Publications by authors named "Vijay Raghavan"

28 Publications

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Exploring the effectiveness of the TSR-based protein 3-D structural comparison method for protein clustering, and structural motif identification and discovery of protein kinases, hydrolases, and SARS-CoV-2's protein via the application of amino acid grouping.

Comput Biol Chem 2021 Jun 29;92:107479. Epub 2021 Mar 29.

Department of Chemistry, University of Louisiana at Lafayette, P.O. Box 44370, Lafayette, LA 70504, USA. Electronic address:

Development of protein 3-D structural comparison methods is essential for understanding protein functions. Some amino acids share structural similarities while others vary considerably. These structures determine the chemical and physical properties of amino acids. Grouping amino acids with similar structures potentially improves the ability to identify structurally conserved regions and increases the global structural similarity between proteins. We systematically studied the effects of amino acid grouping on the numbers of Specific/specific, Common/common, and statistically different keys to achieve a better understanding of protein structure relations. Common keys represent substructures found in all types of proteins and Specific keys represent substructures exclusively belonging to a certain type of proteins in a data set. Our results show that applying amino acid grouping to the Triangular Spatial Relationship (TSR)-based method, while computing structural similarity among proteins, improves the accuracy of protein clustering in certain cases. In addition, applying amino acid grouping facilitates the process of identification or discovery of conserved structural motifs. The results from the principal component analysis (PCA) demonstrate that applying amino acid grouping captures slightly more structural variation than when amino acid grouping is not used, indicating that amino acid grouping reduces structure diversity as predicted. The TSR-based method uniquely identifies and discovers binding sites for drugs or interacting proteins. The binding sites of nsp16 of SARS-CoV-2, SARS-CoV and MERS-CoV that we have defined will aid future antiviral drug design for improving therapeutic outcome. This approach for incorporating the amino acid grouping feature into our structural comparison method is promising and provides a deeper insight into understanding of structural relations of proteins.
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http://dx.doi.org/10.1016/j.compbiolchem.2021.107479DOI Listing
June 2021

Development of a TSR-Based Method for Protein 3-D Structural Comparison With Its Applications to Protein Classification and Motif Discovery.

Front Chem 2020 13;8:602291. Epub 2021 Jan 13.

Department of Chemistry, University of Louisiana at Lafayette, Lafayette, LA, United States.

Development of protein 3-D structural comparison methods is important in understanding protein functions. At the same time, developing such a method is very challenging. In the last 40 years, ever since the development of the first automated structural method, ~200 papers were published using different representations of structures. The existing methods can be divided into five categories: sequence-, distance-, secondary structure-, geometry-based, and network-based structural comparisons. Each has its uniqueness, but also limitations. We have developed a novel method where the 3-D structure of a protein is modeled using the concept of Triangular Spatial Relationship (TSR), where triangles are constructed with the C atoms of a protein as vertices. Every triangle is represented using an integer, which we denote as "key," A key is computed using the length, angle, and vertex labels based on a rule-based formula, which ensures assignment of the same key to identical TSRs across proteins. A structure is thereby represented by a vector of integers. Our method is able to accurately quantify similarity of structure or substructure by matching numbers of identical keys between two proteins. The uniqueness of our method includes: (i) a unique way to represent structures to avoid performing structural superimposition; (ii) use of triangles to represent substructures as it is the simplest primitive to capture shape; (iii) complex structure comparison is achieved by matching integers corresponding to multiple TSRs. Every substructure of one protein is compared to every other substructure in a different protein. The method is used in the studies of proteases and kinases because they play essential roles in cell signaling, and a majority of these constitute drug targets. The new motifs or substructures we identified specifically for proteases and kinases provide a deeper insight into their structural relations. Furthermore, the method provides a unique way to study protein conformational changes. In addition, the results from CATH and SCOP data sets clearly demonstrate that our method can distinguish alpha helices from beta pleated sheets and . Our method has the potential to be developed into a powerful tool for efficient structure-BLAST search and comparison, just as BLAST is for sequence search and alignment.
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http://dx.doi.org/10.3389/fchem.2020.602291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838567PMC
January 2021

Frontline Healthcare Workers' Knowledge, Perception and Risk Prevention Practices Regarding COVID-19 in Afghanistan: A Cross-Sectional Study.

Med Sci (Basel) 2021 Jan 8;9(1). Epub 2021 Jan 8.

Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.

