Publications by authors named "Ramya Krishnan"

24 Publications

  • Page 1 of 1

Targeted gene silencing in the nervous system with CRISPR-Cas13.

Sci Adv 2022 01 19;8(3):eabk2485. Epub 2022 Jan 19.

Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA.

Cas13 nucleases are a class of programmable RNA-targeting CRISPR effector proteins that are capable of silencing target gene expression in mammalian cells. Here, we demonstrate that RfxCas13d, a Cas13 ortholog with favorable characteristics to other family members, can be delivered to the mouse spinal cord and brain to silence neurodegeneration-associated genes. Intrathecally delivering an adeno-associated virus vector encoding an RfxCas13d variant programmed to target superoxide dismutase 1 (SOD1), a protein whose mutation can cause amyotrophic lateral sclerosis, reduced SOD1 mRNA and protein in the spinal cord by >50% and improved outcomes in a mouse model of the disorder. We further show that intrastriatally delivering an RfxCas13d variant programmed to target huntingtin (HTT), a protein whose mutation is causative for Huntington’s disease, led to a ~50% reduction in HTT protein in the mouse brain. Our results establish RfxCas13d as a versatile platform for knocking down gene expression in the nervous system.
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http://dx.doi.org/10.1126/sciadv.abk2485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769545PMC
January 2022

Does Choice of Steroid Matter for Treatment of Chronic Low Back Pain with Sacroiliac Joint Injections: a Retrospective Study.

Curr Pain Headache Rep 2021 Mar 24;25(5):34. Epub 2021 Mar 24.

Department of Anesthesia, Yale University School of Medicine, New Haven, CT, USA.

Purpose Of Review: Prevalence of chronic low back pain (cLBP) is increasing. Sacroiliac joint (SIJ) is a common source of cLBP, but data behind its diagnosis and treatment is controversial. There is moderate quality evidence for effectiveness of therapeutic SIJ injections. However, there are no studies comparing the two most common steroid preparations, methylprednisolone (MTP) and triamcinolone (TAC) in SIJ injections.

Recent Findings: After institutional IRB approval, a retrospective chart review was conducted to evaluate the effectiveness of SIJ injections in terms of pain relief at 1-month follow-up and compare MTP versus TAC. All injections were performed by a single pain physician with fluoroscopic guidance.

Results: Sixty-five percent of patients in the MTP group and 57% patients in the TAC group had >50% pain relief at 1-month follow-up, with no statistical difference between the two groups. Patients in the TAC group had significantly greater BMI and consisted of higher proportion of smokers (72% patients in TAC group versus 39% patients in the MTP group, p-value 0.004). Other sources of pain such as facet joints were unmasked post-procedurally after SIJ injections, with this unmasking being significant for the TAC group. Opiate use decreased in the MTP group from 35% pre-procedurally to 20% post-procedurally, and this difference did not reach statistical significance. Both MTP and TAC are effective in providing pain relief for SIJ pain at 1-month follow-up, with no statistical difference between the two types of steroids. Although not statistically significant, there is a modest reduction in opiate use in the MTP group.
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http://dx.doi.org/10.1007/s11916-021-00942-7DOI Listing
March 2021

Assessing the Completeness of Reporting in Preclinical Oncolytic Virus Therapy Studies.

Mol Ther Oncolytics 2019 Sep 21;14:179-187. Epub 2019 May 21.

Clinical Epidemiology Program, BLUEPRINT Translational Research Group, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.

Irreproducibility of preclinical findings could be a significant barrier to the "bench-to-bedside" development of oncolytic viruses (OVs). A contributing factor is the incomplete and non-transparent reporting of study methodology and design. Using the NIH Principles and Guidelines for Reporting Preclinical Research, a core set of seven recommendations, we evaluated the completeness of reporting of preclinical OV studies. We also developed an evidence map identifying the current trends in OV research. A systematic search of MEDLINE and Embase identified all relevant articles published over an 18 month period. We screened 1,554 articles, and 236 met our -defined inclusion criteria. Adenovirus (43%) was the most commonly used viral platform. Frequently investigated cancers included colorectal (14%), skin (12%), and breast (11%). Xenograft implantation (61%) in mice (96%) was the most common animal model. The use of preclinical reporting guidelines was listed in 0.4% of articles. Biological and technical replicates were completely reported in 1% of studies, statistics in 49%, randomization in 1%, blinding in 2%, sample size estimation in 0%, and inclusion/exclusion criteria in 0%. Overall, completeness of reporting in the preclinical OV therapy literature is poor. This may hinder efforts to interpret, replicate, and ultimately translate promising preclinical OV findings.
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http://dx.doi.org/10.1016/j.omto.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586991PMC
September 2019

Spontaneous middle lobe torsion in a patient with multicentric Castleman disease: A case report.

