are natural products, which makes the collection of a benchmarking set difficult. To address this knowledge gap, a data set composed of natural product structures and their associated protein targets was generated by cross-referencing 20 publicly available natural product databases with the bioactivity database ChEMBL. This data set contains 5589 compound-target pairs for 1943 unique compounds and 1023 unique targets. A synthetic data set comprising 107 190 compound-target pairs for 88 728 unique compounds and 1907 unique targets was used to train -nearest neighbors, random forest, and multilayer perceptron models. The predictive performance of each model was assessed by stratified 10-fold cross-validation and benchmarking on the newly collected natural product data set. Strong performance was observed for each model during cross-validation with area under the receiver operating characteristic (AUROC) scores ranging from 0.94 to 0.99 and Boltzmann-enhanced discrimination of receiver operating characteristic (BEDROC) scores from 0.89 to 0.94. When tested on the natural product data set, performance dramatically decreased with AUROC scores ranging from 0.70 to 0.85 and BEDROC scores from 0.43 to 0.59. However, the implementation of a model stacking approach, which uses logistic regression as a meta-classifier to combine model predictions, dramatically improved the ability to correctly predict the protein targets of natural products and increased the AUROC score to 0.94 and BEDROC score to 0.73. This stacked model was deployed as a web application, called STarFish, and has been made available for use to aid in target identification for natural products.
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http://dx.doi.org/10.1021/acs.jcim.9b00489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291623PMC
November 2019

Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation.

Proc Natl Acad Sci U S A 2019 10 23;116(41):20446-20452. Epub 2019 Sep 23.

UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN 37831;

Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e., the collection of 3-dimensional structures they adopt, and this remains an immense challenge in structural biology. Attempts to determine this ensemble computationally have been hitherto hampered by the necessity of reweighting molecular dynamics (MD) results or biasing simulation in order to match ensemble-averaged experimental observables, operations that reduce the precision of the generated model because different structural ensembles may yield the same experimental observable. Here, by employing enhanced sampling MD we reproduce the experimental small-angle neutron and X-ray scattering profiles and the NMR chemical shifts of the disordered N terminal (SH4UD) of c-Src kinase without reweighting or constraining the simulations. The unbiased simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which gives rise to a heterogeneous ensemble of structures that cannot be described by simple polymer theory. SH4UD adopts transient helices, which are found away from known phosphorylation sites and could play a key role in the stabilization of structural regions necessary for phosphorylation. Our findings indicate that adequately sampled molecular simulations can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.
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http://dx.doi.org/10.1073/pnas.1907251116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789927PMC
October 2019

A Multifunctional Cosolvent Pair Reveals Molecular Principles of Biomass Deconstruction.

J Am Chem Soc 2019 08 31;141(32):12545-12557. Epub 2019 Jul 31.

Department of Chemical and Environmental Engineering, Bourns College of Engineering , University of California, Riverside , 900 University Avenue , Riverside , California 92521 , United States.

The complex structure of plant cell walls resists chemical or biological degradation, challenging the breakdown of lignocellulosic biomass into renewable chemical precursors that could form the basis of future production of green chemicals and transportation fuels. Here, experimental and computational results reveal that the effect of the tetrahydrofuran (THF)-water cosolvents on the structure of lignin and on its interactions with cellulose in the cell wall drives multiple synergistic mechanisms leading to the efficient breakdown and fractionation of biomass into valuable chemical precursors. Molecular simulations show that THF-water is an excellent "theta" solvent, such that lignin dissociates from itself and from cellulose and expands to form a random coil. The expansion of the lignin molecules exposes interunit linkages, rendering them more susceptible to depolymerization by acid-catalyzed cleavage of aryl-ether bonds. Nanoscale infrared sensors confirm cosolvent-mediated molecular rearrangement of lignin in the cell wall of micrometer-thick hardwood slices and track the disappearance of lignin. At bulk scale, adding dilute acid to the cosolvent mixture liberates the majority of the hemicellulose and lignin from biomass, allowing unfettered access of cellulolytic enzymes to the remaining cellulose-rich material, allowing them to sustain high rates of hydrolysis to glucose without enzyme deactivation. Through this multiscale analysis, synergistic mechanisms for biomass deconstruction are identified, portending a paradigm shift toward first-principles design and evaluation of other cosolvent methods to realize low cost fuels and bioproducts.
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http://dx.doi.org/10.1021/jacs.8b10242DOI Listing
August 2019

Branched-Chain Fatty Acid Content Modulates Structure, Fluidity, and Phase in Model Microbial Cell Membranes.

