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Dive into the research topics where Yonas Alamneh is active.

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Featured researches published by Yonas Alamneh.


Biochemical Pharmacology | 2011

Protective efficacy of catalytic bioscavenger, paraoxonase 1 against sarin and soman exposure in guinea pigs §

Manojkumar Valiyaveettil; Yonas Alamneh; Peter Rezk; Lionel Biggemann; Michael W. Perkins; Alfred M. Sciuto; Bhupendra P. Doctor; Madhusoodana P. Nambiar

Human paraoxonase 1 (PON1) has been portrayed as a catalytic bioscavenger which can hydrolyze large amounts of chemical warfare nerve agents (CWNAs) and organophosphate (OP) pesticides compared to the stoichiometric bioscavengers such as butyrylcholinesterase. We evaluated the protective efficacy of purified human and rabbit serum PON1 against nerve agents sarin and soman in guinea pigs. Catalytically active PON1 purified from human and rabbit serum was intravenously injected to guinea pigs, which were 30 min later exposed to 1.2 × LCt₅₀ sarin or soman using a microinstillation inhalation exposure technology. Pre-treatment with 5 units of purified human and rabbit serum PON1 showed mild to moderate increase in the activity of blood PON1, but significantly increased the survival rate with reduced symptoms of CWNA exposure. Although PON1 is expected to be catalytic, sarin and soman exposure resulted in a significant reduction in blood PON1 activity. However, the blood levels of PON1 in pre-treated animals after exposure to nerve agent were higher than that of untreated control animals. The activity of blood acetylcholinesterase and butyrylcholinesterase and brain acetylcholinesterase was significantly higher in PON1 pre-treated animals and were highly correlated with the survival rate. Blood O₂ saturation, pulse rate and respiratory dynamics were normalized in animals treated with PON1 compared to controls. These results demonstrate that purified human and rabbit serum PON1 significantly protect against sarin and soman exposure in guinea pigs and support the development of PON1 as a catalytic bioscavenger for protection against lethal exposure to CWNAs.


Antimicrobial Agents and Chemotherapy | 2014

Validation of a Novel Murine Wound Model of Acinetobacter baumannii Infection

Mitchell G. Thompson; Chad C. Black; Rebecca L. Pavlicek; Cary L. Honnold; Matthew C. Wise; Yonas Alamneh; Jay K. Moon; Jennifer L. Kessler; Yuanzheng Si; Robert Williams; Suleyman Yildirim; Benjamin C. Kirkup; Romanza K. Green; Eric R. Hall; Thomas J. Palys; Daniel V. Zurawski

ABSTRACT Patients recovering from traumatic injuries or surgery often require weeks to months of hospitalization, increasing the risk for wound and surgical site infections caused by ESKAPE pathogens, which include A. baumannii (the ESKAPE pathogens are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). As new therapies are being developed to counter A. baumannii infections, animal models are also needed to evaluate potential treatments. Here, we present an excisional, murine wound model in which a diminutive inoculum of a clinically relevant, multidrug-resistant A. baumannii isolate can proliferate, form biofilms, and be effectively treated with antibiotics. The model requires a temporary, cyclophosphamide-induced neutropenia to establish an infection that can persist. A 6-mm-diameter, full-thickness wound was created in the skin overlying the thoracic spine, and after the wound bed was inoculated, it was covered with a dressing for 7 days. Uninoculated control wounds healed within 13 days, whereas infected, placebo-treated wounds remained unclosed beyond 21 days. Treated and untreated wounds were assessed with multiple quantitative and qualitative techniques that included gross pathology, weight loss and recovery, wound closure, bacterial burden, 16S rRNA community profiling, histopathology, peptide nucleic acid-fluorescence in situ hybridization, and scanning electron microscopy assessment of biofilms. The range of differences that we are able to identify with these measures in antibiotic- versus placebo-treated animals provides a clear window within which novel antimicrobial therapies can be assessed. The model can be used to evaluate antimicrobials for their ability to reduce specific pathogen loads in wounded tissues and clear biofilms. Ultimately, the mouse model approach allows for highly powered studies and serves as an initial multifaceted in vivo assessment prior to testing in larger animals.


Chemico-Biological Interactions | 2013

Modulation of cholinergic pathways and inflammatory mediators in blast-induced traumatic brain injury.