(1) Background: As of 13 December 2020, Afghanistan reported around 48,952 confirmed COVID-19 cases and 1960 deaths. Lack of knowledge and perceptions among healthcare workers (HCWs) can pose challenges to disease control. Therefore, targeted, timely assessment of knowledge and perceptions are needed to address practices that might hinder efforts to stop the spreading of COVID-19 in Afghanistan. This study aimed to assess COVID-19-related knowledge, perceptions, and risk prevention practices (KPP) among frontline HCWs in Afghanistan; (2) Methods: A cross-sectional study was conducted with the support of field teams who were deployed in Afghanistan, surveyed from 14 to 22 April 2020 in eight provinces in Afghanistan with varying cumulative incidence of COVID-19 cases. A 28-item KPP survey instrument was adapted from other internationally validated questionnaires related to COVID-19. (3) Results: The survey was conducted among 213 frontline HCWs engaged in screening and treating COVID-19 patients. Survey results indicated that basic awareness of COVID-19 was 100% across all the participants. Knowledge and understanding of COVID-19 transmission, symptoms, incubation period and complications associated with COVID-19 are comprehensive and high (>90%), except available treatment for COVID-19 (84%). HCWs' perceptions towards the prevention and control of COVID-19 were positive. However, only 63% believed that the use of N-95 face masks and disposable and fluid-resistant gowns (76%) could prevent COVID-19 transmission. This survey showed high knowledge and positive perception (72%), and only 48% of frontline HCWs had shown risk prevention practices. Addressing their perceptions and placing additional focus on practices across all health facilities is recommended as a preparedness measure.
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http://dx.doi.org/10.3390/medsci9010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838898PMC
January 2021

Enhancement of the chiroptical response of α-amino acids via N-substitution for molecular structure determination using vibrational circular dichroism.

Chirality 2020 05 1;32(5):564-578. Epub 2020 Mar 1.

Department of Chemistry, Vanderbilt University, Nashville, Tennessee.

The chiroptical response in the form of vibrational circular dichroism (VCD) in the midinfrared region is found to be enhanced when a hydrogen of amino group of l-tryptophan is substituted with acetyl, acryloyl, or maleyl group. The order of preference for VCD enhancement is found to be acryloyl > acetyl > maleyl group. The resulting experimental VCD spectra are also found to be satisfactorily reproduced by the quantum mechanical (QM) predicted spectra. The QM predicted spectra were simulated using the conformer populations, (a) predicted by Gibbs energies and (b) optimized to maximize the similarity between experimental and predicted VCD spectra. It is found that the conformer populations predicted by Gibbs energies do not yield the maximum possible similarity between experimental and the QM predicted spectra. This work identifies the N-substitution of α-amino acids and determining the conformer populations that best reproduce the experimental spectra as two new approaches for molecular structure determination.
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http://dx.doi.org/10.1002/chir.23205DOI Listing
May 2020

Peyssonnosides A-B, Unusual Diterpene Glycosides with a Sterically Encumbered Cyclopropane Motif: Structure Elucidation Using an Integrated Spectroscopic and Computational Workflow.

J Org Chem 2019 07 18;84(13):8531-8541. Epub 2019 Jun 18.

Parker H. Petit Institute for Bioengineering and Bioscience , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.

Two sulfated diterpene glycosides featuring a highly substituted and sterically encumbered cyclopropane ring have been isolated from the marine red alga Peyssonnelia sp. Combination of a wide array of 2D NMR spectroscopic experiments, in a systematic structure elucidation workflow, revealed that peyssonnosides A-B (1-2) represent a new class of diterpene glycosides with a tetracyclo [7.5.0.0.0] tetradecane architecture. A salient feature of this workflow is the unique application of quantitative interproton distances obtained from the rotating frame Overhauser effect spectroscopy (ROESY) NMR experiment, wherein the β-d-glucose moiety of 1 was used as an internal probe to unequivocally determine the absolute configuration, which was also supported by optical rotatory dispersion (ORD). Peyssonnoside A (1) exhibited promising activity against liver stage Plasmodium berghei and moderate antimethicillin-resistant Staphylococcus aureus (MRSA) activity, with no cytotoxicity against human keratinocytes. Additionally, 1 showed strong growth inhibition of the marine fungus Dendryphiella salina indicating an antifungal ecological role in its natural environment. The high natural abundance and novel carbon skeleton of 1 suggests a rare terpene cyclase machinery, exemplifying the chemical diversity in this phylogenetically distinct marine red alga.
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http://dx.doi.org/10.1021/acs.joc.9b00884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614789PMC
July 2019

Role of Bisphosphonates as Adjuvants of Surgery in Giant Cell Tumor of Spine.

Int J Spine Surg 2018 Dec 21;12(6):695-702. Epub 2018 Dec 21.

Department of Orthopaedics, All India Institute of Medical Sciences, New Delhi, India.

Background: The role of bisphosphonates is well established in giant cell tumor of bone (GCTB) of extremities, but its role in spine GCTB is still not established. Our main purpose was to evaluate the role of bisphosphonates in spinal GCTB with the help of radiologic assessment.

Methods: A retrospective analysis of all spine GCTB patients who underwent an operation from July 2005 to January 2014 was done. Patients of spine GCTB in whom bisphosphonates were given constituted the study group. This group was compared to patients in whom bisphosphonates were not given. Preoperative and postoperative radiographs and CT scans were studied. A thorough evaluation of the presence of sclerosis was done on them. Bisphosphonates were considered to be effective if either sclerosis or new bone formation was present.