J Med Imaging Radiat Oncol 2019 Apr 23;63(2):225-227. Epub 2018 Nov 23.

Department of Medical Imaging, The Townsville Hospital, Townsville, Queensland, Australia.

We describe a rare case of middle lobe lung torsion in a patient with a tension hydrothorax secondary to multicentric Castleman disease. The case demonstrates the difficulty of diagnosing torsion prospectively, and the possible sequelae of delayed detection. Although imaging features can be confusing, an awareness of this condition and careful image interpretation by radiologists could facilitate early recognition and management of a torted lobe.
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http://dx.doi.org/10.1111/1754-9485.12837DOI Listing
April 2019

A Heuristic Evaluation to Assess Use of After Visit Summaries for Supporting Continuity of Care.

Appl Clin Inform 2018 07 12;9(3):714-724. Epub 2018 Sep 12.

Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.

Background: Outpatient providers often do not receive discharge summaries from acute care providers prior to follow-up visits. These outpatient providers may use the after-visit summaries (AVS) that are given to patients to obtain clinical information. It is unclear how effectively AVS support care coordination between clinicians.

Objectives: Goals for this effort include: (1) developing usability heuristics that may be applied both for assessment and to guide generation of medical documents in general, (2) conducting a heuristic evaluation to assess the use of AVS for communication between clinicians, and (3) providing recommendations for generating AVS that effectively support both patient/caregiver use and care coordination.

Methods: We created a 17-item heuristic evaluation instrument for assessing usability of medical documents. Eight experts used the instrument to assess each of four simulated AVS. The simulations were created using examples from two hospitals and two pediatric patient cases developed by the National Institute of Standards and Technology.

Results: Experts identified 224 unique usability problems ranging in severity from mild to catastrophic. Content issues (e.g., missing medical history, marital status of a 2-year-old) were rated as most severe, but widespread formatting and structural problems (e.g., inconsistent indentation, fonts, and headings; confusing ordering of information) were so distracting that they significantly reduced readers' ability to efficiently use the documents. Overall, issues in the AVS from Hospital 2 were more severe than those in the AVS from Hospital 1.

Conclusion: The new instrument allowed for quick, inexpensive evaluations of AVS. Usability issues such as unnecessary information, poor organization, missing information, and inconsistent formatting make it hard for patients, caregivers, and clinicians to use the AVS. The heuristics in the new instrument may be used as guidance to adapt electronic health record systems so that they generate more useful and usable medical documents.
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http://dx.doi.org/10.1055/s-0038-1668093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135642PMC
July 2018

Isolation and characterization of a novel 1-aminocyclopropane-1-carboxylate (ACC) deaminase producing plant growth promoting marine Gammaproteobacteria from crops grown in brackish environments. Proposal for Pokkaliibacter plantistimulans gen. nov., sp. nov., Balneatrichaceae fam. nov. in the order Oceanospirillales and an emended description of the genus Balneatrix.

Syst Appl Microbiol 2018 Nov 11;41(6):570-580. Epub 2018 Aug 11.

CSIR-National Institute of Interdisciplinary Science and Technology, Thiruvananthapuram, Kerala, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. Electronic address:

Three novel strains namely, L1E11, L1E4 and 228 were isolated as part of an ongoing study on 1-aminocyclopropane-1-carboxylate (ACC) deaminase expressing rhizobacteria from crops cultivated in saline affected coastal agro-ecosystems of Kerala, India. The novel strains were positive for many properties that are beneficial to plant growth including ACC deaminase (ACCd) activity that ranged from 1.87±0.27 to 2.88±0.71μmol of α-ketobutyrate/hr/mg of total protein. Presence of other traits such as biofilm formation, siderophore production, phosphate solubilisation, utilisation of root derived compounds and ability to colonise host roots indicates its plant-associated life style. In complement, the genomic data reveals gene features for higher adaptation to plant-associated environments. In-planta assays showed that L1E11 can promote and protect pokkali rice plants from 200mM NaCl stress. Phylogenetic, chemotaxonomic, phenotypic and genomic characterisation indicates that the novel strains belong to a novel genus and species of the order Oceanospirillales for which the names Pokkaliibacter gen. nov., and Pokkaliibacter plantistimulans sp. nov., are proposed with L1E11 (=DSM 28732=MCC 2992) as the type strain. Further, on the basis of low 16S rRNA sequence similarity, phylogenetic divergence, source of isolation and few differences in the phenotypic properties against its nearest taxon, a new family Balneatrichaceae fam. nov., is proposed to accommodate the two genera Balneatrix and Pokkaliibacter gen.nov. with Balneatrix as the type genus. An emended description of the genus Balneatrix is also presented.
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http://dx.doi.org/10.1016/j.syapm.2018.08.003DOI Listing
November 2018

Dimethyl fumarate potentiates oncolytic virotherapy through NF-κB inhibition.

Sci Transl Med 2018 01;10(425)

Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.

Resistance to oncolytic virotherapy is frequently associated with failure of tumor cells to get infected by the virus. Dimethyl fumarate (DMF), a common treatment for psoriasis and multiple sclerosis, also has anticancer properties. We show that DMF and various fumaric and maleic acid esters (FMAEs) enhance viral infection of cancer cell lines as well as human tumor biopsies with several oncolytic viruses (OVs), improving therapeutic outcomes in resistant syngeneic and xenograft tumor models. This results in durable responses, even in models otherwise refractory to OV and drug monotherapies. The ability of DMF to enhance viral spread results from its ability to inhibit type I interferon (IFN) production and response, which is associated with its blockade of nuclear translocation of the transcription factor nuclear factor κB (NF-κB). This study demonstrates that unconventional application of U.S. Food and Drug Administration-approved drugs and biological agents can result in improved anticancer therapeutic outcomes.
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http://dx.doi.org/10.1126/scitranslmed.aao1613DOI Listing
January 2018

Multi-modal Potentiation of Oncolytic Virotherapy by Vanadium Compounds.

Mol Ther 2018 01 24;26(1):56-69. Epub 2017 Oct 24.

Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Canada. Electronic address:

Oncolytic viruses (OV) are an emerging class of anticancer bio-therapeutics that induce antitumor immunity through selective replication in tumor cells. However, the efficacy of OVs as single agents remains limited. We introduce a strategy that boosts the therapeutic efficacy of OVs by combining their activity with immuno-modulating, small molecule protein tyrosine phosphatase inhibitors. We report that vanadium-based phosphatase inhibitors enhance OV infection in vitro and ex vivo, in resistant tumor cell lines. Furthermore, vanadium compounds increase antitumor efficacy in combination with OV in several syngeneic tumor models, leading to systemic and durable responses, even in models otherwise refractory to OV and drug alone. Mechanistically, this involves subverting the antiviral type I IFN response toward a death-inducing and pro-inflammatory type II IFN response, leading to improved OV spread, increased bystander killing of cancer cells, and enhanced antitumor immune stimulation. Overall, we showcase a new ability of vanadium compounds to simultaneously maximize viral oncolysis and systemic anticancer immunity, offering new avenues for the development of improved immunotherapy strategies.
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http://dx.doi.org/10.1016/j.ymthe.2017.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763159PMC
January 2018

Novosphingobium pokkalii sp nov, a novel rhizosphere-associated bacterium with plant beneficial properties isolated from saline-tolerant pokkali rice.

Res Microbiol 2017 Feb - Mar;168(2):113-121. Epub 2016 Sep 14.

Biotechnology Department, National Institute for Interdisciplinary Science and Technology (CSIR), Thiruvananthapuram, 695 019, Kerala, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110 001, India. Electronic address:

Pokkali rice varieties are known for their saline tolerance when specifically grown in coastal saline affected agri-fields of southern Kerala. These fields are prone to seawater intrusion. During characterization of phytobeneficial rhizobacteria from this pokkali rice, L3E4 was isolated. This strain showed some plant growth-promoting functions (production of indole acetic acid (IAA), acetoin, and siderophore), biofilm formation and capacity to use a wide range of plant-derived organic compounds. In planta assay under axenic conditions showed a positive effect of L3E4 on pokkali rice growth; importantly, it was able to attach and colonize pokkali rice roots in the presence of natural seawater, a key adaptation required for survival in pokkali rice fields. Phylogenetic analysis using 16S rRNA, recA, and gyrB gene sequences showed that strain L3E4 belongs to the genus Novosphingobium, with Novosphingobium capsulatum GIFU 11526 and Novosphingobium rhizosphaerae JM.1 being the nearest phylogenetic relatives. In addition, DNA-DNA hybridization analysis and phenotypic traits established that this strain belongs to a novel Novosphingobium species, for which we propose the name Novosphingobium pokkalii sp. nov. The type strain is represented by strain L3E4 (=MTCC 12357 = KCTC 42224).
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http://dx.doi.org/10.1016/j.resmic.2016.09.001DOI Listing
March 2017

First-in-class small molecule potentiators of cancer virotherapy.

Sci Rep 2016 05 26;6:26786. Epub 2016 May 26.

Departments of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.

The use of engineered viral strains such as gene therapy vectors and oncolytic viruses (OV) to selectively destroy cancer cells is poised to make a major impact in the clinic and revolutionize cancer therapy. In particular, several studies have shown that OV therapy is safe and well tolerated in humans and can infect a broad range of cancers. Yet in clinical studies OV therapy has highly variable response rates. The heterogeneous nature of tumors is widely accepted to be a major obstacle for OV therapeutics and highlights a need for strategies to improve viral replication efficacy. Here, we describe the development of a new class of small molecules for selectively enhancing OV replication in cancer tissue. Medicinal chemistry studies led to the identification of compounds that enhance multiple OVs and gene therapy vectors. Lead compounds increase OV growth up to 2000-fold in vitro and demonstrate remarkable selectivity for cancer cells over normal tissue ex vivo and in vivo. These small molecules also demonstrate enhanced stability with reduced electrophilicity and are highly tolerated in animals. This pharmacoviral approach expands the scope of OVs to include resistant tumors, further potentiating this transformative therapy. It is easily foreseeable that this approach can be applied to therapeutically enhance other attenuated viral vectors.
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http://dx.doi.org/10.1038/srep26786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880900PMC
May 2016

Arthrobacter pokkalii sp nov, a Novel Plant Associated Actinobacterium with Plant Beneficial Properties, Isolated from Saline Tolerant Pokkali Rice, Kerala, India.

PLoS One 2016 10;11(3):e0150322. Epub 2016 Mar 10.

Biotechnology Department, National Institute for Interdisciplinary Science and Technology (CSIR), Thiruvananthapuram, 695 019, Kerala, India.

A novel yellow colony-forming bacterium, strain P3B162T was isolated from the pokkali rice rhizosphere from Kerala, India, as part of a project study aimed at isolating plant growth beneficial rhizobacteria from saline tolerant pokkali rice and functionally evaluate their abilities to promote plant growth under saline conditions. The novel strain P3B162T possesses plant growth beneficial traits such as positive growth on 1-aminocyclopropane-1-carboxylic acid (ACC), production of indole acetic acid (IAA) and siderophore. In addition, it also showed important phenotypic characters such as ability to form biofilm and utilization of various components of plant root exudates (sugars, amino acids and organic acids), clearly indicating its lifestyle as a plant rhizosphere associated bacterium. Taxonomically, the novel strain P3B162T was affiliated to the genus Arthrobacter based on the collective results of phenotypic, genotypic and chemotaxonomic analyses. Moreover, molecular analysis using 16S rRNA gene showed Arthrobacter globiformis NBRC 12137T, Arthrobacter pascens DSM 20545T and Arthrobacter liuii DSXY973T as the closely related phylogenetic neighbours, showing more than 98% 16S rRNA similarity values, whereas the recA gene analysis displayed Arthrobacter liuii JCM 19864T as the nearest neighbour with 94.7% sequence similarity and only 91.7% to Arthrobacter globiformis LMG 3813T and 88.7% to Arthrobacter pascens LMG 16255T. However, the DNA-DNA hybridization values between strain P3B162T, Arthrobacter globiformis LMG 3813T, Arthrobacter pascens LMG 16255T and Arthrobacter liuii JCM 19864T was below 50%. In addition, the novel strain P3B162T can be distinguished from its closely related type strains by several phenotypic characters such as colony pigment, tolerance to NaCl, motility, reduction of nitrate, hydrolysis of DNA, acid from sucrose, cell wall sugars and cell wall peptidoglycan structure. In conclusion, the combined results of this study support the classification of strain P3B162T as a novel Arthrobacter species and we propose Arthrobacter pokkalii sp.nov.as its name. The type strain is P3B162T (= KCTC 29498T = MTCC 12358T).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150322PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786123PMC
August 2016

Single Molecule Cluster Analysis dissects splicing pathway conformational dynamics.