Manojkumar Valiyaveettil; Yonas Alamneh; Stacey-Ann Miller; Rasha Hammamieh; Peethambaran Arun; Ying Wang; Yanling Wei; Samuel Oguntayo; Joseph B. Long; Madhusoodana P. Nambiar

Cholinergic activity has been recognized as a major regulatory component of stress responses after traumatic brain injury (TBI). Centrally acting acetylcholinesterase (AChE) inhibitors are also being considered as potential therapeutic candidates against TBI mediated cognitive impairments. We have evaluated the expression of molecules involved in cholinergic and inflammatory pathways in various regions of brain after repeated blast exposures in mice. Isoflurane anesthetized C57BL/6J mice were restrained and placed in a prone position transverse to the direction of the shockwaves and exposed to three 20.6 psi blast overpressures with 1-30 min intervals. Brains were collected at the 6h time point after the last blast exposure and subjected to cDNA microarray and microRNA analysis. cDNA microarray analysis showed significant changes in the expression of cholinergic (muscarinic and nicotinic) and gammaaminobutyric acid and glutamate receptors in the midbrain region along with significant changes in multiple genes involved in inflammatory pathways in various regions of the brain. MicroRNA analysis of cerebellum revealed differential expression of miR-132 and 183, which are linked to cholinergic anti-inflammatory signaling, after blast exposure. Changes in the expression of myeloperoxidase in the cerebellum were confirmed by Western blotting. These results indicate that early pathologic progression of blast TBI involves dysregulation of cholinergic and inflammatory pathways related genes. Acute changes in molecules involved in the modulation of cholinergic and inflammatory pathways after blast TBI can cause long-term central and peripheral pathophysiological changes.


Biochemical and Biophysical Research Communications | 2010

Efficient hydrolysis of the chemical warfare nerve agent tabun by recombinant and purified human and rabbit serum paraoxonase 1.

Manojkumar Valiyaveettil; Yonas Alamneh; Lionel Biggemann; Iswarduth Soojhawon; Bhupendra P. Doctor; Madhusoodana P. Nambiar

Paraoxonase 1 (PON1) has been described as an efficient catalytic bioscavenger due to its ability to hydrolyze organophosphates (OPs) and chemical warfare nerve agents (CWNAs). It is the future most promising candidate as prophylactic medical countermeasure against highly toxic OPs and CWNAs. Most of the studies conducted so far have been focused on the hydrolyzing potential of PON1 against nerve agents, sarin, soman, and VX. Here, we investigated the hydrolysis of tabun by PON1 with the objective of comparing the hydrolysis potential of human and rabbit serum purified and recombinant human PON1. The hydrolysis potential of PON1 against tabun, sarin, and soman was evaluated by using an acetylcholinesterase (AChE) back-titration Ellman method. Efficient hydrolysis of tabun (100 nM) was observed with ∼25-40 mU of PON1, while higher concentration (80-250 mU) of the enzyme was required for the complete hydrolysis of sarin (11 nM) and soman (3 nM). Our data indicate that tabun hydrolysis with PON1 was ∼30-60 times and ∼200-260 times more efficient than that with sarin and soman, respectively. Moreover, the catalytic activity of PON1 varies from source to source, which also reflects their efficiency of hydrolyzing different types of nerve agents. Thus, efficient hydrolysis of tabun by PON1 suggests its promising potential as a prophylactic treatment against tabun exposure.


Toxicology Letters | 2011

Recombinant paraoxonase 1 protects against sarin and soman toxicity following microinstillation inhalation exposure in guinea pigs

Manojkumar Valiyaveettil; Yonas Alamneh; Peter Rezk; Michael W. Perkins; Alfred M. Sciuto; Bhupendra P. Doctor; Madhusoodana P. Nambiar

To explore the efficacy of paraoxonase 1 (PON1) as a catalytic bioscavenger, we evaluated human recombinant PON1 (rePON1) expressed in Trichoplusia ni larvae against sarin and soman toxicity using microinstillation inhalation exposure in guinea pigs. Animals were pretreated intravenously with catalytically active rePON1, followed by exposure to 1.2 X LCt₅₀ sarin or soman. Administration of 5 units of rePON1 showed mild increase in the blood activity of the enzyme after 30 min, but protected the animals with a significant increase in survival rate along with minimal signs of nerve agent toxicity. Recombinant PON1 pretreated animals exposed to sarin or soman prevented the reduction of blood O₂ saturation and pulse rate observed after nerve agent exposure. In addition, rePON1 pretreated animals showed significantly higher blood PON1, acetylcholinesterase (AChE), and butyrylcholinesterase activity after nerve agent exposure compared to the respective controls without treatments. AChE activity in different brain regions of rePON1 pretreated animals exposed to sarin or soman were also significantly higher than respective controls. The remaining activity of blood PON1, cholinesterases and brain AChE in PON1 pretreated animals after nerve agent exposure correlated with the survival rate. In summary, these data suggest that human rePON1 protects against sarin and soman exposure in guinea pigs.