Results: A total of 13 cases of spine GCT underwent operation from July 2005 to January 2014. All patients of GCTB spine who underwent an operation after 2008 at our institute were given bisphosphonates postoperatively. Of 13 cases, bisphosphonates were given postoperatively in 6 patients: 5 patients were female and 1 patient was male. Of these 6 patients, 3 patients had sacrum GCTB and 1 patient each had T9, T11, and L5 vertebrae GCTB. Average follow-up period was 39.33 months (minimum follow-up was 18 months and maximum follow-up was 72 months). Postoperative sclerosis was present in all 6 patients. No recurrence of the tumor was present in the bisphosphonate group, but 2 patients had a recurrence in the group that did not receive bisphosphonates.

Conclusions: Bisphosphonates are effective and safe adjuvant therapy along with appropriate surgical intervention in spinal GCTBs and may have a role in decreasing the recurrence of this tumor.
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http://dx.doi.org/10.14444/5087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314347PMC
December 2018

Absolute Configurations of Naturally Occurring [5]- and [3]-Ladderanoic Acids: Isolation, Chiroptical Spectroscopy, and Crystallography.

J Nat Prod 2018 12 18;81(12):2654-2666. Epub 2018 Dec 18.

Department of Chemistry , Vanderbilt University , Nashville , Tennessee 37235 , United States.

We have isolated mixtures of [5]- and [3]-ladderanoic acids 1a and 2a from the biomass of an anammox bioreactor and have separated the acids and their phenacyl esters for the first time by HPLC. The absolute configurations of the naturally occurring acids and their phenacyl esters are assigned as R at the site of side-chain attachment by comparison of experimental specific rotations with corresponding values predicted using quantum chemical (QC) methods. The absolute configurations for 1a and 2a were independently verified by comparison of experimental Raman optical activity spectra with corresponding spectra predicted using QC methods. The configurational assignments of 1a and 2a and of the phenacyl ester of 1a were also confirmed by X-ray crystallography.
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http://dx.doi.org/10.1021/acs.jnatprod.8b00458DOI Listing
December 2018

Reaching for the Stars in the Brain: Polymer-Mediated Gene Delivery to Human Astrocytes.

Mol Ther Nucleic Acids 2018 Sep 28;12:645-657. Epub 2018 Jun 28.

Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address:

Astrocytes, the "star-shaped" glial cells, are appealing gene-delivery targets to treat neurological diseases due to their diverse roles in brain homeostasis and disease. Cationic polymers have successfully delivered genes to mammalian cells and hence present a viable, non-immunogenic alternative to widely used viral vectors. In this study, we investigated the gene delivery potential of a series of arginine- and polyethylene glycol-modified, siloxane-based polyethylenimine analogs in primary cultured human neural cells (neurons and astrocytes) and in mice. Plasmid DNAs encoding luciferase reporter were used to measure gene expression. We hypothesized that polyplexes with arginine would help in cellular transport of the DNA, including across the blood-brain barrier; polyethylene glycol will stabilize polyethylenimine and reduce its toxicity while maintaining its DNA-condensing ability. Polyplexes were non-toxic to human neural cells and red blood cells. Cellular uptake of polyplexes and sustained gene expression were seen in human astrocytes as well as in mouse brains post-intravenous-injections. The polyplexes also delivered and expressed genes driven by astrocyte-restricted glial fibrillary acidic protein promoters, which are weaker than viral promoters. To our knowledge, the presented work validates a biocompatible and effective polymer-facilitated gene-delivery system for both human brain cells and mice for the first time.
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http://dx.doi.org/10.1016/j.omtn.2018.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082920PMC
September 2018

Biases introduced by filtering electronic health records for patients with "complete data".

J Am Med Inform Assoc 2017 Nov;24(6):1134-1141

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

Objective: One promise of nationwide adoption of electronic health records (EHRs) is the availability of data for large-scale clinical research studies. However, because the same patient could be treated at multiple health care institutions, data from only a single site might not contain the complete medical history for that patient, meaning that critical events could be missing. In this study, we evaluate how simple heuristic checks for data "completeness" affect the number of patients in the resulting cohort and introduce potential biases.

Materials And Methods: We began with a set of 16 filters that check for the presence of demographics, laboratory tests, and other types of data, and then systematically applied all 216 possible combinations of these filters to the EHR data for 12 million patients at 7 health care systems and a separate payor claims database of 7 million members.

Results: EHR data showed considerable variability in data completeness across sites and high correlation between data types. For example, the fraction of patients with diagnoses increased from 35.0% in all patients to 90.9% in those with at least 1 medication. An unrelated claims dataset independently showed that most filters select members who are older and more likely female and can eliminate large portions of the population whose data are actually complete.

Discussion And Conclusion: As investigators design studies, they need to balance their confidence in the completeness of the data with the effects of placing requirements on the data on the resulting patient cohort.
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http://dx.doi.org/10.1093/jamia/ocx071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080680PMC
November 2017

Specific optical rotation is a versatile tool for the identification of critical micelle concentration and micellar growth of tartaric acid-based diastereomeric amphiphiles.

Chirality 2017 Dec 9;29(12):836-846. Epub 2017 Oct 9.

Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.