Nat Methods 2015 Nov 28;12(11):1077-84. Epub 2015 Sep 28.

Department of Chemistry, Single Molecule Analysis Group, University of Michigan, Ann Arbor, Michigan, USA.

We report Single Molecule Cluster Analysis (SiMCAn), which utilizes hierarchical clustering of hidden Markov modeling-fitted single-molecule fluorescence resonance energy transfer (smFRET) trajectories to dissect the complex conformational dynamics of biomolecular machines. We used this method to study the conformational dynamics of a precursor mRNA during the splicing cycle as carried out by the spliceosome. By clustering common dynamic behaviors derived from selectively blocked splicing reactions, SiMCAn was able to identify the signature conformations and dynamic behaviors of multiple ATP-dependent intermediates. In addition, it identified an open conformation adopted late in splicing by a 3' splice-site mutant, invoking a mechanism for substrate proofreading. SiMCAn enables rapid interpretation of complex single-molecule behaviors and should prove useful for the comprehensive analysis of a plethora of dynamic cellular machines.
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http://dx.doi.org/10.1038/nmeth.3602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890712PMC
November 2015

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing.

Nat Commun 2015 Mar 30;6:6410. Epub 2015 Mar 30.

Center for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.

In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.
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http://dx.doi.org/10.1038/ncomms7410DOI Listing
March 2015

High-throughput titration of luciferase-expressing recombinant viruses.

J Vis Exp 2014 Sep 19(91):51890. Epub 2014 Sep 19.

Center for Innovative Cancer Research, Ottawa Hospital Research Institute; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa;

Standard plaque assays to determine infectious viral titers can be time consuming, are not amenable to a high volume of samples, and cannot be done with viruses that do not form plaques. As an alternative to plaque assays, we have developed a high-throughput titration method that allows for the simultaneous titration of a high volume of samples in a single day. This approach involves infection of the samples with a Firefly luciferase tagged virus, transfer of the infected samples onto an appropriate permissive cell line, subsequent addition of luciferin, reading of plates in order to obtain luminescence readings, and finally the conversion from luminescence to viral titers. The assessment of cytotoxicity using a metabolic viability dye can be easily incorporated in the workflow in parallel and provide valuable information in the context of a drug screen. This technique provides a reliable, high-throughput method to determine viral titers as an alternative to a standard plaque assay.
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http://dx.doi.org/10.3791/51890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828131PMC
September 2014

Pharmacological modulation of anti-tumor immunity induced by oncolytic viruses.

Front Oncol 2014 23;4:191. Epub 2014 Jul 23.

Center for Innovative Cancer Research, Ottawa Hospital Research Institute , Ottawa, ON , Canada ; Faculty of Medicine, University of Ottawa , Ottawa, ON , Canada.

Oncolytic viruses (OVs) not only kill cancer cells by direct lysis but also generate a significant anti-tumor immune response that allows for prolonged cancer control and in some cases cures. How to best stimulate this effect is a subject of intense investigation in the OV field. While pharmacological manipulation of the cellular innate anti-viral immune response has been shown by several groups to improve viral oncolysis and spread, it is increasingly clear that pharmacological agents can also impact the anti-tumor immune response generated by OVs and related tumor vaccination strategies. This review covers recent progress in using pharmacological agents to improve the activity of OVs and their ability to generate robust anti-tumor immune responses.
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http://dx.doi.org/10.3389/fonc.2014.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108035PMC
August 2014

Thoracic melioidosis: a diagnostic dilemma.

Asian Cardiovasc Thorac Ann 2015 Feb 31;23(2):219-20. Epub 2014 Jan 31.

Department of Cardiothoracic Surgery, Townsville Hospital, Queensland, Australia.

