Publications by authors named "Rahul Suresh"

34 Publications

Nanotechnology based solutions to combat zoonotic viruses with special attention to SARS, MERS, and COVID 19: Detection, protection and medication.

Microb Pathog 2021 Oct 12;159:105133. Epub 2021 Aug 12.

Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia.

Zoonotic viruses originate from birds or animal sources and responsible for disease transmission from animals to people through zoonotic spill over and presents a significant global health concern due to lack of rapid diagnostics and therapeutics. The Corona viruses (CoV) were known to be transmitted in mammals. Early this year, SARS-CoV-2, a novel strain of corona virus, was identified as the causative pathogen of an outbreak of viral pneumonia in Wuhan, China. The disease later named corona virus disease 2019 (COVID-19), subsequently spread across the globe rapidly. Nano-particles and viruses are comparable in size, which serves to be a major advantage of using nano-material in clinical strategy to combat viruses. Nanotechnology provides novel solutions against zoonotic viruses by providing cheap and efficient detection methods, novel, and new effective rapid diagnostics and therapeutics. The prospective of nanotechnology in COVID 19 is exceptionally high due to their small size, large surface-to-volume ratio, susceptibility to modification, intrinsic viricidal activity. The nano-based strategies address the COVID 19 by extending their role in i) designing nano-materials for drug/vaccine delivery, ii) developing nano-based diagnostic approaches like nano-sensors iii) novel nano-based personal protection equipment to be used in prevention strategies.This review aims to bring attention to the significant contribution of nanotechnology to mitigate against zoonotic viral pandemics by prevention, faster diagnosis and medication point of view.
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http://dx.doi.org/10.1016/j.micpath.2021.105133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358084PMC
October 2021

Stereoselective tandem iridium-catalyzed alkene isomerization-cope rearrangement of ω-diene epoxides: efficient access to acyclic 1,6-dicarbonyl compounds.

Chem Sci 2021 Jul 9;12(27):9328-9332. Epub 2021 Jun 9.

Schulich Faculty of Chemistry, Technion - Israel Institute of Technology Technion City 3200009 Haifa Israel

The Cope rearrangement of 2,3-divinyloxiranes, a rare example of epoxide C-C bond cleavage, results in 4,5-dihydrooxepines which are amenable to hydrolysis, furnishing 1,6-dicarbonyl compounds containing two contiguous stereocenters at the 3- and 4-positions. We employ an Ir-based alkene isomerization catalyst to form the reactive 2,3-divinyloxirane with complete regio- and stereocontrol, which translates into excellent control over the stereochemistry of the resulting oxepines and ultimately to an attractive strategy towards 1,6-dicarbonyl compounds.
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http://dx.doi.org/10.1039/d1sc02575aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278922PMC
July 2021

Expression of cell type incongruent alpha-cardiac actin 1 subunit in medulloblastoma reveals a novel mechanism for cancer cell survival and control of migration.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab064. Epub 2021 Apr 23.

Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.

Background: Alterations in actin subunit expression have been reported in multiple cancers, but have not been investigated previously in medulloblastoma.

Methods: Bioinformatic analysis of multiple medulloblastoma tumor databases was performed to profile mRNA levels. Western blot was used to verify protein expression in established medulloblastoma cell lines. Immunofluorescence microscopy was performed to assess ACTC1 localization. Stable cell lines with ACTC1 overexpression were generated and shRNA knockdown of ACTC1 was accomplished. We used PARP1 cleavage by Western blot as a marker of apoptosis and cell survival was determined by FACS viability assay and colony formation. Cell migration with overexpression or knockdown of ACTC1 was determined by the scratch assay. Stress fiber length distribution was assessed by fluorescence microscopy.

Results: mRNA expression is highest in SHH and WNT medulloblastoma among all subgroups. ACTC1 protein was confirmed by Western blot in SHH subgroup and Group 3 subgroup cell lines with the lowest expression in Group 3 cells. Microscopy demonstrated ACTC1 co-localization with F-actin. Overexpression of ACTC1 in Group 3 cells abolished the apoptotic response to Aurora kinase B inhibition. Knockdown of ACTC1 in SHH cells and in Myc overexpressing SHH cells induced apoptosis, impaired colony formation, and inhibited migration. Changes in stress fiber length distribution in medulloblastoma cells are induced by alterations in ACTC1 abundance.

Conclusions: Alpha-cardiac actin (ACTC1) is expressed in SHH medulloblastoma. Expression of this protein in medulloblastoma modifies stress fiber composition and functions in promoting resistance to apoptosis induced by mitotic inhibition, enhancing cell survival, and controlling migration.
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http://dx.doi.org/10.1093/noajnl/vdab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320690PMC
April 2021

Using Peer Support to Strengthen Mental Health During the COVID-19 Pandemic: A Review.

Front Psychiatry 2021 12;12:714181. Epub 2021 Jul 12.

Peer Support Centre, McGill University, Montreal, QC, Canada.

The coronavirus (COVID-19) pandemic has had a significant impact on society's overall mental health. Measures such as mandated lockdowns and physical distancing have contributed to higher levels of anxiety, depression, and other metrics indicating worsening mental health. Peer support, which is peer-to-peer provided social and emotional support, is an underutilized and effective mental health resource that can potentially be used to ameliorate mental health during these times. This review aims to summarize the toll that this pandemic has had on society's mental health as found in peer-reviewed literature from October 2019 to March 2021, as well as suggest the utility of peer support to address these needs. References for this review were chosen through searches of PubMed, Web of Science, and Google Scholar for articles published between October 2019 and March 2021 that used the terms: "coronavirus," "COVID-19," "mental health," "anxiety," "depression," "isolation," "mental health resources," "peer support," "online mental health resources," and "healthcare workers." Articles resulting from these searches and relevant references cited in those articles were reviewed. Articles published in English, French and Italian were included. This pandemic has ubiquitously worsened the mental health of populations across the world. Peer support has been demonstrated to yield generally positive effects on the mental health of a wide variety of recipients, and it can be provided through numerous accessible mediums. Peer support can overall be beneficial for improving mental health during the COVID-19 pandemic and may be an effective tool should similar events arise in the future, although the presence of a few conflicting studies suggests the need for additional research.
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http://dx.doi.org/10.3389/fpsyt.2021.714181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310946PMC
July 2021

A first principle study of heme molecule as an active adsorbent for halogenated hydrocarbons.