Four novel tartaric acid-based diastereomeric chiral amphiphiles, two being enantiomers of the other two, have been synthesized and investigated using chiroptical spectroscopic methods, along with tensiometry and dynamic light scattering experiments. We found that an inflection point in specific optical rotation (SOR) values at ~0.32 mM corresponds to the critical micelle concentration (CMC). The increase in magnitude of SOR values beyond CMC corresponds to the growth of aggregates. For enantiomers, oppositely signed SOR values were observed, ruling out the possibility for the presence of aggregation size mediated artefacts. SOR values did not exhibit concentration dependence for a chiral tartaric acid based non-aggregating analogue further establishing the absence of artefacts or anomalous interaction of tartaric acid based head group with solvent. Electronic circular dichroism spectra showed no significant changes in band positions or intensities with concentration. Due to the requirement for higher concentrations (~200 mM) needed to obtain vibrational circular dichroism spectra, these measurements are not found to be useful for studying concentration dependent properties of chiral amphiphiles.
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http://dx.doi.org/10.1002/chir.22767DOI Listing
December 2017

The Long 3'UTR mRNA of Is Essential for Translation-Dependent Plasticity of Spontaneous Release in .

J Neurosci 2017 11 27;37(44):10554-10566. Epub 2017 Sep 27.

Department of Biology, Volen National Center for Complex Systems and National Center for Behavioral Genomics, Brandeis University, Waltham, Massachusetts 02454-9110,

A null mutation of the gene () was generated using homologous recombination. Null animals survive to larval and pupal stages due to a large maternal contribution of mRNA, which consists of a short 3'-untranslated region (UTR) form lacking regulatory elements that guide local translation. The selective loss of the long 3'UTR mRNA in -null larvae allows us to test its role in plasticity. Development and evoked function of the larval neuromuscular junction are surprisingly normal, but the resting rate of miniature excitatory junctional potentials (mEJPs) is significantly lower in mutants. Mutants also lack the ability to increase mEJP rate in response to spaced depolarization, a type of activity-dependent plasticity shown to require both transcription and translation. Consistent with this, overexpression of miR-289 in wild-type animals blocks plasticity of spontaneous release. In addition to the defects in regulation of mEJP rate, CaMKII protein is largely lost from synapses in the mutant. All phenotypes are non-sex-specific and rescued by a fosmid containing the entire wild-type locus, but only viability and CaMKII localization are rescued by genomic fosmids lacking the long 3'UTR. This suggests that synaptic CaMKII accumulates by two distinct mechanisms: local synthesis requiring the long 3'UTR form of mRNA and a process that requires zygotic transcription of mRNA. The origin of synaptic CaMKII also dictates its functionality. Locally translated CaMKII has a privileged role in regulation of spontaneous release, which cannot be fulfilled by synaptic CaMKII from the other pool. As a regulator of synaptic development and plasticity, CaMKII has important roles in both normal and pathological function of the nervous system. shows high conservation between and humans, underscoring the usefulness of in modeling its function. -null mutants remain viable throughout development, enabling morphological and electrophysiological characterization. Although the structure of the synapse is normal, maternally contributed CaMKII does not localize to synapses. Zygotic production of mRNA with a long 3'-untranslated region is necessary for modulating spontaneous neurotransmission in an activity-dependent manner, but not for viability. These data argue that regulation of CaMKII localization and levels by local transcriptional processes is conserved. This is the first demonstration of distinct functions for mRNA variants.
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http://dx.doi.org/10.1523/JNEUROSCI.1313-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666580PMC
November 2017

Absolute configuration of an axially chiral sulfonate determined from its optical rotatory dispersion, electronic circular dichroism, and vibrational circular dichroism spectra.

Chirality 2017 Nov 18;29(11):670-676. Epub 2017 Aug 18.

Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.

The absolute configuration (AC) of an axially chiral sulfonate (aCSO), 3,5-dimethyl-2-(naphthalen-1-yl)-6-(naphthalen-1-yl)benzenesulfonate (labeled as aCSO5), was investigated using optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectroscopies. All three methods led to the same conclusion and the AC of aCSO5 is reliably determined to be (-)-(aR, aR), or conversely (+)-(aS, aS).
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http://dx.doi.org/10.1002/chir.22739DOI Listing
November 2017

To Avoid Chasing Incorrect Chemical Structures of Chiral Compounds: Raman Optical Activity and Vibrational Circular Dichroism Spectroscopies.

Chemphyschem 2017 Sep 4;18(18):2459-2465. Epub 2017 Aug 4.

Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Nashville, TN, 37235, USA.