J Phys Chem B 2019 07 28;123(27):5814-5821. Epub 2019 Jun 28.

Department of Chemical and Environmental Engineering , University of Cincinnati , Cincinnati , Ohio 45221 , United States.

Recent progress in understanding the importance and origins of lipid rafts in microbial cell membranes has focused attention on membranes containing branched-chain fatty acids. The working hypothesis is that branched fatty acids increase the fluidity of the bilayer, analogous to unsaturated fatty acids in membranes of higher organisms. Here, we perform a series of 7 μs long atomistic simulations on biomimetic, branched-chain lipid containing bilayer patches, systematically varying the amount of the straight-chain fatty acid component, 16:0, from 7.0 to 47.3 mol %. The simulations reveal thickening and ordering of the bilayer as well as higher bilayer viscosity and bending modulus with increasing 16:0 content, thus providing quantitative support that branched fatty acids increase the bilayer fluidity. A sharp transition in these properties is observed at ∼20% 16:0 content, resembling a phase change. The simulations provide the first access to ordered disordered phases in a bacterial cell membrane mimic containing branched-chain lipids. Granted several assumptions, a comparison of these phases provides estimates of physical properties such as hydrophobic mismatch (∼1.2 Å), difference in bending moduli (∼15.7 ), and the line tension (∼0.6 pN) for a putative lipid raft in the cell membrane of an organism such as or .
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http://dx.doi.org/10.1021/acs.jpcb.9b04326DOI Listing
July 2019

A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies.

Chem Biol Interact 2019 Aug 7;309:108698. Epub 2019 Jun 7.

(b)Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093-0650, USA. Electronic address:

Structure-guided design of novel pharmacologically active molecules relies at least in part on functionally relevant accuracy of macromolecular structures for template based drug design. Currently, about 95% of all macromolecular X-ray structures available in the PDB (Protein Data Bank) were obtained from diffraction experiments at low, cryogenic temperatures. However, it is known that functionally relevant conformations of both macromolecules and pharmacological ligands can differ at higher, physiological temperatures. We describe in this article development and properties of new human acetylcholinesterase (AChE) crystals of space group P3 and a new unit cell, amenable for room-temperature X-ray diffraction studies. We co-crystallized hAChE in P3 unit cell with the reversible inhibitor 9-aminoacridine that binds at the base of the active center gorge in addition to inhibitors that span the full length of the gorge, donepezil (Aricept, E2020) and AChE specific inhibitor BW284c51. Their new low temperature P3 space group structures appear similar to those previously obtained in the different P321 unit cell. Successful solution of the new room temperature 3.2 Å resolution structure of BW284c51*hAChE complex from large P3 crystals enables us to proceed with studying room temperature structures of lower affinity complexes, such as oxime reactivators bound to hAChE, where temperature-related conformational diversity could be expected in both oxime and hAChE, which could lead to better informed structure-based design under conditions approaching physiological temperature.
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http://dx.doi.org/10.1016/j.cbi.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679772PMC
August 2019

Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase.

J Biol Chem 2019 07 28;294(27):10607-10618. Epub 2019 May 28.

the Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831

Exposure to organophosphorus compounds (OPs) may be fatal if untreated, and a clear and present danger posed by nerve agent OPs has become palpable in recent years. OPs inactivate acetylcholinesterase (AChE) by covalently modifying its catalytic serine. Inhibited AChE cannot hydrolyze the neurotransmitter acetylcholine leading to its build-up at the cholinergic synapses and creating an acute cholinergic crisis. Current antidotes, including oxime reactivators that attack the OP-AChE conjugate to free the active enzyme, are inefficient. Better reactivators are sought, but their design is hampered by a conformationally rigid portrait of AChE extracted exclusively from 100K X-ray crystallography and scarcity of structural knowledge on human AChE (hAChE). Here, we present room temperature X-ray structures of native and VX-phosphonylated hAChE with an imidazole-based oxime reactivator, RS-170B. We discovered that inhibition with VX triggers substantial conformational changes in bound RS-170B from a "nonproductive" pose (the reactive aldoxime group points away from the VX-bound serine) in the reactivator-only complex to a "semi-productive" orientation in the VX-modified complex. This observation, supported by concurrent molecular simulations, suggested that the narrow active-site gorge of hAChE may be significantly more dynamic than previously thought, allowing RS-170B to reorient inside the gorge. Furthermore, we found that small molecules can bind in the choline-binding site hindering approach to the phosphorous of VX-bound serine. Our results provide structural and mechanistic perspectives on the reactivation of OP-inhibited hAChE and demonstrate that structural studies at physiologically relevant temperatures can deliver previously overlooked insights applicable for designing next-generation antidotes.
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http://dx.doi.org/10.1074/jbc.RA119.008725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615692PMC
July 2019

Controlling the Revolving and Rotating Motion Direction of Asymmetric Hexameric Nanomotor by Arginine Finger and Channel Chirality.

ACS Nano 2019 06 28;13(6):6207-6223. Epub 2019 May 28.

Nanomotors in nanotechnology are as important as engines in daily life. Many ATPases are nanoscale biomotors classified into three categories based on the motion mechanisms in transporting substrates: linear, rotating, and the recently discovered revolving motion. Most biomotors adopt a multisubunit ring-shaped structure that hydrolyzes ATP to generate force. How these biomotors control the motion direction and regulate the sequential action of their multiple subunits is intriguing. Many ATPases are hexameric with each monomer containing a conserved arginine finger. This review focuses on recent findings on how the arginine finger controls motion direction and coordinates adjacent subunit interactions in both revolving and rotating biomotors. Mechanisms of intersubunit interactions and sequential movements of individual subunits are evidenced by the asymmetrical appearance of one dimer and four monomers in high-resolution structural complexes. The arginine finger is situated at the interface of two subunits and extends into the ATP binding pocket of the downstream subunit. An arginine finger mutation results in deficiency in ATP binding/hydrolysis, substrate binding, and transport, highlighting the importance of the arginine finger in regulating energy transduction and motor function. Additionally, the roles of channel chirality and channel size are discussed as related to controlling one-way trafficking and differentiating the revolving and rotating mechanisms. Finally, the review concludes by discussing the conformational changes and entropy conversion triggered by ATP binding/hydrolysis, offering a view different from the traditional concept of ATP-mediated mechanochemical energy coupling. The elucidation of the motion mechanism and direction control in ATPases could facilitate nanomotor fabrication in nanotechnology.
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http://dx.doi.org/10.1021/acsnano.8b08849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595433PMC
June 2019

Real-time tracking of surgical instruments based on spatio-temporal context and deep learning.

Comput Assist Surg (Abingdon) 2019 10 14;24(sup1):20-29. Epub 2019 Feb 14.

Lab of Laparoscopic Technique and Engineering, Qilu Hospital of Shandong University , Jinan , China.

ABSTARCT Real-time tool tracking in minimally invasive-surgery (MIS) has numerous applications for computer-assisted interventions (CAIs). Visual tracking approaches are a promising solution to real-time surgical tool tracking, however, many approaches may fail to complete tracking when the tracker suffers from issues such as motion blur, adverse lighting, specular reflections, shadows, and occlusions. We propose an automatic real-time method for two-dimensional tool detection and tracking based on a spatial transformer network (STN) and spatio-temporal context (STC). Our method exploits both the ability of a convolutional neural network (CNN) with an in-house trained STN and STC to accurately locate the tool at high speed. Then we compared our method experimentally with other four general of CAIs' visual tracking methods using eight existing online and in-house datasets, covering both abdominal, cardiac and retinal clinical cases in which different surgical instruments were employed. The experiments demonstrate that our method achieved great performance with respect to the accuracy and the speed. It can track a surgical tool without labels in real time in the most challenging of cases, with an accuracy that is equal to and sometimes surpasses most state-of-the-art tracking algorithms. Further improvements to our method will focus on conditions of occlusion and multi-instruments.
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http://dx.doi.org/10.1080/24699322.2018.1560097DOI Listing
October 2019