J Mol Model 2021 Jun 25;27(7):209. Epub 2021 Jun 25.

Department of Medical Physics, Bharathiar University, Coimbatore, India.

Heme, a biomolecule with complex structure and unique properties and strong adsorption of oxygen, is utilized as an adsorbing material for haloalkene gas molecules. It has been systematically investigated employing density functional theory. Among the haloalkene gases chosen in the present study, the interaction energy is maximum for CDFM (-10.66 kcal/mol) and lowest for TFM (-5.02 kcal/mol). The calculated bond stabilization energy for heme-haloalkene complexes correlates with findings of interaction energy. The noncovalent interaction between heme and haloalkenes is confirmed from the topological analysis. The energy gap values decrease on adsorption of haloalkenes along with a decrease in reactivity of the complexes.
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http://dx.doi.org/10.1007/s00894-021-04821-1DOI Listing
June 2021

Adsorptive removal of noxious atrazine using graphene oxide nanosheets: Insights to process optimization, equilibrium, kinetics, and density functional theory calculations.

Environ Res 2021 09 6;200:111428. Epub 2021 Jun 6.

Department of Chemical Engineering, Khalifa University, P.O. Box 127788, Abu Dhabi, United Arab Emirates.

Atrazine is a toxic herbicide whose alarming rate of contamination in the drinking water and wastewater poses a severe threat to the environment and human health. Here in this study, the graphene oxide (GO) nanosheets were prepared using Hummers' method with minor modification and studied as a potential adsorbent for atrazine removal from simulated wastewater. The spectroscopy and microscopic analysis confirmed the successful formation of GO with a multilayer structure resembling the crumpled sheets with random stacking. The Response Surface Methodology (RSM) employing Box Behnken design (BBD) was successfully developed to predict the optimal conditions for maximal atrazine removal as adsorbent dosage 121.45 mg/L; initial feed concentration 27.03 mg/L; temperature 27.69 °C, pH 5.37, and time 180 min. The atrazine adsorption onto GO was found to be higher in acidic pH and lower temperature. Density functional theory (DFT) calculation of adsorbent-adsorbate complex in the implicit solvent medium suggests adsorption affinity energy of -24.4 kcal/mol for atrazine. A careful observation of the molecules configuration and binding energy showed that the π-π interactions and hydrogen bonds played a significant role in the adsorption phenomena. Langmuir isotherm suited well to the adsorption process with a maximum adsorption capacity of 138.19 mg/g, at 318 K. The fitness of kinetic models for atrazine adsorption onto GO nanosheets were in following order Ho < Sobkowsk-Czerwi < Avrami model based on their correlation coefficient (R) values. Reusability analysis showed that GO nanosheets could be effectively recycled using 0.01 N NaOH up to six cycles of atrazine removal. Thus, this study provided a theoretical and experimental basis for the potential application of GO nanosheets as a novel adsorbent for the removal of hazardous atrazine.
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http://dx.doi.org/10.1016/j.envres.2021.111428DOI Listing
September 2021

Program evaluation of a student-led peer support service at a Canadian university.

Int J Ment Health Syst 2021 May 31;15(1):54. Epub 2021 May 31.

McGill University, Montreal, Canada.

Background: University students often experience numerous financial, social and emotional stressors that can affect their mental health. The Peer Support Centre (PSC) is a pilot project that was established to provide peer support to students in these stressful conditions. We wanted to investigate whether peer support is a viable form of support that would benefit university students. The objective of this study is to determine whether the organization was indeed providing a beneficial service to students and if it was fulfilling the needs of the students that visited the service.

Methods: After a support session, students and peer support providers completed an anonymous questionnaire regarding their self-reported mental wellbeing using the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7) metrics, and Outcome Rating Scale (ORS). They were also asked about their experience with previous professional mental health services as well as their experience at the PSC. With the data collected from 1043 students and 797 volunteers from September 2016-March 2020, a program evaluation was conducted for quality improvement purposes.

Results: The PSC is used by students of different sexes, genders, and ethnicities. Students reported having a low ORS score, moderate anxiety as per the GAD-7 and moderate depression according to the PHQ-9. They find it easy to use and rely on it as an alternative form of support when they approach barriers that prevent them from accessing professional services. Lastly, the peer support providers feel very validated in their role and overall quite prepared and helpful when helping their fellow peers.

Conclusions: The establishment of a student service that provides peer support would be beneficial to the members of a university/college campus.
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http://dx.doi.org/10.1186/s13033-021-00479-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165510PMC
May 2021

The remodelling of actin composition as a hallmark of cancer.

Transl Oncol 2021 Jun 21;14(6):101051. Epub 2021 Mar 21.

Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Faculty of Medicine, McGill University, Montreal, Canada. Electronic address:

Actin is a key structural protein that makes up the cytoskeleton of cells, and plays a role in functions such as division, migration, and vesicle trafficking. It comprises six different cell-type specific isoforms: ACTA1, ACTA2, ACTB, ACTC1, ACTG1, and ACTG2. Abnormal actin isoform expression has been reported in many cancers, which led us to hypothesize that it may serve as an early biomarker of cancer. We show an overview of the different actin isoforms and highlight mechanisms by which they may contribute to tumorigenicity. Furthermore, we suggest how the aberrant expression of actin subunits can confer cells with greater proliferation ability, increased migratory capability, and chemoresistance through incorporation into the normal cellular F-actin network and altered actin binding protein interaction. Studying this fundamental change that takes place within cancer cells can further our understanding of neoplastic transformation in multiple tissue types, which can ultimately aid in the early-detection, diagnosis and treatment of cancer.
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http://dx.doi.org/10.1016/j.tranon.2021.101051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008238PMC
June 2021

Adoptive transfer of immature myeloid cells lacking NF-κB p50 (p50-IMC) impedes the growth of MHC-matched high-risk neuroblastoma.

Mol Oncol 2021 Jul 2;15(7):1783-1796. Epub 2021 May 2.

Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.