A chemical structure (CS) identifies the connectivities between atoms, and the nature of those connections, for a given elemental composition. For chiral molecules, in addition to the identification of CS, the identification of the correct absolute configuration (AC) is also needed. Several chiral natural products are known whose CSs were initially misidentified and later corrected, and these errors were often discovered during the total synthesis of natural products. In this work, we present a new and convenient approach that can be used with Raman optical activity (ROA) and vibrational circular dichroism (VCD) spectroscopies, to distinguish between the correct and incorrect CSs of chiral compounds. This approach involves analyzing the spectral similarity overlap between experimental spectra and those predicted with advanced quantum chemical theories. Significant labor needed for establishing the correct CSs via chemical syntheses of chiral natural products can thus be avoided.
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http://dx.doi.org/10.1002/cphc.201700764DOI Listing
September 2017

Dual plasmonic gold nanostars for photoacoustic imaging and photothermal therapy.

Nanomedicine (Lond) 2017 Mar 9;12(5):457-471. Epub 2017 Feb 9.

School of Physics, National University of Ireland Galway, Ireland.

Aim: To fabricate multimodal nanoconstruct that act as a single node for photoacoustic imaging (PAI) and photothermal therapy (PTT) in the fight against cancer.

Materials & Methods: Dual plasmonic gold nanostars (DPGNS) were chemically synthesized by reducing gold precursor using ascorbic acid and silver ions as shape directing agent. PAI and PTT were performed using commonly available 1064 nm laser source on DPGNS embedded tumor xenografts on mice.

Results & Conclusion: Photoacoustic amplitude increase with longer wavelength source and with silica coating of DPGNS. The in vivo photothermal capability of DPGNS resulted in a significant decrease in the tumor cellular area. DPGNS exhibited potential for single node diagnosis and therapy with longer wavelength facilitating deeper imaging and therapy.
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http://dx.doi.org/10.2217/nnm-2016-0318DOI Listing
March 2017

First Room Temperature Chiral Anionic Liquid Forming Micelles and Reverse Micelles.

J Phys Chem B 2017 02 8;121(7):1629-1639. Epub 2017 Feb 8.

Department of Chemistry, Vanderbilt University , Nashville, Tennesse 37235, United States.

We report the first chiral surface active anionic liquid, T12M, derived from biodegradable tartaric acid, and its unusual properties. T12M features unprecedented combination of characteristics not found in other ionic liquids (ILs): (a) T12M is the first surface active ionic liquid that is fully chiral, by virtue of the presence of chirality in both anionic headgroup and the counterion; (b) T12M remains as room temperature IL for 3 days and then transforms to a semisolid with melting point at ∼55 °C. The d-spacings in solid T12M, and T12M lyophilized from its aqueous solution, are 13.89 and 14.54 Å, respectively. (c) Tartaric acid is unconventional and unprecedented starting material for the synthesis of ILs. (d) T12M dissolves in both hydrogen bonding (water) and non-hydrogen bonding (chloroform) solvents and forms anionic chiral micellar aggregates (CMAs) and reverse-CMAs, at very low concentrations 0.32 mM and ∼10 mM, respectively. (e) CMAs of T12M adopt structures ranging from spherical to lamellar in shape in water in the 10-200 mM range; however, the zeta potential remained constant at ∼ -13 mV. The alkyl chains, are interdigited in the CMAs of T12M in water to form lamellar structures and are extended outward to form reverse micelles in CHCl.
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http://dx.doi.org/10.1021/acs.jpcb.6b11964DOI Listing
February 2017

Configurationally Stable Chiral Dithia-Bridged Hetero[4]helicene Radical Cation: Electronic Structure and Absolute Configuration.

Chem Asian J 2017 Jan 5;12(1):31-35. Epub 2016 Dec 5.

Chair of Organic Chemistry I, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestrasse 42, 91054 Erlangen, Germany.

A stable chiral hetero[4]helicene radical cation was synthesized and characterized by UV/Vis absorption and EPR spectroscopy, as well as X-ray crystallography. For the first time, a combination of chiroptical methods involving ECD, ORD, and VCD, supported by quantum mechanical predictions, enabled the elucidation of the absolute configuration of such open-shell helical species.
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http://dx.doi.org/10.1002/asia.201601452DOI Listing
January 2017

Data interchange using i2b2.

J Am Med Inform Assoc 2016 09 5;23(5):909-15. Epub 2016 Feb 5.

Partners Healthcare, Boston, MA, USA Harvard Medical School, Boston, MA, USA Massachusetts General Hospital, Boston, MA, USA.

Objective: Reinventing data extraction from electronic health records (EHRs) to meet new analytical needs is slow and expensive. However, each new data research network that wishes to support its own analytics tends to develop its own data model. Joining these different networks without new data extraction, transform, and load (ETL) processes can reduce the time and expense needed to participate. The Informatics for Integrating Biology and the Bedside (i2b2) project supports data network interoperability through an ontology-driven approach. We use i2b2 as a hub, to rapidly reconfigure data to meet new analytical requirements without new ETL programming.

Materials And Methods: Our 12-site National Patient-Centered Clinical Research Network (PCORnet) Clinical Data Research Network (CDRN) uses i2b2 to query data. We developed a process to generate a PCORnet Common Data Model (CDM) physical database directly from existing i2b2 systems, thereby supporting PCORnet analytic queries without new ETL programming. This involved: a formalized process for representing i2b2 information models (the specification of data types and formats); an information model that represents CDM Version 1.0; and a program that generates CDM tables, driven by this information model. This approach is generalizable to any logical information model.

