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Dartmouth, MA, United States

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. Source

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 Source

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. Source

Ravichandran E.,University of Massachusetts Dartmouth | Ravichandran E.,Aurobindo Pharma United States Inc | Janardhanan P.,University of Massachusetts Dartmouth | Patel K.,University of Massachusetts Dartmouth | And 5 more authors.
Pharmaceutical Research | Year: 2016

Purpose: A double-mutant E224A/E262A full-length botulinum neurotoxin (BoNT) Type A with structural similarity to native BoNT/A but lacking the endopeptidase activity provides an ideal surrogate for testing pharmacokinetics and immunochemical characteristics of BoNT. Methods: We determined lethality (LD50) of deactivated recombinant botulinum neurotoxin (drBoNT/A) to be 24.0 μg by intraperitoneal route (i.p). The polypeptide drBoNT/A labeled with near infra-red dye 800 (NIR 800) was used to examine its distribution to different organs using whole body imaging when administered to mice via intravenous (i.v) or i.p route. Also, drBoNT/A was used to evaluate its immunogenicity in Balb/C mice model. Results: drBoNT/A was found to be highly immunogenic when tested under various in vivo conditions in Balb/C mice model. For the first time we have demonstrated that a full length 150 kDa drBoNT/A, by administering via inhalation route in mice model, has evoked both circulating immunoglobulin levels of IgG and secretory IgA at the mucosal surface. The immunoglobulin levels were sufficient enough to protect against the challenge dose of native BoNT toxin in mice model. Tissue distribution of drBoNT/A seems to be similar to that of native toxin. Conclusions: Based on the characteristics described in this report this nontoxic holotoxin protein will assist us to explore the window of opportunity available for therapeutic treatment in case of unnatural poisoning, and also it can be an effective vaccine candidate. © 2015 Springer Science+Business Media. Source

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. Source

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