High-risk neuroblastomas harbor abundant myeloid cells that suppress antitumor immunity and support tumor growth. Macrophages lacking the inhibitory NF-κB p50 subunit adopt a pro-inflammatory phenotype. We now report that murine 9464D neuroblastoma cells, which express high levels of exogenous MYCN, grow slower in syngeneic p50(f/f);Lys-Cre mice that lack p50 in macrophages and neutrophils, compared with p50(f/f) littermates. Tumors in p50(f/f);Lys-Cre mice possess increased numbers of total and activated CD4 and CD8 T cells, and depletion of both of these T-cell populations accelerates tumor growth. Anti-PD-1 T-cell checkpoint blockade, or DNA methyltransferase and histone deacetylase inhibition, further slows tumor growth. In addition, adoptive transfer of immature myeloid cells lacking NF-κB p50 (p50-IMC), generated either from the bone marrow of p50 mice or via nucleofection of a p50 sgRNA:Cas9 complex into wild-type hematopoietic progenitors, also slowed growth of MHC-matched 9464D tumors but not of MHC-mismatched Neuro2A tumors. These findings further validate the utility of targeting myeloid NF-κB p50 as a strategy for cancer therapy and demonstrate activity of p50-IMC generated by gene editing of syngeneic marrow cells, a cell product relevant to clinical translation.
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http://dx.doi.org/10.1002/1878-0261.12904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253086PMC
July 2021

NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma.

J Immunother Cancer 2020 01;8(1)

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Background: Macrophages and dendritic cells lacking the transcription factor nuclear factor kappa B p50 are skewed toward a proinflammatory phenotype, with increased cytokine expression and enhanced T cell activation; additionally, murine melanoma, fibrosarcoma, colon carcinoma, and glioblastoma grow slower in p50 mice. We therefore evaluated the efficacy of p50-negative immature myeloid cells (p50-IMCs) adoptively transferred into tumor-bearing hosts. Immature cells were used to maximize tumor localization, and pretreatment with 5-fluorouracil (5FU) was examined due to its potential to impair marrow production of myeloid cells, to target tumor myeloid cells and to release tumor neoantigens.

Methods: Wild-type (WT)-IMC or p50-IMC were generated by culturing lineage-negative marrow cells from WT or p50 mice in media containing thrombopoietin, stem cell factor and Flt3 ligand for 6 days followed by monocyte colony-stimulating factor for 1 day on ultralow attachment plates. Mice inoculated with Hi-Myc prostate cancer (PCa) cells or K-Ras pancreatic ductal carcinoma (PDC)-luciferase cells received 5FU followed 5 days later by three doses of 10 immature myeloid cells (IMC) every 3-4 days.

Results: PCa cells grew slower in p50 mice, and absence of host p50 prolonged the survival of mice inoculated orthotopically with PDC cells. IMC from Cytomegalovirus (CMV)-luciferase mice localized to tumor, nodes, spleen, marrow, and lung. 5FU followed by p50-IMC slowed PCa and PDC tumor growth, ~3-fold on average, in contrast to 5FU followed by WT-IMC, 5FU alone or p50-IMC alone. Slowed tumor growth was evident for 93% of PCa but only 53% of PDC tumors; we therefore focused on PCa for additional IMC analyses. In PCa, p50-IMC matured into F4/80 macrophages, as well as CD11bF4/80CD11c conventional dendritic cells (cDCs). In both tumor and draining lymph nodes, p50-IMC generated more macrophages and cDCs than WT-IMC. Activated tumor CD8 T cells were increased fivefold by p50-IMC compared with WT-IMC, and antibody-mediated CD8 T cell depletion obviated slower tumor growth induced by 5FU followed by p50-IMC.

Conclusions: 5FU followed by p50-IMC slows the growth of murine prostate and pancreatic carcinoma and depends on CD8 T cell activation. Deletion of p50 in patient-derived marrow CD34 cells and subsequent production of IMC for adoptive transfer may contribute to the therapy of these and additional cancers.
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http://dx.doi.org/10.1136/jitc-2019-000244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057444PMC
January 2020

Ab initio studies of adsorption of Haloarenes on Heme group.

J Mol Model 2019 Dec 13;26(1). Epub 2019 Dec 13.

Department of Medical Physics, Bharathiar University, Coimbatore, India.

In the present investigation, we have employed heme as a material for absorbing haloarenes due to its unique structural property, abundant availability, non-toxic nature and its dynamic nature in absorbing oxygen molecule. Haloarenes are toxic gases that are released into atmosphere as an aftermath of various refrigerants. Using first principle study, the absorption of haloarenes on heme molecule was systematically investigated. Fluorine, Chlorine, Bromine and Iodine substituted Haloarenes were allowed to interact with heme molecule with metal ion at +2, +3 and + 4 oxidation states of both low and high spin states. The TD-DFT analysis shows that the heme is a better absorbent at +3 and + 4 oxidation states of Fe ion at low spin state. Among the haloarenes, the interaction energy between IHA and Fe ion at +4 state is maximum with -1.877 eV. The HOMO-LUMO band gap decreases with increase in oxidation state and the orbital delocalization is maximum for high oxidation state. The delocalization of these electronic orbitals shows the active interaction between the heme molecule and haloarene which was confirmed by the DOS plot and the LP to LP* transition in NBO analysis. The absorbing nature of heme was further extended to hexahaloarenes, where heme still stand as a strong absorbing candidate for these toxic gases. The detailed study of the interaction between heme and haloarenes showed that heme at low spin state and with both +3 and + 4 oxidation states can be employed as an absorbent for Haloarenes. Graphical abstract.
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http://dx.doi.org/10.1007/s00894-019-4205-2DOI Listing
December 2019

Challenges in Clinical Management of Radiation-Induced Illnesses During Exploration Spaceflight.