The diagnosis of melioidosis can be difficult, and it is frequently described as "the great mimicker". We report a case of thoracic melioidosis presenting as a mediastinal mass with impending superior vena cava obstruction. With the presumptive diagnosis of mediastinal tumor, the patient underwent surgery for tissue sampling, and a purulent collection was found. The clinical syndromes of melioidosis and the diagnostic dilemma are discussed.
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http://dx.doi.org/10.1177/0218492314521823DOI Listing
February 2015

Ruptured thymoma managed via thoracotomy.

Asian Cardiovasc Thorac Ann 2013 Dec 16;21(6):744-5. Epub 2013 Jul 16.

Department of Cardiothoracic Surgery, Royal Perth Hospital, Perth, Australia.

Thymomas rarely present with chest pain due to hemorrhage. This could cause shortness of breath if it ruptures into the pleural space, and is best managed surgically. We describe the case of an 83-year-old woman who presented with such symptoms. Computed tomography showed a ruptured mediastinal mass with pleural effusion. She was managed successfully by thoracotomy with excision of the mass and drainage of the effusion. Histopathology revealed a ruptured thymoma with infarction and necrosis.
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http://dx.doi.org/10.1177/0218492312470668DOI Listing
December 2013

Biased Brownian ratcheting leads to pre-mRNA remodeling and capture prior to first-step splicing.

Nat Struct Mol Biol 2013 Dec 17;20(12):1450-7. Epub 2013 Nov 17.

Department of Chemistry, Single Molecule Analysis Group, University of Michigan, Ann Arbor, Michigan, USA.

The spliceosome is a dynamic ribonucleoprotein (RNP) machine that catalyzes the removal of introns during the two transesterification steps of eukaryotic pre-mRNA splicing. Here we used single-molecule fluorescence resonance energy transfer to monitor the distance of the 5' splice site (5' SS) and branch point (BP) of pre-mRNA in affinity-purified spliceosomes stalled by a mutation in the DExD/H-box helicase Prp2 immediately before the first splicing step. Addition of recombinant Prp2 together with NTP and protein cofactor Spp2 rearranges the spliceosome-substrate complex to reversibly explore conformations with proximal 5' SS and BP that accommodate chemistry. Addition of Cwc25, a small heat-stable splicing factor, then strongly biases this equilibrium toward the proximal conformation, promoting efficient first-step splicing. The spliceosome thus functions as a biased Brownian ratchet machine where a helicase unlocks thermal fluctuations subsequently rectified by a cofactor 'pawl', a principle possibly widespread among the many helicase-driven RNPs.
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http://dx.doi.org/10.1038/nsmb.2704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867266PMC
December 2013

Zunongwangia mangrovi sp. nov., isolated from mangrove (Avicennia marina) rhizosphere, and emended description of the genus Zunongwangia.

Int J Syst Evol Microbiol 2014 Feb 14;64(Pt 2):545-550. Epub 2013 Oct 14.

Laboratory of Microbiology, Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato-cho,Hakodate 041-8611, Japan.

A Gram-stain-negative, strictly aerobic, slightly halophilic, non-motile and rod-shaped bacterial strain, designated P2E16(T), was isolated from mangrove (Avicennia marina) rhizosphere, collected at Devipattinam mangroves, Tamil Nadu, India. Strain P2E16(T) grew optimally at pH 7.0-8.0, at 25-28 °C and in the presence of 2-3% (w/v) NaCl. 16S rRNA gene analysis showed that strain P2E16(T) was phylogenetically closely related to the genus Zunongwangia, with Zunongwangia profunda SM-A87(T) as the closest related type strain (98.2% 16S rRNA gene sequence similarity) and less than 93% 16S rRNA gene sequence similarity to all other members of the family Flavobacteriaceae. Strain P2E16(T) contained MK-6 as the major respiratory quinone, phosphatidylethanolamine as the predominant polar lipid and iso-C(15 : 0) (17.8%), iso-C(17 : 0) 3-OH (15.1%), C(15 : 0) (12.8%), iso-C(17 : 1)ω9c (9.8%), iso-C(15 : 1) G (9.0%), and summed feature 3 (comprising C(16 : 1)ω7c and/or iso-C(15 : 0) 2-OH; 7.1%) as the major fatty acids. The DNA G+C content was 34.3 mol%. Differential phenotypic properties, together with the phylogenetic distinctiveness and low DNA-DNA relatedness demonstrated that strain P2E16(T) was distinct from the type strain of Zunongwangia profunda. On the basis of these presented data, strain P2E16(T) is considered to represent a novel species of the genus Zunongwangia, for which the name Zunongwangia mangrovi sp. nov. is proposed. The type strain is P2E16(T) ( = DSM 24499(T) = LMG 26237(T) = KCTC 23496(T)). An emended description of the genus Zunongwangia is also provided.
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http://dx.doi.org/10.1099/ijs.0.053512-0DOI Listing
February 2014

Localised ascending aortic dissection managed conservatively.