Results: Eight PCORnet CDRN sites have implemented this approach and generated a CDM database without a new ETL process from the EHR. This enables federated querying within the CDRN and compatibility with the national PCORnet Distributed Research Network.

Discussion: We have established a way to adapt i2b2 to new information models without requiring changes to the underlying data. Eight Scalable Collaborative Infrastructure for a Learning Health System sites vetted this methodology, resulting in a network that, at present, supports research on 10 million patients' data.

Conclusion: New analytical requirements can be quickly and cost-effectively supported by i2b2 without creating new data extraction processes from the EHR.
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http://dx.doi.org/10.1093/jamia/ocv188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997035PMC
September 2016

Macro influencers of electronic health records adoption.

Int J Electron Healthc 2015 ;8(1):76-94

3 IBM Bay Area Lab, 1001 E Hillsdale Blvd., Suite 400, Foster City, CA 94404, USA.

While adoption rates for electronic health records (EHRs) have improved, the reasons for significant geographical differences in EHR adoption within the USA have remained unclear. To understand the reasons for these variations across states, we have compiled from secondary sources a profile of different states within the USA, based on macroeconomic and macro health-environment factors. Regression analyses were performed using these indicator factors on EHR adoption. The results showed that internet usage and literacy are significantly associated with certain measures of EHR adoption. Income level was not significantly associated with EHR adoption. Per capita patient days (a proxy for healthcare need intensity within a state) is negatively correlated with EHR adoption rate. Health insurance coverage is positively correlated with EHR adoption rate. Older physicians (>60 years) tend to adopt EHR systems less than their younger counterparts. These findings have policy implications on formulating regionally focused incentive programs.
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http://dx.doi.org/10.1504/ijeh.2015.071644DOI Listing
December 2015

Sustained Epigenetic Drug Delivery Depletes Cholesterol-Sphingomyelin Rafts from Resistant Breast Cancer Cells, Influencing Biophysical Characteristics of Membrane Lipids.

Langmuir 2015 Oct 15;31(42):11564-73. Epub 2015 Oct 15.

Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic , 9500 Euclid Avenue, Cleveland, Ohio 44195, United States.

Cell-membrane lipid composition can greatly influence biophysical properties of cell membranes, affecting various cellular functions. We previously showed that lipid synthesis becomes altered in the membranes of resistant breast cancer cells (MCF-7/ADR); they form a more rigid, hydrophobic lipid monolayer than do sensitive cell membranes (MCF-7). These changes in membrane lipids of resistant cells, attributed to epigenetic aberration, significantly affected drug transport and endocytic function, thus impacting the efficacy of anticancer drugs. The present study's objective was to determine the effects of the epigenetic drug, 5-aza-2'-deoxycytidine (DAC), delivered in sustained-release nanogels (DAC-NGs), on the composition and biophysical properties of membrane lipids of resistant cells. Resistant and sensitive cells were treated with DAC in solution (DAC-sol) or DAC-NGs, and cell-membrane lipids were isolated and analyzed for lipid composition and biophysical properties. In resistant cells, we found increased formation of cholesterol-sphingomyelin (CHOL-SM) rafts with culturing time, whereas DAC treatment reduced their formation. In general, the effect of DAC-NGs was greater in changing the lipid composition than with DAC-sol. DAC treatment also caused a rise in levels of certain phospholipids and neutral lipids known to increase membrane fluidity, while reducing the levels of certain lipids known to increase membrane rigidity. Isotherm data showed increased lipid membrane fluidity following DAC treatment, attributed to decrease levels of CHOL-SM rafts (lamellar beta [Lβ] structures or ordered gel) and a corresponding increase in lipids that form lamellar alpha-structures (Lα, liquid crystalline phase). Sensitive cells showed marginal or insignificant changes in lipid profile following DAC-treatment, suggesting that epigenetic changes affecting lipid biosynthesis are more specific to resistant cells. Since membrane fluidity plays a major role in drug transport and endocytic function, treatment of resistant cells with epigenetic drugs with altered lipid profile could facilitate anticancer drug transport to overcome acquired drug resistance in a combination therapy.
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http://dx.doi.org/10.1021/acs.langmuir.5b02601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725703PMC
October 2015

Controllable synthesis of tetrapod gold nanocrystals with precisely tunable near-infrared plasmon resonance towards highly efficient surface enhanced Raman spectroscopy bioimaging.

J Mater Chem B 2015 Oct 24;3(37):7377-7385. Epub 2015 Aug 24.

School of Chemical Engineering, Northwest University, 229 Taibai Rd, Xi'an, Shannxi 710069, P. R. China.