PLOS ONE | 2012

Rapid Release of Tissue Enzymes into Blood after Blast Exposure: Potential Use as Biological Dosimeters

Peethambaran Arun; Samuel Oguntayo; Yonas Alamneh; Cary L. Honnold; Ying Wang; Manojkumar Valiyaveettil; Joseph B. Long; Madhusoodana P. Nambiar

Explosive blast results in multiple organ injury and polytrauma, the intensity of which varies with the nature of the exposure, orientation, environment and individual resilience. Blast overpressure alone may not precisely indicate the level of body or brain injury after blast exposure. Assessment of the extent of body injury after blast exposure is important, since polytrauma and systemic factors significantly contribute to blast-induced traumatic brain injury. We evaluated the activity of plasma enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and creatine kinase (CK) at different time points after blast exposure using a mouse model of single and repeated blast exposures to assess the severity of injury. Our data show that activities of all the enzymes in the plasma were significantly increased as early as 1 h after blast exposure. The elevated enzyme activity remained up to 6 h in an overpressure dose-dependent manner and returned close to normal levels at 24 h. Head-only blast exposure with body protection showed no increase in the enzyme activities suggesting that brain injury alone does not contribute to the systemic increase. In contrast to plasma increase, AST, ALT and LDH activity in the liver and CK in the skeletal muscle showed drastic decrease at 6 h after blast exposures. Histopathology showed mild necrosis at 6 h and severe necrosis at 24 h after blast exposures in liver and no changes in the skeletal muscle suggesting that the enzyme release from the tissue to plasma is probably triggered by transient cell membrane disruption from shockwave and not due to necrosis. Overpressure dependent transient release of tissue enzymes and elevation in the plasma after blast exposure suggest that elevated enzyme activities in the blood can be potentially used as a biological dosimeter to assess the severity of blast injury.


Toxicology in Vitro | 2012

Hydrolysis potential of recombinant human skin and kidney prolidase against diisopropylfluorophosphate and sarin by in vitro analysis

Michael Costante; Lionel Biggemann; Yonas Alamneh; Iswarduth Soojhawon; Radley Short; Savita V. Nigam; Gregory E. Garcia; Bhupendra P. Doctor; Manojkumar Valiyaveettil; Madhusoodana P. Nambiar

Human prolidase (PROL), which has structural homology to bacterial organophosphate acid anhydrolase that hydrolyze organophosphates and nerve agents has been proposed recently as a potential catalytic bioscavenger. To develop PROL as a catalytic bioscavenger, we evaluated the in vitro hydrolysis efficiency of purified recombinant human PROL against organophosphates and nerve agents. Human liver PROL was purified by chromatographic procedures, whereas recombinant human skin and kidney PROL was expressed in Trichoplusia ni larvae, affinity purified and analyzed by gel electrophoresis. The catalytic efficiency of PROL against diisopropylfluorophosphate (DFP) and nerve agents was evaluated by acetylcholinesterase back-titration assay. Partially purified human liver PROL hydrolyzed DFP and various nerve agents, which was abolished by specific PROL inhibitor showing the specificity of hydrolysis. Both the recombinant human skin and kidney PROL expressed in T. ni larvae showed ∼99% purity and efficiently hydrolyzed DFP and sarin. In contrast to human liver PROL, both skin and kidney PROL showed significantly low hydrolyzing potential against nerve agents soman, tabun and VX. In conclusion, compared to human liver PROL, recombinant human skin and kidney PROL hydrolyze only DFP and sarin showing the substrate specificity of PROL from various tissue sources.


Neuroscience Letters | 2013

Contribution of systemic factors in the pathophysiology of repeated blast-induced neurotrauma.

Manojkumar Valiyaveettil; Yonas Alamneh; Ying Wang; Peethambaran Arun; Samuel Oguntayo; Yanling Wei; Joseph B. Long; Madhusoodana P. Nambiar

