Institute of Advanced science

Dartmouth, MA, United States

Institute of Advanced science

Dartmouth, MA, United States
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Mukkavalli S.,University of Massachusetts Dartmouth | Chalivendra V.,University of Massachusetts Dartmouth | Singh B.R.,Institute of Advanced science
OpenNano | Year: 2017

In order to exhibit its potential benefits, a drug must cross the epithelial barrier of the intestinal mucosa for transportation into systemic circulation. Several approaches have been proposed to overcome these barriers, including enhancing drug potency through the use of bioenhancers. The concurrent application of bio-enhancers with pharmaceuticals is not a new development, but has been used for thousands of years. The traditional medical system used in India (Ayurveda) has utilized formulations including metal powders (bhasma) to treat a large number of health issues. However, without the support of modern science, these methodologies are largely ignored throughout the western world. Recent studies have begun to examine not only structure and compositional studies but also studies targeted at understanding the mode of action of these materials. Preliminary studies carried out below indicate the potential of these powders to act as non-reactive bio-enhancer for drug delivery. © 2017 The Authors


PubMed | Brookhaven National Laboratory and Institute of Advanced science
Type: | Journal: Scientific reports | Year: 2015

Clostridium botulinum neurotoxin (BoNT) is released as a progenitor complex, in association with a non-toxic-non-hemagglutinin protein (NTNH) and other associated proteins. We have determined the crystal structure of M type Progenitor complex of botulinum neurotoxin E [PTC-E(M)], a heterodimer of BoNT and NTNH. The crystal structure reveals that the complex exists as a tight, interlocked heterodimer of BoNT and NTNH. The crystal structure explains the mechanism of molecular assembly of the complex and reveals several acidic clusters at the interface responsible for association at low acidic pH and disassociation at basic/neutral pH. The similarity of the general architecture between the PTC-E(M) and the previously determined PTC-A(M) strongly suggests that the progenitor M complexes of all botulinum serotypes may have similar molecular arrangement, although the neurotoxins apparently can take very different conformation when they are released from the M complex.


Chang T.-W.,University of Massachusetts Dartmouth | Janardhanan P.,University of Massachusetts Dartmouth | Mello C.M.,U.S. Army | Singh B.R.,Institute of Advanced science | Cai S.,University of Massachusetts Dartmouth
Applied Biochemistry and Biotechnology | Year: 2016

Botulinum neurotoxin (BoNT), a category A agent, is the most toxic molecule known to mankind. The endopeptidase activity of light chain domain of BoNT is the cause for the inhibition of the neurotransmitter release and the flaccid paralysis that leads to lethality in botulism. Currently, antidotes are not available to reverse the flaccid paralysis caused by BoNT. In the present study, a non-radioactive-based systematic evolution of ligands by exponential enrichment (SELEX) process is developed by utilizing surface plasmon resonance to monitor the binding enrichment. Two RNA aptamers have been identified as strong binders against light chain of botulinum neurotoxin type A. These two aptamers showed strong inhibition activity on LCA, with IC50 in nanomolar range. Inhibition kinetic studies reveal mid nanomolar KI and non-competitive nature of their inhibition, suggesting that they have strong potential as antidotes that can reverse the symptom caused by BoNT/A. More importantly, we observed that the 2′-fluorine-pyrimidine-modified RNA aptamers identified here do not change their binding and biological activities. This observation could lead to a cost-effective way for SELEX, by using regular nucleotide during SELEX, and 2′-fluorine-pyrimidine-modified nucleotide for final application to enhance their RNase-resistance. © 2016 Springer Science+Business Media New York


PubMed | U.S. Army, University of Massachusetts Dartmouth and Institute of Advanced science
Type: Journal Article | Journal: Applied biochemistry and biotechnology | Year: 2016

Botulinum neurotoxin (BoNT), a category A agent, is the most toxic molecule known to mankind. The endopeptidase activity of light chain domain of BoNT is the cause for the inhibition of the neurotransmitter release and the flaccid paralysis that leads to lethality in botulism. Currently, antidotes are not available to reverse the flaccid paralysis caused by BoNT. In the present study, a non-radioactive-based systematic evolution of ligands by exponential enrichment (SELEX) process is developed by utilizing surface plasmon resonance to monitor the binding enrichment. Two RNA aptamers have been identified as strong binders against light chain of botulinum neurotoxin type A. These two aptamers showed strong inhibition activity on LCA, with IC50 in nanomolar range. Inhibition kinetic studies reveal mid nanomolar KI and non-competitive nature of their inhibition, suggesting that they have strong potential as antidotes that can reverse the symptom caused by BoNT/A. More importantly, we observed that the 2-fluorine-pyrimidine-modified RNA aptamers identified here do not change their binding and biological activities. This observation could lead to a cost-effective way for SELEX, by using regular nucleotide during SELEX, and 2-fluorine-pyrimidine-modified nucleotide for final application to enhance their RNase-resistance.


Singh B.R.,Institute of Advanced science
Botulinum Journal | Year: 2016

The highly toxic nature of botulinum neurotoxins and their placement in category A biothreat agents list under tier 1 biosecurity regulations always attract public attention about any possibility of a new form of this agent. Last time, a new type of botulinum neurotoxin (type G) was discovered was over 40 years ago, and that was not even known to cause human botulism epidemiologically. Therefore, when a novel botulinum neurotoxin was isolated from an infant botulism case in California, it became a major concern for the public health and biothreat agencies. There has been controversy among the scientists about its nomenclature. The scientific debate has been robust, and although the novel neurotoxin is now confirmed to be a hybrid of types A and F botulinum neurotoxins, the issue of calling it a new serotype (H) remains unsettled. Copyright © 2015 Inderscience Enterprises Ltd.