Aerosp Med Hum Perform 2019 Nov;90(11):966-977

Analysis of historical solar particle events (SPEs) provides context for some understanding of acute radiation exposure risk to astronauts who will travel outside of low-Earth orbit. Predicted levels of radiation exposures to exploration crewmembers could produce some health impacts, including nausea, emesis, and fatigue, though more severe clinical manifestations are unlikely. Using current models of anticipated physiological sequelae, we evaluated the clinical challenges of managing radiation-related clinical concerns during exploration spaceflight. A literature review was conducted to identify terrestrial management standards for radiation-induced illnesses, focusing on prodromal symptom treatment. Terrestrial management was compared to current spaceflight medical capabilities to identify gaps and highlight challenges involved in expanding capabilities for future exploration spaceflight. Current spaceflight medical resources, such as those found on the International Space Station, may be sufficient to manage some aspects of radiation-induced illness, although effective treatment of all potential manifestations would require substantial expansion of capabilities. Terrestrial adjunctive therapies or more experimental treatments are unavailable in current spaceflight medical capabilities but may have a role in future management of acute radiation exposure. Expanded medical capabilities for managing radiation-induced illnesses could be included onboard future exploration vehicles. However, this would require substantial research, time, and funding to reach flight readiness, and vehicle limitations may restrict such capabilities for exploration missions. The benefits of including expanded capabilities should be weighed against the likelihood of significant radiation exposure and extensive mission design constraints.
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http://dx.doi.org/10.3357/AMHP.5370.2019DOI Listing
November 2019

Antimicrobial efficacy of medium chain fatty acids as root canal irrigants: An in vitro study.

J Indian Soc Pedod Prev Dent 2019 Jul-Sep;37(3):258-264

Department of Conservative Dentistry and Endodontics, PSM College of Dental Science and Research, Thrissur, Kerala, India.

Background: Enterococcus faecalis and Candida albicans are the microbes that are most resistant to elimination by disinfecting agents and are the causative agents for reinfection of the root canal treated teeth. Medium chain fatty acids (MCFAs), which are the main components of coconut oil, are proven antimicrobial agents. Thus, the aim of this study was to evaluate their antimicrobial efficacy against E. faecalis and C. albicans.

Methodology: Ninety extracted single-rooted mandibular premolar teeth were decoronated, biomechanically prepared, autoclaved, and divided into three groups (n = 30): Group A (inoculated with E. faecalis), Group B (inoculated with C. albicans), and Group C (control group). Each group was again subdivided into three groups (n = 10) and irrigated with lauric acid (LA), decanoic acid (DA), and octanoic acid, respectively, for 5 min. Paper point samples were taken from canal walls and transferred into Brain Heart Infusion broth and potato dextrose broth and placed in an incubator at 37°C. The appearance of tubidity was checked at 24, 48, 72, and 96 h using direct contact test. The data were then statistically analyzed using the analysis of variance and Tukey honestly significant difference post hoc tests.

Results: Among the three MCFAs, LA showed the maximum inhibitory against E. faecalis at 24 h and the inhibitory activity decreased considerably at 48, 72, and 96 h. DA was the most effective against C. albicans with a maximum inhibition at 48 h. DA also showed significant substantivity at 72 and 96 h.

Conclusion: Within the limitations of this study, it can be concluded that MCFAs show promising antimicrobial efficacy against E. faecalis and C. albicans.
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http://dx.doi.org/10.4103/JISPPD.JISPPD_63_19DOI Listing
November 2019

Supplying a pharmacy for NASA exploration spaceflight: challenges and current understanding.

NPJ Microgravity 2019 13;5:14. Epub 2019 Jun 13.

6National Aeronautics and Space Administration (NASA), Johnson Space Center, Houston, TX 77058 USA.

In order to maintain crew health and performance during long-duration spaceflight outside of low-Earth orbit, NASA and its international partners must be capable of providing a safe and effective pharmacy. Given few directed studies of pharmaceuticals in the space environment, it is difficult to characterize pharmaceutical effectiveness or stability during spaceflight; this in turn makes it challenging to select an appropriate formulary for exploration. Here, we present the current state of literature regarding pharmaceutical stability, metabolism, and effectiveness during spaceflight. In particular, we have attempted to highlight the gaps in current knowledge and the difficulties in translating terrestrial-based drug studies to a meaningful interpretation of drug stability, safety, and effectiveness in space. We hope to identify high-yield opportunities for future research that might better define and mitigate pharmaceutical risk for exploration missions.
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http://dx.doi.org/10.1038/s41526-019-0075-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565689PMC
June 2019

Pro-inflammatory cytokine Interleukin-1β (IL-1β) controls Leishmania infection.

Cytokine 2018 12 23;112:27-31. Epub 2018 Aug 23.

Trident Academy of Creative Technology, Bhubaneswar, Odisha 751024, India. Electronic address:

Leishmania is an obligate intracellular parasite uses low pH phagolysosomal compartments of host macrophages as their final abode. IL-1β is a pro inflammatory cytokine, which is secreted by immune cells to trigger inflammation and this has been found profoundly in the lesions caused by Leishmania pathogens. But the specific role of this cytokine on host cell macrophages during infection has not been fully explored. Here in, we have showed that prolonged exposure of IL-1β on macrophages increases the parasite burden. Pre-treatment of bone marrow derived macrophages (BMDM) with IL-1β also generates significantly higher amount of anti-inflammatory cytokine IL-10. As IL-10 plays crucial role in the establishment of infection, enhanced production of IL-10 observed upon IL-1β treatment could contribute to the progression of the disease. By quantifying the production of Nitric oxide (NO), we further report that the pretreatment of IL-1β fails to produce the nitric oxide. By measuring the footpad thickness in two different mice strains of differential susceptibility we showed IL-1β treatment increases parasitic burden. As our results shows that the exposure of IL-1β helps in disease progression, IL-1β signalling may be an attractive target for future therapeutic intervention.
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http://dx.doi.org/10.1016/j.cyto.2018.06.033DOI Listing
December 2018

Progression from the Common Lymphoid Progenitor to B/Myeloid PreproB and ProB Precursors during B Lymphopoiesis Requires C/EBPα.

J Immunol 2018 09 30;201(6):1692-1704. Epub 2018 Jul 30.

Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231

The C/EBPα transcription factor is required for myelopoiesis, with prior observations suggesting additional contributions to B lymphopoiesis. expression is evident in common lymphoid progenitor (CLP) and preproB cells but is absent in proB and preB cells. We previously observed that marrow lacking the +37 kb enhancer is impaired in producing B cells upon competitive transplantation. Additionally, a enhancer/promoter-hCD4 transgene is expressed in B/myeloid CFU. Extending these findings, pan-hematopoietic murine enhancer deletion using Mx1-Cre leads to expanded CLP, fewer preproB cells, markedly reduced proB and preB cells, and reduced mature B cells, without affecting T cell numbers. In contrast, enhancer deletion at the proB stage using Mb1-Cre does not impair B cell maturation. Further evaluation of CLP reveals that the transgene is expressed almost exclusively in Flt3 multipotent CLP versus B cell-restricted Flt3 CLP. In vitro, hCD4 preproB cells produce both B and myeloid cells, whereas hCD4 preproB cells only produce B cells. Additionally, a subset of hCD4 preproB cells express high levels of RAG1-GFP, as seen also in proB cells. Global gene expression analysis indicates that hCD4 preproB cells express proliferative pathways, whereas B cell development and signal transduction pathways predominate in hCD4 preproB cells. Consistent with these changes, enhancer-deleted preproB cells downmodulate cell cycle pathways while upregulating B cell signaling pathways. Collectively, these findings indicate that C/EBPα is required for Flt3 CLP maturation into preproB cells and then for proliferative B/myeloid preproB cells to progress to B cell-restricted preproB cells and finally to proB cells.
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http://dx.doi.org/10.4049/jimmunol.1800244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125169PMC
September 2018

Absence of host NF-κB p50 induces murine glioblastoma tumor regression, increases survival, and decreases T-cell induction of tumor-associated macrophage M2 polarization.

Cancer Immunol Immunother 2018 Oct 21;67(10):1491-1503. Epub 2018 Jul 21.

Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University, CRB I, Rm 253, 1650 Orleans St., Baltimore, MD, 21231, USA.

High-grade gliomas harbor abundant myeloid cells that suppress anti-tumor immunity and support tumor growth. Targeting transcription factors, such as NF-κB p50, that mediate suppressive myeloid M2 polarization may prove therapeutic. GL261-Luc glioblastoma cells were inoculated into wild-type and p50 mice, followed by analysis of tumor growth, survival, tumor myeloid cells, and T cells. The absence of host p50 slows tumor growth and enables regression in 30% of recipients, leading to prolonged survival. Tumors developing in p50 mice possess a greater concentration of tumor-infiltrating myeloid cells (TIMs) than those in wild-type mice. TIMs are predominantly F4/80 macrophages which, along with tumor-associated microglia, express increased pro-inflammatory M1 and reduced immune-suppressive M2 markers. In p50 mice, total tumor CD4 T cells are threefold more abundant, whereas CD8 T-cell numbers are unchanged, and both produce increased IFNγ and Granzyme B. Naïve splenic p50 CD8 T cells manifest increased activation, whereas naïve p50 and WT CD4 T cells show similar Th1, Th2, and Th17 polarization. Antibody targeting CD4, but not CD8, fully obviates the p50 survival advantage. Combined CD4 and CD8 T-cell depletion reverses myeloid M2 polarization in wild-type hosts, without affecting myeloid M1 polarization in p50 hosts. Finally, gliomas grow similarly in p50(f/f) and p50(f/f);Lysozyme-Cre mice, the latter having reduced p50 specifically in myeloid cells and tumor microglia. Thus, high-grade glioma T cells play a key role in directing M2 polarization of tumor myeloid cells, and reducing NF-κB p50 in both tumor myeloid cells and T cells may contribute to glioma therapy.
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http://dx.doi.org/10.1007/s00262-018-2184-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168375PMC
October 2018

Do not fear the Framingham: Practical application to properly evaluate and modify cardiovascular risk in commercial divers.

Undersea Hyperb Med 2018 Jan-Feb;45(1):75-82

Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, Texas.

Introduction: In April 2016 the Association of Diving Contractors International (ADCI) consensus guidelines began recommending annual cardiovascular risk stratification of commercial divers using the Framingham Risk Score (FRS). For those at elevated risk, further testing is recommended. This approach has raised concerns about potential operational and financial impacts. However, the prevalence of elevated cardiovascular risk and need for additional testing among commercial divers is not known.

Methods: Clinical data required to calculate the FRS was abstracted for 190 commercial divers in two cohorts. Population demographics, FRS distribution, contributions of risk factors and effect of interventions on reducing risk-factor burden were assessed.

Results: Mean FRS score was 1.68 ± 6.35 points, with 13 divers (6.8%) at intermediate risk and none at high 10-year risk. In these 13 divers, the mean contributions to the FRS were from age (6.5 points), cholesterol (3.1 pts.), smoking (1.3 pts.), highdensity lipoprotein (1 pt.), and systolic blood pressure (0.8 pts). The youngest age group had a significantly higher modifiable risk core than the oldest age group (5.87 vs. 1.2 points, P ⟨ 0.001). All 13 intermediate risk divers could have been reclassified as low-risk with successful treatment of modifiable risk factors.

Discussion: The prevalence of elevated cardiovascular risk among commercial divers is low, and treatment of modifiable risk factors could reclassify those at intermediate risk to low risk. Therefore, FRS implementation coupled with intensive risk-reduction strategies for at risk-divers may help improve diver health and prolong the careers of divers while limiting the need for additional testing and adverse operational impact.
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October 2019

MANAGEMENT OF DIABETES DURING AIR TRAVEL: A SYSTEMATIC LITERATURE REVIEW OF CURRENT RECOMMENDATIONS AND THEIR SUPPORTING EVIDENCE.

Endocr Pract 2018 Feb;24(2):205-219

Objective: Individuals with diabetes are increasingly seeking pretravel advice, but updated professional recommendations remain scant. We performed a systematic review on diabetes management during air travel to summarize current recommendations, assess supporting evidence, and identify areas of future research.

Methods: A systematic review of the English literature on diabetes management during air travel was undertaken utilizing PubMed and MEDLINE. Publications regarding general travel advice; adjustment of insulin and noninsulin therapies; and the use of insulin pumps, glucometers and subcutaneous glucose sensors at altitude were included. Gathered information was used to create an updated summary of glucose-lowering medication adjustment during air travel.

Results: Sixty-one publications were identified, most providing expert opinion and few offering primary data (47 expert opinion, 2 observational studies, 2 case reports, 10 device studies). General travel advice was uniform, with increasing attention to preflight security. Indications for oral antihyperglycemic therapy adjustments varied. There were few recommendations on contemporary agents and on nonhypoglycemic adverse events. There was little consensus on insulin adjustment protocols, many antedating current insulin formulations. Most publications advocated adjusting insulin pump time settings after arrival; however, there was disagreement on timing and rate adjustments. Glucometers and subcutaneous glucose sensors were reported to be less accurate at altitude, but not to an extent that would preclude their clinical use.