Blast-induced traumatic brain injury is complex and involves multiple factors including systemic pathophysiological factors in addition to direct brain injuries. We hypothesize that systemic activation of platelets/leukocytes plays a major role in the development and exacerbation of brain injury after blast exposure. A mouse model of repeated blast exposure that results in significant neuropathology, neurobehavioral changes and regional specific alterations in various biomolecules in the brain was used for the proposed study. Activation of platelets was evaluated by flow cytometry and serotonin content was analyzed by ELISA. Expression of myeloperoxidase was analyzed by Western blotting. Histopathology of the brain was used to assess blast-induced cerebral vasoconstriction. The data showed an increase in the activation of platelets at 4h after repeated blast exposures, indicating changes in platelet phenotype in blast neurotrauma. Platelet serotonin concentration showed a significant decrease at 4h after blast with a concurrent increase in the plasma serotonin levels, confirming the early onset of platelet activation after repeated blast exposures. Blood, plasma and brain myeloperoxidase enzyme activity and expression was increased in repeated blast exposed mice at multiple time points. Histopathological analysis of the brains of blast exposed mice showed constriction of blood vessels compared to the respective controls, a phenomenon similar to the reported cerebral vasoconstriction in blast affected victims. These results suggest that repeated blast exposure leads to acute activation of platelets/leukocytes which can augment the pathological effects of brain injury. Platelet/leukocyte targeted therapies can be evaluated as potential acute treatment strategies to mitigate blast-induced neurotrauma.


Journal of Rehabilitation Research and Development | 2012

Preliminary studies on differential expression of auditory functional genes in the brain after repeated blast exposures

Manojkumar Valiyaveettil; Yonas Alamneh; Stacy-Ann Miller; Rasha Hammamieh; Ying Wang; Peethambaran Arun; Yanling Wei; Samuel Oguntayo; Madhusoodana P. Nambiar

The mechanisms of central auditory processing involved in auditory/vestibular injuries and subsequent tinnitus and hearing loss in Active Duty servicemembers exposed to blast are not currently known. We analyzed the expression of hearing-related genes in different regions of the brain 6 h after repeated blast exposures in mice. Preliminary data showed that the expression of the deafness-related genes otoferlin and otoancorin was significantly changed in the hippocampus after blast exposures. Differential expression of cadherin and protocadherin genes, which are involved in hearing impairment, was observed in the hippocampus, cerebellum, frontal cortex, and midbrain after repeated blasts. A series of calcium-signaling genes that are known to be involved in auditory signal processing were also found to be significantly altered after repeated blast exposures. The hippocampus and midbrain showed significant increase in the gene expression of hearing loss-related antioxidant enzymes. Histopathology of the auditory cortex showed more significant injury in the inner layer compared to the outer layer. In summary, mice exposed to repeated blasts showed injury to the auditory cortex and significant alterations in multiple genes in the brain known to be involved in age- or noise-induced hearing impairment.


Toxicology in Vitro | 2011

In vitro efficacy of paraoxonase 1 from multiple sources against various organophosphates.

Manojkumar Valiyaveettil; Yonas Alamneh; Lionel Biggemann; Iswarduth Soojhawon; Heba A. Farag; Prashasthi Agrawal; Bhupendra P. Doctor; Madhusoodana P. Nambiar

Paraoxonase 1 (PON1) has been described as a potential catalytic bioscavenger due to its ability to hydrolyze organophosphate (OP) insecticides and nerve agents. In vitro catalytic efficiency of purified human and rabbit serum PON1 against different OP substrates was compared to human recombinant PON1, expressed in Trichoplusia ni larvae. Highly purified human and rabbit serum PON1s were prepared by multiple chromatography methods. Purified enzymes showed higher catalytic activity with the substrate p-nitrophenyl acetate compared to diethyl paraoxon. The hydrolyzing potential of PON1s against multiple OPs was evaluated by using an in vitro acetylcholinesterase back-titration assay. Significant differences in the catalytic efficiency of all the three PON1s with regard to various OP substrates were observed. Purified PON1s showed higher catalytic activity towards diisopropylfluorophosphate followed by diethylparaoxon compared to dimethyl paraoxon. Heat inactivation or incubation of PON1 with specific inhibitor resulted in complete loss of the enzyme catalytic activity indicating that OP hydrolysis was intrinsic to PON1. In conclusion, purified PON1s from multiple sources show significant differences in the catalytic activity against several OP substrates. These results underscore the importance of systematic analysis of candidate PON1 molecules for developing as an effective catalytic bioscavenger against toxic OPs and chemical warfare nerve agents.

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Madhusoodana P. Nambiar

Walter Reed Army Institute of Research

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Manojkumar Valiyaveettil

Walter Reed Army Institute of Research

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Daniel V. Zurawski

Walter Reed Army Institute of Research

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Peethambaran Arun

Walter Reed Army Institute of Research

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Samuel Oguntayo

Walter Reed Army Institute of Research

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Ying Wang

Walter Reed Army Institute of Research

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Bhupendra P. Doctor

Walter Reed Army Institute of Research

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Lionel Biggemann

Walter Reed Army Institute of Research

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Yanling Wei

Walter Reed Army Institute of Research

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Joseph B. Long

Walter Reed Army Institute of Research

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