Heart Lung Circ 2012 May 11;21(5):303-4. Epub 2012 Apr 11.

Department of Cardiothoracic Surgery, Royal Perth Hospital, Australia.

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http://dx.doi.org/10.1016/j.hlc.2012.03.001DOI Listing
May 2012

Contributions of the thalamocortical system towards sound-specific auditory plasticity.

Neurosci Biobehav Rev 2011 Nov 22;35(10):2155-61. Epub 2011 Feb 22.

Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada.

The function of the auditory cortex is dynamic. Although auditory cortical plasticity can be induced through various approaches such as learning, experience and sensory deprivation, a common property is the frequency-specificity; the change in neuronal receptive field or functional maps is highly specific to the frequency content of the acquired sound. This unique property suggests that precise frequency information must be relayed to the auditory cortex. It is well known that the auditory thalamocortical pathway is the only neural substrate that sends precise frequency information to the auditory cortex. This review addresses the impact of the auditory thalamocortical system on cortical plasticity. The frequency-specificity of auditory cortical plasticity and the tonotopic features of the auditory thalamocortical system are briefly presented. A discussion of the decisive role of thalamocortical system follows. After an exploration of a possible synaptic mechanism, a thalamocortical model is proposed to better interpret the neural mechanisms underlying frequency-specific plasticity of the auditory cortex.
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http://dx.doi.org/10.1016/j.neubiorev.2011.02.010DOI Listing
November 2011

Two-dimensional surface properties of an antimicrobial hydantoin at the air-water interface: an experimental and theoretical study.

Colloids Surf B Biointerfaces 2010 Aug 3;79(1):136-41. Epub 2010 Apr 3.

Chemical Laboratory, Physical and Inorganic Chemistry Division, Central Leather Research Institute, Council of Scientific and Industrial Research (CSIR), Adyar, Chennai 600020, India.

5,5-Acetamidomethyl-5-methylimidazolidine-2,4-dione shows antimicrobial activity against bacteria at millimolar concentrations well above its critical micellar concentration (cmc). Two-dimensional surface properties were investigated using Langmuir Film Balance to understand the membrane-active nature and nanomaterial behavior of this hydantoin derivative. Hydantoin forms an expanded nanofilm at air-water interface. The maximum limiting surface area (A(0)) and collapse pressure (pi(c)) are dependent on hydantoin concentration. Hydantoin undergoes a change in orientation at the interface, in the pressure region 2.5 and 7.5 mNm(-1), corresponding to surface areas 51-15 and 41-12A(2)molecule(-1), respectively. A large collapse pressure (pi(c)) in LB film indicates a role for hydrophobic interactions in the self-assembly of hydantoin. Surface areas computed using Connolly method, are in good agreement with the experimental results. Monolayer studies suggest a dispersed state for hydantoin when its concentration is below cmc, suggesting a mechanism for the observed bacteriostatic activity of hydantoin. In the present study, it has been found for the first time that the minimum inhibitory concentration (MIC) of the hydantoin is very close to its cmc.
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http://dx.doi.org/10.1016/j.colsurfb.2010.03.042DOI Listing
August 2010

Icosahedral DNA nanocapsules by modular assembly.

Angew Chem Int Ed Engl 2009 ;48(23):4134-7

National Centre for Biological Sciences, TIFR, GKVK, Bellary Road, Bangalore, 560 065, India.

It's a trap! DNA polyhedra formed through molecular self-assembly may function as nanocapsules for the targeted delivery of encapsulated entities. This functional aspect was demonstrated for the most complex DNA-based platonic solid: During the stepwise amalgamation of discrete polyhedra to form icosahedra, gold nanoparticles (GNPs) were encapsulated from solution (see illustration and TEM image of icosahedral cages containing GNPs).
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http://dx.doi.org/10.1002/anie.200806000DOI Listing
June 2009
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