Conclusion: Recommendations for diabetes management during air travel vary significantly and are mostly based on expert opinion. Data from systematic investigation on glucose-lowering medication adjustment protocols may support the development of a future consensus statement.

Abbreviations: CSII = continuous subcutaneous insulin infusion (device) DPP-4 = dipeptidyl peptidase 4 EGA = error grid analysis GDH = glucose dehydrogenase GOX = glucose oxidase GLP1 = glucagon-like peptide-1 NPH = neutral protamine Hagedorn SGLT2 = sodium-glucose cotransporter-2.
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http://dx.doi.org/10.4158/EP171954.RADOI Listing
February 2018

A Catalytic Enantioselective Iodocyclization Route to Dihydrooxazines.

Org Lett 2018 03 12;20(5):1300-1303. Epub 2018 Feb 12.

Department of Organic Chemistry, Indian Institute of Science , Bangalore-560012, India.

The first catalytic enantioselective synthesis of 5,6-dihydro-4H-1,2-oxazines bearing an oxygen-containing quaternary stereogenic center has been developed through iodoetherification of γ,δ-unsaturated oximes. This operationally straightforward reaction is catalyzed by Cinchona alkaloids-based bifunctional tertiary aminothiourea derivatives and furnishes the products generally in good to excellent yields and with moderate to high enantioselectivities (up to 97:3 er).
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http://dx.doi.org/10.1021/acs.orglett.8b00002DOI Listing
March 2018

Absence of myeloid Klf4 reduces prostate cancer growth with pro-atherosclerotic activation of tumor myeloid cells and infiltration of CD8 T cells.

PLoS One 2018 11;13(1):e0191188. Epub 2018 Jan 11.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

The microenvironment of prostate cancer often includes abundant tumor-associated macrophages (TAMs), with their acquisition of an M2 phenotype correlating with local aggressiveness and metastasis. Tumor-derived M-CSF contributes to TAM M2 polarization, and M-CSF receptor inhibition slows prostate cancer growth in model systems. As additional cytokines can direct TAM M2 polarization, targeting downstream transcription factors could avoid resistance. Klf4 and C/EBPβ each contribute to monocyte development, and reduced expression of macrophage Klf4 or C/EBPβ favors their adoption of a pro-inflammatory M1 state. We find that a Hi-Myc C57BL/6 prostate cancer line grows more slowly in syngeneic Klf4(f/f);Lys-Cre compared with Klf4(f/f) mice when inoculated subcutaneously, but grows equally rapidly in C/EBPβ(f/f);Lys-Cre and C/EBPβ(f/f) hosts. In the absence of myeloid Klf4, TAMs have reduced expression of surface mannose receptor and Fizz1 mRNA, both M2 markers. Global gene expression analysis further revealed activation of pro-inflammatory, pro-atherosclerotic pathways. Analysis of tumor-infiltrating lymphocytes (TILs) demonstrated markedly increased activated CD8 T cell numbers, and CD8 T cell depletion obviated the inhibitory effect of myeloid Klf4 deletion on prostate cancer growth. These findings suggest that reducing expression or activity of the Klf4 transcription factor in tumor myeloid cells may contribute to prostate cancer therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191188PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764416PMC
February 2018

Root Canal Configuration of Human Permanent Mandibular First Molars of an Indo-Dravidian Population Based in Southern India: An Study.

J Pharm Bioallied Sci 2017 Nov;9(Suppl 1):S68-S72

Department of Conservative Dentistry, JKK Nataraja Dental College and Hospital, Komarapalayam, Tamil Nadu, India.

Aim: This study aims to analyze root canal configuration of human permanent mandibular first molars of an indo-Dravidian population based in southern India.

Materials And Methods: A total of 1147 mandibular first permanent molars were collected, cleansed, and stored. The number of roots was recorded, access preparations made, pattern of orifices recorded after pulpal floor debridement, dye injected into the canals using apical negative pressure and subjected to a clearing technique. They were then analyzed using a stereo microscope and the canal configurations recorded (Vertucci). The number of roots, the pattern of orifices and canal configuration were recorded.

Results: The pattern of orifices was triangular (87.9%), rectangular (8.5%), C-shaped (3.0%), and two orifice pattern (0.6%). About 95.6% of teeth had two roots, and 4.4% had three roots. The most common canal system configuration in mesial root was Vertucci type IV (52.3%), followed by type II (35%). Root canal configuration of the distal root revealed type I configuration in 62.7%, followed by types II (14.5%) and IV (12.4%). The distolingual root had a type I configuration.

Conclusion: Awareness of canal configuration, adequate clinical skills, use of specialized techniques of diagnosis, debridement and obturation will pave the way for successful treatment outcomes.
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http://dx.doi.org/10.4103/jpbs.JPBS_163_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731046PMC
November 2017

Dysrhythmias in Laypersons During Centrifuge-Simulated Suborbital Spaceflight.

Aerosp Med Hum Perform 2017 Nov;88(11):1008-1015

Introduction: There are limited data on cardiac dysrhythmias in laypersons during hypergravity exposure. We report layperson electrocardiograph (ECG) findings and tolerance of dysrhythmias during centrifuge-simulated suborbital spaceflight.

Methods: Volunteers participated in varied-length centrifuge training programs of 2-7 centrifuge runs over 0.5-2 d, culminating in two simulated suborbital spaceflights of combined +Gz and +Gx (peak +4.0 Gz, +6.0 Gx, duration 5 s). Monitors recorded pre- and post-run mean arterial blood pressure (MAP), 6-s average heart rate (HR) collected at prespecified points during exposures, documented dysrhythmias observed on continuous 3-lead ECG, self-reported symptoms, and objective signs of intolerance on real-time video monitoring.

Results: Participating in the study were 148 subjects (43 women). Documented dysrhythmias included sinus pause (N = 5), couplet premature ventricular contractions (N = 4), bigeminy (N = 3), accelerated idioventricular rhythm (N = 1), and relative bradycardia (RB, defined as a transient HR drop of >20 bpm; N = 63). None were associated with subjective symptoms or objective signs of acceleration intolerance. Episodes of RB occurred only during +Gx exposures. Subjects had a higher post-run vs. pre-run MAP after all exposures, but demonstrated no difference in pre- and post-run HR. RB was more common in men, younger individuals, and subjects experiencing more centrifuge runs.