Tetrapod gold nanocrystals, to be the core of surface-enhanced Raman spectroscopy (SERS) nanoprobes, with tunable localized surface plasmon resonance (LSPR) from 650 nm to 785 nm in the Vis-NIR region have been successfully prepared by a facile seeded growth approach. The local electromagnetic field distribution and the huge extinction cross section of the tetrapod gold nanocrystals were simulated by a finite-difference time-domain method. Both the calculated and experimental results reveal that the LSPR property of the tetrapod gold nanocrystals is closely dependent on the morphology features of their tips, where a strong field enhancement appears. These tetrapod nanocrystals have exhibited a good capability not only for Raman signal enhancement but also when successfully utilized as NIR SERS bioimaging nanoprobes. In vitro SERS imaging of stained breast cancer cells has also been demonstrated. The tetrapod gold nanocrystals developed here with a precisely tunable LSPR offer advantages of enhanced signal quality, good stability and better biocompatibility in SERS imaging, which has great potential for various biomedical applications.
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http://dx.doi.org/10.1039/c5tb00785bDOI Listing
October 2015

Exploitation of 3D stereotactic surface projection for predictive modelling of Alzheimer's disease.

Int J Data Min Bioinform 2013 ;7(2):146-65

Center for Advanced Computer Studies, University of Louisiana at Lafayette, 301 E. Lewis St., 201-G Oliver Hall (ACTR), Lafayette, LA 70503, USA.

Alzheimer's Disease (AD) is one major cause of dementia. Previous studies have indicated that the use of features derived from Positron Emission Tomography (PET) scans lead to more accurate and earlier diagnosis of AD, compared to the traditional approaches that use a combination of clinical assessments. In this study, we compare Naive Bayes (NB) with variations of Support Vector Machines (SVMs) for the automatic diagnosis of AD. 3D Stereotactic Surface Projection (3D-SSP) is utilised to extract features from PET scans. At the most detailed level, the dimensionality of the feature space is very high. Hence we evaluate the benefits of a correlation-based feature selection method to find a small number of highly relevant features; we also provide an analysis of selected features, which is generally supportive of the literature. However, we have also encountered patterns that may be new and relevant to prediction of the progression of AD.
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http://dx.doi.org/10.1504/ijdmb.2013.053194DOI Listing
March 2014

Atropisomeric dihydroanthracenones as inhibitors of multiresistant Staphylococcus aureus.

J Med Chem 2013 Apr 16;56(8):3257-72. Epub 2013 Apr 16.

Institut für Pharmazeutische Biologie und Biotechnologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, Geb. 26.23, 40225 Düsseldorf, Germany.

Two bisdihydroanthracenone atropodiastereomeric pairs, including homodimeric flavomannin A (1) and the previously unreported flavomannin B (2), two new unsymmetrical dimers (3 and 4), and two new mixed dihydroanthracenone/anthraquinone dimers (5 and 6) were isolated from Talaromyces wortmannii , an endophyte of Aloe vera . The structures of 2-6 were elucidated by extensive NMR and mass spectrometric analyses. The axial chirality of the biaryls was determined using TDDFT ECD and VCD calculations, the combination of which however did not allow the assignment of the central chirality elements of 1. The compounds exhibited antibacterial activity against Staphylococcus aureus , including (multi)drug-resistant clinical isolates. Reporter gene analyses indicated induction of the SOS response for some of the derivatives, suggesting interference with DNA structure or metabolism. Fluorescence microscopy demonstrated defective segregation of the bacterial chromosome and DNA degradation. Notably, the compounds showed no cytotoxic activity, encouraging their further evaluation as potential starting points for antibacterial drug development.
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http://dx.doi.org/10.1021/jm301816aDOI Listing
April 2013

Neuroblast lineage-specific origin of the neurons of the Drosophila larval olfactory system.

Dev Biol 2013 Jan 10;373(2):322-37. Epub 2012 Nov 10.

National Centre for Biological Sciences, TIFR, UAS-GKVK Campus, Bangalore 560065, India.

The complete neuronal repertoire of the central brain of Drosophila originates from only approximately 100 pairs of neural stem cells, or neuroblasts. Each neuroblast produces a highly stereotyped lineage of neurons which innervate specific compartments of the brain. Neuroblasts undergo two rounds of mitotic activity: embryonic divisions produce lineages of primary neurons that build the larval nervous system; after a brief quiescence, the neuroblasts go through a second round of divisions in larval stage to produce secondary neurons which are integrated into the adult nervous system. Here we investigate the lineages that are associated with the larval antennal lobe, one of the most widely studied neuronal systems in fly. We find that the same five neuroblasts responsible for the adult antennal lobe also produce the antennal lobe of the larval brain. However, there are notable differences in the composition of larval (primary) lineages and their adult (secondary) counterparts. Significantly, in the adult, two lineages (lNB/BAlc and adNB/BAmv3) produce uniglomerular projection neurons connecting the antennal lobe with the mushroom body and lateral horn; another lineage, vNB/BAla1, generates multiglomerular neurons reaching the lateral horn directly. lNB/BAlc, as well as a fourth lineage, vlNB/BAla2, generate a diversity of local interneurons. We describe a fifth, previously unknown lineage, BAlp4, which connects the posterior part of the antennal lobe and the neighboring tritocerebrum (gustatory center) with a higher brain center located adjacent to the mushroom body. In the larva, only one of these lineages, adNB/BAmv3, generates all uniglomerular projection neurons. Also as in the adult, lNB/BAlc and vlNB/BAla2 produce local interneurons which, in terms of diversity in architecture and transmitter expression, resemble their adult counterparts. In addition, lineages lNB/BAlc and vNB/BAla1, as well as the newly described BAlp4, form numerous types of projection neurons which along the same major axon pathways (antennal tracts) used by the antennal projection neurons, but which form connections that include regions outside the "classical" olfactory circuit triad antennal lobe-mushroom body-lateral horn. Our work will benefit functional studies of the larval olfactory circuit, and shed light on the relationship between larval and adult neurons.
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http://dx.doi.org/10.1016/j.ydbio.2012.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045504PMC
January 2013