Ravichandran E.,Institute of Advanced science | Singh B.R.,Institute of Advanced science
Botulinum Journal | Year: 2016

Clostridium botulinum toxin is one of the potent and classic molecules known to this modern scientific research field. It has dualistic characters: on one hand it causes botulism by blocking release of acetylcholine at the cholinergic nerve endings and on the other hand the same toxin molecule when administered locally at sub-lethal dose relieves various neuromuscular disorders. If the toxin is used intentionally as an act of terrorism, FDA approved therapeutic agents would be needed to recover from the illness. In addition, to prevent from such situations in the future and to protect public from botulism, there is a strong need for a mucosal vaccine. Creating a multivalent mucosal vaccine delivery system would ease the burden at the time of delivery and reduce the cost. Copyright © 2015 Inderscience Enterprises Ltd.


Li B.,Huazhong Agricultural University | Li J.,Huazhong Agricultural University | Xia J.,Huazhong Agricultural University | Kennedy J.F.,Institute of Advanced Science | And 2 more authors.
Carbohydrate Polymers | Year: 2011

Konjac glucomannan and chitosan blend films with different blend ratio were gamma irradiated up to 80 kGy, The mechanical properties achieved their maximum under 25 kGy dose, the tensile strength and breaking elongation of KC2 were enhanced about 40% and 30%, respectively. No change occurred in the primary group such as hydroxyl and acetyl of the blend films during irradiation. The effect of irradiation decreased with the increase of konjac glucomannan content, and the blend film KC2 irradiated by 25 kGy had the highest cystallinity. The miscibility of KGM and CHI in the blend film also played an important role in keeping its morphology, in addition to the content of chitosan when the films were irradiated. 25 kGy gamma irradiation was not only a useful sterilization method for the film biomaterial but also an efficient modification method for enhancing the properties of KC2. © 2010 Elsevier Ltd.


Kumar R.,Institute of Advanced science | Cai S.,University of Massachusetts Dartmouth | Ojadi E.,University of Massachusetts Dartmouth | Singh B.R.,Institute of Advanced science
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2015

Botulinum neurotoxins (BoNTs) are the most poisonous substances known to mankind, which act on the peripheral nervous system leading to flaccid paralysis. Although co-crystal structure of BoNT/A light chain (LC) reveals some unique features of the biological function of this molecule, structural characteristics in solution reveal its dynamic features, not available through the published crystal structures. In this study, we have examined internal flexibility of this molecule by measuring rotational correlation time as a function of viscosity, using frequency domain fluorescence anisotropy decay technique. Fluorescence anisotropy decay of BoNT/A LC resolved sub-nanosecond local motion (faster component), interpreted as internal flexibility of the molecule was affected significantly with viscosity. Both local and global movements were affected by viscosity, which indicates the accessibility of protein core and flexibility of overall structure. In conclusion, this work demonstrates the presence of flexibility in the internal peptide segments, which appears to play a significant role in BoNT/A LC biological function. © 2015 Elsevier B.V.


Kumar R.,Institute of Advanced science | Dhaliwal H.P.,University of Massachusetts Dartmouth | Kukreja R.V.,Institute of Advanced science | Singh B.R.,Institute of Advanced science | Singh B.R.,Prime Inc
Seminars in Neurology | Year: 2016

Botulinum neurotoxin (BoNT) produced by Clostridium botulinum is the most potent molecule known to mankind. Higher potency of BoNT is attributed to several factors, including structural and functional uniqueness, target specificity, and longevity. Although BoNT is an extremely toxic molecule, it is now increasingly used for the treatment of disorders related to muscle hyperactivity and glandular hyperactivity. Weakening of muscles due to peripheral action of BoNT produces a therapeutic effect. Depending on the target tissue, BoNT can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. In recent observations of the analgesic properties of BoNT, the toxin modifies the sensory feedback loop to the central nervous system. Differential effects of BoNT in excitatory and inhibitory neurons provide a unique therapeutic tool. In this review the authors briefly summarize the structure and mechanism of actions of BoNT on motor and sensory neurons to explain its therapeutic effects and future potential. © 2016 by Thieme Medical Publishers, Inc.


PubMed | University of Massachusetts Dartmouth and Institute of Advanced science
Type: Journal Article | Journal: Seminars in neurology | Year: 2016

Botulinum neurotoxin (BoNT) produced by Clostridium botulinum is the most potent molecule known to mankind. Higher potency of BoNT is attributed to several factors, including structural and functional uniqueness, target specificity, and longevity. Although BoNT is an extremely toxic molecule, it is now increasingly used for the treatment of disorders related to muscle hyperactivity and glandular hyperactivity. Weakening of muscles due to peripheral action of BoNT produces a therapeutic effect. Depending on the target tissue, BoNT can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. In recent observations of the analgesic properties of BoNT, the toxin modifies the sensory feedback loop to the central nervous system. Differential effects of BoNT in excitatory and inhibitory neurons provide a unique therapeutic tool. In this review the authors briefly summarize the structure and mechanism of actions of BoNT on motor and sensory neurons to explain its therapeutic effects and future potential.

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