Discussion: Dysrhythmias in laypersons undergoing simulated suborbital spaceflight were well tolerated, though RB was frequently noted during short-duration +Gx exposure. No subjects demonstrated associated symptoms or objective hemodynamic sequelae from these events. Even so, heightened caution remains warranted when monitoring dysrhythmias in laypersons with significant cardiopulmonary disease or taking medications that modulate cardiac conduction.Suresh R, Blue RS, Mathers CH, Castleberry TL, Vanderploeg JM. Dysrhythmias in laypersons during centrifuge-stimulated suborbital spaceflight. Aerosp Med Hum Perform. 2017; 88(11):1008-1015.
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http://dx.doi.org/10.3357/AMHP.4910.2017DOI Listing
November 2017

Sustained Accelerated Idioventricular Rhythm in a Centrifuge-Simulated Suborbital Spaceflight.

Aerosp Med Hum Perform 2017 Aug;88(8):789-793

Introduction: Hypergravitational exposures during human centrifugation are known to provoke dysrhythmias, including sinus dysrhythmias/tachycardias, premature atrial/ventricular contractions, and even atrial fibrillations or flutter patterns. However, events are generally short-lived and resolve rapidly after cessation of acceleration. This case report describes a prolonged ectopic ventricular rhythm in response to high G exposure.

Case Report: A previously healthy 30-yr-old man voluntarily participated in centrifuge trials as a part of a larger study, experiencing a total of 7 centrifuge runs over 48 h. Day 1 consisted of two +Gz runs (peak +3.5 Gz, run 2) and two +Gx runs (peak +6.0 Gx, run 4). Day 2 consisted of three runs approximating suborbital spaceflight profiles (combined +Gx and +Gz). Hemodynamic data collected included blood pressure, heart rate, and continuous three-lead electrocardiogram. Following the final acceleration exposure of the last Day 2 run (peak +4.5 Gx and +4.0 Gz combined, resultant +6.0 G), during a period of idle resting centrifuge activity (resultant vector +1.4 G), the subject demonstrated a marked change in his three-lead electrocardiogram from normal sinus rhythm to a wide-complex ectopic ventricular rhythm at a rate of 91-95 bpm, consistent with an accelerated idioventricular rhythm (AIVR). This rhythm was sustained for 2 m, 24 s before reversion to normal sinus. The subject reported no adverse symptoms during this time.

Discussion: While prolonged, the dysrhythmia was asymptomatic and self-limited. AIVR is likely a physiological response to acceleration and can be managed conservatively. Vigilance is needed to ensure that AIVR is correctly distinguished from other, malignant rhythms to avoid inappropriate treatment and negative operational impacts.Suresh R, Blue RS, Mathers C, Castleberry TL, Vanderploeg JM. Sustained accelerated idioventricular rhythm in a centrifuge-simulated suborbital spaceflight. Aerosp Med Hum Perform. 2017; 88(8):789-793.
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http://dx.doi.org/10.3357/AMHP.4896.2017DOI Listing
August 2017

Utility of real-time three-dimensional echocardiography in improved assessment of a mitral valve papillary fibroelastoma.

Clin Case Rep 2017 07 16;5(7):1193-1195. Epub 2017 May 16.

Division of Cardiology Department of Internal Medicine University of Texas Medical Branch 301 University Blvd Galveston 77555 Texas.

Primary cardiac tumors are exceedingly rare. They are usually first identified by transthoracic echocardiography. However, transesophageal echocardiography (TEE), with the aid of real-time three-dimensional (3D) imaging, can provide additional important mass characteristics. We present a case that demonstrates the usefulness of 3D TEE in characterizing a papillary fibroelastoma.
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http://dx.doi.org/10.1002/ccr3.996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494387PMC
July 2017

Complement-mediated 'bystander' damage initiates host NLRP3 inflammasome activation.

J Cell Sci 2016 05 22;129(9):1928-39. Epub 2016 Mar 22.

Department of Cell Biology and Molecular Genetics and the Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA

Complement activation has long been associated with inflammation, primarily due to the elaboration of the complement anaphylotoxins C5a and C3a. In this work, we demonstrate that the phagocytosis of complement-opsonized particles promotes host inflammatory responses by a new mechanism that depends on the terminal complement components (C5b-C9). We demonstrate that during the phagocytosis of complement-opsonized particles, the membrane attack complex (MAC) of complement can be transferred from the activating particle to the macrophage plasma membrane by a 'bystander' mechanism. This MAC-mediated bystander damage initiates NLRP3 inflammasome activation, resulting in caspase-1 activation and IL-1β and IL-18 secretion. Inflammasome activation is not induced when macrophages phagocytize unopsonized particles or particles opsonized with serum deficient in one of the terminal complement components. The secretion of IL-1β and IL-18 by macrophages depends on NLRP3, ASC (also known as PYCARD) and caspase-1, as macrophages deficient in any one of these components fail to secrete these cytokines following phagocytosis. The phagocytosis of complement-opsonized particles increases leukocyte recruitment and promotes T helper 17 cell (TH17) biasing. These findings reveal a new mechanism by which complement promotes inflammation and regulates innate and adaptive immunity.
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http://dx.doi.org/10.1242/jcs.179291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893798PMC
May 2016

Simultaneous transcriptional profiling of Leishmania major and its murine macrophage host cell reveals insights into host-pathogen interactions.

BMC Genomics 2015 Dec 29;16:1108. Epub 2015 Dec 29.

Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, 20742, USA.

Background: Parasites of the genus Leishmania are the causative agents of leishmaniasis, a group of diseases that range in manifestations from skin lesions to fatal visceral disease. The life cycle of Leishmania parasites is split between its insect vector and its mammalian host, where it resides primarily inside of macrophages. Once intracellular, Leishmania parasites must evade or deactivate the host's innate and adaptive immune responses in order to survive and replicate.