Chiroptical spectroscopy of natural products: avoiding the aggregation effects of chiral carboxylic acids.

J Nat Prod 2012 Aug 9;75(8):1441-50. Epub 2012 Aug 9.

Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.

Determination of the absolute configurations and predominant conformations of chiral natural products, occurring as carboxylic acids, using chiroptical spectroscopic methods becomes challenging due to the formation of solute aggregates (in the form of dimers, etc.) and/or solute-solvent complexes resulting from intermolecular hydrogen bonding with solvent. A hypothesis that such aggregation effects can be avoided by using corresponding sodium salts or acid anhydrides for chiroptical spectroscopic measurements has been tested. For this purpose, vibrational circular dichroism, electronic circular dichroism, and optical rotatory dispersion spectra for disodium salts of two natural products, hibiscus acid and garcinia acid, and the anhydride of acetylated garcinia acid have been measured. These experimental spectra are analyzed in combination with quantum chemical calculations of corresponding spectra. The spectral analysis for sodium salts and anhydride turned out to be simpler, suggesting that the conversion of carboxylic acids to corresponding salts or anhydride can be advantageous for the application of chiroptical spectroscopy.
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http://dx.doi.org/10.1021/np300341zDOI Listing
August 2012

Hypotheses generation as supervised link discovery with automated class labeling on large-scale biomedical concept networks.

BMC Genomics 2012 Jun 11;13 Suppl 3:S5. Epub 2012 Jun 11.

Center for Advanced Computer Studies, University of Louisiana at Lafayette, Lafayette, LA 70504, USA.

Computational approaches to generate hypotheses from biomedical literature have been studied intensively in recent years. Nevertheless, it still remains a challenge to automatically discover novel, cross-silo biomedical hypotheses from large-scale literature repositories. In order to address this challenge, we first model a biomedical literature repository as a comprehensive network of biomedical concepts and formulate hypotheses generation as a process of link discovery on the concept network. We extract the relevant information from the biomedical literature corpus and generate a concept network and concept-author map on a cluster using Map-Reduce frame-work. We extract a set of heterogeneous features such as random walk based features, neighborhood features and common author features. The potential number of links to consider for the possibility of link discovery is large in our concept network and to address the scalability problem, the features from a concept network are extracted using a cluster with Map-Reduce framework. We further model link discovery as a classification problem carried out on a training data set automatically extracted from two network snapshots taken in two consecutive time duration. A set of heterogeneous features, which cover both topological and semantic features derived from the concept network, have been studied with respect to their impacts on the accuracy of the proposed supervised link discovery process. A case study of hypotheses generation based on the proposed method has been presented in the paper.
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http://dx.doi.org/10.1186/1471-2164-13-S3-S5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394427PMC
June 2012

Peripheral fibroma with calcification (report of two cases).

J Indian Dent Assoc 1982 Mar;54(3):103-5

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March 1982

Evidence for myosin heterogeneity inDrosophila melanogaster.

Authors:
K Vijay Raghavan

Wilehm Roux Arch Dev Biol 1981 Sep;190(5):297-300

Tata Institute of Fundamental Research, Homi Bhabha Road, 400005, Bombay, India.

Electrophoresis of myosin extracts from larvae and adult tissues ofDrosophila melanogaster under non-dissociating conditions indicate that two of the bands seen are myosins. They stain for Ca ATPase activity and when cut and re-run under dissociating conditions are found to contain a myosin heavy chain that co-migrates with rabbit skeletal muscle myosin heavy chain. One of the forms of myosin seen is found primarily in extracts from the leg. The other is common to the adult fibrillar flight muscles and the larval body wall muscles.The electrophoretic evidence for two myosin types is strengthened by the histochemical demonstration of two myofibrillar ATPases on the basis of their lability to acid or alkali preincubation. The myofibrillar ATPase in the leg and the Tergal Depressor of the Trochanter (TDT) are shown to be relatively acid labile and alkali stable. The larval body wall muscles and the adult fibrillar flight muscles have an ATPase which is acid stable and alkali labile. This distribution of the two myofibrillar ATPase coincides with that predicted by electrophoresis of extracts from whole tissue and also locates the two myosins to specific muscle types.
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http://dx.doi.org/10.1007/BF00848758DOI Listing
September 1981
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