Results: We performed transcriptome profiling using RNA-seq to simultaneously identify global changes in murine macrophage and L. major gene expression as the parasite entered and persisted within murine macrophages during the first 72 h of an infection. Differential gene expression, pathway, and gene ontology analyses enabled us to identify modulations in host and parasite responses during an infection. The most substantial and dynamic gene expression responses by both macrophage and parasite were observed during early infection. Murine genes related to both pro- and anti-inflammatory immune responses and glycolysis were substantially upregulated and genes related to lipid metabolism, biogenesis, and Fc gamma receptor-mediated phagocytosis were downregulated. Upregulated parasite genes included those aimed at mitigating the effects of an oxidative response by the host immune system while downregulated genes were related to translation, cell signaling, fatty acid biosynthesis, and flagellum structure.

Conclusions: The gene expression patterns identified in this work yield signatures that characterize multiple developmental stages of L. major parasites and the coordinated response of Leishmania-infected macrophages in the real-time setting of a dual biological system. This comprehensive dataset offers a clearer and more sensitive picture of the interplay between host and parasite during intracellular infection, providing additional insights into how pathogens are able to evade host defenses and modulate the biological functions of the cell in order to survive in the mammalian environment.
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http://dx.doi.org/10.1186/s12864-015-2237-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696162PMC
December 2015

Transcriptomic profiling of gene expression and RNA processing during Leishmania major differentiation.

Nucleic Acids Res 2015 Aug 6;43(14):6799-813. Epub 2015 Jul 6.

Department of Cell Biology and Molecular Genetics, 3128 Bioscience Research Building, University of Maryland, College Park, MD 20742, USA Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20742, USA

Protozoan parasites of the genus Leishmania are the etiological agents of leishmaniasis, a group of diseases with a worldwide incidence of 0.9-1.6 million cases per year. We used RNA-seq to conduct a high-resolution transcriptomic analysis of the global changes in gene expression and RNA processing events that occur as L. major transforms from non-infective procyclic promastigotes to infective metacyclic promastigotes. Careful statistical analysis across multiple biological replicates and the removal of batch effects provided a high quality framework for comprehensively analyzing differential gene expression and transcriptome remodeling in this pathogen as it acquires its infectivity. We also identified precise 5' and 3' UTR boundaries for a majority of Leishmania genes and detected widespread alternative trans-splicing and polyadenylation. An investigation of possible correlations between stage-specific preferential trans-splicing or polyadenylation sites and differentially expressed genes revealed a lack of systematic association, establishing that differences in expression levels cannot be attributed to stage-regulated alternative RNA processing. Our findings build on and improve existing expression datasets and provide a substantially more detailed view of L. major biology that will inform the field and potentially provide a stronger basis for drug discovery and vaccine development efforts.
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http://dx.doi.org/10.1093/nar/gkv656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538839PMC
August 2015

The generation of macrophages with anti-inflammatory activity in the absence of STAT6 signaling.

J Leukoc Biol 2015 Sep 5;98(3):395-407. Epub 2015 Jun 5.

*Department of Cell Biology and Molecular Genetics and Maryland Pathogen Research Institute and Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, USA

Macrophages readily change their phenotype in response to exogenous stimuli. In this work, macrophages were stimulated under a variety of experimental conditions, and phenotypic alterations were correlated with changes in gene expression. We identified 3 transcriptionally related populations of macrophages with immunoregulatory activity. They were generated by stimulating cells with TLR ligands in the presence of 3 different "reprogramming" signals: high-density ICs, PGE2, or Ado. All 3 of these cell populations produced high levels of transcripts for IL-10 and growth and angiogenic factors. They also secreted reduced levels of inflammatory cytokines IL-1β, IL-6, and IL-12. All 3 macrophage phenotypes could partially rescue mice from lethal endotoxemia, and therefore, we consider each to have anti-inflammatory activity. This ability to regulate innate-immune responses occurred equally well in macrophages from STAT6-deficient mice. The lack of STAT6 did not affect the ability of macrophages to change cytokine production reciprocally or to rescue mice from lethal endotoxemia. Furthermore, treatment of macrophages with IL-4 failed to induce similar phenotypic or transcriptional alterations. This work demonstrates that there are multiple ways to generate macrophages with immunoregulatory activity. These anti-inflammatory macrophages are transcriptionally and functionally related to each other and are quite distinct from macrophages treated with IL-4.
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http://dx.doi.org/10.1189/jlb.2A1114-560RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541501PMC
September 2015

Transcriptome from circulating cells suggests dysregulated pathways associated with long-term recurrent events following first-time myocardial infarction.

J Mol Cell Cardiol 2014 Sep 4;74:13-21. Epub 2014 May 4.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester 55905 MN, USA; Center for Regenerative Medicine, Mayo Clinic, 200 First Street SW, Rochester 55905 MN, USA; Division of General Internal Medicine and Transplant Center, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester 55905 MN, USA. Electronic address:

Background: Whole-genome gene expression analysis has been successfully utilized to diagnose, prognosticate, and identify potential therapeutic targets for high-risk cardiovascular diseases. However, the feasibility of this approach to identify outcome-related genes and dysregulated pathways following first-time myocardial infarction (AMI) remains unknown and may offer a novel strategy to detect affected expressome networks that predict long-term outcome.

Methods And Results: Whole-genome expression microarray on blood samples from normal cardiac function controls (n=21) and first-time AMI patients (n=31) within 48-hours post-MI revealed expected differential gene expression profiles enriched for inflammation and immune-response pathways. To determine molecular signatures at the time of AMI associated with long-term outcomes, transcriptional profiles from sub-groups of AMI patients with (n=5) or without (n=22) any recurrent events over an 18-month follow-up were compared. This analysis identified 559 differentially-expressed genes. Bioinformatic analysis of this differential gene-set for associated pathways revealed 1) increasing disease severity in AMI patients is associated with a decreased expression of genes involved in the developmental epithelial-to-mesenchymal transition pathway, and 2) modulation of cholesterol transport genes that include ABCA1, CETP, APOA1, and LDLR is associated with clinical outcome.

Conclusion: Differentially regulated genes and modulated pathways were identified that were associated with recurrent cardiovascular outcomes in first-time AMI patients. This cell-based approach for risk stratification in AMI could represent a novel, non-invasive platform to anticipate modifiable pathways and therapeutic targets to optimize long-term outcome for AMI patients and warrants further study to determine the role of metabolic remodeling and regenerative processes required for optimal outcomes.
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http://dx.doi.org/10.1016/j.yjmcc.2014.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115027PMC
September 2014
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